CADTH Reimbursement Review

Pembrolizumab (Keytruda)

Sponsor: Merck Canada Inc.

Therapeutic area: Early-stage triple-negative breast cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Breast cancer is the most frequently diagnosed cancer in females in Canada, with projected estimates of about 27,700 new cases in 2021. It was estimated that 5,400 females would die from the disease in the same year. Fewer males are affected, with an estimated 290 new cases and 55 related deaths in 2021.³ Triple-negative breast cancer (TNBC) is an invasive form of breast cancer, affecting 10% to 20% of patients.^4,5 It is most common in women younger than 40 years; African-American women; and women with a BRCA1 mutation.^5,6 It is well established that patients with the BRCA1 mutation are more likely to develop TNBC than patients with other mutations.^5,7,8 Triple-negative breast cancer is distinguished by the absence of an estrogen receptor (ER) and a progesterone receptor (PR) and by no expression of the HER2-negative gene.^6,8,9 The clinician groups consulted highlighted that patients with TNBC have a higher risk of recurrence and death than patients with other types of breast cancer. The clinician groups noted that patients with a pathological complete response (pCR) have on average a 5-year disease-free survival of 85% to 90% for localized disease,⁶ while those with no pCR have a higher recurrence rate. Most patients with breast cancer, including TNBC, present with no symptoms at early stages of the disease. Breast changes such as firm or hard lumps, a lump in the armpit, changes in breast size and shape, changes to the nipple, and discharge from the nipples are some common symptoms reported. Additional symptoms—such as bone pain, weight loss, nausea, appetite loss, shortness of breath, cough, headache, double vision, and muscle weakness—may manifest with tumour size increase or spread to other organs.^6,9

The standard approach for early-stage TNBC is neoadjuvant chemotherapy (NACT) for cT1c or greater tumours. According to the experts consulted, this approach allows for clinical downstaging (better chance of clear margins, breast-conserving surgery, and potential avoidance of completion axillary node dissection) and prognostication (patients achieving pCR having excellent long-term outcomes). Several NACT regimens are available in practice. The clinical experts and clinician groups highlighted that the sequential use of anthracycline-taxane (or taxane-anthracycline) combination chemotherapy (standard: every 3 weeks; dose dense: every 2 weeks) was standard of practice across jurisdictions in Canada. The clinical experts consulted also noted that dose-dense AC (doxorubicin-cyclophosphamide) every 2 weeks for 4 cycles followed by paclitaxel every 2 weeks for 4 cycles, with carboplatin often added, is the preferred NACT regimen in Canadian practice.

The objective of this report is to perform a systematic review of the beneficial and harmful effects of pembrolizumab for the treatment of adult patients with early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input, clinician group input, and input from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, the Canadian Breast Cancer Network (CBCN) and Rethink Breast Cancer, provided input for this review. The CBCN patient input was based on an online survey (the CBCN’s 2017 Lived Experience Breast Cancer Patient Survey), telephone interviews, and a literature review of current studies and grey literature. The Rethink Breast Cancer input was based on general observations and insights gathered through various ongoing initiatives (including patients’ blogs, virtual support groups, working groups, and patient advisory boards), through telephone interviews with 2 patients and a caregiver to 1 of the patients, and through a focus group with 7 patients from the TNBC working group.

Respondents from both patient groups highlighted that TNBC is a rare subtype of breast cancer that is relatively more aggressive and has a higher rate of recurrence and poorer prognosis than other breast cancers. Respondents in both groups expressed lack of access to effective treatment as an unmet need. Respondents from the CBCN highlighted the need for treatment options that will reduce the risk of disease recurrence, delay disease progression, control disease, improve quality of life (QoL), and reduce severity of side effects from treatments. Respondents from Rethink Breast Cancer indicated that they are willing to tolerate additional side effects and reduced QoL in exchange for a treatment that can control TNBC.

Respondents in both patient groups who had received pembrolizumab stated that the treatment was effective and improved their QoL, with tolerable or minimal side effects. The most common adverse events (AEs) reported by patients who had experience with pembrolizumab included fatigue, colitis, and diarrhea. Respondents in both groups noted challenges in differentiating whether the side effects were due to pembrolizumab or to chemotherapy, given that they received treatments concurrently. One patient in the Rethink Breast Cancer group reported that pembrolizumab had effectively reduced their tumour size but that they had experienced AEs such as hives, skin conditions, and thyroid issues, while other patients noted experiencing minimal side effects with pembrolizumab. One caregiver mentioned that, overall, pembrolizumab treatment had been a positive experience, with side effects being somewhat of a challenge. Patient respondents who had received pembrolizumab indicated that they would recommend pembrolizumab to other patients with TNBC.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Pathological complete response, overall survival (OS), and event-free survival (EFS) were considered clinically meaningful outcomes by the clinical experts consulted during the CADTH review. The experts highlighted that the treatment goal for high-risk, early-stage TNBC is to reduce the risk of breast cancer recurrence and improve survival in patients. The clinical experts stated that pCR is associated with improvement in disease-free survival in TNBC, that not all patients respond to current treatment options, and that pCR rates are approximately 50% in patients receiving chemotherapy. The clinical experts indicated that staging approaches and routine breast tumour biopsy characterization of ER, PR, and HER2 status are currently in place to identify patients in Canada.

The experts generally agreed that the use of immunotherapy will cause a paradigm shift in practice for the treatment of TNBC. The clinical experts advised that patients who meet the inclusion criteria outlined in the KEYNOTE-522 study would be best suited for treatment. In the opinion of the experts, patients with pre-existing serious autoimmune diseases may not be eligible for this regimen. The experts added that patients with T1a/T1B N0 (node 0) are also not eligible due to the early-stage disease (regardless of coexisting autoimmune conditions), as these patients will likely have surgery upfront. In addition, the experts indicated that patients with less serious autoimmune conditions and patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 should weigh the pros and cons of the new regimen while considering older standard options in lower risk TNBC cases. The experts highlighted that there are currently no biomarkers to assess treatment response early on in patients with TNBC. The experts noted that in practice settings, patients will undergo a physical exam before each cycle in the neoadjuvant setting and that imaging scans may be used to rule out disease progression and review the patient’s fit for surgery.

According to the clinical experts, disease progression (tumour enlargement unless pseudoprogression is suspected) and the occurrence of AEs, particularly autoimmune toxicities (any grade 4 treatment-related AEs or grade 2 to 3 AEs not improving to grade 1 with supportive care or dose modifications), would be considered when deciding treatment discontinuation.

Clinician Group Input

Two clinician group inputs were provided: 1 from the Ontario Health–Cancer Care Ontario (OH-CCO) Breast Cancer Drug Advisory Committee (based on input from 2 clinicians) and 1 from The Ottawa Hospital Cancer Centre (TOHCC) Breast Disease Site Group (based on input from 15 medical oncologists). The OH-CCO’s Drug Advisory Committee provides timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. TOHCC aims to provide each person affected by cancer with world-class care, exceptional service, and compassion.

Both clinician groups identified NACT and then adjuvant chemotherapy as the current Canadian treatment paradigm for patients with TNBC. Both groups considered achieving long-term cure, improving OS and EFS, and delaying disease progression as important treatment goals. Both groups identified the lack of effective treatment options for patients with TNBC, limited pCR rates, the highest recurrence and death rates among the types of breast cancer, and the overall death rates among patients with breast cancer as unmet needs. Both groups anticipate that pembrolizumab will fit into the current treatment paradigm as a new treatment standard for TNBC. Both groups agreed that it would not be appropriate to recommend patients with TNBC to try other treatments before initiating pembrolizumab. Both clinician groups consulted considered tumour shrinkage (clinically or radiographically), improvement in pCR, and EFS as clinically meaningful outcomes when assessing treatment response.

The views of the clinician groups were, overall, consistent with the clinical experts consulted by CADTH.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Clinical Evidence

Pivotal Study

Description of Study

KEYNOTE-522 is an ongoing, phase III, randomized, multi-centre, double-blind, placebo-controlled trial. The primary objective of KEYNOTE-522 is to evaluate pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared with placebo plus chemotherapy as neoadjuvant therapy followed by continued placebo as adjuvant therapy for patients with high-risk, early-stage TNBC. The study was initiated in March 2017 and has 194 participating centres across 21 countries in North America (7 centres in Canada), South America, Europe, Asia, and Australia.¹⁰

Enrolled patients were male or female, 18 years and older, and newly diagnosed; had a locally advanced, centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) guidelines; were previously untreated; and had a locally advanced nonmetastatic (M0) TNBC as per the current American Joint Committee on Cancer (AJCC) staging criteria for breast cancer, assessed by an investigator based on radiological and/or clinical assessment (T1c, N1 to N2; T2 to T4d; N0 to N2).¹⁰

Pathological complete response using the absence of invasive cancer in the breast irrespective of no invasive residual disease in breast or nodes; noninvasive breast residuals allowed (no invasive residual disease in breast or nodes; noninvasive breast residuals allowed [ypT0/Tis ypN0] definition; assessed by a local pathologist) and EFS (assessed by an investigator) were co-primary outcomes investigated in the KEYNOTE-522 trial. Overall survival, safety, and tolerability, and health-related QoL (HRQoL) (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30], the European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire [EORTC QLQ-BR23], and the EQ-5D-5L questionnaire) were other secondary and exploratory outcomes investigated.

Patients were randomized in a 2:1 ratio based on 3 stratification factors: nodal status (positive versus negative); tumour size (T1/T2 versus T3/T4); and choice of carboplatin regimen (every 3 weeks or weekly).

By the fourth interim analysis (IA4) data cut-off (March 23, 2021), 1,608 patients had been screened and 1,174 randomized to 1 of the 2 trial arms. In total, 784 patients received pembrolizumab plus chemotherapy treatment, and 390 patients received placebo plus chemotherapy. The majority of the patients enrolled were female (1 man was enrolled), younger than 65 years, White, and pre-menopausal and had an ECOG PS of 0. More than 80% of patients were programmed death ligand 1 (PD-L1) positive. In the neoadjuvant phase, more patients in the pembrolizumab plus chemotherapy arm (24.2%) had discontinued study intervention than in the placebo plus chemotherapy arm (14.9%). In the adjuvant phase, the most common reason for discontinuation was AEs (5.4%) in the pembrolizumab group and relapse or recurrence (4.6%) or withdrawal by participant (4.4%) in the placebo group.¹⁰

Efficacy

Overall, almost all patients in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (99.2%) and all patients in the placebo plus chemotherapy followed by placebo arm (100%) reported at least 1 AE by the March 23, 2021, data cut-off. Adverse events of grade 3 or higher were slightly higher (82.4%) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm than in the placebo plus chemotherapy followed by placebo arm (78.7%). The most common AEs in both arms were nausea, alopecia, anemia, and neutropenia.¹⁰

Adverse events of grade 3 to 5 reported in at least 5% of patients were also generally similar in both treatment arms and included neutropenia (35.23% versus 34.4%), decreased neutrophil count (19% versus 23.7%), anemia (19.5% versus 15.7%), febrile neutropenia (18.4% versus 16.2%), and decreased white blood cell count (6.4% versus 2.8%) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm versus the placebo plus chemotherapy followed by placebo arm. Overall, AEs resulting in death in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (0.9%) were consistent with the placebo plus chemotherapy followed by placebo arm (0.3%). Adverse events leading to discontinuation of any study intervention in the combined neoadjuvant and adjuvant phases was higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (29.9%) than in the placebo plus chemotherapy followed by placebo arm (15.4%). Overall, the incidence of AEs leading to dose reduction of chemotherapy was generally similar between the pembrolizumab plus chemotherapy followed by pembrolizumab arm (12.8%) and the placebo plus chemotherapy followed by placebo arm (11.3%).¹⁰

Notable harms were more common in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (43.6%) than in the placebo plus chemotherapy followed by placebo arm (21.9%). The most common notable harms reported in the 2 study arms are presented in Table 2.10

Table 2 presents a summary of key results from the KEYNOTE-522 study.

Overall Survival

By the IA4 data cut-off (March 23, 2021), 135 out of 297 pre-specified events had occurred, representing approximately 45% of the information fraction for OS for the final analyses. The median OS was not estimable, and the hazard ratio (HR) obtained in the comparison of pembrolizumab plus chemotherapy followed by pembrolizumab versus placebo plus chemotherapy followed by placebo was 0.72 (95% confidence interval [CI], 0.51 to 1.02; P [1 sided] = 0.0321377).¹⁰

Pathological Complete Response Rate (Using ypT0/Tis ypN0)

At the IA1 data cut-off (September 24, 2018), the pCR rate was 64.8% (95% CI, 59.9% to 69.5%) in patients receiving pembrolizumab plus chemotherapy in the neoadjuvant phase and 51.2% (95% CI, 44.1% to 58.3%) in patients receiving placebo plus chemotherapy. At IA2 (April 24, 2019), the treatment difference in pCR rate (pembrolizumab plus chemotherapy versus placebo plus chemotherapy) was 9.2% (95% CI, 2.8% to 15.6%; P = 0.00221). The pCR rate (95% CI) for pembrolizumab plus chemotherapy in the neoadjuvant phase was 64.0% (95% CI, 60.2% to 67.6%), compared to 54.7% (95% CI, 49.1% to 60.1%) for placebo plus chemotherapy. At IA4 (March 23, 2021), the pCR rate in the patients receiving pembrolizumab plus chemotherapy in the neoadjuvant phase was 63% (95% CI, 59.5% to 66.4%) and in patients receiving placebo plus chemotherapy was 55% (95% CI, 50.6% to 60.6%). The pCR rate was not formally tested in IA4.¹⁰

Event-Free Survival

At the IA4 data cut-off (March 23, 2021), the median EFS was not estimable in either study arm. The EFS HR between the 2 arms was 0.63 (95% CI, 0.48 to 0.82; P [1 sided] = 0.0003093). The findings were consistent with data observed across IAs (in IA2, the EFS HR was 0.63 [95% CI, 0.43 to 0.93]; in IA3, the EFS HR was 0.65 [95% CI, 0.48 to 0.88]). Five pre-specified sensitivity analyses were conducted for EFS in the intention-to-treat (ITT) population. The results of the sensitivity analyses were consistent with the primary analysis (sensitivity analysis 1: the EFS HR was 0.64 [95% CI, 0.48 to 0.84]; sensitivity analysis 2: the EFS HR was 0.63 [95% CI, 0.48 to 0.82]; sensitivity analysis 3: the EFS HR was 0.65 [95% CI, 0.50 to 0.85]; sensitivity analysis 4: the EFS HR was 0.63 [95% CI, 0.48 to 0.84]; sensitivity analysis 5: the EFS HR was 0.63 [95% CI, 0.48 to 0.82]).¹⁰

Health-Related QoL

Multiplicity adjustments for type I error rate were not conducted for HRQoL outcomes, and P values were nominal. The findings were considered exploratory.

European Organisation for Research and Treatment of Cancer QLQ-C30

Neoadjuvant phase: Compliance rates in the neoadjuvant phase were similar at baseline for EORTC QLQ-C30 in both the pembrolizumab plus chemotherapy arm and the placebo plus chemotherapy arm among all patients (92.0% versus 95.8%). After 21 weeks of follow-up in the neoadjuvant phase, the completion rate among all patients was 80.7% in each arm. The mean change from baseline in global health status–QoL score was –11.24 (95% CI, –12.82 to –9.66) versus –10.20 (95% CI, –12.30 to –8.10) in the pembrolizumab plus chemotherapy versus the placebo plus chemotherapy arms at the IA4 data cut-off (March 23, 2021). The physical functioning scale difference in least squares (LS) mean scores in patients receiving pembrolizumab plus chemotherapy compared to placebo plus chemotherapy was –2.85 (95% CI, –5.11 to –0.60). The LS mean differences in change from baseline between groups for global health status–QoL score and functional scores were –1.04 (95% CI, –3.46 to 1.38) and –2.85 (95% CI, –5.11 to –0.60), respectively. The LS mean difference between groups for emotional functioning was –0.69 (95% CI, –3.13 to 1.75).¹⁰

Adjuvant phase: Compliance rates in the adjuvant phase were similar at baseline for EORTC QLQ-C30 in both the pembrolizumab and placebo arms among all participants (90.7% versus 91.9%) at the March 23, 2021, data cut-off. After 24 weeks of follow-up in the adjuvant phase, the compliance rate among patients was 82.4% versus 80.8% in the pembrolizumab versus placebo arms. Scores obtained in the different subscales in the pembrolizumab arm versus the placebo arm at the IA4 data cut-off (March 23, 2021) were as follows: global health status–QoL (mean change from baseline: 2.47 [95% CI, 1.05 to 3.88] versus 2.88 [95% CI, 1.05 to 4.71]); physical functioning (mean change from baseline: 1.60 [95% CI, 0.46 to 2.75] versus 3.18 [95% CI, 1.70 to 4.66]); and emotional functioning scales (mean change from baseline: –1.53 [95% CI, –3.03 to –0.03] versus –0.92 [95% CI, –2.88 to 1.04]). The LS mean differences between groups for global health status–QoL score, physical functioning, and emotional functioning were –0.41 (95% CI, –2.60 to 1.77), –1.57 (95% CI, –3.36 to 0.21), and –0.60 (95% CI, –2.99 to 1.79), respectively.¹⁰

European Organisation for Research and Treatment of Cancer QLQ-BR23

Neoadjuvant phase: Compliance rates in the neoadjuvant phase were similar at baseline for EORTC QLQ-BR23 in both the pembrolizumab plus chemotherapy arm and the placebo plus chemotherapy arm among all participants (91.6% versus 94.8%) at the March 23, 2021, data cut-off. After 21 weeks of follow-up in the neoadjuvant phase, the compliance rate for all patients was 80.5% versus 80.4% in the pembrolizumab plus chemotherapy arm versus the placebo plus chemotherapy arm. The mean change from baseline scores obtained in the pembrolizumab plus chemotherapy arm versus the placebo plus chemotherapy arm was –9.92 (95% CI, –11.34 to –8.49) versus –9.78 (95% CI, –11.53 to –8.03). The LS mean difference between groups for the EORTC QLQ-BR23 Breast Symptoms score was –0.13 (95% CI, –1.92 to 1.65).¹⁰

Adjuvant phase: Compliance rates in the adjuvant phase were similar at baseline for EORTC QLQ-BR23 in both the pembrolizumab and placebo arms among all participants (90.5% and 92.2%, respectively) at the March 23, 2021, data cut-off. After 24 weeks of follow-up, the compliance rate was 82.2% and 80.7% in the pembrolizumab and placebo arms, respectively. The mean change from baseline scores obtained in the pembrolizumab arm when compared to the placebo arm was –5.73 (95% CI, –7.32 to –4.15) versus –6.02 (95% CI, –8.04 to –4.01). The LS mean difference between groups for the EORTC QLQ-BR23 Breast Symptoms score was 0.29 (95% CI, –2.05 to 2.63).¹⁰

EQ Visual Analogue Scale

Neoadjuvant phase: Compliance rates in the neoadjuvant phase were similar at baseline for the EQ Visual Analogue Scale (VAS) in both the pembrolizumab plus chemotherapy arm and the placebo plus chemotherapy arm among all participants (92.8% versus 96.3%, respectively) at the March 23, 2021, data cut-off. After 21 weeks of follow-up in the neoadjuvant phase, the compliance rate was 80.8% versus 81.0% in the pembrolizumab plus chemotherapy arm and the placebo plus chemotherapy arm, respectively. The mean change from baseline in EQ VAS scores in the pembrolizumab plus chemotherapy arm versus the placebo plus chemotherapy arm was –8.98 (95% CI, –10.48 to –7.47) versus –7.36 (95% CI, – 9.34 to –5.38). The LS mean difference between groups for the EQ VAS score was –1.61 (95% CI, –3.87 to 0.64).¹⁰

Adjuvant phase: Compliance rates in the adjuvant phase were similar at baseline for EQ VAS in both the pembrolizumab and placebo arms among all participants (91.7% versus 91.9%). After 24 weeks of follow-up in the adjuvant phase, the compliance rate was 82.2% versus 80.3% in the pembrolizumab versus placebo arms. The mean change from baseline in EQ VAS scores in the pembrolizumab arm was 1.83 (95% CI, 0.66 to 3.00) compared to 2.42 (95% CI, 0.91 to 3.93) in the placebo arm. The LS mean difference between groups for the EQ VAS was –0.59 (95% CI, –2.40 to 1.23).¹⁰

Harms

Overall, almost all patients in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (99.2%) and all patients in the placebo plus chemotherapy followed by placebo arm (100%) reported at least 1 AE by the March 23, 2021, data cut-off. Adverse events of grade 3 or higher were slightly higher (82.4%) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm than in the placebo plus chemotherapy followed by placebo arm (78.7%). The most common AEs in both arms were nausea, alopecia, anemia, and neutropenia.¹⁰

Adverse events of grade 3 to 5 reported in at least 5% of patients were also generally similar in both treatment arms and included neutropenia (35.23% versus 34.4%), decreased neutrophil count (19% versus 23.7%), anemia (19.5% versus 15.7%), febrile neutropenia (18.4% versus 16.2%), and decreased white blood cell count (6.4% versus 2.8%) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm versus the placebo plus chemotherapy followed by placebo arm. Overall, AEs resulting in death in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (0.9%) were consistent with the placebo plus chemotherapy followed by placebo arm (0.3%). Adverse events leading to discontinuation of any study intervention in the combined neoadjuvant and adjuvant phases was higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (29.9%) than in the placebo plus chemotherapy followed by placebo arm (15.4%). Overall, the incidence of AEs leading to dose reduction of chemotherapy was generally similar between the pembrolizumab plus chemotherapy followed by pembrolizumab arm (12.8%) and the placebo plus chemotherapy followed by placebo arm (11.3%).¹⁰

Notable harms were more common in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (43.6%) than in the placebo plus chemotherapy followed by placebo arm (21.9%). The most common notable harms reported in the 2 study arms are presented in Table 2.¹⁰

Table 2: Summary of Key Results From Pivotal Study

AE = adverse event; CI = confidence interval; EFS = event-free survival; IA = interim analysis; NE = not estimable; OS = overall survival; pCR = pathological complete response; PD = progressed disease; SAE = serious adverse event; vs. = versus; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Note: Data cut-off: March 23, 2021 (IA4), and September 24, 2018 (IA1).

^aBased on Cox regression model with the Efron method of tie handling, with treatment as a covariate, stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

^bOne-sided P value based on log-rank test stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

^cBased on Miettinen and Nurminen method, stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

^dOne-sided P value for testing H0: difference in % = 0 vs. H1: difference in % > 0.

^eFrom product limit (Kaplan–Meier) method for censored data.

^fDefined as an action taken of dose reduced, drug interrupted, or drug withdrawn. Grades are based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0.

Source: Clinical Study Report.¹⁰

Critical Appraisal

KEYNOTE-522 is a randomized, double-blind, multi-centre, phase III trial. A 2:1 randomization scheme was implemented that allowed more patients in the pembrolizumab plus chemotherapy followed by pembrolizumab arm than in the placebo plus chemotherapy followed by placebo arm. The baseline and demographic characteristics of patients were considered well balanced in both study arms, and the risk of selection bias was considered low. The double-blind trial design lowered the risk of performance bias from the assessment of pCR, EFS, and OS outcomes. Subjective outcomes like HRQoL and safety also had a low risk of bias due to the double-blind nature of the trial. Overall survival, EFS, pCR, and HRQoL were considered clinically meaningful outcomes investigated in the trial by the clinical experts, clinician groups, and patient groups consulted during the review. All interim and subgroup analyses were pre-specified in the statistical plan. Multiplicity adjustments for type I error were conducted for pCR, EFS, and OS according to a pre-specified statistical hierarchy plan. Subgroup and HRQoL analyses were not adjusted for type I error; therefore, the findings were considered exploratory. The magnitude of benefit of pembrolizumab plus chemotherapy followed by pembrolizumab in the adjuvant phase in improving HRQoL is uncertain due to the lack of multiplicity adjustments to account for type I error in the analyses conducted.

The reimbursement request was submitted for CADTH review pre–Notice of Compliance (NOC), and the request aligned with the proposed Health Canada indication (indicated for the treatment of adult patients with early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery). The inclusion and exclusion criteria of the KEYNOTE-522 study were considered appropriate, and the baseline and demographic characteristics were considered generalizable to Canadian practice by the clinical experts consulted. Most patients enrolled had an ECOG PS of 0 or 1. The clinical experts agreed that they may consider administering pembrolizumab to patients with an ECOG PS of 2 but would not offer treatment to patients with an ECOG PS of 3 or greater. Therefore, the magnitude of benefit of pembrolizumab in patients who did not meet the inclusion criteria outlined in the KEYNOTE-522 study is uncertain. The dosage of pembrolizumab aligns with the Health Canada NOC indication, and the clinical experts anticipate dose modifications in practice to manage treatment-related toxicity. The choice of comparator for both neoadjuvant and adjuvant phases in the KEYNOTE-522 study was considered appropriate by the experts, given that the study was initiated before capecitabine or olaparib were available for public funding. Pathological complete response, EFS, and OS are validated outcomes recommended by the FDA for trials that include patients with TNBC.^11,12 The clinical experts considered the outcomes important for patients with TNBC in Canadian practice. Some patients enrolled in the KEYNOTE-522 study were possibly more exposed to frequent assessments than patients in real-world practice. This may impact the generalizability of the findings to patients in real-world practice. The experts noted that patients are assessed before every cycle in the real world and may not necessarily undergo routine breast MRIs.

Indirect Treatment Comparison

Direct head-to-head clinical trials assessing pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC are limited. The sponsor did not provide any indirect evidence for this review. Published indirect evidence was considered and summarized for this review to address the lack of direct evidence for relevant comparators.

Description and Methods of Published NMA

One published network meta-analysis (NMA) by Miyashita et al. (2020)¹³ was summarized for this review to supplement the assessment of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC. The published NMA did not assess adjuvant treatment of TNBC. The published NMA included 13 randomized controlled trials (RCTs) and 3,008 patients with TNBC.

Eligible studies included patients with TNBC who received treatment that included anthracycline, bevacizumab, pembrolizumab, platinum salts, or other therapies (i.e., chemotherapies aside from the previously noted therapies of interest). The dosing of these interventions was not specified. Outcomes of interest included the rate of pCR (defined as ypT0/is and ypN0) or toxicities, specifically febrile neutropenia, grade 3 or greater thrombocytopenia, nausea/vomiting, and diarrhea. The systematic review only included RCTs and did not report any additional criteria regarding the study design.

Information about the statistical model selected for the NMA was limited. The authors reported that a random effects model was used for the NMA. Heterogeneity within the network was estimated using the I² statistic, where an I² value greater than 50% was considered an indicator of substantial heterogeneity. Inconsistency was evaluated using Q statistics.

Efficacy Results

The analysis of the rate of pCR suggested a higher rate of pCR for treatments that include anthracycline plus pembrolizumab plus platinum salts relative to anthracycline (risk ratio [RR] = 0.58; 95% CI, 0.43 to 0.77) and anthracycline plus platinum salts (RR = 0.79; 95% CI, 0.63 to 0.99). Conclusions could not be drawn for comparisons with anthracycline plus pembrolizumab or for comparison with platinum salts alone due to serious imprecision in the effect estimates.

Harms Results

The analysis of tolerability outcomes in the published NMA that are reported here are specific to the neoadjuvant setting. The analysis of the rate of febrile neutropenia suggested a higher rate of febrile neutropenia than is seen with anthracycline (RR = 0.53; 95% CI, 0.33 to 0.86). Conclusions could not be drawn for comparisons with anthracycline plus pembrolizumab, with anthracycline plus platinum salts, with platinum salts, or with other therapies (“C” node) due to serious imprecision in the effect estimates.

Regarding the analysis of the rate of grade 3 or greater nausea/vomiting, conclusions could not be drawn for comparisons with anthracycline alone, anthracycline in combination with platinum salts, or platinum salts alone due to serious imprecision in the effect estimates. No conclusions could be drawn for comparisons within the analysis of the rate of grade 3 or greater diarrhea due to serious imprecision in the effect estimates.

Critical Appraisal

The results of the published NMA by Miyashita et al. (2020)¹³ were associated with a number of limitations due to the lack of important details about the included trials and the methodology used to perform the NMA. As such, the appropriateness of conducting the NMA is uncertain. Most of the trials contributing to the network were at high risk of bias and are only applicable to the neoadjuvant phase of treatment. There was uncertainty regarding the plausibility of the transitivity assumption as sufficient assessment of potential effect modifiers was not reported. Results that were reported were associated with serious imprecision that limited the ability to draw conclusions for most of the comparisons in the network. Additionally, construction of treatment nodes used in the NMA preclude the ability to draw conclusions regarding comparisons of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy to other specific treatment options for TNBC. Overall, the findings of the NMA are uncertain.

Conclusions

One pivotal study (KEYNOTE-522) and 1 published NMA provided evidence for this CADTH review. No additional evidence directly comparing pembrolizumab plus chemotherapy in the neoadjuvant setting and pembrolizumab in the adjuvant setting with other standard therapies for early-stage TNBC was identified. The pCR rate and EFS were co-primary end points assessed in the KEYNOTE-522 study. Pathological complete response, EFS, OS, and HRQoL (including safety outcomes) investigated in the KEYNOTE-522 trial were considered clinically meaningful by the clinical experts, and they align with outcomes highlighted as important by the patient groups. The median OS and median EFS were not estimable at IA4; thus, there is uncertainty in the effect of the intervention for OS and EFS. The clinical experts considered differences in the pCR rate and percent change, as well as EFS, between the 2 arms clinically meaningful to clinicians and patients in clinical practice. The HRQoL assessments were considered exploratory due to the lack of multiplicity adjustments in the analyses. Both clinical experts and clinician groups stated that neoadjuvant therapy is current standard for TNBC and that pembrolizumab would be the preferred treatment option if it were to receive public funding. The clinical experts considered the safety profile of pembrolizumab plus chemotherapy followed by pembrolizumab manageable in practice. The experts stated that most oncologists have experience using pembrolizumab for other indications and are familiar with AEs due to pembrolizumab. Immune-related AEs are anticipated following the use of pembrolizumab. Both clinical experts and clinician groups considered toxicity and disease progression as important factors when deciding treatment discontinuation in patients. The KEYNOTE-522 study is a randomized, phase III, double-blinded design, and adjustments of multiplicity for type I error were conducted in the analyses of key outcomes OS, PFS, and pCR. The OS findings are interim, with other analyses planned after a pre-specified number of events have occurred. The clinical experts considered the baseline and demographic characteristics of the KEYNOTE-522 study generalizable to Canadian practice.

One published NMA by Miyashita et al. (2020)¹³ was summarized for this review to supplement the assessment of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC. The NMA presented findings of pCR and grade 3 AEs specific to the neoadjuvant setting, which was a key limitation identified. Other methodological limitations—such as the lack of important details reported in the NMA methodology; high risk of bias in the studies included; the lack of information about the characteristics of the trials included in the network; and the imprecision of the estimates reported—precluded definitive conclusions of the findings observed for the different chemotherapy regimens and combinations assessed within the study.

Introduction

Disease Background

Breast cancer is the most frequently diagnosed cancer in females in Canada, with projected estimates of about 27,700 new cases in 2021. It was estimated that 5,400 females would die from the disease in the same year. Fewer males are affected, with an estimated 290 new cases and 55 related deaths in 2021. The predicted 5-year survival is 89% for females and 76% for males.³ Identified risk factors include lifestyle choices such as alcohol use, limited physical activity, not having children, not breastfeeding, birth control use, menopausal hormone therapy, and breast implants; age; inherited gene changes (BRCA1 and BRCA2); family history of breast cancer; personal history of breast cancer; race; and ethnicity.^6,9

Triple-negative breast cancer is an invasive form of breast cancer affecting 10% to 20% of patients.^4,5 It is most common among women younger than 40 years; African-American women; and women who have a BRCA1 mutation.^5,6 It is well established that patients with the BRCA1 mutation are more likely to develop TNBC than patients with other mutations.^5,7,8 Triple-negative breast cancer is distinguished by the absence of an ER and a PR and by no expression of the HER2-negative gene.^6,8,9 The clinician groups consulted during the review highlighted that patients with TNBC have a higher risk of recurrence and death than patients with other types of breast cancer. The clinician groups also noted that patients with a pCR have on average a 5-year disease-free survival of 85% to 90% for localized disease,⁶ while those with no pCR have a higher recurrence rate. More than 50% of patients with early-stage (stage I to III) TNBC are bound to experience recurrence, of which 37% will die in the first 5 years following surgery.⁴

Most patients with breast cancer, including TNBC, present with no symptoms at early stages of the disease. Breast changes such as firm or hard lumps, a lump in the armpit, changes in breast size and shape, changes to the nipple, and discharge from the nipples are some common symptoms reported. Additional symptoms—including bone pain, weight loss, nausea, appetite loss, shortness of breath, cough, headache, double vision, and muscle weakness—may manifest with tumour size increase or spread to other organs.^6,9

Breast cancers can be diagnosed during screening exams using mammograms. In most Canadian provinces and territories, organized screening via mammography at 2- to 3-year intervals is available for women 50 to 74 years of age at an average risk of breast cancer.^14,15 Imaging techniques available include breast ultrasound and radionuclide imaging. Other diagnostic methods include tissue biopsy examinations, hormone receptor status testing, HER2 status testing, complete blood count, blood chemistry tests, tumour marker tests, X-rays, bone scans, and ductography.^6,8,9

Standards of Therapy

The clinical experts and clinician groups consulted during the CADTH review indicated that the standard approach for early-stage TNBC is NACT for cT1c or greater tumours. In the clinical experts’ opinion, this approach allows for clinical downstaging (better chance of clear margins, breast-conserving surgery, and potential avoidance of completion axillary node dissection) and prognostication (those with pCR having excellent long-term outcomes; those without pCR having higher risk of disease recurrence) and can inform post-operative adjuvant chemotherapy decisions (e.g., oral capecitabine for 6 to 8 cycles for those without pCR). Both clinical experts and clinician groups highlighted that pCR is the universally accepted treatment goal for neoadjuvant therapy.

Several NACT regimens are available in practice. The clinical experts and clinician groups consulted during the review highlighted that the sequential use of anthracycline-taxane (or taxane-anthracycline) combination chemotherapy (standard: every 3 weeks; dose dense: every 2 weeks) was standard of practice across jurisdictions in Canada. The experts also noted that carboplatin is increasingly added to the taxane portion of treatment. In patients with BRCA-positive mutations, olaparib will be likely used in the adjuvant setting. As noted by the experts, 4 cycles of dose-dense AC (doxorubicin, cyclophosphamide) twice weekly followed by 4 cycles of paclitaxel twice weekly, with carboplatin often added, is the preferred NACT regimen. When carboplatin is added, dosing can be weekly for 12 cycles or once every 3 weeks for 4 cycles, as highlighted by the experts.

Preferred treatment options outlined in the National Comprehensive Cancer Network guidelines for patients with HER-negative TNBC include anthracyclines (doxorubicin or liposomal doxorubicin), taxanes (paclitaxel), and antimetabolites (capecitabine or gemcitabine). In patients with BRCA1 or BRCA2 mutations, olaparib or talazoparib, as well as platinum (carboplatin or cisplatin), are preferred options.^8,10

Drug

Pembrolizumab is an immunoglobulin G4 monoclonal antibody against the programmed cell death protein 1. By inhibiting the programmed cell death protein 1 receptor from binding to its ligands expressed on T-cells, pembrolizumab restores the cytotoxic T-cell effector function. Combinations of pembrolizumab and chemotherapy were studied in an effort to enhance the antitumour activity of a single agent by creating a tumour microenvironment that stimulates responses to immunotherapy.¹⁰

The Health Canada–recommended dosage of pembrolizumab for adults with early-stage TNBC is either 200 mg IV every 3 weeks or 400 mg IV every 6 weeks, for a total of 1 year of treatment. It is recommended that patients be treated with neoadjuvant pembrolizumab in combination with NACT for 8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity. This should be followed by adjuvant treatment with pembrolizumab as monotherapy for 9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to pembrolizumab as neoadjuvant treatment in combination with NACT should not receive pembrolizumab monotherapy as adjuvant treatment.¹⁰ Key characteristics of pembrolizumab, carboplatin, and paclitaxel are shown in Table 3.

Pembrolizumab underwent a priority review at Health Canada and obtained an NOC on April 13, 2022, for the treatment of adult patients with high-risk, early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery.¹ The reimbursement request is for the treatment of adult patients with early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery. This submission was submitted for CADTH review pre-NOC, and the reimbursement request aligned with the proposed Health Canada indication. The proposed pre-NOC indication differs from the approved indication in the addition of “high-risk” patients to align the population with the KEYNOTE-522 trial population. Pembrolizumab has been previously reviewed by CADTH for other indications.

Table 3: Key Characteristics of Pembrolizumab, Carboplatin, and Paclitaxel

NA = not applicable; NOC = Notice of Compliance; PD-1 = programmed cell death protein 1; PD-L = programmed death ligand.

^aHealth Canada–approved indication.

Source: Pembrolizumab product monograph¹; carboplatin product monograph¹⁶; paclitaxel product monograph.¹⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full patient group input is included in the Stakeholder section of this review.

Two patient groups, the CBCN and Rethink Breast Cancer provided input for this review. The CBCN is a patient-directed charity and a member of the Canadian Cancer Action Network whose mission is to ensure the best quality of care for all Canadians affected by breast cancer through the promotion of information, education, and advocacy activities. Rethink Breast Cancer is a Canadian charity committed to educating, empowering, and advocating for system changes to improve the experience and outcomes of patients with breast cancer, especially for those in underserved groups such as those diagnosed at a younger age, those with metastatic breast cancer, and those who are systemically marginalized due to race, income, or other factors.

The patient input received by the CBCN was based on an online survey (the CBCN’s 2017 Lived Experience Breast Cancer Patient Survey), key informant telephone interviews, and a literature review of current studies and grey literature. Responses from 24 survey participants and 2 telephone interviewees were included in the patient input. All respondents included in the patient input indicated having had a diagnosis of TNBC. Most survey respondents (54%) were diagnosed with stage II TNBC; 8 and 2 respondents, respectively, were diagnosed with stage III and stage I TNBC. None of the survey respondents reported having experience with pembrolizumab treatment. Two patients being interviewed by telephone reported having received pembrolizumab treatment for TNBC, which was diagnosed at stage II and stage IIb in each of the 2 patients, respectively. The input from Rethink Breast Cancer was based on general observations and insights gathered through various ongoing initiatives (including patients’ blogs, virtual support groups, working groups, and patient advisory boards), as well as telephone interviews with 2 patients and with a caregiver to 1 of the patients, and from a focus group with 7 patients from the TNBC working group. Two patients and 1 caregiver interviewed reported having experience with pembrolizumab treatment for TNBC. Both patient interviewees reported being diagnosed with stage III TNBC.

Both patient groups indicated that, given the limited treatment options available, the diagnosis of TNBC has devastating and traumatic impacts on patients’ lives. The input provided by Rethink Breast Cancer indicated that, especially for patients who are diagnosed at a young age, TNBC may have detrimental effects on their well-being in terms of fertility, childcare, relationships, body image, social activities, employment, and mental health. Patients from the CBCN reported that the cost related to managing and treating TNBC would have negative financial impacts. The CBCN indicated that 7 and 12 survey respondents, respectively, had experienced a very large or some financial impact due to their TNBC diagnosis. Some survey respondents reported having difficulties accessing benefit programs that would help reduce the financial burden.

Respondents in the CBCN patient group expected new treatments to improve the following key outcomes: risk of recurrence, delay in disease progression, disease control, QoL, and severity of side effects. Patient respondents in the Rethink Breast Cancer group indicated that they were willing to tolerate additional side effects and detrimental impacts to their QoL in exchange for a new treatment that would be effective in controlling their TNBC. Additionally, patients from both patient groups perceived having access to effective treatments as a challenge and expressed their hope and desire to ensure that patients with TNBC can access effective treatments.

Patient respondents who had direct experience with pembrolizumab treatment indicated that, overall, pembrolizumab was an effective treatment, improved their QoL, and had tolerable or minimal side effects. Respondents in the CBCN input indicated that pembrolizumab was an effective treatment in terms of reducing the risk of recurrence, achieving a pCR, and having tolerable side effects. Key side effects highlighted by respondents in the CBCN included general fatigue, colitis, and diarrhea. Respondents in both patient groups noted similar challenges in attributing whether side effects were due to either pembrolizumab or chemotherapy as they received both treatments concurrently. One patient respondent in the Rethink Breast Cancer group reported that pembrolizumab had effectively reduced the tumour size but that they had experienced side effects such as hives, skin conditions, and thyroid issues. Other patient respondents mentioned having experienced minimal side effects while receiving pembrolizumab. One caregiver cited that, overall, the use of pembrolizumab treatment had been a positive experience, with side effects being somewhat of a challenge. In addition, the caregiver highlighted that ensuring a patient is comfortable, confident, and reassured with the treatment received is of critical concern to caregivers. All patients who had received pembrolizumab indicated they would recommend pembrolizumab to other patients with TNBC.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of TNBC.

Unmet Needs

Pathological complete response, OS, and EFS were considered important outcomes by the clinical experts consulted. The experts noted that pCR is associated with improvement in disease-free survival in TNBC. The clinical experts emphasized that not all patients respond to current treatment options and that pCR rates are approximately 50% in patients receiving chemotherapy. The clinical experts stated that recurrence rates are higher in patients with TNBC than in those with other forms of breast cancer and that the risks of recurrence and death are higher in patients who do not achieve a pCR following treatment.

Place in Therapy

According to the clinical experts, the approval of immunotherapy will cause a paradigm shift in practice for the treatment of TNBC. The experts noted that although carboplatin was administered in the KEYNOTE-522 trial and is increasingly being used in neoadjuvant settings, there is some variation in its administration across jurisdictions in Canada. The experts noted that in the KEYNOTE-522 trial, carboplatin and paclitaxel cycles were administered before the doxorubicin and cyclophosphamide cycles, which is the opposite order to standard practice in Canada. In the opinion of the experts, the new treatment regimen would likely become the new standard of care for patients with TNBC, as currently no adjuvant therapy is administered in the setting of pCR in TNBC.

The clinical experts advised that it would not be appropriate for patients to try other treatments before initiating pembrolizumab combined with chemotherapy. The experts stated that pembrolizumab combined with chemotherapy would be required to be used first, as patients only have “1 chance” at receiving an appropriate neoadjuvant therapy to maximize their chance of pCR. According to the experts, the best therapy that suits a patient’s medical needs and tolerance is prioritized in practice settings.

Patient Population

The clinical experts advised that patients best suited for treatment with pembrolizumab combined with chemotherapy are those that meet the inclusion criteria of the KEYNOTE-522 study. Typically, this will include patients 18 years and older diagnosed with nonmetastatic TNBC, with any clinically node-positive or node-negative patients, if the primary tumour size is cT2 (2 cm) or greater, and with an ECOG PS of 0 to 1.

The experts stated that patients will be routinely identified in practice during consultations with a medical oncologist. The experts indicated that standard breast cancer clinical staging approaches (with no additional testing required) and routine breast tumour biopsy characterization of ER, PR, and HER2 status are used to identify patients. One expert highlighted that jurisdictions with low uptake of neoadjuvant therapy for TNBC may require reminders to their surgical practitioners to refer patients for the therapy, although the anticipated need to inform physicians is low, stated the expert, as neoadjuvant therapy for TNBC with T1c or greater and node-positive disease is standard of care.

The clinical experts advised that patients with pre-existing serious autoimmune diseases, regardless of tumour size or nodes, may not be eligible for this regimen. Patients with T1a/T1B N0 (node 0) are also not eligible due to the early-stage disease (regardless of coexisting autoimmune conditions). According to the experts, these patients will likely have surgery upfront. The experts stated that patients with less serious autoimmune conditions may need to weigh the pros and cons of using pembrolizumab while considering older standard regimens in lower risk TNBC cases.

Assessing Response to Treatment

The experts indicated that there are no biomarkers to select TNBC cases early on during treatment. The experts noted that PD-L1 status has been predictive of benefit in metastatic cases but not in early disease.

The clinical experts stated that patients undergo a physical exam before each cycle, and sometimes imaging scans may be considered during treatments to rule out primary disease progression and to review possible candidacy for breast-sparing surgery. The experts considered evidence of tumour shrinkage, either clinically or radiographically, upon receiving treatment as a clinically meaningful response to treatment. According to the experts, the greater the response (particularly pCR), the better the long-term prognosis. Typically, patients will be assessed before each cycle in the neoadjuvant setting.

Discontinuing Treatment

The clinical experts stated that disease progression (tumour enlargement unless pseudoprogression is suspected) and the occurrence of AEs, particularly autoimmune toxicities (any grade 4 treatment-related AE or grade 2 to 3 AE not improving to grade 1 with supportive care or dose modifications), would be considered when deciding treatment discontinuation.

Prescribing Conditions

The clinical experts advised that chemotherapy infusion units with experience in administering cytotoxic agents and immunotherapy would be appropriate for administering the treatment regimen. The experts advised that a medical oncologist would usually initiate therapy and that treatment monitoring could be performed by either the treating oncologist or extender (e.g., family practitioner in oncology, nurse practitioner, or clinical nurse specialist).

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full clinician group input is included in the Stakeholder section of this review.

Two clinician group inputs were provided: 1 from OH-CCO Breast Cancer Drug Advisory Committee (based on input from 2 clinicians) and 1 from TOHCC Breast Disease Site Group (based on input from 15 medical oncologists). The OH-CCO’s Drug Advisory Committee provides timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. TOHCC aims to provide each person affected by cancer with world-class care, exceptional service, and compassion.

The OH-CCO and TOHCC clinician groups identified NACT and then adjuvant chemotherapy as the current Canadian treatment paradigm for patients with TNBC. Both groups considered achieving long-term cure, improving OS and EFS, and delaying disease progression as important treatment goals. Both groups identified the lack of effective treatment options for patients with TNBC, limited pCR rates, and the highest recurrence and death rates (among forms of breast cancer) as unmet needs. Both groups anticipate that pembrolizumab would fit into the current treatment paradigm as a new treatment standard for TNBC. However, the OH-CCO group mentioned that there is a lack of evidence on combining pembrolizumab with different agents, such as adjuvant capecitabine or adjuvant olaparib, or on comparing treatment effectiveness with different agents. In addition, at least 35% of patients with TNBC would receive capecitabine as the standard of care after the neoadjuvant treatment, whereas adjuvant capecitabine was not allowed in the KEYNOTE-522 trial. The TOHCC group highlighted that the carboplatin and paclitaxel cycles were given before the doxorubicin and cyclophosphamide cycles in the KEYNOTE-522 trial, which is the opposite order to Canadian standard practice.

Both groups agreed that it would be not appropriate to recommend patients with TNBC to try other treatments before initiating pembrolizumab as studies have shown that, in the advanced disease setting, delaying pembrolizumab while giving chemotherapy leads to worse outcomes and patients only have “1 chance” to receive the optimal evidence-based neoadjuvant and adjuvant regimen to achieve cure and prevent systemic recurrences. The clinician groups agreed that high-risk patients with TNBC who meet the eligibility criteria in the KEYNOTE-522 trial would be best suited for the pembrolizumab treatment and that patients with an ECOG PS of 2 to 4 or who have contraindications, such as serious pre-existing autoimmune disorders, would be least suitable for the pembrolizumab treatment.

Both clinician groups consulted considered tumour shrinkage (clinically or radiographically), improved pCR, and EFS as clinically meaningful outcomes to assess treatment response. Both clinician groups described that patients will be assessed for a response based physical examination and radiographic imaging before every cycle of treatment. Both clinician groups highlighted that disease progression or serious AEs (any grade 4 treatment-related AE or grade 2 to 3 AE not improving to grade 1 with supportive care or dose modifications) will be considered when deciding treatment discontinuation. The 2 groups identified hospitals or chemotherapy infusion units with experience in administering cytotoxic agents and immunotherapy as appropriate settings for treatment with pembrolizumab.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

AC = anthracycline-cyclophosphamide; ACT = anthracycline plus cyclophosphamide plus taxane; AJCC = American Joint Committee on Cancer; ECOG PS = Eastern Cooperative Oncology Group Performance Status; pCR = pathological complete response; PD-L1 = programmed death ligand 1; TNBC = triple-negative breast cancer.

Clinical Evidence

The clinical evidence included in the review of pembrolizumab (Keytruda) is presented in 2 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the review.

Systematic Review: Pivotal and Protocol Selected Studies

Objectives

To perform a systematic review of the beneficial and harmful effects of pembrolizumab (200 mg administered intravenously every 3 weeks or 400 mg every 6 weeks) for the treatment of adult patients with early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The systematic review protocol presented here was established before the granting of an NOC from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; HRQoL = health-related quality of life; PD-L1 = programmed death ligand 1; RCT = randomized controlled trial; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TNBC = triple-negative breast cancer; WDAE = withdrawal due to adverse event.

^aDraft product monograph states: “For the neoadjuvant and adjuvant treatment of early-stage TNBC, patients should be treated with neoadjuvant pembrolizumab in combination with chemotherapy for 8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with pembrolizumab as monotherapy for 9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to pembrolizumab as neoadjuvant treatment in combination with chemotherapy should not receive pembrolizumab monotherapy as adjuvant treatment.”

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS (Peer Review of Electronic Search Strategies) checklist.¹⁸

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974—) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Keytruda (pembrolizumab) and TNBC. Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register. No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on March 8, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on July 13, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.¹⁹ Included in this search were the websites of regulatory agencies (the FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented through review of bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Findings From the Literature

Three reports of a single study were identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Description of Study

KEYNOTE-522 is an ongoing, phase III, randomized, multi-centre, double-blind, placebo-controlled trial. The primary objective of KEYNOTE-522 is to evaluate the rate of pCR for pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared with placebo plus chemotherapy as neoadjuvant therapy followed by continued placebo as adjuvant therapy for patients with high-risk, early-stage TNBC.¹⁰

Two primary outcomes, pCR rate (using the no invasive residual disease in breast or nodes; noninvasive breast residuals allowed [ypT0/Tis ypN0] definition) assessed by local pathologist and EFS assessed by investigator, were defined in the study. Overall survival, pCR rate (using no invasive or noninvasive residual disease in breast or nodes [ypT0 ypN0] and no invasive residual disease in breast or nodes; noninvasive breast residuals allowed [ypT0/Tis] definitions), pCR rate in PD-L1 (positive) tumours (combined positive score [CPS] ≥ 1), EFS assessed by the investigator in patients with PD-L1 (positive) tumours (CPS ≥ 1), OS in PD-L1 (positive) tumours (CPS ≥ 1), safety and tolerability, and HRQoL (using the EORTC QLQ-C30, the EORTC QLQ-BR23, and the EQ-5D-5L questionnaire) were some secondary and exploratory outcomes investigated in the study.

Enrolled patients were randomized via an interactive voice response system or integrated web response system in a 2:1 ratio to 1 of the 2 study arms based on 3 stratification factors:

• Nodal status: positive versus negative

• Tumour size: T1 or T2 versus T3 or T4

• Choice of carboplatin regimen: every 3 weeks or weekly

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Study

AC = doxorubicin plus cyclophosphamide; AE = adverse events; AJCC = American Joint Committee on Cancer; ASCO = American Society of Clinical Oncology; AUC = area under the curve; BCS = breast-conserving surgery; CAP = College of American Pathologists; CHF = congestive heart failure; CPS = combined positive score; DRFS = distant recurrence-free survival; EC = epirubicin plus cyclophosphamide; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EFS = event-free survival; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FTV = functional tumour volume; HRQoL = health-related quality of life; IA = interim analysis; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; ORR = objective response rate; OS = overall survival; pCR = pathological complete response; PD-L1 = programmed death ligand 1; q.3.w. = every 3 weeks; RCB = residual cancer burden; RECIST = Response Evaluation Criteria in Solid Tumours; SAE = serious adverse event; TIL = tumour-infiltrating T lymphocytes; TNBC = triple-negative breast cancer; ypTO ypNO = no invasive or noninvasive residual disease in breast or nodes; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Note: Data cut-off: March 23, 2021.

Source: Clinical Study Report.¹⁰

By the IA4 data cut-off (March 23, 2021), 1,608 patients had been screened, of which 1,174 were randomized to 1 of the 2 study arms (refer to Figure 2). In total, 784 patients were randomized to receive pembrolizumab plus chemotherapy and 390 to receive placebo plus chemotherapy. The majority of the patients enrolled were female (1 man was enrolled), younger than 65 years, White, and pre-menopausal and had an ECOG PS of 0. More than 80% of patients were PD-L1 positive.¹⁰

The KEYNOTE-522 trial was initiated in March 2017 and has 194 participating centres across 21 countries in North America (7 sites in Canada), South America, Europe, Asia, and Australia. The last patient was randomized into the study in September 2018. Patients and investigators were blinded to study treatments administered during the trial. The study was conducted in 2 phases: the neoadjuvant phase and the adjuvant phase, as shown in Figure 2.

Study phases

The screening phase took place approximately 28 days before randomization and treatment allocation. Patients were evaluated to determine if they met the inclusion criteria outlined in the protocol.

Following randomization, patients entered the neoadjuvant treatment phase, during which they were treated with the assigned therapy (pembrolizumab plus chemotherapy or placebo plus chemotherapy) for 12 weeks. Assessments and procedures were performed on day 1 of each cycle before the dosing of any study treatment (or before weekly dosing of paclitaxel), unless otherwise specified. Each treatment cycle lasted 3 weeks (21 days). Definitive surgery such as breast-conserving surgery or mastectomy with sentinel lymph node biopsy, with or without axillary lymph node dissection, was performed as part of the local standard of care approximately 3 weeks to 6 weeks following the completion or early discontinuation of the treatments in the neoadjuvant phase.

Figure 2: KEYNOTE-522 Study Design

AJCC = American Joint Committee on Cancer; AUC = area under the curve; CPS = combined positive score; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EFS = event-free survival; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; OS = overall survival; pCR = pathological complete response; PD-L1 = programmed death ligand 1; PRO = patient-reported outcome; Q3W = every 3 weeks; QW = every week; TNBC = triple-negative breast cancer; vs. = versus.

Note: Data cut-off date: March 23, 2021. Neoadjuvant chemotherapy as follows: carboplatin AUC5 every 3 weeks or AUC1.5 every week plus paclitaxel 80 mg/m² every week in the first 12 weeks and then doxorubicin 60 mg/m² or epirubicin 90 mg/m² every 3 weeks plus cyclophosphamide 600 mg/m² every 3 weeks in the subsequent 12 weeks.

pCR (ypT0/Tis ypN0) = no residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy at time of definitive surgery (noninvasive breast residuals [i.e., in situ cancer] allowed).

EFS = time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause.

pCR (ypT0 ypN0) = no residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy at time of definitive surgery.

pCR (ypT0/Tis) = no residual invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy at time of definitive surgery.

Source: Sponsor-submitted reimbursement package²; Schmid et al. (2020).²²

Following surgery, patients entered the adjuvant treatment phase (30 days to 60 days after definitive surgery). Post-operative radiation therapy was acceptable in accordance with the standard of care, as applicable, and administered before or concurrently with systemic adjuvant treatment. If the patient was found to have disease progression before surgery, they were not allowed to proceed with the adjuvant treatment phase. Participants received either pembrolizumab or placebo every 3 weeks for 9 cycles (each cycle lasting 21 days).

Study treatment continued until completion of treatment (17 cycles [approximately 1 year] of pembrolizumab or placebo), disease progression in the neoadjuvant phase, recurrence (local or distance) after surgery, unacceptable AE(s), intercurrent illness that prevented further administration of treatment, investigator’s decision to withdraw the participant from treatment, pregnancy of the patient, noncompliance with treatment or procedure requirements, consent withdrawal, loss to follow-up, death, or administrative reasons that required treatment discontinuation.¹⁰

Post-Treatment Visits

Early Discontinuation Visit

An early discontinuation visit was conducted for patients who discontinued all protocol-specified treatments after the first treatment, cycle 1, through the adjuvant treatment phase. Early discontinuation procedures were recommended if the discontinuation visit occurred 30 days from the last dose of study treatment, at the time of the mandatory safety follow-up visit.

Safety Follow-Up Visits

Mandatory safety follow-up visits were conducted approximately 30 days (± 3 days) following the end of the neoadjuvant treatment phase, definitive surgery, and adjuvant treatment phase. In the event of an early discontinuation visit, a 30-day safety follow-up visit (30 days ± 3 days) was performed.

Long-Term Follow-Up for Disease Status and Survival

Long-term follow-up was planned every 3 months (± 1 month), then every 6 months (± 1 month) in years 3 to 4, and annually after 5 years for assessment of recurrent disease; or for metastatic disease for the first 2 years following adjuvant treatment. Any additional tests, investigations, or imaging assessments for recurrent or metastatic disease (e.g., bone or liver scan) were conducted at the discretion of the patient’s treating physician, and per local standard of care, or at the time of symptoms.

Treatment phase

Patients who discontinued treatment received follow-up by telephone every 6 months (± 1 month) for OS until consent withdrawal from trial, loss to follow-up, death, or end of the study, whichever came first.¹⁰

Populations

Inclusion and Exclusion Criteria

To be eligible, patients 18 years and older were required to have centrally confirmed TNBC, as defined by the most recent ASCO–CAP guidelines; have previously untreated, locally advanced nonmetastatic (M0) TNBC, defined per current AJCC staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment (T1c, N1 to N2; T2 to T4d, N0 to N2); provide a core needle biopsy consisting of at least 2 separate tumour cores from the primary tumour at screening; have an ECOG PS of 0 or 1 within 10 days of treatment initiation; have adequate organ function; and have left ventricular ejection fraction of at least 50% or at least an institution lower limit of normal as assessed by echocardiogram or multigated acquisition scan.¹⁰

Patients were excluded from the study if they had received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months; had a history of (noninfectious) pneumonitis that required steroids or current pneumonitis; or had significant cardiovascular disease such as a history of myocardial infarction, acute coronary syndrome, or coronary angioplasty, stenting, or bypass grafting within the last 6 months, or congestive heart failure of New York Heart Association class II to IV, or a history of congestive heart failure of New York Heart Association class III or IV.¹⁰

Table 7: Summary of Baseline Characteristics at IA4—Intention-to-Treat Population

CPS = combined positive score; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FISH = fluorescence in situ hybridization; IA = interim analysis; IHC = immunohistochemistry; M0 = nonmetastatic; PD-L1 = programmed death ligand 1; q.3.w. = every three weeks.

Note: Data cut-off: March 23, 2021.

^aMissing values in race and ethnicity are mainly because France is not permitted to report this information.

^bMissing value in menopausal status is from 1 male participant.

^cMissing value in HER2 status is from the participant with missing IHC but with a FISH-negative result.

Source: Clinical Study Report.¹⁰

Baseline Characteristics

At the time of IA4, all patients (except for 1 in the pembrolizumab plus chemotherapy arm) were female and most were younger than 65 years, White, non-Hispanic or Latino, and pre-menopausal and had an ECOG PS of 0. Most patients (> 80%) had a tumour tissue PD-L1 expression score that was a CPS of 1 or higher. All patients enrolled had nonmetastatic disease, with the majority in both study arms having stage II disease. Table 7 presents the baseline and demographic characteristics of patients enrolled in the KEYNOTE-522 study at IA4.¹⁰

Interventions

Patients were randomized in a 2:1 ratio to 1 of the 2 study arms.

Arm 1

Pembrolizumab plus chemotherapy (pembrolizumab every 3 weeks, plus paclitaxel weekly, plus carboplatin every 3 weeks or weekly for 4 cycles, followed by pembrolizumab plus doxorubicin or epirubicin plus cyclophosphamide every 3 weeks for 4 cycles) as neoadjuvant therapy before surgery, followed by 9 cycles of pembrolizumab every 3 weeks as adjuvant therapy post-surgery.

Arm 2

Placebo plus chemotherapy (placebo every 3 weeks, plus paclitaxel weekly, plus carboplatin every 3 weeks or weekly for 4 cycles, followed by placebo plus doxorubicin or epirubicin plus cyclophosphamide every 3 weeks for 4 cycles) as neoadjuvant therapy before surgery, followed by 9 cycles of placebo every 3 weeks as adjuvant therapy post-surgery.¹⁰

Treatment Administration

Each cycle referred to in this section is 21 days.

Pembrolizumab: Administered at a 200 mg fixed dose via IV every 3 weeks, in the neoadjuvant and adjuvant treatment phases. The expected duration for the treatment was 12 months. A fixed-dose regimen was implemented to simplify the dosing regimen to be more convenient for physicians and to reduce potential for dosing errors.

Placebo: Composed of normal saline plus dextrose administered via IV every 3 weeks in the neoadjuvant and adjuvant treatment phases.

Chemotherapy (treatment 1):

• Carboplatin: Area under the curve 5 (IV, every 3 weeks, on day 1 of cycles 1 to 4 of the paclitaxel and carboplatin regimen) or area under the curve 1.5 (IV, weekly, on days 1, 8, and 15 of cycles 1 to 4 of the paclitaxel and carboplatin regimen).

• Paclitaxel: Administered at 80 mg/m², IV, weekly, on days 1, 8, and 15 of cycles 1 to 4 of the paclitaxel and carboplatin regimen.

Followed by (treatment 2):

• Doxorubicin: 60 mg/m², IV, every 3 weeks, on day 1 of cycles 1 to 4 of the doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide regimen, or

• Epirubicin: 90 mg/m², IV, every 3 weeks, on day 1 of cycles 1 to 4 of the doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide regimen, plus

• Cyclophosphamide: 600 mg/m², IV, every 3 weeks, on day 1 of cycles 1 to 4 of the doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide regimen.

Dose Modification

In the event of drug-related toxicity, including severe or life-threatening AEs, pembrolizumab was withheld. Dosing interruptions were permitted in the case of medical or surgical events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, or holidays). Patients were to resume study therapy within 6 weeks of the scheduled interruption, unless otherwise discussed with the sponsor. Dose modification strategies for other chemotherapy agents were allowed in the study protocol. Local guidelines and practices were recommended if dosing was different from the sponsor’s recommendations. In the event that a dose delay did not lead to chemotherapy discontinuation, patients were allowed to resume treatment with the next scheduled dose in the regimen and continue on treatment to complete the full number of cycles per protocol.¹⁰

Treatment Discontinuation Criteria

Patients were allowed to discontinue 1 or more components of the study treatment at the discretion of the investigator in case of untoward effects. During the first part of the combination therapy, if 1 or more than 1 component of the regimen was discontinued due to toxicity, the investigator was required to consult and select 1 of many options outlined in the protocol for the patient at the investigator’s discretion.¹⁰ The investigator or sponsor was allowed to discontinue study treatment if the treatment was considered inappropriate, if the trial plan was violated, or for administrative or other safety reasons. A patient had to discontinue treatment but was permitted to remain in the trial and continue to receive follow-up and monitoring in the trial for the following reasons:

• Request from the patient or patient’s legally acceptable representative to discontinue treatment

• Unacceptable adverse experiences

• Intercurrent illness that prevents further administration of treatment

• Investigator’s decision to withdraw the patient from study treatment due to disease progression or other reasons

• Confirmed positive serum pregnancy test

• Noncompliance with trial treatment or procedure requirements

If the discontinuation from treatment was considered permanent, the patient was not allowed to restart treatment.¹⁰

Withdrawal From the Trial

Patients were allowed to withdraw from the trial if the patient or patient’s legally acceptable representative withdrew consent. Patients who withdrew from the trial were not permitted to receive treatment and were not followed at scheduled protocol visits. The patient underwent an early discontinuation visit procedure at the time of discontinuation.¹⁰

Concomitant Medications

All concomitant medications were documented, including all prescription and over-the-counter medications, herbal supplements, and IV medications and fluids. Reported concomitant interventions and concomitant use of steroid interventions were generally balanced between treatment groups. Supportive care was permitted for managing drug-related toxicities. Any supportive therapy or vaccination allowed during the trial was at the discretion of the investigator and/or the patient’s primary physician. Treatments considered necessary for patients’ welfare were allowed at the discretion of the investigator. Medications prohibited during the trial included immunotherapy, chemotherapy, or investigational agents not specified in the protocol; radiation therapy (except for radiation therapy post-surgery according to the standard of care, that is, in cases of breast-conserving surgery or large primary tumour or for patients with positive lymph nodes); live vaccines within 30 days before the first dose of trial treatment and during the trial (except for inactivated seasonal influenza vaccines); and glucocorticoids for any purpose other than to modulate the symptoms for an immune-related AE or for use as a pre-medication for chemotherapeutic agents specified in the protocol. Table 8 presents information on participants with specific concomitant medications (incidence > 0% in 1 or more treatment groups).¹⁰

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are further summarized below. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.

Table 8: Participants With Specific Concomitant Medication at IA4—All Participants as Treated Population

IA = interim analysis.

Note: Every participant is counted a single time for each applicable specific concomitant medication. A participant with multiple concomitant medications within a medication category is counted a single time for that category. Database cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE = adverse event; AJCC = American Joint Committee on Cancer; EFS = event-free survival; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life; irAE = immune-related adverse event; OS = overall survival; pCR = pathological complete response; SAE = serious adverse event; ypTO ypNO = no invasive or noninvasive residual disease in breast or nodes; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Source: Clinical Study Report.¹⁰

Efficacy Measurement for Primary and Secondary Outcomes

Imaging (e.g., CT, MRI, bone scan) was performed at the discretion of the investigator, as per the local standard of care. Disease assessments were performed per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, if applicable.

Definitive Surgery

Patients underwent definitive surgery as per local standard of care, 3 weeks to 6 weeks after the completion of neoadjuvant treatments. Breast tissues obtained during surgery were staged according to the AJCC guidelines and assessed for surgical margins by a local pathologist.

Pathologists reviewing and interpreting surgical specimens for pCR assessment were blinded to treatment assignment. All pathologists received formal training, and a procedure manual was provided that outlined standard guidelines for localization of tumour bed, handling of lymph nodes, and pathological evaluation of specimens. Regional pathologist(s) served as adjudicators or consultants for cases for which the site pathologist was uncertain of the pCR outcome. Tissue samples of patients who did not achieve a pCR were collected and submitted to designated central laboratories for translational research.

Disease Progression Determination

Breast MRI was performed in patients with locally advanced TNBC who chose to participate for more accurate clinical staging of the primary tumour and axilla lymphadenopathy and to ensure the primary tumour and regional lymph node staging fulfilled the protocol-required criteria. Breast MRI and MRI were scheduled for patients who provided consent to participate in these assessments as follows:

• At screening (before first dose of study drug)

• After the neoadjuvant treatment phase, treatment 1 cycle 4

• After the neoadjuvant treatment phase, treatment 2 cycle 4 (before definitive surgery)

Breast MRI performed as part of the routine clinical management was acceptable for initial screening tumour imaging if it had diagnostic quality and had been performed within 28 days before the first dose of the trial treatment.²

For the patients who chose to receive breast MRIs at protocol-specified time points, measurement of the baseline lesions, changes from the baseline, and objective response were assessed by the investigator per RECIST 1.1. Central confirmation assessment of complete response or partial response were not conducted. Imaging assessments for recurrent or metastatic disease were conducted at the discretion of the treating physician, per local standard of care, or at the time of symptoms.²

Health-Related QoL

Health-related QoL measures were assessed using the EORTC QLQ-C30, the EORTC QLQ-BR23, and the EQ-5D-5L questionnaire. A detailed discussion and critical appraisal of EORTC QLQ-C30 and EORTC QLQ-BR23 is available in Appendix 3. Patients completed the questionnaires at the following pre-specified time points:

• Neoadjuvant treatment phase:

  • On day 1 of cycle 1 of treatment 1

  • On day 1 of cycles 1 and 4 of treatment 2

• Adjuvant treatment phase:

  • On day 1 of cycles 1, 5, and 9

• At the early discontinuation visit

• At long-term follow-up visits (after the adjuvant treatment phase, questionnaires were completed every 12 months for 2 years or until progression, whichever was earlier)²

The EORTC QLQ-C30 is a multidimensional, cancer-specific, self-administered measure of HRQoL. The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status–QoL scale, and 5 single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as perceived financial impact of the disease.²³ The EORTC QLQ-C30 uses a 1-week recall period to assess functional status and symptoms. All scales and single-item measures are scored from 0 to 100. Scale sum scores are transformed such that a high score on the functional scales represents a high (or healthy) level of functioning, a high score on the symptom scales represents a high level of symptomatology, and a high score on the global health status–QoL scale represents a high HRQoL.²⁴

The EORTC QLQ-BR23 includes an additional 23 items that are specific to breast cancer, with 5 multi-item scales assessing systemic therapy side effects, arm symptoms, breast symptoms, body image, and sexual functioning, as well as single items assessing sexual enjoyment, hair loss, and future perspective.²⁵ All scales range in score from 0 to 100, and higher scores represent higher response. Thus, a high score for functioning represents high functioning, while a high symptom score represents a high symptom burden. The EORTC QLQ-BR23 is not a free-standing instrument as it does not measure a multi-dimensional construct of body image; instead, the EORTC QLQ-BR23 is administered in conjunction with the EORTC QLQ-C30.²⁵

The EQ-5D-5L questionnaire consists of 2 separate elements. The first is the utility score (or descriptive system), which captures health states across 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each unique health state is defined by combining response levels from each of the 5 dimensions. The second component, the EQ VAS, records the respondent’s self-rated health on a vertical VAS ranging from 0 to 100, where the end points are labelled “best imaginable health state” (100) and “worst imaginable health state” (0).²

Harms Outcomes

Safety parameters such as incidence of AEs, serious AEs including fatal serious AEs, immune-related AEs, laboratory abnormalities, rates of dose interruption and discontinuation due to AEs, and events of clinical interest were monitored throughout the trial.²

Statistical Analysis

Sample Size and Power Calculation

A total sample size of 1,150 was initially planned for the study. The sample size was determined based on the EFS.²

Pathological Complete Response Rate: ypT0/Tis ypN0

Pathological complete response rate using the ypT0/Tis ypN0 definition was a co-primary end point of the KEYNOTE-522 trial. The pCR analysis was planned after enrolment was completed, when at least 1,000 patients had completed surgery (if they continued treatment), after approximately 6 months of neoadjuvant treatment. A sample size of about 1,000 was needed to achieve approximately 95% power to detect a true pCR rate difference of 15% between pembrolizumab plus chemotherapy and placebo plus chemotherapy at an alpha of 0.5% (1 sided). The sample size calculation was based on the following assumptions:

• Alpha of 0.5% is allocated to the pCR hypothesis.

• The underlying pCR is 50% in the placebo plus chemotherapy arm, and there is a 15% increase in pCR in the pembrolizumab plus chemotherapy arm (pCR of 65%) in patients with locally advanced TNBC.

• The dropout rate is approximately 10%.²

In addition, a Hwang-Shih-DeCani alpha-spending function with gamma parameter (0) was used to assign group sequential boundaries that controlled the type I error.² The assumptions for a pCR rate of 50% in the placebo plus chemotherapy arm was based on estimates observed by Sikov et al. (2015)²⁶ and von Minckwitz et al. (2014).²⁷

Event-Free Survival

Event-free survival was a co-primary end point of the KEYNOTE-522 trial. The final analysis of the trial is EFS event driven and planned after approximately 327 EFS events have been observed, unless the study is terminated early. A pre-specified alpha level of 2% (1 sided) and a sample size of 1,150 were needed to achieve approximately 80% power to detect EFS in patients with locally advanced TNBC, assuming that the true HR (pembrolizumab versus placebo) was 0.71. This value was based on evidence published in a meta-analysis by Cortazar et al. (2014)²⁸ that suggested that approximately 50% of patients may become disease-free in the long-term. The sponsor applied a cure rate model to accommodate decreases in failure over time.² The calculations were based on the following assumptions:

• Event-free survival follows a Poisson mixture model (cure rate model with decreasing failure rate) distribution with an approximately 78% EFS rate at 36 months and an approximately 50% cure rate in the placebo arm.

• There is an enrolment period of 18 months and at least 84 months of follow-up.

• There is a yearly dropout rate of 2% and an additional approximately 3% to 5% dropout rate after surgery.

The EFS control rate of 78% was estimated from an updated report of the sponsor.² In addition, the Lan-DeMets O’Brien-Fleming approximation alpha-spending function was applied to assign group sequential boundaries that control type I error.²

Overall Survival

Overall survival was a secondary end point assessed in the KEYNOTE-522 trial. In the event that the null hypothesis for EFS was rejected at any IA, the final OS analysis was planned as an event-driven outcome, after approximately 297 OS events have occurred, unless the study was terminated early. A pre-specified alpha of 2% (1 sided) and a sample size of approximately 1,150 were required for approximately 79.7% power to detect OS events in patients with locally advanced TNBC, assuming that the true HR (pembrolizumab versus placebo) was 0.70. The sponsor applied a cure rate model for decreases in failure over time based on evidence published in a meta-analysis by Cortazar et al. (2014)²⁸ that suggested that approximately 50% of patients may become disease-free in the long-term.² The sponsor’s calculations were based on the following assumptions:

• Overall survival follows a Poisson mixture model (cure rate model with decreasing failure rate) distribution with an approximately 81% OS rate at 36 months and an approximately 50% cure rate in the placebo arm.

• There is an enrolment period of 18 months and at least 84 months of follow-up.

• There is a yearly dropout rate of 3%.

A Lan-DeMets O’Brien-Fleming approximation alpha-spending function was used to assign group sequential boundaries that control the type I error.²

Analyses, Multiple Testing Procedure, and Alpha Spending

Dual hypothesis testing was conducted in the KEYNOTE-522 trial, and multiplicity adjustments were conducted for 2 primary objectives (EFS and pCR) and 1 secondary hypothesis (OS), as presented in Figure 3.

Figure 3: Multiplicity Strategy for the KEYNOTE-522 Trial

EFS = event-free survival; H = hypothesis; OS = overall survival; pCR = pathological complete response; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed

Source: Sponsor-submitted reimbursement package.²

The dual primary hypotheses tested the superiority of pembrolizumab compared to placebo in pCR (ypT0/Tis ypN0) or EFS in patients with locally advanced TNBC. The secondary hypothesis tested the superiority of OS in patients with locally advanced TNBC. The overall type I error was controlled at an alpha level of 2.5% (1 sided); 0.5% initially allocated to the pCR (ypT0/Tis ypN0) hypothesis, and 2.0% initially allocated to the EFS hypothesis. The study was considered a success if pCR (ypT0/Tis ypN0) or EFS demonstrated a statistically significant difference at either preplanned IAs or the full analysis under multiplicity control.²

The graphical method by Maurer and Bretz was used; this method allowed the study hypotheses to be tested more than once, and in the situation where the null hypothesis was rejected, the alpha allocated to that hypothesis was reallocated to other hypothesis tests.²

Planned Analyses

Two IAs were planned for the pCR (ypT0/Tis ypN0) rate, while EFS analyses were planned annually after 2 years of study initiation. Seven efficacy IAs were planned in addition to the final analysis for the KEYNOTE-522 trial. No futility boundary was defined as the sponsor had no plans to stop the study for futility. Table 10 presents all preplanned IAs.²

Primary Outcome Analyses

Pathological Complete Response Rate

The stratified Miettinen and Nurminen method was used to compare the pCR rates between the 2 treatment arms based on 3 definitions. The difference in pCR rate and its 95% CI from the stratified Miettinen and Nurminen method with strata weighting by sample size was reported for patients with locally advanced TNBC and for patients with PD-L1 (positive) tumours. The stratification factors used for randomization were applied during the analysis.²

In the primary pCR analysis, as per clinical judgment, patients who used the same neoadjuvant regimens but different doses or schedules from those specified in the study may not have been considered as using new anticancer therapy in neoadjuvant treatment before definitive surgery.

Sensitivity analyses were conducted for pCR rates using the Cochran-Mantel-Haenszel test, and associated odds ratios and 95% CIs were calculated.²

Table 10: Planned Interim Analyses, End Points Evaluated, and Drivers of Timing

EFS = event-free survival; FA = final analysis; IA = interim analysis; NR = not reported; OS = overall survival; pCR = pathological complete response; TBD = to be determined; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Source: Sponsor-submitted reimbursement package.²

Event-Free Survival

The Kaplan–Meier method was used to estimate the EFS curve for each treatment group. The treatment difference in EFS was assessed using the stratified log-rank test. A stratified Cox proportional hazard model using the Efron method of tie handling was used to assess the magnitude of the treatment difference (i.e., HR) between the 2 treatments. The HR with the 95% CI and Kaplan–Meier estimates with the corresponding 95% CIs at 2 years, 3 years, and 5 years were reported. The stratification factors used for randomization were applied to both the stratified log-rank test and the stratified Cox model.²

For the primary analysis, the true date of event was approximated as the date of the first assessment for which the event was objectively documented. Patients who did not experience an event at the time of data analysis were censored at the date they were last known to be alive and event free (Table 11).

The proportional hazards assumption was examined using a graphical and analytical approach. A plot of the log[-log] of the survival function versus time for EFS was planned for the comparison of the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms. In the event of a violation of the proportional hazard assumption, a sensitivity analysis was planned based on a 2-step weighted Cox model approach, as described by Mehrotra et al. (2012).²⁹ Sensitivity analyses were planned based on the censoring rules presented in Table 11.

Table 11: Censoring Rules for the Primary Analysis and Sensitivity Analyses 1 and 2 of EFS

EFS = event-free survival.

^aThe new anticancer therapy in sensitivity analysis 1 is defined as any post-surgery new oncology drugs or post-surgery radiation to treat metastatic disease.

^bThe new anticancer therapy in sensitivity analysis 2 is defined as the radiation and/or oncology drugs to treat metastatic disease.

Source: Sponsor-submitted reimbursement package.²

Subgroup Analyses

To determine whether the treatment effect was consistent across various subgroups, the estimate of the between-group treatment effect (with a nominal 95% CI) for the primary end points was estimated and plotted within each category of the following classification variables in patients with locally advanced TNBC and in patients with PD-L1 (positive) tumours (CPS ≥ 1)²:

• Nodal status: positive versus negative.

• Tumour size: T1/T2 versus T3/T4.

• Choice of carboplatin: every 3 weeks versus weekly.

• Tumour PD-L1 status using different cut-off values for CPS (applies to all patients with locally advanced TNBC): CPS greater than or equal to 1 versus CPS less than 1; CPS greater than or equal to 10 versus CPS less than 10; CPS greater than or equal to 20 versus CPS less than 20.

• Overall stage: stage II versus stage III.

• Menopausal status (for women only): pre- versus post-menopausal.

• Age: younger than 65 years versus 65 years and older.

• Geographic region: Europe, Israel, North America, and Australia versus Asia versus rest of world.

• Ethnic origin: Hispanic versus non-Hispanic.

• ECOG PS: 0 versus 1.

• HER2 status: immunohistochemistry of 2 or higher (but fluorescence in situ hybridization negative) versus immunohistochemistry of 0 to 1 or higher.

• Lactate dehydrogenase greater than the upper limit of normal versus less than or equal to the upper limit of normal.

Secondary Outcome Analyses

Overall Survival

The Kaplan–Meier method was used to estimate the OS survival curves. The treatment difference in survival was assessed using a stratified log-rank test. A stratified Cox proportional hazard model with the Efron method of tie handling was used to assess the magnitude of the treatment difference. The HR and its 95% CI from the stratified Cox model, with a single treatment covariate, was reported for patients with locally advanced TNBC and for individuals with PD-L1 (positive) tumours. The stratification factors used for randomization were applied, as stratification factors to both the stratified log-rank test and the stratified Cox model. Kaplan–Meier estimates and the corresponding 95% CIs at 3 years and 5 years were provided for OS.²

The secondary hypothesis of OS in patients with locally advanced TNBC was tested according to the hypotheses testing plan as described in the statistical analysis plan (SAP). The study initially allocated an alpha of zero, 1 sided, to test OS. And OS was tested only when the null hypothesis for EFS was rejected. Boundaries were defined at each planned IA, derived using a cure model and a Lan-DeMets O’Brien-Fleming spending function. The spending time was defined as 1 for the final analysis. In the event that EFS, but not OS, was found to be positive at any interim, OS continued to be followed.²

Crossover between study arms was not permitted in the KEYNOTE-522 trial. Adjustment for the effect of crossover on OS was performed as an exploratory analysis using the rank-preserving structural failure time 2-stage model as proposed by Robins and Tsiatis.²

Analysis Populations

Efficacy analysis populations: The ITT population was analyzed for primary efficacy analyses. All randomized patients were included in this population in the treatment group to which they were randomized.

Safety analysis populations: The all participants as treated (APaT) population was used for the analysis of safety data in the KEYNOTE-522 trial. The APaT population consisted of all randomized patients who received at least 1 study treatment. Patients were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data using the APaT population. Patients who received an incorrect study treatment for the entire treatment period were included in the treatment group corresponding to the study treatment actually received. Any patient who received an incorrect study treatment for 2 cycles but received the correct treatment for all other cycles was assessed according to the correct treatment group, and a narrative was provided for events that occurred during the cycle for which the patient was incorrectly dosed. At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 study treatment was required for inclusion in the analysis of each specific parameter.²

Patient-reported outcomes analysis populations: Patient-reported outcomes analyses (for HRQoL) were based on the full analysis set population, defined as randomized patients who had at least 1 patient-reported outcomes assessment and received at least 1 study treatment.²

Protocol Amendments

The original protocol was approved on December 6, 2016. Four protocol amendments were made before the IA4 data cut-off.

Amendment 1 (December 16, 2016): The protocol was amended to clarify the dose modification guidelines provided for paclitaxel and carboplatin and to incorporate mandatory overdose language for the pembrolizumab program.

Amendment 2 (May 1, 2018): The protocol was amended to adjust the timing of IA1 to occur after at least 500 patients have or would have completed surgery; to add a second IA (IA2) for pCR; and to increase the sample size from approximately 855 to approximately 1,150 based on a revision to the assumed EFS rate at 36 months in the control arm.

Amendment 3 (October 17, 2018): The protocol was amended to add an analysis of EFS at IA2 and to adjust the timing of IA2.

Amendment 4 (February 26, 2020): The protocol was amended to clarify an adjustment of efficacy boundaries at IAs for EFS based on the actual number of events observed.¹⁰

Results

Patient Disposition

By the IA4 data cut-off (March 23, 2021), 1,608 patients had been screened, 434 participants had failed screening, and 1,174 patients had been successfully randomized in a 2:1 ratio to receive either pembrolizumab plus chemotherapy followed by pembrolizumab (n = 784) or placebo plus chemotherapy followed by placebo (n = 390). Overall, 1,172 patients (99.8%) received at least 1 study intervention. By the IA4 cut-off date, no patient was on any study intervention. Table 12 summarizes patient disposition in the ITT population at IA4.¹⁰

In the neoadjuvant phase, more patients in the pembrolizumab plus chemotherapy arm (24.2%) had discontinued the study intervention than in the placebo plus chemotherapy arm (14.9%). In the adjuvant phase, the most common reason for discontinuation was AEs (5.4%) in the pembrolizumab group and relapse or recurrence (4.6%) and withdrawal by participant (4.4%) in the placebo arm. The median duration of follow-up for the ITT population was similar between the 2 treatment groups (37.8 [range = 2.7 to 48.0] months versus 37.6 [range = 3.4 to 47.6] months in the pembrolizumab plus chemotherapy followed by pembrolizumab arm versus the placebo plus chemotherapy followed by placebo arm).¹⁰

Table 12: Patient Disposition at IA4—ITT Population

IA = interim analysis; ITT = intention to treat.

Note: Data cut-off date: March 23, 2021.

^aPatients who had completed all treatments included participants who completed adjuvant treatment.

^bPatients discontinued in neoadjuvant phase included participants who discontinued on or after neoadjuvant treatment 1, on or after neoadjuvant treatment 2, or on or after definitive surgery.

^cPatients discontinued due to relapse or recurrence in the neoadjuvant phase are participants who had surgery but did not receive adjuvant treatment.

^dPatients discontinued in adjuvant phase included participants who discontinued on or after adjuvant radiation only or on adjuvant treatment.

Source: Clinical Study Report.¹⁰

Premature Unblinding

In total, 81 (6.9%) of the 1,174 patients enrolled were prematurely unblinded due to the following reasons:

• Sponsor-approved nonemergency unblinding requests for patients who had disease progression or recurrence, knowing their study treatment would guide future treatment plans (n = 57)

• Inadvertent unblinding of investigator site and/or sponsor personnel (n = 5)

• Emergency unblinding (n = 19)¹⁰

Protocol Deviations

Important protocol deviations are highlighted in Table 13.

Exposure to Study Treatments

Neoadjuvant phase

The median duration of exposure to study treatment for all drugs in the neoadjuvant phase was similar in both arms: pembrolizumab plus chemotherapy (22.1 weeks [range = 0.1 to 34.1 weeks]) and placebo plus chemotherapy (22.1 weeks [range = 0.1 to 31.1 weeks]).¹⁰

Adjuvant phase

The median duration of exposure to study treatment in the adjuvant phase was similar between the pembrolizumab plus chemotherapy group (24.1 weeks [range = 0.1 to 37.7 weeks]) and the placebo plus chemotherapy group (24.1 weeks [range = 0.1 to 39.7 weeks]). Table 14 presents a summary of drug exposure in the neoadjuvant and adjuvant phases.¹⁰

Table 13: Summary of Protocol Deviations Considered to Be Clinically Important by Trial Investigators at IA4—ITT Population

AJCC = American Joint Committee on Cancer; ASCO = American Society of Clinical Oncology; CAP = College of American Pathologists; IA = interim analysis; ITT = intention to treat; TNBC = triple-negative breast cancer.

Note: Every patient is counted a single time for each applicable row and column. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 14: Summary of Drug Exposure in the Neoadjuvant and Adjuvant phase at IA4—APaT Population

APaT = all participants as treated; IA = interim analysis; NA = not applicable; q.3.w. = every 3 weeks.

Note: Patients who did not have neoadjuvant treatments but had surgery are included in the APaT population in the neoadjuvant phase. Patients who had post-surgery radiation therapy but did not have adjuvant treatment are included in the APaT population in the adjuvant phase. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported below.

Overall Survival

By the IA4 data cut-off (March 23, 2021), 135 of 297 predefined events had occurred, representing approximately 45% of the information fraction required for OS. The OS hypothesis was tested at an alpha level of 2.5% following the successful achievement of EFS analysis according to the multiplicity strategy outlined in the sponsor’s SAP. The median OS was not estimable, and the HR obtained in the comparison between the 2 arms stratified by nodal status, tumour size, and choice of carboplatin schedule was 0.72 (95% CI, 0.51 to 1.02; P [1 sided] = 0.0321377).¹⁰

The success criterion for the secondary OS hypothesis was not met because the P value did not cross the multiplicity-adjusted, 1-sided pre-specified P value boundary (0.00085861) defined for statistical significance. Table 15 and Figure 4 present the OS findings in the ITT population at the IA4 data cut-off. Overall survival continues to be followed in the KEYNOTE-522 study.¹⁰

Table 15: Overall Survival at IA4—ITT Population

CI = confidence interval; IA = interim analysis; ITT = intention to treat; NACT = neoadjuvant chemotherapy; NE = not estimable; NR = not reached; OS = overall survival; vs. = versus.

Note: Data cut-off date: March 23, 2021.

^aFrom product-limit (Kaplan–Meier) method for censored data.

^bBased on Cox regression model with the Efron method of tie handling, with treatment as a covariate, stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4) and choice of carboplatin (every three weeks vs. weekly).

^cOne-sided P value based on log-rank test stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly). The multiplicity-adjusted, 1-sided, pre-specified P value boundary for statistical significance was P = 0.00085861.

Source: Clinical Study Report.¹⁰

Figure 4: Kaplan–Meier Estimates of Overall Survival at IA4—ITT Population

IA = interim analysis; ITT = intention to treat; MK-3475 = pembrolizumab.

Note: Data cut-off date: March 23, 2021.

Source: Clinical study Report.¹⁰

Pathological Complete Response Rate (ypT0/Tis ypN0)

The pCR rate at the IA1 data cut-off (September 24, 2018) was 64.8% (95% CI, 59.9% to 69.5%) in the group receiving pembrolizumab plus chemotherapy in the neoadjuvant phase and 51.2% (95% CI, 44.1% to 58.3%) in the group receiving placebo plus chemotherapy. The difference in pCR rate between groups was 13.6% (95% CI, 5.4% to 21.8%; P = 0.00055).

At IA2 (April 24, 2019), the treatment difference in the pCR rate (pembrolizumab plus chemotherapy versus placebo plus chemotherapy) was 9.2% (95% CI, 2.8% to 15.6%; P = 0.00221). The pCR rate (95% CI) for pembrolizumab plus chemotherapy at the neoadjuvant phase was 64.0% (95% CI, 60.2% to 67.6%) compared to 54.7% (95% CI, 49.1% to 60.1%) for placebo plus chemotherapy.

A supportive analysis of the primary pCR end point was conducted with all randomized participants at IA4. The pCR rate in patients receiving pembrolizumab plus chemotherapy was 63% (95% CI, 59.5% to 66.4%) in the neoadjuvant phase, and in patients receiving placebo plus chemotherapy the pCR rate was 55% (95% CI, 50.6% to 60.6%). Pathological complete response was not tested formally based on the statistical hierarchy at IA4 in the ITT population. The difference in pCR rate between groups was 7.5% (95% CI, 1.6% to 13.4%).¹⁰ The pCR rates observed in both study arms at IA1 and IA4 are presented in Table 16.

Pathological Complete Response Rate Using Alternative Definitions

The pCR rates using the ypT0 ypN0 and ypT0/Tis definitions are presented in Table 17. The pCR rates were consistent with the primary findings (using the ypT0/Tis ypN0 definition).¹⁰

Subgroup Analyses

Table 18 presents the pCR in the subgroups¹⁰ identified in the CADTH protocol.

Event-Free Survival

At the IA4 data cut-off (March 23, 2021), a total of 123 events (15.7%) had occurred in the pembrolizumab plus chemotherapy followed by pembrolizumab arm and 93 events (23.8%) in the placebo plus chemotherapy followed by placebo arm.¹⁰ The median EFS was not estimable in either study arm at the IA4 data cut-off (March 23, 2021). The EFS HR stratified by nodal status, tumour size, and choice of carboplatin schedule obtained between the 2 study arms was 0.63 (95% CI, 0.48 to 0.82; P [1 sided] = 0.0003093). The number of patients with reported distant recurrence was 7.7% in the pembrolizumab plus chemotherapy followed by pembrolizumab arm compared to 13.1% in the placebo plus chemotherapy followed by placebo arm.

Table 16: Pathological Complete Response (ypT0/Tis ypN0) at IA1 and IA4—ITT Population

CI = confidence interval; IA = interim analysis; ITT = intention to treat; n = number of participants; pCR = pathological complete response; vs. = versus; ypTO/Tis ypNO = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Note: Data cut-off date: September 24, 2018; March 23, 2021.

^aBased on Miettinen and Nurminen method stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

^bOne-sided P value for testing hypothesis 0: difference in percentage = 0, vs. hypothesis 1: difference in percentage greater than 0.

^cAt IA4, pCR was not formally tested according to the statistical plan.

Source: Clinical Study Report.¹⁰

Table 17: Analysis of pCR using the ypT0 ypN0 and ypT0/Tis definitions IA4—ITT population

CI = confidence interval; IA = interim analysis; ITT = intention to treat; pCR = pathological complete response; vs. = versus; ypTO/Tis = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed; ypTO ypNO = no invasive or noninvasive residual disease in breast or nodes.

Note: Data cut-off date: March 23, 2021.

^aBased on Miettinen and Nurminen method stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

Source: Clinical Study Report.¹⁰

Table 18: Pathological Complete Response (ypT0/Tis ypN0) by Subgroups at IA4—ITT Population

CI = confidence interval; CPS = combined positive score; IA = interim analysis; ITT = intention to treat; pCR = pathological complete response; PD-L1 = programmed death ligand 1; vs. = versus; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Note: Multiplicity adjustments were not conducted in the subgroup analyses to adjust type I error. Data cut-off date: March 23, 2021.

^aFor overall population and the PD-L1 subgroup, analysis is based on the Miettinen and Nurminen method, stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4) and choice of carboplatin (every 3 weeks vs. weekly). For other subgroups, analysis is based on an unstratified Miettinen and Nurminen method.

Source: Clinical Study Report.¹⁰

The study met the success criterion for EFS at IA4 (the P value crossed the pre-specified boundary for statistical significance [0.00516941]).¹⁰The findings were consistent with data observed across IAs (at IA2 [data cut-off: April 24, 2019], EFS HR values were 0.63 [95% CI, 0.43 to 0.93]; at IA3, EFS HR was 0.65 [95% CI, 0.48 to 0.88]). Table 19 and Figure 5 present the findings of EFS at IA4 in the ITT population.

Table 19: Event-Free Survival at IA4—ITT Population

CI = confidence interval; EFS = event-free survival; IA = interim analysis; ITT = intention to treat; NE = not estimable; NR = not reached; PD = progressive disease; Q = quarter; vs = vs.

Note: Data cut-off date: March 23, 2021.

^aFrom product-limit (Kaplan–Meier) method for censored data.

^bBased on Cox regression model with the Efron method of tie handling with treatment as a covariate stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

^cOne-sided P value based on log-rank test stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly).

Source: Clinical Study Report.¹⁰

Figure 5: Kaplan–Meier Estimates of Event-Free Survival at IA4—ITT Population

Chemo = chemotherapy; CI = confidence interval; EFS = event-free survival; HR = hazard ratio; IA = interim analysis; ITT = intention to treat; Pembro = pembrolizumab; Pbo = placebo.

Note: Data cut-off date: March 23, 2021.

Source: Sponsor-submitted reimbursement package.²

Sensitivity Analyses for EFS

Five pre-specified sensitivity analyses were conducted for EFS in the ITT population. The results of the sensitivity analyses were consistent with the primary analysis.

Sensitivity analysis 1: This analysis was similar to the primary analysis, except different censoring rules were applied (any events after 2 consecutive missed disease assessments or after initiation of post-surgery new anticancer therapy were censored at last disease assessment before the earlier date of ≥ 2 consecutive missed disease assessments and initiation of post-surgery new anticancer therapy, and if there were no events before new anticancer therapy, patients were censored at last disease assessment before initiation of post-surgery new anticancer treatment). The EFS HR was 0.64 (95% CI, 0.48 to 0.84).

Sensitivity analysis 2: Similar to the primary analysis, except that new anticancer therapy to treat metastatic disease was also considered in defining an EFS event. The EFS HR was 0.63 (95% CI, 0.48 to 0.82).

Sensitivity analysis 3: Similar to the primary analysis, except that positive margins at a patient’s last surgery were excluded from the EFS event definition. The EFS HR was 0.65 (95% CI, 0.50 to 0.85).

Sensitivity analysis 4: Similar to the primary analysis, except that both positive margins at a patient’s last surgery and second primary malignancy were excluded from the EFS event definition. The EFS HR was 0.63 (95% CI, 0.48 to 0.84).

Sensitivity analysis 5: Similar to the primary analysis, except that second breast primary malignancy was included in the EFS event definition. The EFS HR was 0.63 (95% CI, 0.48 to 0.82).¹⁰

Subgroup Analyses¹⁰

Table 20 presents findings of EFS in the subgroups identified in the CADTH review protocol.

Health-Related QoL

The findings presented are for the March 23, 2021, data cut-off using the full analysis set population.

European Organisation for Research and Treatment of Cancer QLQ-C30

Neoadjuvant phase: Compliance rates in the neoadjuvant phase were similar at baseline for EORTC QLQ-C30 in both the pembrolizumab plus chemotherapy and the placebo plus chemotherapy arms (92.0% versus 95.8%). After 21 weeks of follow-up in the neoadjuvant phase, the completion rate among all patients was 80.7% versus 80.7% in the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms, respectively. The LS mean difference between groups for global health status–QoL score and physical functioning score was –1.04 (95% CI, –3.46 to 1.38) and –2.85 (95% CI, –5.11 to –0.60), respectively. The LS mean difference between groups for emotional functioning was –0.69 (95% CI, –3.13 to 1.75) at the March 23, 2021, data cut-off. Table 21, Figure 6, and Figure 7 summarize the change from neoadjuvant baseline in EORTC QLQ-C30 global health status–QoL, emotional functioning, and physical functioning at neoadjuvant week 21.¹⁰

Table 20: Event-Free Survival by Subgroups at IA4—ITT Population

CI = confidence interval; CPS = combined positive score; HR = hazard ratio; IA = interim analysis; ITT = intention to treat; PD-L1 = programmed death ligand 1; vs. = versus; ypT0/Tis ypN0 = no invasive residual disease in breast or nodes; noninvasive breast residuals allowed.

Note: Multiplicity adjustments were not conducted in the subgroup analyses to adjust for type I error. Data cut-off date: March 23, 2021.

^aFor the overall population and the PD-L1 subgroup, analysis is based on the Miettinen and Nurminen method, stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (every 3 weeks vs. weekly). For other subgroups, analysis is based on an unstratified Miettinen and Nurminen method.

Source: Clinical Study Report.¹⁰

Table 21: Summary of Change From Neoadjuvant Baseline in EORTC QLQ-C30 Global Health Status–QoL, Physical Functioning, and Emotional Functioning at Neoadjuvant Week 21—FAS Population

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; LS = least squares; QoL = quality of life; SD = standard deviation.

Note: A high score in a functional scale represents a high (or healthy) level of functioning, a high score in the global health status–QoL represents a high QoL, and a high score for a symptom scale or item represents a high level of symptomatology or problems. Data cut-off date: March 23, 2021.

^aFor neoadjuvant baseline and neoadjuvant week 21, n is the number of participants in each treatment group with nonmissing assessments at the specific time point.

^bFor change from neoadjuvant baseline, n is the number of participants in the analysis population in each treatment group.

^cBased on Constrained' longitudinal data analysis (cLDA) model with the patient-reported outcome score as the response variable, and with treatment by time point interaction, stratification factors (nodal status [positive vs. negative], tumour size [T1/T2 vs. T3/T4], and choice of carboplatin [every 3 weeks vs. weekly]) as covariates.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report.¹⁰

Figure 6: Change From Neoadjuvant Baseline for EORTC QLQ-C30 Global Health Status–QoL and Functional Scales at Neoadjuvant Week 21—FAS Population

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab; QoL = quality of life.

Note: For global health status–QoL score and all functional scales, a higher score denotes better health-related QoL or function. For symptoms scales, a higher score denotes worse symptoms. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Figure 7: Change From Neoadjuvant Baseline for EORTC QLQ-C30 Symptom Scales or Items at Neoadjuvant Week 21—FAS Population

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab.

Note: For global health status–QoL score and all functional scales, a higher score denotes better health-related QoL or function. For symptoms scales, a higher score denotes worse symptoms. Database cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Adjuvant phase: Compliance rates in the adjuvant phase were similar at baseline for EORTC QLQ-C30 in both the pembrolizumab and placebo arms (90.7% versus 91.9%) at the March 23, 2021, data cut-off. After 24 weeks of follow-up in the adjuvant phase, the compliance rate among patients was 82.4% versus 80.8% in the pembrolizumab versus placebo arms. The LS mean difference between groups for global health status–QoL score, physical functioning, and emotional functioning was –0.41 (95% CI, –2.60 to 1.77), –1.57 (95% CI, –3.36 to 0.21), and –0.60 (95% CI, –2.99 to 1.79), respectively, at the March 23, 2021, data cut-off. Table 22, Figure 8, and Figure 9 summarize the change from adjuvant baseline in EORTC QLQ-C30 global health status–QoL, physical functioning, and emotional functioning at adjuvant week 24.¹⁰

Table 22: Summary of Change From Adjuvant Baseline in EORTC QLQ-C30 Global Health Status–QoL, Physical Functioning, and Emotional Functioning at Adjuvant Week 24—FAS Population

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; LS = least squares; QoL = quality of life; SD = standard deviation.

Note: A high score in a functional scale represents a high (or healthy) level of functioning, a high score in the global health status–QoL represents a high QoL, and a high score for a symptom scale or item represents a high level of symptomatology or problems. Data cut-off date: March 23, 2021.

^aFor neoadjuvant baseline and neoadjuvant week 21, n is the number of participants in each treatment group with nonmissing assessments at the specific time point.

^bFor change from neoadjuvant baseline, n is the number of participants in the analysis population in each treatment group.

^cBased on Constrained' longitudinal data analysis (cLDA) model with the patient-reported outcome score as the response variable, and with treatment by time point interaction, stratification factors (nodal status [positive vs. negative], tumour size [T1/T2 vs. T3/T4], and choice of carboplatin [every 3 weeks vs. weekly]) as covariates.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report.¹⁰

Figure 8: Change From Adjuvant Baseline for EORTC QLQ-C30 Global Health Status–QoL and Functional Scales at Adjuvant Week 24—FAS Population

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab; QoL = quality of life.

Note: For global health status–QoL score and all functional scales, a higher score denotes better health-related QoL or function. For symptom scales, a higher score denotes worse symptoms. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Figure 9: Change From Adjuvant Baseline for EORTC QLQ-C30 Symptom Scales or Items at Adjuvant Week 24—FAS Population

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab.

Note: For global health status–quality of life score and all functional scales, a higher score denotes better health-related quality of life or function. For symptoms scales, a higher score denotes worse symptoms. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 23: Summary of Change From Neoadjuvant Baseline in EORTC QLQ-BR23 Breast Symptoms at Neoadjuvant Week 21—FAS Population

CI = confidence interval; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; FAS = full analysis set; LS = least squares; SD = standard deviation.

Note: A high score in a functional scale represents a high (or healthy) level of functioning, a high score in the global health status–quality of life represents a high quality of life, and a high score for a symptom scale or item represents a high level of symptomatology or problems. Data cut-off date: March 23, 2021.

^aFor neoadjuvant baseline and neoadjuvant week 21, n is the number of participants in each treatment group with nonmissing assessments at the specific time point.

^bFor change from neoadjuvant baseline, n is the number of participants in the analysis population in each treatment group.

^cBased on Constrained' longitudinal data analysis (cLDA) model with the patient-reported outcome score as the response variable, and with treatment by time point interaction, stratification factors (nodal status [positive vs. negative], tumour size [T1/T2 vs. T3/T4], and choice of carboplatin [every 3 weeks vs. weekly]) as covariates.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report.¹⁰

European Organisation for Research and Treatment of Cancer QLQ-BR23

Neoadjuvant phase: Compliance rates in the neoadjuvant phase were similar at baseline for the EORTC QLQ-BR23 in both the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms (91.6% versus 94.8%) at the March 23, 2021, data cut-off. After 21 weeks of follow-up in the neoadjuvant phase, the compliance rate for all patients was 80.5% versus 80.4% in the pembrolizumab plus chemotherapy arm versus the placebo plus chemotherapy arm. The LS mean difference between groups for the EORTC QLQ-BR23 Breast Symptoms score was –0.13 (95% CI, –1.92 to 1.65). Table 23 summarizes change from the neoadjuvant baseline in EORTC QLQ-BR23 Breast Symptoms score at neoadjuvant week 21. Figure 10 and Figure 11 summarize the change from the neoadjuvant baseline in EORTC QLQ-BR23 functional and symptom scales or items at neoadjuvant week 21.¹⁰

Adjuvant phase: Compliance rates in the adjuvant phase were similar at baseline for EORTC QLQ-BR23 in both the pembrolizumab and placebo arms (90.5% versus 92.2%, respectively) at the March 23, 2021, data cut-off. After 24 weeks of follow-up, the compliance rate was 82.2% versus 80.7% in the pembrolizumab and placebo arms, respectively. The LS mean difference between groups for the EORTC QLQ-BR23 Breast Symptoms score was 0.29 (95% CI, –2.05 to 2.63). Table 24 summarizes change from adjuvant baseline in EORTC QLQ-BR23 Breast Symptoms score at adjuvant week 24. Figure 12 and Figure 13 summarize the change from adjuvant baseline in EORTC QLQ-BR23 functional and symptom scales or items at adjuvant week 24.¹⁰

Figure 10: Change From Neoadjuvant Baseline for EORTC QLQ-BR23 Functional Scales or Items at Neoadjuvant Week 21—FAS Population

EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab.

Note: For global health status–quality of life score and all functional scales, a higher score denotes better health-related quality of life or function. For symptom scales, a higher score denotes worse symptoms. If the patient did not lose any hair, then “upset by hair loss” is imputed as the lowest score (0). Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Figure 11: Change From Neoadjuvant Baseline for EORTC QLQ-BR23 Symptom Scales or Items at Neoadjuvant Week 21—FAS Population

EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab.

Note: For global health status–quality of life score and all functional scales, a higher score denotes better health-related quality of life or function. For symptoms scales, a higher score denotes worse symptoms. If the patient did not lose any hair, then “upset by hair loss” is imputed as the lowest score (0). Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 24: Summary of Change From Adjuvant Baseline in EORTC QLQ-BR23 Breast Symptoms at Adjuvant Week 24—FAS Population

CI = confidence interval; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; FAS = full analysis set; LS = least squares; SD = standard deviation.

Note: A high score in a functional scale represents a high (or healthy) level of functioning, a high score in the global health status–quality of life represents a high quality of life, and a high score for a symptom scale or item represents a high level of symptomatology or problems. Data cut-off date: March 23, 2021.

^aFor neoadjuvant baseline and neoadjuvant week 21, n is the number of participants in each treatment group with nonmissing assessments at the specific time point.

^bFor change from neoadjuvant baseline, nis the number of participants in the analysis population in each treatment group.

^cBased on Constrained' longitudinal data analysis (cLDA) model with the patient-reported outcome score as the response variable, and with treatment by time point interaction, stratification factors (nodal status [positive vs. negative], tumour size [T1/T2 vs. T3/T4], and choice of carboplatin [every 3 weeks vs. weekly]) as covariates.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report.¹⁰

EQ Visual Analogue Scale

Neoadjuvant phase: Compliance rates in the neoadjuvant phase were similar at baseline for the EQ VAS in both the pembrolizumab plus chemotherapy and placebo plus chemotherapy arms (92.8% versus 96.3%, respectively) at the March 23, 2021, data cut-off. After 21 weeks of follow-up in the neoadjuvant phase, the compliance rate was 80.8% versus 81.0% in the pembrolizumab plus chemotherapy arm versus the placebo plus chemotherapy arm. The LS mean difference between groups for the EQ VAS score was –1.61 (95% CI, –3.87 to 0.64). Table 25 summarizes change from neoadjuvant baseline in EQ VAS at neoadjuvant week 21, and Figure 14 summarizes the change from neoadjuvant baseline in EQ VAS across time at neoadjuvant week 21.¹⁰

Adjuvant phase: Compliance rates in the adjuvant phase were similar at baseline for the EQ VAS in both the pembrolizumab and placebo arms (91.7% versus 91.9%). After 24 weeks of follow-up in the adjuvant phase, the compliance rate was 82.2% versus 80.3% in the pembrolizumab and placebo arms, respectively. The LS mean difference between groups for the EQ VAS was –0.59 (95% CI, –2.40 to 1.23). Table 26 summarizes change from adjuvant baseline in EQ VAS at adjuvant week 24, and Figure 15 summarizes the change from adjuvant baseline in EQ VAS across time observed at adjuvant week 24.¹⁰

Figure 12: Change From Adjuvant Baseline for EORTC QLQ-BR23 Functional Scales or Items at Adjuvant Week 24—FAS Population

EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab.

Note: For global health status–quality of life score and all functional scales, a higher score denotes better health-related quality of life or function. For symptoms scales, a higher score denotes worse symptoms. If the patient did not lose any hair, then “upset by hair loss” is imputed as the lowest score (0). Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Figure 13: Change From Adjuvant Baseline for EORTC QLQ-BR23 Symptom Scales or Items at Adjuvant Week 24—FAS Population

EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Breast Cancer–Specific Quality of Life Questionnaire; FAS = full analysis set; LS = least squares; MK-3475 = pembrolizumab.

Note: For global health status–quality of life score and all functional scales, a higher score denotes better health-related quality of life or function. For symptom scales, a higher score denotes worse symptoms. If the patient did not lose any hair, then “upset by hair loss” is imputed as the lowest score (0). Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 25: Summary of Change From Neoadjuvant Baseline in EQ VAS at Neoadjuvant Week 21—FAS Population

CI = confidence interval; EQ VAS = EQ Visual Analogue Scale; FAS = full analysis set; LS = least squares; SD = standard deviation.

Note: Data cut-off date: March 23, 2021.

^aFor neoadjuvant baseline and neoadjuvant week 21, nis the number of participants in each treatment group with nonmissing assessments at the specific time point.

^bFor change from neoadjuvant baseline, nis the number of participants in the analysis population in each treatment group.

^cBased on Constrained’ longitudinal data analysis (cLDA) model with the patient-reported outcome score as the response variable, and with treatment by time point interaction, stratification factors (nodal status [positive vs. negative], tumour size [T1/T2 vs. T3/T4], and choice of carboplatin [every 3 weeks vs. weekly]) as covariates.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report.¹⁰

Table 26: Summary of Change From Adjuvant Baseline in EQ VAS at Adjuvant Week 24—FAS Population

CI = confidence interval; EQ VAS = EQ Visual Analogue Scale; FAS = full analysis set; LS = least squares; SD = standard deviation.

Note: Data cut-off date: March 23, 2021.

^aFor neoadjuvant baseline and neoadjuvant week 21, nis the number of participants in each treatment group with nonmissing assessments at the specific time point.

^bFor change from neoadjuvant baseline, n is the number of participants in the analysis population in each treatment group.

^cBased on Constrained' longitudinal data analysis (cLDA) model with the patient-reported outcome score as the response variable, and with treatment by time point interaction, stratification factors (nodal status [positive vs. negative], tumour size [T1/T2 vs. T3/T4], and choice of carboplatin [every 3 weeks vs. weekly]) as covariates.

^dP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report.¹⁰

Figure 14: Empirical Mean Change From Neoadjuvant Baseline in EQ VAS Across Time—FAS Population

EQ VAS = EQ Visual Analogue Scale; FAS = full analysis set; MK-3475 = pembrolizumab.

Note: Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Harms

Only those harms identified in the CADTH review protocol are reported below. The safety evaluation of all participants in combined phases (neoadjuvant and adjuvant) obtained at the IA4 (March 23, 2021) data cut-off are presented in Table 27.

Adverse Events

Overall, 99.2% of patients enrolled in the pembrolizumab plus chemotherapy followed by pembrolizumab arm and 100% in the placebo plus chemotherapy followed by placebo arm reported at least 1 AE by the March 23, 2021, data cut-off. Adverse events of grade 3 or higher occurred in 82.4% of patients in the pembrolizumab plus chemotherapy followed by pembrolizumab arm and 78.7% in the placebo plus chemotherapy followed by placebo arm. Table 27 presents an overview of AEs in the pembrolizumab plus chemotherapy followed by pembrolizumab arm and the placebo plus chemotherapy followed by placebo arm.¹⁰

The most frequently reported AEs (occurring in > 30% of patients) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm were nausea, alopecia, anemia, neutropenia, fatigue, constipation, diarrhea, vomiting, and increased alanine aminotransferase (ALT). In the placebo plus chemotherapy followed by placebo arm, nausea, alopecia, anemia, neutropenia, fatigue, constipation, diarrhea, and arthralgia were the most frequently reported AEs. Overall, incidences of the most frequently reported AEs (incidence ≥ 30%) were generally similar between the 2 treatment groups. More patients receiving pembrolizumab in the adjuvant phase had serious AEs than did patients receiving placebo in the adjuvant phase.

More deaths due to AEs were reported in the pembrolizumab plus chemotherapy followed by pembrolizumab arm than in the placebo plus chemotherapy followed by placebo arm. More patients discontinued treatment due to an AE in the pembrolizumab plus chemotherapy followed by pembrolizumab arm than in the placebo plus chemotherapy followed by placebo arm. Table 28 summarizes AEs occurring in at least 10% of patients receiving pembrolizumab plus chemotherapy followed by pembrolizumab and placebo plus chemotherapy followed by placebo in the KEYNOTE-522 trial.¹⁰

Figure 15: Empirical Mean Change From Adjuvant Baseline in EQ VAS Across Time—FAS Population

EQ VAS = EQ Visual Analogue Scale; FAS = full analysis set; MK-3475 = pembrolizumab.

Note: Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 27: Summary of Adverse Events Occurring in the Combined Neoadjuvant and Adjuvant phase at IA4—APaT Population

APaT = all participants as treated; IA = interim analysis.

Note: Included adverse events starting from the first treatment including definitive surgery and radiation therapy and up to 30 days after the last treatment including definitive surgery and radiation therapy for the nonserious adverse events and up to 90 days after the last treatment including definitive surgery and radiation therapy for the serious adverse events. Medical Dictionary for Regulatory Activities–preferred terms “neoplasm progression,” “malignant neoplasm progression,” and “disease progression” not related to the drug are excluded. Data cut-off date: March 23, 2021.

^aDefined as an action taken of dose reduced, drug interrupted, or drug withdrawn. Grades are based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0.

Source: Clinical Study Report.¹⁰

Table 28: Summary of Adverse Events Occurring in at Least 10% of Patients in the Combined Neoadjuvant and Adjuvant phases at IA4—APaT Population

APaT = all participants as treated; IA = interim analysis.

Note: Every participant is counted a single time for each applicable specific adverse event. A specific adverse event appears in this report only if its incidence in 1 or more of the columns meets the incidence criterion in the report title, after rounding. Included are adverse events starting from the first treatment including definitive surgery and radiation therapy and up to 30 days after the last treatment including definitive surgery and radiation therapy for the nonserious adverse events and up to 90 days after the last treatment including definitive surgery and radiation therapy for the serious adverse events. Medical Dictionary for Regulatory Activities–preferred terms “neoplasm progression,” “malignant neoplasm progression,” and “disease progression” not related to the drug are excluded. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Grade 3 to 5 Adverse Events

The incidence of grade 3 to 5 AEs reported in at least 5% of patients in either treatment group by the IA4 data cut-off (March 23, 2021) are presented in Table 29. The overall incidence of grade 3 to 5 AEs during the combined phases was similar in the 2 treatment arms (82.4% of patients receiving pembrolizumab plus chemotherapy followed by pembrolizumab versus 78.7% receiving placebo plus chemotherapy followed by placebo). The most frequent grade 3 to 5 AEs (occurring in ≥ 5% of patients in either arm) reported in both arms included neutropenia, decreased neutrophil count, anemia, febrile neutropenia, and decreased white blood cell count. In the pembrolizumab plus chemotherapy followed by pembrolizumab arm, the incidence of increased ALT (6.4%) was higher than in the placebo plus chemotherapy followed by placebo arm (2.8%).¹⁰

Mortality

By the March 23, 2021, data cut-off, deaths due to AEs, other than “neoplasm progression,” “malignant neoplasm progression,” and “disease progression,” were included in the frequency counts for fatal AEs.

The overall incidence of AEs resulting in death in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (0.9%) was consistent with the placebo plus chemotherapy followed by placebo arm (0.3%). Table 30 summarizes AEs resulting in death reported in patients receiving either study treatment.¹⁰

Table 29: Grade 3 to 5 Adverse Events Occurring in at Least 5% of Patients in the Combined Neoadjuvant and Adjuvant phases at IA4—APaT Population

APaT = all participants as treated; IA = interim analysis.

Note: Every participant is counted a single time for each applicable specific adverse event. A specific adverse event appears in this report only if its incidence in 1 or more of the columns meets the incidence criterion in the report title, after rounding. Included are adverse events starting from the first treatment including definitive surgery and radiation therapy and up to 30 days after the last treatment including definitive surgery and radiation therapy for the nonserious adverse events and up to 90 days after the last treatment including definitive surgery and radiation therapy for the serious adverse events. Grades are based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0. Medical Dictionary for Regulatory Activities–preferred terms “neoplasm progression,” “malignant neoplasm progression,” and “disease progression” not related to the drug are excluded. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Table 30: Deaths due to AEs Occurring in Patients in the Combined Neoadjuvant and Adjuvant phases at IA4—APaT Population

AE = adverse event; APaT = all participants as treated; IA = interim analysis.

Note: Every participant is counted a single time for each applicable specific adverse event. Included are adverse events starting from the first treatment including definitive surgery and radiation therapy and up to 30 days after the last treatment including definitive surgery and radiation therapy for the nonserious adverse events and up to 90 days after the last treatment including definitive surgery and radiation therapy for the serious adverse events. Grades are based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0. Medical Dictionary for Regulatory Activities–preferred terms “neoplasm progression,” “malignant neoplasm progression,” and “disease progression” not related to the drug are excluded. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Discontinuations due to Adverse Events

By the March 23, 2021, data cut-off, the overall incidence of AEs resulting in the discontinuation of any study intervention during the combined phases was higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (29.9%) than in the placebo plus chemotherapy followed by placebo arm (15.4%). The most frequently reported AEs (incidence ≥ 1%) resulting in discontinuation of any study intervention in the pembrolizumab plus chemotherapy followed by pembrolizumab arm were increased ALT (3.1%), neutropenia (2.0%), increased aspartate aminotransferase (1.8%), febrile neutropenia (1.5%), infusion-related reaction (1.3%), and peripheral neuropathy (1.0%). For the placebo plus chemotherapy followed by placebo arm, the most frequently reported AEs (incidence ≥ 1%) resulting in discontinuation of any study intervention were neutropenia (1.5%), peripheral neuropathy (1.3%), and increased ALT (1.3%).¹⁰ Discontinuations due to AEs were higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm than in the placebo plus chemotherapy followed by placebo arm.

Dose Reduction due to AEs

As no dose reductions were allowed for pembrolizumab (200 mg once every 3 weeks) or placebo; all dose reductions occurred in chemotherapy during the neoadjuvant phase. The overall incidences of AEs resulting in dose reduction of chemotherapy were generally similar between the pembrolizumab plus chemotherapy (12.8%) and placebo plus chemotherapy arms (11.3%). The most frequently reported AEs (incidence ≥ 1%) resulting in dose reduction of chemotherapy in the pembrolizumab plus chemotherapy followed by pembrolizumab arm were febrile neutropenia (3.3%), neutropenia (2.8%), and decreased neutrophil count (1.1%). For the placebo plus chemotherapy followed by placebo arm, the most frequently reported AEs (incidence ≥ 1%) resulting in dose reduction of chemotherapy were febrile neutropenia (2.6%), neutropenia (2.3%), and decreased neutrophil count (1.5%).¹⁰

Notable Harms

The overall incidence of notable harms identified during the combined phases was higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (43.6%) than in the placebo plus chemotherapy followed by placebo arm (21.9%). Table 31 presents a summary of the proportion of patients reporting AEs identified in the CADTH review protocol in the pembrolizumab plus chemotherapy followed by pembrolizumab arm versus the placebo plus chemotherapy followed by placebo arm.¹⁰

Table 31: Notable Harms Occurring in Patients in the Combined Neoadjuvant and Adjuvant phases at IA4—APaT Population

APaT = all participants as treated; IA = interim analysis.

Note: Every participant is counted a single time for each applicable specific adverse event. A participant with multiple adverse events within a bolded term is counted a single time for that bolded term. “Infusion-related reaction” includes infusion-related reactions due to pembrolizumab and chemotherapy, for example paclitaxel.

Included are adverse events starting from the first treatment including definitive surgery and radiation therapy and up to 30 days after the last treatment including definitive surgery and radiation therapy for the nonserious adverse events and up to 90 days after the last treatment including definitive surgery and radiation therapy for the serious adverse events. Data cut-off date: March 23, 2021.

Source: Clinical Study Report.¹⁰

Critical Appraisal

Internal Validity

KEYNOTE-522 is a randomized, double-blind, placebo-controlled, phase III study. A 2:1 randomization scheme was implemented centrally using an interactive voice response system–integrated web response system, stratified by 3 factors: nodal status (positive versus negative), tumour size (T1/T2 versus T3/T4), and choice of carboplatin regimen (every 3 weeks versus weekly). The baseline and demographic characteristics of patients were well balanced between the 2 groups, and the risk of selection bias was considered low.

Patients, investigators, and pathologists were blinded to the treatment regimens in the KEYNOTE-522 trial. The preparation and dispensing of pembrolizumab and placebo was performed by an unblinded member of the trial site personnel who was not involved in trial assessments. The incidence of AEs, particularly immune-related reactions resulting from the use of pembrolizumab, may have revealed the treatments administered to patients and investigators. However, how often this may have occurred is uncertain. More patients (24.2%) receiving pembrolizumab plus chemotherapy in the neoadjuvant phase had discontinued the study intervention than had patients receiving placebo plus chemotherapy (14.9%). The most common cause of discontinuations was AEs. Most discontinuations in the neoadjuvant phase for patients receiving pembrolizumab plus chemotherapy treatment were due to AEs (14.3%), physician decision (4.1%), and patient withdrawal from study (3.7%). Similarly, more patients receiving pembrolizumab discontinued in the adjuvant phase than did patients receiving placebo. The most common reasons for discontinuations in patients receiving pembrolizumab were AEs (5.4%), relapse or recurrence (2.6%), and patient withdrawal (2.8%). Safety outcomes may have been overestimated in patients receiving pembrolizumab compared to patients receiving placebo. The extent and direction of bias due to treatment knowledge is uncertain.

Pathologists reviewing and interpreting specimens for pCR following surgery were blinded for treatment assessment. Event-free survival was assessed per RECIST 1.1 guidelines, which are validated for tumour assessments. The assessment of EFS may also have been influenced by treatment knowledge, given that it was assessed by investigator. However, the double-blind nature of the trial reduced the risk of assessment bias. In the case of unblinding, there is a potential for detection bias by the investigator that may impact the findings of EFS at assessment, likely favouring the pembrolizumab plus chemotherapy arm, although the extent of any bias is uncertain. There is also a potential risk of performance bias for other subjective outcomes, such as HRQoL and safety, although the direction and extent of any bias is uncertain.

Pathological complete response, EFS, OS, HRQoL, and safety outcomes were considered relevant according to the clinical experts consulted. Overall survival and pCR are validated outcomes for oncology trials, and EFS has been validated as a surrogate end point for accelerated or regular approval by regulatory agencies for trials in breast cancer.^11,12,30,31 Censoring rules for EFS and sensitivity analyses were reported in the SAP. Crossing over from 1 study arm to the other was not permitted during the trial, which preserved treatment differences observed in the randomized arms for OS. A Cox proportional hazard model, which relies on the assumption of proportional hazard in both treatment groups was used to assess OS and EFS survival curves. The visual assessment of the Kaplan–Meier curve for EFS did not suggest any violation of the proportional hazard, suggesting that the EFS HRs were accurate, given that the ratio of HR was approximately constant throughout the trial. The visual assessment of the Kaplan–Meier curve for OS suggests that the proportional hazard assumption may have been violated at given points (at 15.5 months and meet at 22 months) where both curves crossed in the trial. The violation of the proportional hazard assumption in the OS curves adds uncertainty to the interpretation of the OS HR finding reported at IA4 since it differs over time throughout the trial. In addition, the median OS and EFS was not estimable at IA4 due to data immaturity, which adds uncertainty to the findings observed.

Health-related QoL was assessed using the EORTC QLQ-C30, the EORTC QLQ-BR23, and the EQ-5D-5L questionnaire. The EORTC QLQ-C30 is a cancer-specific instrument that has been validated in many cancer populations. The EORTC QLQ-BR23 is a modified version designed for breast cancer patients. These questionnaires were considered validated in patients with TNBC. Health-related QoL reporting is subjective, and there is always a potential for unblinding; however, the risk of performance bias is low. Because the EORTC QLQ-BR23 is more tailored to breast cancer patients, it focuses on identifying treatment-related side effects. Construct validity was assessed, and minimal important differences (MIDs) were derived using anchor-based approaches. Approximately 20% of patients had missing data at follow-up for HRQoL measures. The sponsor described methods to address missing data for HRQoL. These methods were considered appropriate but conservative by the CADTH review team. Thus, there remains a potential for attrition bias, which introduces uncertainty into the findings given that many patients who received pembrolizumab plus chemotherapy in the neoadjuvant setting discontinued (the majority due to AEs) and did not receive treatment in the adjuvant phase. In addition, multiplicity adjustments were not conducted to account for the type I error rate, so the findings were considered exploratory (hence, conclusions could not be drawn).

The study was powered to detect a true pCR rate of 15% between pembrolizumab plus chemotherapy versus placebo plus chemotherapy at an alpha level of 0.5% (1 sided), with an underlying assumption of a pCR rate of 50% in the placebo plus chemotherapy arm. The clinical experts considered the effect size clinically meaningful. The study was also powered to detect a true HR of 0.71 between pembrolizumab plus chemotherapy versus placebo plus chemotherapy for EFS at an alpha level of 2% (1 sided). The sponsor provided a rationale for the margins defined for pCR and EFS in the SAP. The clinical experts considered the pre-specified HR between the 2 study arms clinically meaningful.

There was a low risk of bias due to selective reporting as all the outcomes pre-specified in the protocol were reported. All IAs were pre-specified in the protocol, and stopping rules were adequately outlined in the SAP. The approaches used to preserve alpha and the power in the IAs were considered appropriate. Efficacy analyses were conducted using the ITT populations, which maintains randomization and minimizes the risk of bias that may be introduced by comparing groups that differ in prognostic factors. Health-related QoL analyses were based on the full analysis set. Interim analyses were planned and performed by an independent data monitoring committee.

The type I error rate was adjusted during the analyses of pCR, EFS, and OS using the overall family-wise error rate approach. Sensitivity analyses and adjustments for covariates were conducted for pCR and EFS, and the findings were consistent with the primary analysis of the ITT population. Pathological complete response assessed at IA4 was not formally tested based on the statistical hierarchy; thus, the findings at IA4 were considered exploratory.

All subgroup analyses were pre-specified in the protocol. The subgroup analyses may not have been powered to detect a difference between the 2 treatment arms. In addition, multiplicity adjustments were not conducted to account for the type I error rate; thus, the findings were considered exploratory. Some CIs observed in the analyses were imprecise and included the null value. There were also no between-group tests conducted for the subgroup analyses.

Protocol deviations and premature unblinding were reported for patients receiving either 1 of the study treatments in the KEYNOTE-522 study (6.9% of patients experienced premature unblinding in total). The proportion of patients with significant protocol deviations was slightly higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (3.6%) than in the placebo plus chemotherapy followed by placebo arm (2.1%). The most common reasons were violation of inclusion criteria and patients being dispensed study interventions other than what was assigned in the trial schedule. Patients who had unblinded treatments continued to be monitored in the trial. Patients who were unblinded in both the neoadjuvant and adjuvant phases were required to end all study treatment and entered the early discontinuation phase; they were then followed for 6 months via phone.

The SAP outlined the methods used to account for missing data for the primary outcomes, secondary outcomes, and safety outcomes. The treatment duration for each treatment administered in the neoadjuvant setting was comparable in both arms since patients in both groups received similar treatment regimens of chemotherapy in addition to pembrolizumab or placebo. In the adjuvant phase, treatment duration did not differ as patients received pembrolizumab or placebo for a similar number of cycles.

External Validity

The reimbursement request is for the treatment of adult patients with early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment after surgery. The reimbursement request was submitted for CADTH review pre-NOC, and the request aligned with the proposed Health Canada indication.

KEYNOTE-522 was conducted in a multinational setting, with 194 sites in 21 countries (7 sites in Canada). The inclusion and exclusion criteria of KEYNOTE-522 were considered appropriate by the clinical experts. KEYNOTE-522 excluded patients who had received prior therapy (chemotherapy, radiation, or targeted therapy), patients with significant cardiovascular disease, and patients who had a history of pneumonitis or current pneumonitis. Thus, the magnitude of benefit of pembrolizumab plus chemotherapy to patients in real-world practice presenting with 1 or more characteristics identified in the exclusion criteria in the KEYNOTE-522 study is uncertain. In addition, more than 25% of patients screened in the KEYNOTE-522 trial were not enrolled, suggesting that the participants in the trial may not be fully representative of the patient population in real-world settings. The experts highlighted that in current practice, patients are not routinely required to have a left ventricular ejection fraction of at least 50% or greater than or equal to the institution lower limit of normal as assessed by echocardiogram or multigated acquisition scan to be eligible to receive treatment. Both experts agreed that they would not offer pembrolizumab to patients with an ECOG PS of 3 or greater. However, the experts noted that they would offer pembrolizumab to patients with an ECOG PS of 2, while considering factors such as comorbidities. The clinical experts considered the baseline characteristics generalizable to patients in the Canadian setting.

The dosage of pembrolizumab aligns with the Health Canada NOC indication. Dose modifications were allowed for all study drugs used in the KEYNOTE-522 trial, except pembrolizumab (it was recommended that pembrolizumab be withheld in case of drug-related toxicities), and outlined in the protocol. The clinical experts considered the chemotherapy regimens administered during the trial appropriate and reflective of Canadian practice. However, the clinical experts noted that some dose and cycle schedules implemented in the KEYNOTE-522 study were different from Canadian practice. The experts noted that carboplatin and paclitaxel cycles were administered before the doxorubicin and cyclophosphamide cycles in the KEYNOTE-522 study, which is the opposite order to some jurisdictions in Canadian practice. The experts highlighted that clinicians may maintain an anthracycline plus cyclophosphamide plus taxane schedule, or they may switch the sequence to taxanes and carboplatin first and then anthracycline-cyclophosphamide to correspond to the administration implemented in KEYNOTE-522. The sponsor-submitted indication states that pembrolizumab in combination with chemotherapy is recommended for high-risk patients with early-stage TNBC. The sponsor did not specify the chemotherapy regimen in the indication. It is therefore uncertain whether the addition of pembrolizumab to chemotherapy agents not used in the KEYNOTE-522 trial will result in similar benefits as those seen for the chemotherapy agents (including dosing and cycles of administration) used in the KEYNOTE-522 trial.

The clinical experts agreed that dose adjustments anticipated in practice would be similar to those implemented in the KEYNOTE-522 trial. The clinical experts also highlighted that drug discontinuations are expected in practice, although clinicians will generally encourage patients to complete all cycles of chemotherapy by implementing dose reductions in situations of toxicity.

The clinical experts noted that the choice of NACT used in the KEYNOTE-522 study was appropriate and reflective of treatments administered in neoadjuvant setting. The clinician group input from the Drug Advisory Committee of the OH-CCO noted that capecitabine and olaparib (for patients with a BRCA1 or 2 mutation) are currently available for patients in the adjuvant setting in Canada. The clinical experts consulted indicated that, since the publication of CREATE-X, capecitabine has been employed as a standard adjuvant option in TNBC if there is no pCR.³² The clinical experts stated that at the time of trial initiation, the CREATE-X study had not been published and so capecitabine would not have been considered as comparator, and the use of olaparib in patients with a BRCA1 or 2 mutation in the adjuvant setting is recent (reported in 2021).³³ Thus, the use of placebo in the adjuvant setting was considered appropriate in the absence of the standard of care therapies highlighted. The Drug Advisory Committee of OH-CCO indicated that it is unclear how pembrolizumab will fit with capecitabine or Olaparib given that capecitabine was not allowed in the KEYNOTE-522 trial. The clinician group highlighted uncertainty associated with choosing the best-suited drug in the adjuvant setting owing to lack of evidence relating to combining the agents or the comparative efficacy of the agents in the patient population.

The clinical experts considered the duration of follow-up implemented in the KEYNOTE-522 study appropriate. The clinical experts noted that the concomitant medications allowed in the KEYNOTE-522 study were also commonly used in Canadian practice. The experts did not identify any major concerns or discrepancies between the trial and real-world settings in terms of concomitant medication use and duration of follow-up.

Pathological complete response, EFS, and OS are validated outcomes recommended by regulatory agencies for trials that include patients with TNBC. The clinical experts considered the outcomes important for patients with TNBC in Canadian practice.

Concomitant medications commonly used by patients in the trial were generally considered appropriate by the clinical experts consulted.

Some patients in the KEYNOTE-522 study were possibly exposed to frequent assessments compared to patients in real-world practice. This may impact the generalizability of the findings to patients in real-world practice. Both the clinical experts and clinician groups consulted indicated that patients in real-world practice are assessed before every cycle of treatment (physical and clinical exams conducted) and that frequent breast scans and MRIs are not routine in practice.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

Direct head-to-head clinical trials assessing pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC are limited. Indirect evidence was considered and summarized for this review to address the lack of direct evidence for relevant comparators.

The sponsor did not provide any indirect evidence for this review. A focused literature search for NMAs dealing with TNBC was run in MEDLINE All (1946–) on March 8, 2022. No search limits were applied. Indirect treatment comparisons were selected for full-text review using the same criteria as for the systematic review (Table 5). Two published NMAs were identified from the NMA literature search and reviewed (Miyashita et al. [2020]¹³ and Li et al. [2022]³⁴). The published NMA by Li et al.³⁴ was excluded because the results were limited to a ranking of comparisons (pairwise comparisons between pembrolizumab and other active treatments were not available). In total, 1 published NMA, by Miyashita et al. (2020),¹³ was summarized for this review.

Description and Methods of Published NMA

Objectives

The objective of the published NMA was to define the overall most effective neoadjuvant systemic therapy for TNBC by comparing the efficacy and safety of different regimens containing anthracycline, bevacizumab, pembrolizumab, and platinum salts in patients with TNBC.

Study Selection Methods

The authors performed a systematic review to select studies for inclusion in the NMA. Eligible studies included patients with TNBC who received neoadjuvant treatment that included different combinations of medications of special interest (anthracycline, bevacizumab, pembrolizumab, or platinum salts) or chemotherapy without the medications of special interest. The dosing of these interventions was not specified. Outcomes of interest included the rate of pCR (defined as ypT0/is and ypN0) or toxicities, specifically febrile neutropenia, grade 3 or greater thrombocytopenia, nausea/vomiting, and diarrhea. The systematic review only included RCTs and did not report any additional criteria regarding the study design.

The literature search was conducted in March 2020 using MEDLINE, Embase, and Web of Science and supplemented by manual searches of secondary sources including references of initially identified articles and reviews. Articles were screened and selected independently by 2 reviewers. A third author was consulted to resolve any discrepancies between the 2 reviewers. Information about the data extraction process was not reported.

The Cochrane risk of bias tool (version 1)³⁵ was used to assess the risk of bias in the RCTs included in the NMA. The risk of bias was indicated by labelling RCTs as having high, low, or unclear risk of bias. Studies were not excluded based on the risk of bias. A quality assessment of included studies was not reported.

Published NMA Analysis Methods

Information about the statistical model selected for the NMA was limited. The authors reported that a random effects model was used for the NMA. Heterogeneity within the network was estimated using the I² statistic, where an I² value greater than 50% was considered an indicator of substantial heterogeneity. Inconsistency was evaluated using Q statistics.

No further information regarding the NMA methods or assessment of heterogeneity or inconsistency was provided.

No sensitivity analyses were reported. Some of the trials included patients with and without TNBC. In these trials, patients with TNBC were equally randomized across groups and were investigated in subgroup analyses for the pCR outcome. Only patients with TNBC were included in the analysis of pCR in the NMA. All patients, regardless of diagnosis, were included in the analysis of safety outcomes.

Interventions of included trials were grouped into 8 categories corresponding to the therapies involved, representing up to 8 treatment nodes in each of the analyses. The categories (treatment nodes) were as follows:

• anthracycline

• anthracycline plus bevacizumab

• anthracycline plus B plus platinum salts

• anthracycline plus pembrolizumab

• anthracycline plus platinum salts

• anthracycline plus pembrolizumab plus platinum salts

• not a medication of special interest to the published NMA

• platinum salts.

The anthracycline plus pembrolizumab plus platinum salts category included evidence from 1 trial for 1 treatment, which was the intervention of interest to this review (pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy).

Results of Published NMA

Summary of Included Studies

A total of 1,476 articles were identified in the systematic review, 673 of which were assessed for eligibility. Thirteen RCTs were included in the NMA. The eligible studies included a total of 3,008 patients with TNBC, with the number of patients included in each study ranging from 49 to 602. The published NMA reported a summary of the main characteristics of the trial included in the NMA (refer to publication for characteristics of included trials¹³). This summary included the publication year, treatment regimens, study design, number of patients, age of patients, stage of cancer, and definition of TNBC used. Additional information about the included studies was not reported. The year of publication ranged from 2012 to 2020. Most of the trials were open label (92%) and multi-centre (77%). The pivotal trial for pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy was the only double-blind trial included in the NMA. The authors of the published NMA reported that the age and stage of patients and the definition of TNBC that was used were similar among the included trials.

Most of the studies included in the NMA had a high risk of bias due to inadequate blinding (> 75%), and approximately half the studies had a high risk of bias due to the inadequate random sequence generation and/or allocation concealment. Additionally, some of the studies were at a high risk of bias due to selective reporting (< 25%), incomplete outcome data (< 25%), and other sources of bias (< 25%).

Results

The analysis of pCR, febrile neutropenia, nausea/vomiting, and diarrhea include 19, 15, 17, and 14 comparisons, respectively. The analysis of thrombocytopenia did not include the treatments that include the anthracycline plus pembrolizumab plus platinum salts treatment node; the reason for this was not reported. The anthracycline plus pembrolizumab plus platinum salts node was connected to the networks through the anthracycline plus pembrolizumab node. Please refer to the publication for a graphical depiction of the evidence networks.¹³

A summary of the results for the comparison of treatments that include anthracycline plus pembrolizumab plus platinum salts in terms of rate of pCR, febrile neutropenia, grade 3 or greater nausea/vomiting, and grade 3 or greater diarrhea is provided in Table 32. The relative risks for pCR and harms for relevant comparators relative to anthracycline plus pembrolizumab plus platinum salts are shown. The authors reported that the NMAs did not exhibit significant heterogeneity or inconsistency based on the I² and Q statistics.

Table 32: Results for Comparisons of Treatment to Anthracycline Plus Pembrolizumab Plus Platinum Salts, Miyashita et al. (2020) NMA

CI = confidence interval; NA = not applicable; NMA = network meta-analysis; NR = not reported; pCR = pathological complete response; RE = random effects.

Source: Miyashita et al. (2020).¹³

The analysis of the rate of pCR suggested a higher rate of pCR for anthracycline plus pembrolizumab plus platinum salts relative to anthracycline (relative risk = 0.58; 95% CI, 0.43 to 0.77) and anthracycline plus platinum salts (relative risk = 0.79; 95% CI, 0.63 to 0.99). Conclusions could not be drawn for comparisons with anthracycline plus pembrolizumab or with platinum salts alone due to serious imprecision in the effect estimates.

The analysis of the rate of febrile neutropenia suggested a higher rate of febrile neutropenia for anthracycline plus pembrolizumab plus platinum salts when compared to anthracycline (relative risk = 0.53; 95% CI, 0.33 to 0.86). Conclusions could not be drawn for comparisons with anthracycline plus pembrolizumab, anthracycline plus platinum salts, or platinum salts alone due to serious imprecision in the effect estimates.

Regarding the analysis of the rate of grade 3 or greater nausea/vomiting, conclusions could not be drawn for comparisons with anthracycline alone or in combination platinum salts, or with platinum salts alone, due to serious imprecision in the effect estimates. A comparison to anthracycline plus pembrolizumab was not included in this analysis.

No conclusions could be drawn for comparisons within the analysis of the rate of grade 3 or greater diarrhea due to serious imprecision in the effect estimates.

Critical Appraisal of Published NMA

The NMA by Miyashita et al. (2020) was associated with a number of limitations due to the lack of important details about the included trials and methodology used to perform the NMA. The systematic review informing the NMA was limited to RCTs in which patients received treatment that included anthracycline, bevacizumab, pembrolizumab, or platinum salts, which did not capture studies of comparisons to some of the treatments of interest to this review. The trials that were included and informed the NMA were at high risk of bias, particularly due to blinding, randomization, and/or allocation concealment. The authors did not report on potential effect modifiers, and few characteristics of the included trials were reported. The authors stated that the age and stage of patients and the definition of TNBC that was used were similar among the included trials, but the assessment of potential effect modifiers did not extend beyond this. For example, no information was provided about dosage used, duration of follow-up, treatment duration, route of administration, or supportive care provided. Therefore, it is unclear whether the transitivity assumption was plausible (i.e., whether the trials were jointly randomizable). A statistical assessment of methodological heterogeneity was performed using the I² statistic, which did not indicate significant heterogeneity in any of the analyses. The Q statistics were used to evaluate inconsistency. Additional information about the assessment of inconsistency was not provided. As tests for inconsistency have low power and may fail to detect inconsistency or incoherence, the absence of statistically significant inconsistency is not evidence for the absence of inconsistency. As a result, consistency in the networks is uncertain. No information was provided about an assessment of model fit, and no justification for the use of a random effects model was provided. Additional information about the statistical model used for the NMA was not reported; therefore, its appropriateness is uncertain.

The NMA was constructed using nodes that related to the interventions of interest to the published NMA (i.e., anthracycline, bevacizumab, pembrolizumab, and platinum salts). In doing so, the network did not account for differences in dose intensity or the administration schedule, and it combined different medications within the same node. Further, the NMA was focused on the neoadjuvant treatment phase, so the results of the network do not inform comparisons of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy to other specific treatment options (i.e., the results are only applicable to the neoadjuvant treatment phase). In addition, details about the node construction were limited. For example, the number of studies and number of patients included in the analysis of toxicity outcomes were not clearly reported. No information was provided regarding the exclusion of treatments that include anthracycline plus pembrolizumab plus platinum salts from the NMA of the rate of grade 3 or greater thrombocytopenia.

The lack of information about the characteristics of the trials, the treatments included in the network, and the node construction also hinders the assessment of generalizability of the results of the NMA to treatments used for the treatment of TNBC in Canadian clinical practice.

Summary

One published NMA by Miyashita et al. (2020)¹³ was summarized for this review to supplement the assessment of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC. The NMA included 13 articles and 3,008 patients with TNBC. The NMA grouped treatments based on the inclusion of anthracycline, bevacizumab, pembrolizumab, and platinum salts and constructed the network based on these treatment groups (nodes). The analysis of the rate of pCR suggested a higher rate of pCR with treatments that include anthracycline plus pembrolizumab plus platinum salts relative to treatments that include anthracycline and treatments that include anthracycline plus platinum salts. The analysis of the rate of febrile neutropenia suggested a higher rate of febrile neutropenia with anthracycline plus pembrolizumab plus platinum salts compared to treatments that include anthracycline. The analysis of the rate of grade 3 or greater nausea/vomiting and the rate of grade 3 or greater diarrhea suggested no difference was observed between treatments . The results of the NMA published NMA by Miyashita et al. (2020) were associated with a number of limitations due to the lack of important details about the included trials and methodology used to perform the NMA. As such, there is low confidence in the results, and they should be interpreted with caution. Additionally, construction of treatment nodes used in the NMA preclude the ability to draw conclusions regarding comparisons of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy to other specific treatment options for TNBC.

Discussion

Summary of Available Evidence

The CADTH systematic review included 1 pivotal trial (KEYNOTE-522) submitted by the sponsor and 1 published NMA identified via the searches. Additional input from 2 patient groups, 2 clinician groups, and 2 clinician experts was also considered during the review.

KEYNOTE-522 is an ongoing, phase III, randomized, multi-centre, double-blind, placebo-controlled trial. The primary objective is to evaluate pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared with placebo plus chemotherapy as neoadjuvant therapy followed by continued placebo as adjuvant therapy for patients with high-risk, early-stage TNBC. KEYNOTE-522 was initiated in March 2017 with 194 participating centres across 21 countries in North America (7 centres in Canada), South America, Europe, Asia, and Australia.¹⁰

Enrolled patients were male or female; were 18 years and older; were newly diagnosed; had a locally advanced, centrally confirmed TNBC, as defined by the most recent ASCO–CAP guidelines; were previously untreated; and had a locally advanced nonmetastatic (M0) TNBC as per the current AJCC staging criteria for breast cancer assessed by an investigator based on radiological and/or clinical assessment (T1c, N1 to N2; T2 to T4d, N0 to N2). Patients were randomized in a 2:1 ratio into 1 of the 2 trial arms based on 3 stratification factors: nodal status (positive versus negative), tumour size (T1/T2 versus T3/T4), and choice of carboplatin regimen (every 3 weeks or weekly). Co-primary end points investigated in the KEYNOTE-522 trial were pCR rate (using the ypT0/Tis ypN0 definition) assessed by a local pathologist and EFS assessed by an investigator. Overall survival, HRQoL, and safety outcomes were some secondary and exploratory outcomes assessed in the trial.¹⁰ These outcomes were considered clinically meaningful by the clinical experts, clinician groups, and patient groups consulted during the CADTH review.

By the IA4 data cut-off (March 23, 2021), 1,608 patients had been screened and 1,174 were randomized to 1 of the 2 trial arms via a centralized interactive voice response system–integrated web response system. In total, 784 patients received pembrolizumab plus chemotherapy treatment followed by pembrolizumab, and 390 patients received placebo plus chemotherapy followed by placebo. The majority of the patients enrolled were female (1 man enrolled), were younger than 65 years, were White, were pre-menopausal, and had an ECOG PS of 0. More than 80% of patients randomized had PD-L1-positive status.¹⁰

Interpretation of Results

Efficacy

The CADTH review protocol identified OS, pCR, EFS, HRQoL, safety, and reduction in symptom severity as important outcomes for patients, clinicians, and drug plans. All outcomes (except symptom severity) were pre-specified in the KEYNOTE-522 protocol before the IA4 data cut-off (March 23, 2021), and the findings are presented in this review. The type I error rate was adequately accounted for during the analyses of EFS, OS, and pCR using the family-wise error rate. The stopping rules were presented in the SAP. Sensitivity analyses were conducted for EFS, and the results were consistent with the primary analyses. The HRQoL and subgroup analyses conducted were not controlled for multiple comparisons, so there is an increased risk of type I error; thus, conclusions could not be drawn for these outcomes.

The median OS was not estimable at the IA4 data cut-off (March 23, 2021) due to data immaturity, limiting the ability to draw conclusions for this outcome. The HR obtained in the comparison of pembrolizumab plus chemotherapy followed by pembrolizumab versus placebo plus chemotherapy followed by placebo was 0.72 (95% CI, 0.51 to 1.02). The final OS analysis is planned to take place alongside the final EFS analysis once a pre-specified number of events have accrued in both study arms.

The pCR rate was achieved at the IA1 data cut-off (September 21, 2018). The pCR rate was 64.8% (95% CI, 59.9% to 69.5%) in the pembrolizumab plus chemotherapy arm and 51.2% (95% CI, 44.1% to 58.3%) in the placebo plus chemotherapy arm. The percent difference estimated between pembrolizumab plus chemotherapy and placebo plus chemotherapy was 13.6% (95% CI, 5.4% to 21.8%; P [1 sided] = 0.00055). At IA2 (April 24, 2019), the treatment difference in pCR rate (pembrolizumab plus chemotherapy versus placebo plus chemotherapy) was 9.2% (95% CI, 2.8% to 15.6%; P = 0.00221). The pCR rate for pembrolizumab plus chemotherapy at the neoadjuvant phase was 64.0% (95% CI, 60.2% to 67.6%), compared to 54.7% (95% CI, 49.1% to 60.1%) for placebo plus chemotherapy. The pCR rate obtained at the IA4 data cut-off (March 23, 2021) was consistent with IA1, although not tested according to the statistical hierarchy. Thus, pCR rate findings at IA4 are considered exploratory. The clinical experts consulted during the review considered the pCR rate in the pembrolizumab plus chemotherapy arm clinically meaningful. Pathological complete response has been approved as a surrogate outcome for OS by different regulatory agencies, including the FDA.

Event-free survival was assessed as a co-primary outcome in the KEYNOTE-522 trial. Event-free survival has been validated by regulatory agencies, including the FDA, as an important outcome to be investigated in trials with patients with TNBC.^11,12,30,31 The median EFS was not estimable at IA4 (March 23, 2021) due to data immaturity. The HR obtained in the comparison of the pembrolizumab plus chemotherapy followed by pembrolizumab arm versus the placebo plus chemotherapy followed by placebo arm was 0.63 (95% CI, 0.48 to 0.82). The clinical experts consulted considered the finding clinically meaningful. The number of patients with reported distant recurrence was 7.7% in the pembrolizumab plus chemotherapy followed by pembrolizumab arm, compared to 13.1% in the placebo plus chemotherapy followed by placebo arm. The clinical experts considered the findings clinically meaningful since distant recurrence implies metastatic disease.

The clinician and patient groups consulted during the CADTH review highlighted improvement in HRQoL as an important treatment goal for patients with early-stage TNBC. Health-related QoL was measured using 3 questionnaires (EORTC QLQ-C30, EORTC QLQBR23, and EQ-5D-5L). Because the analyses of HRQoL were not adjusted for multiple comparisons, conclusions could not be drawn for this outcome. The experts expressed that they expect decreases in HRQoL in practice in this curative setting.

All subgroup analyses were pre-specified before the interim data cut-offs; however, multiplicity adjustments were not conducted to adjust for alpha inflation. The findings were considered exploratory; thus, no definitive conclusions were made.

The KEYNOTE-522 study eligibility criteria included only patients with an ECOG PS of 0 or 1. As a result, the benefit and safety of pembrolizumab plus chemotherapy in the neoadjuvant setting followed by pembrolizumab in the adjuvant setting is unknown in patients with an ECOG PS greater than 1 in the real-world setting, particularly in patients with an ECOG PS of 2, who may be considered for therapy. The clinical experts consulted generally agreed that patients with early-stage TNBC with an ECOG PS of 2 would benefit from the treatment with pembrolizumab, although they would not consider patients with an ECOG PS of 3 or greater eligible to receive pembrolizumab treatment.

As highlighted by the clinical experts, anthracycline-taxane combination chemotherapy regimens are usually used to treat patients with early-stage TNBC, most commonly a dose-dense AC (doxorubicin, cyclophosphamide) every 2 weeks for 4 cycles followed by paclitaxel every 2 weeks for 4 cycles, with carboplatin often added. The experts also noted that pCR is a widely accepted goal for neoadjuvant therapy, and these chemotherapy agents are all supported by international guidelines. When carboplatin is added, it can be weekly for 12 cycles or every 3 weeks for 4 cycles. The experts also noted that patients with a BRCA1- or 2-positive mutation may likely receive olaparib in the adjuvant setting based on the results obtained in the OLYMPIA study. The experts noted that in the KEYNOTE-522 trial, carboplatin and paclitaxel cycles were administered before the doxorubicin and cyclophosphamide cycles, which is the opposite order to standard practice in Canada. They further highlighted that most clinicians will likely adhere to anthracycline-cyclophosphamide-taxane; however, they may switch the sequence to taxane and carboplatin first, and then anthracycline, to correspond to the treatment administration of the KEYNOTE-522 trial.

One published NMA by Miyashita et al. (2020)¹³ was summarized for this review to supplement the assessment of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC. The NMA included 13 articles and 3,008 patients with TNBC. The NMA grouped treatments based on the inclusion of anthracycline, bevacizumab, pembrolizumab, and platinum salts and constructed the network based on these treatment groups (nodes). The analysis of the rate of pCR suggested a higher rate of pCR with treatments that include anthracycline plus pembrolizumab plus platinum salts relative to treatments that include anthracycline and treatments that included anthracycline plus platinum salts.

Harms

Overall, almost all patients enrolled in both study arms of KEYNOTE-522 (99.2% in the pembrolizumab plus chemotherapy followed by pembrolizumab arm and 100.0% in the placebo plus chemotherapy followed by placebo arm) reported at least 1 AE by the IA4 (March 23, 2021) data cut-off. Adverse events of grade 3 or greater were slightly higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (82.4%) than in the placebo plus chemotherapy followed by placebo arm (78.7%). The most common AEs in both arms were nausea, alopecia, anemia, and neutropenia.¹⁰ There were more serious AEs reported in patients receiving pembrolizumab plus chemotherapy followed by pembrolizumab (approximately 15% more) than in patients receiving placebo plus chemotherapy followed by placebo.

Adverse events of grade 3 to 5 commonly reported in at least 5% of patients were generally similar in both treatment arms. These AEs included neutropenia (35.2% versus 34.4%), decreased neutrophil count (19% versus 23.7%), anemia (19.5% versus 15.7%), febrile neutropenia (18.4% versus 16.2%), and decreased white blood cell count (6.4% versus 2.8%) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm and the placebo plus chemotherapy followed by placebo arm, respectively. Overall, AEs resulting in death in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (0.9%) were consistent with the placebo plus chemotherapy followed by placebo arm (0.3%). Adverse events leading to discontinuation of any study intervention in the combined neoadjuvant and adjuvant phases were higher in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (29.9%) than in the placebo plus chemotherapy followed by placebo arm (15.4%). Overall, the incidence of AEs leading to dose reduction of chemotherapy was generally similar between the pembrolizumab plus chemotherapy (12.8%) and the placebo plus chemotherapy (11.3%) arms.¹⁰

Notable harms were more common in the pembrolizumab plus chemotherapy followed by pembrolizumab arm (43.6%) than in the placebo plus chemotherapy followed by placebo arm (21.9%). The most common notable harms were adrenal insufficiency (2.6% versus 0.0%), colitis (1.7% versus 0.8%), hyperthyroidism (5.2% versus 1.8%), hypophysitis (1.9% versus 0.3%), hypothyroidism (15.1% versus 5.7%), infusion-related reactions (18% versus 11.6%), nephritis (0.9% versus 0.0%), pneumonitis (2.2% versus 1.5%), severe skin reactions (5.7% versus 1%), and type 1 diabetes mellitus (0.5% versus 0.3%) in the pembrolizumab plus chemotherapy followed by pembrolizumab arm versus the placebo plus chemotherapy followed by placebo arm.¹⁰ The clinical experts noted that they would expect more AEs in the pembrolizumab group given that an additional treatment has been added to the regimen. They also noted that in practice they would try to keep patients on treatment as much as possible (e.g., by using dose adjustments).

The published indirect treatment comparison by Miyashita et al. (2020),¹³ which assessed the rate of febrile neutropenia, suggested a higher rate of febrile neutropenia with anthracycline plus pembrolizumab plus platinum salts when compared to treatments that included anthracycline. The analysis of the rate of grade 3 or greater nausea/vomiting and the rate of grade 3 or greater diarrhea suggested no difference was observed between treatments. No definitive conclusions could be drawn from the findings due to imprecision in the estimates obtained and other methodological limitations identified in NMA (the lack of important details about the included trials and methodology used to perform the NMA). As such, there is low confidence in the results, and they should be interpreted with caution. Additionally, construction of treatment nodes used in the NMA preclude the ability to draw conclusions regarding comparisons of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy to other specific treatment options for TNBC.

The clinical experts consulted agreed that the toxicity profile of pembrolizumab plus chemotherapy followed by pembrolizumab was manageable in practice, and they highlighted the importance of immune-related AEs associated with the use of pembrolizumab. The experts noted that pembrolizumab is currently being used in practice for other indications and that AEs, particularly immune-related AEs specific to pembrolizumab, are already known to clinicians. Therefore, the therapy can be managed in practice, and no extra activities to manage AEs are needed.

Conclusions

One pivotal study (KEYNOTE-522) and 1 published NMA provided evidence for this CADTH review. No additional evidence directly comparing pembrolizumab plus chemotherapy in the neoadjuvant setting and pembrolizumab in the adjuvant setting with other standard therapies for early-stage TNBC was identified. The pCR rate and EFS were co-primary end points assessed in the KEYNOTE-522 study. Pathological complete response, EFS, OS, and HRQoL (including safety outcomes) investigated in the KEYNOTE-522 trial were considered clinically meaningful by the clinical experts, and they align with outcomes highlighted as important by the patient groups. The median OS and median EFS were not estimable at IA4; thus, there is uncertainty in the effect of the intervention for OS and EFS. The clinical experts considered the pCR rate (and percent change) and EFS between the 2 arms clinically meaningful to clinicians and patients in clinical practice. The HRQoL assessments were considered exploratory due to the lack of multiplicity adjustments in the analyses. Both clinical experts and clinician groups stated that neoadjuvant therapy is current standard for TNBC and that pembrolizumab would be the preferred treatment option if it were to receive public funding. The clinical experts considered the safety profile of pembrolizumab plus chemotherapy followed by pembrolizumab manageable in practice. The experts stated that most oncologists have experience using pembrolizumab for other indications and are familiar with AEs due to pembrolizumab. Immune-related AEs are anticipated following the use of pembrolizumab. Clinical experts and clinician groups both considered toxicity and disease progression as important factors when deciding treatment discontinuation in patients. The KEYNOTE-522 study is a randomized, phase III, double-blinded design, and adjustments of multiplicity for the type I error were conducted in the analyses of key outcomes OS, PFS, and pCR. The OS findings are interim, with other analyses planned after a pre-specified number of events have occurred. The clinical experts considered the baseline and demographic characteristics of the KEYNOTE-522 study generalizable to Canadian practice.

One published NMA, by Miyashita et al. (2020), was summarized for this review to supplement the assessment of pembrolizumab plus chemotherapy as neoadjuvant therapy followed by continued pembrolizumab monotherapy as adjuvant therapy compared to other treatments for adult patients with early-stage TNBC. The NMA presented findings of pCR and grade 3 AEs specific to the neoadjuvant setting, which was a key limitation identified. Other methodological limitations—such as the lack of important details reported in the NMA methodology; high risk of bias in the studies included; lack of information about the characteristics of the trials included in the network; and imprecision of the estimates reported—precluded definitive conclusions of the findings observed for the different chemotherapy regimens and combinations assessed within the study.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: March 8, 2022

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits:

• Conference abstracts: excluded

Table 33: Syntax Guide