CADTH Reimbursement Review

Pembrolizumab in Combination With Lenvatinib (Keytruda and Lenvima)

Sponsor: Merck Canada Inc.

Therapeutic area: Advanced endometrial 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

Endometrial cancer is the most common gynecological cancer in Canada.¹ It usually occurs in patients over the age of 50 years, with an average age at diagnosis of 60 years.² Diagnosis of endometrial cancer commonly occurs at an early stage for approximately 80% of patients.^1,3,4 The prognosis depends primarily on tumour stage, tumour histology, and grade.

In terms of histology, there are 2 subtypes. Type I endometrial cancers are low-grade (1 or 2) endometrioid tumours and represent 80% of patients.^1,3,5 Type II endometrial cancers account for 10% to 20% of patients and include grade 3 endometroid tumours as well as tumours of non-endometroid cancers.^1,3 The 5-year survival rates are approximately 80% to 90% and 20% for type I and type II endometrial cancer, respectively. The prognosis for patients with recurrent endometrial cancer is poor, with a median survival of about 12 months.⁶ Molecular testing of cancer biomarkers during endometrial biopsy assists in identifying treatment options and stratifying risk.¹ Two molecular cancer biomarkers commonly assessed are microsatellite instability (MSI) and mismatch repair (MMR) protein expression.⁷ Based on the variability of DNA microsatellite lengths, endometrial cancer can be classified into microsatellite instability-high (MSI-H), microsatellite instability-low (MSI-L), and microsatellite stable (MSS).^7,8 Based on the DNA MMR status, endometrial cancer can be classified into mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR). In clinical practice and in clinical trials, the terms dMMR and MSI-H are often used interchangeably, while non-MSI-H and pMMR are also interchangeable.^7-10

Treatment options for endometrial cancer are dependent on stage and pathologic factors after initial surgery and based on estimated risk of disease recurrence.^11-13 Individuals diagnosed with advanced or recurrent endometrial cancer may require adjuvant radiotherapy and/or chemotherapy, depending on the extent and location of spread and/or pathologic risk factors. The current standard of care for patients with advanced or recurrent disease is platinum-based chemotherapy as a doublet or single drug.^14,15 The most common platinum-based therapies are carboplatin and paclitaxel.^11,14-16 However, for patients with advanced or recurrent endometrial cancer who have progressed on or after platinum-based chemotherapy, there is currently no established, standard effective or curative second-line therapy.^11,15 In clinical practice, these patients are typically re-treated with platinum-based chemotherapy, but the response is poor. Response rates ranging from 10% to 15% have been observed among all available treatment options.¹⁵ The clinical experts consulted by CADTH indicated that there is a great unmet need for effective therapies with acceptable toxicity profiles for patients with dMMR or MSI-H recurrent or advanced endometrial cancer who have progressed on or after treatment with a platinum-containing regimen.

Pembrolizumab (PEM) is an inhibitor of programmed cell death receptor 1 (PD-1). The recommended dose is 200 mg every 3 weeks or 400 mg every 6 weeks administered as an IV infusion for up to 24 months or until disease progression or unacceptable toxicity. Health Canada has issued market authorization for PEM in various indications, such as classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, urothelial carcinoma, melanoma, non–small cell lung carcinoma, renal cell carcinoma, head and neck squamous cell carcinoma, and colorectal cancer.⁸ The Health Canada–approved indication of interest for this review is PEM in combination with lenvatinib (LEN) for the treatment of adult patients with advanced endometrial carcinoma that is not MSI-H or dMMR who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation.⁸ The CADTH reimbursement request aligns with this Health Canada indication (refer to Table 3).

The objective of this clinical review is to review the beneficial and harmful effects of PEM in combination with LEN (PEM + LEN) for the treatment of adult patients with advanced endometrial carcinoma that is not MSI-H or dMMR who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation.

Stakeholder Perspectives

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

Patient Input

This section was prepared by CADTH staff based on the input provided by patient groups.

The input from patient advocacy groups for PEM + LEN for the treatment of advanced endometrial cancer was provided by Colorectal Cancer Resource & Action Network (CCRAN) in collaboration with the Canadian Cancer Society (CCS) and the Canadian Cancer Survivor Network (CCSN). CCRAN is a Canadian not-for-profit patient advocacy group focusing on patients with colorectal cancer, with an extended mandate to support other cancer populations that lack capacity or representative patient groups.

The information provided by CCS was collected through an online survey conducted from October 22, 2021, to November 3, 2021, with 22 responders from Canada (20 patients and 2 caregivers). CCSN conducted an outreach survey on December 5, 2021, and provided feedback from 1 patient in Canada with endometrial cancer. CCRAN provided additional feedback from 1 caregiver and 3 patients with advanced endometrial cancer through telephone interviews that took place from December 1, 2021, to December 14, 2021 in Canada.

The 3 patient groups reported that individuals with endometrial cancer experience physical symptoms (e.g., vaginal bleeding, pelvic pain, diarrhea, nausea, and fatigue) and psychological symptoms (feeling isolated and lonely). Some of the patients expressed substantial frustration related to their long diagnostic journeys, noting that the lengthy time periods may have contributed to disease progression and an advanced stage at diagnosis. Endometrial cancer negatively affects quality of life (QoL) for patients and their families. Many patients report issues with work, daily chores, and socialization. Caregivers and family members have to take on additional responsibilities and deal with stress and anxiety.

Regarding current treatment, patients reported experience with a variety of options, including surgery, chemotherapy, and hormonal therapy. The CCSN survey and CCRAN interviews captured a general lack of efficacy and debilitating side effects of the standard of care treatments indicated for the management of advanced endometrial cancer.

Three patients in Canada had experience with PEM + LEN combination therapy, whether through a clinical trial or private pay plan. Two of these 3 patients reported significant amelioration of cancer-induced symptoms, with disease regression and superior QoL, after 26 months of therapy in 1 case and after 4 months of therapy in the other. They reported being able to function at an almost normal level and resume their daily activities. Treatment-induced side effects were reported by 2 of the patients and included diarrhea, fatigue, and urinary tract infection. One patient experienced a dose reduction of LEN (to 10 mg/day from 14 mg/day) due to a headache at the beginning of the treatment. Patients appreciated having access to an oral treatment (LEN) as well as the short infusion time for PEM (30 minutes to 45 minutes every 3 weeks).

Key outcomes identified by patient advocacy groups as important to patients with endometrial cancer include improved symptoms, cancer control, fewer side effects, good QoL, and extension of survival.

Overall, the CCRAN patient group indicated that there is an urgent, unmet need for the treatment of patients with advanced endometrial cancer. The group emphasized that patients need access to treatments with fewer side effects that would extend and improve the quality of their lives. CCRAN strongly supports the use of PEM + LEN combination therapy as a second-line treatment option for MSS patients or pMMR tumours patients that are inoperable, metastatic, and/or recurrent.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The clinical experts consulted for this review indicated that currently, there is a lack of treatment options and no standard second-line therapy for individuals with metastatic or recurrent endometrial carcinoma. Both clinical experts noted that most patients undergoing current therapies show low response rates, short durations of response, and progression. This represents a critical unmet need in this patient population.

The clinical experts indicated that patients with endometrial carcinoma who have progressed on platinum chemotherapy currently receive cytotoxic treatments, such as carboplatin and paclitaxel, doxorubicin, or pegylated liposomal doxorubicin. Additional chemotherapeutic drugs that can be taken occasionally include topotecan, gemcitabine, pemetrexed ifosfamide, and hormonal treatments (megestrol acetate, tamoxifen). The described treatments are not considered curative and have low expected response rates and short durations.

Both clinical experts indicated that PEM + LEN combination therapy would become standard second-line therapy for patients with endometrial cancer after recurrence or failure of typical platinum-based regimens. This treatment combination would address the underlying disease process. The clinical experts were of the view that it would be preferable to initiate treatment with the drug under review before other therapies.

Clinical experts indicated that currently, there is no evidence to support re-treatment with the same drugs in the event of relapse.

Clinical experts agreed that patients with endometrial carcinoma who experience recurrent or progressive disease following platinum-containing chemotherapy and have a good Eastern Cooperative Oncology Group Performance Status (ECOG PS) (i.e., 0 or 1) would benefit most from PEM + LEN combination therapy. The experts also indicated that, while not supported by clinical trial evidence, the treatment might be extended to patients with an ECOG PS of 2 if they were appropriately informed and motivated. The experts noted that there is currently a lack of data on treatment response among patients with other histologic endometrial cancer types of (e.g., carcinosarcoma, endometrial leiomyosarcoma, and endometrial stromal sarcomas). One expert indicated that unstable central nervous system (CNS) metastases should be treated with neurosurgical resection and post-operative cranial irradiation before considering treatment with PEM + LEN combination therapy.

Regarding the identification of patients, 1 clinical expert mentioned that standard practice includes a clinical examination by an oncologist, diagnostic imaging, and biopsies. The other expert noted that biomarker testing for MMR status through immunohistochemistry (IHC) staining is used in many centres in Canada.

The clinical experts reported that treatment with PEM + LEN combination therapy would be least suitable in patients with a poor ECOG PS (3 or 4). In addition, 1 expert noted that patients with a history of multiple lines of chemotherapy or an intolerance of or contraindications to PEM would be least suited to receive the drug under review.

According to the clinical experts, treatment response in clinical practice is evaluated through imaging (e.g., CT, MRI), assessment of clinical symptoms, and physical exam findings. One expert noted that treatment benefit for most biologics would include the absence of progression and good tolerance of the treatment.

Both experts agreed that improved progression-free survival (PFS) and overall survival (OS), maintained or improved QoL, and control of symptoms can be considered clinically meaningful responses to the treatment under review. Treatment response should be assessed every 12 weeks to 16 weeks (3 months to 4 months).

According to the clinical experts, treatment with PEM + LEN combination therapy should be discontinued in the case of disease progression (confirmed clinically or on imaging) or the appearance of serious immune adverse events (AEs) or intolerable treatment toxicities.

Both experts noted that, if toxicity or tolerability issues are related to LEN, it would be reasonable to continue treatment with PEM alone, if the patient is benefiting from it.

Clinical experts consulted by CADTH indicated that treatment administration and monitoring of patients with endometrial cancer should be undertaken by a specialist, namely a gynecologic oncologist or a medical oncologist. Treatment monitoring can potentially be conducted by a general practitioner in oncology with supervision by 1 of the specialists.

The experts recommended administering PEM + LEN in an infusion setting with appropriate monitoring capabilities, such as a hospital or oncology clinic. In terms of companion diagnostics, 1 expert noted that detection of MMR status through IHC staining would be required.

In reference to dosing, clinical experts consulted by CADTH noted that fixed dosing would be applied for PEM and anticipated that dose modifications of LEN would be common in clinical practice. One clinical expert indicated that less frequent administrations (i.e., over 6-week periods) would be better for patients, clinicians, and health centres.

One clinical expert expressed concerns about the high cost of the treatment under review and indicated that the costs might improve with increased availability of other PD-L1 inhibitors on the market.

Clinician Group Input

One joint clinician submission was provided by 7 physicians on behalf of the Ontario Health (Cancer Care Ontario) Gynecology Cancer Drug Advisory Committee. The clinician group noted the absence of currently available therapies for patients with recurrent or progressive endometrial cancer. The group recognized the unmet needs of this patient population, indicating that most patients remain unresponsive to available treatments and highlighting a need for better-tolerated treatment options. The clinician group stated that the LEN + PEM combination could be used second-line as a preferred option for all patients with endometrial cancer who experienced a recurrence or progression after platinum-based chemotherapy. Prolonged life, delayed disease progression, symptomatic relief, partial response, full response, and improved health-related quality of life (HRQoL) were identified as the most important treatment goals. In terms of assessing response to treatment, the clinician group stated that imaging, clinical exam, and symptomatic improvement should be assessed in clinical practice. The clinician group also advised that LEN in combination with PEM should be discontinued if a patient experiences disease progression or intolerable side effects related to the treatment. Lastly, outpatient hospital settings were noted as appropriate treatment settings for these patients.

Of note, 5 out of 7 physicians provided CADTH with a conflict of interest declaration in the clinician group input.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may have an impact on 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 Studies and Protocol Selected Studies

Description of Studies

KEYNOTE-775 is an ongoing, phase III, multi-centre, randomized, open-label, active-controlled superiority study comparing PEM + LEN to treatment of physician’s choice (TPC) for the treatment of adult patients 18 years of age or older with advanced endometrial carcinoma who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation. The KEYNOTE-775 trial included a total of 827 patients: 697 with pMMR disease and 130 with dMMR disease. This review focuses on patients with pMMR disease only. A total of 697 patients with pMMR disease were randomized in a 1-to-1 ratio to receive PEM + LEN (n = 346) or TPC (n = 351). The primary outcomes were PFS and OS. The secondary outcomes included objective response rate (ORR) and HRQoL (measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] Global Health Status [GHS] scale). The exploratory outcomes included duration of response (DOR) and other HRQoL measurements (i.e., the EORTC QLQ-30, the EORTC QLQ Endometrial Cancer Module [EORTC QLQ-EN24] Urological Symptoms Score, and the 5-Level EQ-5D [EQ-5D-5L]).

The findings of this study were based on the first interim analysis (IA1) with a data cut-off date of October 26, 2020. However, it was indicated that the success criteria for the study hypotheses of PFS, OS, and ORR were all met at IA1; consequently, the second interim analysis (IA2) was not required.^17,18

Efficacy Results

The key efficacy findings of the KEYNOTE-775 trial are summarized in Table 2. Based on an interim analysis, PEM + LEN combination therapy demonstrated a statistically significant and clinical meaningful improvement in OS compared to TPC (hazard ratio [HR] = 0.68; 95% confidence interval [CI], 0.56 to 0.84; P = 0.0001). Such improvements were also reported in key subgroup analyses of patients with an ECOG PS of 0 (HR = 0.56; 95% CI, 0.42 to 0.75), patients with non-endometrioid cancer (HR = 0.56; 95% CI, 0.42 to 0.74), and patients with 1 prior line of systemic therapy (HR = 0.61; 95% CI, 0.47 to 0.78).

Similarly, PEM + LEN combination therapy showed a statistically significant and clinical meaningful improvement in PFS compared to TPC (HR = 0.60; 95% CI, 0.50 to 0.72; P = 0.0001). Key subgroup analyses of PFS were consistent with the primary analysis (i.e., HR < 1) in patients with an ECOG PS of 0 (HR = 0.57; 95% CI, 0.45 to 0.72) and patients with an ECOG PS of 1 (HR = 0.65; 95% CI, 0.49 to 0.86), patients with endometrioid cancer (HR = 0.59; 95% CI, 0.46 to 0.76), patients with non-endometrioid cancer (HR = 0.56; 95% CI, 0.43 to 0.73), and patients with 1 prior line of systemic therapy (HR = 0.52; 95% CI, 0.42 to 0.65).

Overall, no obvious between-group differences in change from baseline were observed in the patient-reported or HRQoL outcomes.

In addition, ORR was statistically significantly higher in patients receiving PEM + LEN combination therapy than in those receiving TPC. The between-group difference (PEM + LEN versus TPC) was 15.2% (95% CI, 9.1% to 21.4%; P < 0.0001). The results for ORR are in line with the survival benefit seen for OS and PFS.

Harms Results

The key harms findings of the KEYNOTE-775 trial are shown in Table 2 in this section and in tables 49 to 54 in Appendix 3. The proportion of patients with at least 1 treatment-emergent adverse event (TEAE) appeared similar in the PEM + LEN and TPC groups (99.7% in each). The frequency of serious adverse events (SAEs) was higher in the PEM + LEN arm than in the TPC arm. However, when adjusted for exposure, the incidence of SAEs appeared to be similar between the 2 treatment groups. That is, the number of SAEs per 100 person-months was 9.83 versus 9.40 in the PEM + LEN and TPC groups, respectively (Table 49). More patients discontinued the study medication due to AEs with PEM + LEN than with TPC (PEM + LEN versus TPC: 31.0% versus 8.3%). The notable AEs (i.e., the AEs of special interest for this review) were higher in the PEM + LEN group versus the TPC group. The higher incidence of notable harms in the PEM + LEN group was driven primarily by hypothyroidism, hyperthyroidism, and hypertension. Overall, the clinical experts consulted by CADTH for this review agreed that the safety profile of PEM + LEN observed in this study appeared consistent with the known safety profile of each individual drug (PEM or LEN). No additional safety signals were identified. Additionally, the clinical experts indicated that the AEs observed in the study were generally manageable through dose interruption or discontinuation of PEM, LEN, or both, or with LEN dose reduction (with or without concomitant steroid therapy).

Table 2: Summary of Key Results From Pivotal and Protocol Selected Studies

AE = adverse event; CI = confidence interval; DC = discontinuation; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 GHS = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Global Health Status; FAS = full analysis set; HR = hazard ratio; ITT = intention to treat; LEN = lenvatinib; LSM = least squares mean; MMR = mismatch repair; ORR = objective response rate; OS = overall survival; PEM = pembrolizumab; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; PFS = progression-free survival; pMMR = mismatch repair proficient; PRO = patient-reported outcome; SAE = serious adverse event; SD = standard deviation; TEAE = treatment-emergent adverse event; TPC = treatment of physician’s choice; vs. = versus.

^aFrom the 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 ECOG PS, geographic region, and prior history of pelvic radiation.

^cOne-sided P value based on log-rank test stratified by ECOG PS, geographic region, and prior history of pelvic radiation. The P value has been adjusted for multiple testing.

^dBased on a constrained longitudinal data analysis model with PRO scores as the response variable with covariates for treatment by study visit interaction, stratification factors, MMR status, ECOG PS, geographic region, and prior history of pelvic radiation. Note: For baseline and week 12, N is the number of patients in each treatment group with non-missing assessments at the specific time point; for change from baseline, N is the number of patients in the analysis population in each treatment group with at least 1 measurement. The P value has not been adjusted for multiple testing.

^eBased on the Miettinen and Nurminen method stratified by ECOG PS, geographic region, and prior history of pelvic radiation.

^fOne-sided P value for testing. H0 means the difference in percentage equals 0, whereas H1 means the difference in percentage is greater than 0. The P value has been adjusted for multiple testing.

^gFor DOR, the + symbol indicates there is no progressive disease at the time of last disease assessment.

Source: Clinical Study Report.¹⁹

Critical Appraisal

The included pivotal study (KEYNOTE-775) was relatively well-designed. This section discusses its methodological limitations.

The KEYNOTE-775 trial was an open-label trial. Study investigators and patients were aware of their treatment status, which increases the risk of detection and performance biases that have the potential to influence subjective outcome reporting (i.e., safety and HRQoL). The direction of anticipated bias related to these outcomes is unclear.

In the pMMR population, it was noted that 47 patients (13.7%) in the PEM + LEN group and 37 patients (11.4%) in the TPC group received antineoplastic drugs as concomitant medications (Table 19). The impact of those concomitant anticancer drugs on the comparative efficacy assessment between the 2 treatment groups remains unknown. Nevertheless, due to the very small number of patients using these individual drugs (e.g., carboplatin, cisplatin, doxorubicin, paclitaxel, LEN, and PEM), the clinical experts consulted for this review considered the unknown potential impact on the comparative efficacy assessment (PEM + LEN versus TPC) to be negligible.

The patient-reported and HRQoL outcome — the EORTC QLQ-C30 GHS — was assessed as a secondary outcome. However, it was not controlled for type I error. The other patient-reported and HRQoL outcomes (the EORTC QLQ-C30 Physical Functioning scale, the EORTC QLQ-EN24 Urological Symptoms Score, and EQ-5D Visual Analogue Score [VAS] score) were assessed as exploratory outcomes. There is a potential risk of bias because of the large number of patients who did not have complete measures, substantial missing data on all of these outcomes, and the open-label nature of the study design. As well, there may have been differential recall bias. Overall, the magnitude and direction of the impact of these missing data and recall bias on the patient-reported and HRQoL outcomes are unknown. The HRQoL findings should be viewed as supportive evidence only.

The primary analyses of PFS, OS, and ORR were based on intention-to-treat (ITT) analysis. In the pMMR population, important protocol deviations were reported for 17 patients: 9 (2.6%) in the LEN + PEM group and 8 (2.3%) in the TPC group. No per-protocol analysis was conducted to assess whether the per-protocol analysis was consistent with the ITT analysis. However, given that the proportion of patients with important deviations was relatively low and balanced across both groups, the impact on comparative efficacy findings (PEM + LEN versus TPC) is expected to be negligible.

Furthermore, the median follow-up duration for pMMR was 12.2 months, which is relatively short; this may mean that survival data (e.g., OS) are evolving. Although the protocol-specified criteria were met for the efficacy analyses, monitoring for safety and efficacy is ongoing. The sponsor provided a final descriptive analysis (cut-off date: March 1, 2022 ||||||||||||||||||||||||||||||||||||||||||||, the results of the final analysis appeared consistent with that observed in IA1 (cut-off date: October 26, 2020). (Refer to Appendix 5.)

This study was a multinational, multi-centre trial with 67 sites in 21 countries. A total of 58 patients in Canada participated in the trial at 11 sites in Canada. According to the clinical experts consulted for this review, the KEYNOTE-775 study population (i.e., adult patients with advanced pMMR endometrial carcinoma who have disease progression following prior platinum-based systemic therapy in any setting and are not candidates for curative surgery or radiation) is considered reflective of the requested target population. There is no concern about generalizing the findings from the pivotal study to Canadian clinical settings.

Indirect Comparisons

No indirect comparison evidence was identified.

Other Relevant Evidence

One additional relevant study (KEYNOTE-146) included in the sponsor’s submission to CADTH was considered to provide additional longer-term evidence for this review.

Description of Study

KEYNOTE-146 is an ongoing, multinational, open-label, single-arm phase Ib and II study of PEM + LEN in patients with selected solid tumours, including endometrial carcinoma. This review reports only on the cohort of patients with advanced non-MSI-H or pMMR endometrial cancer.

Included patients were adults (≥ 18 years old) with histologically and/or cytologically confirmed advanced pMMR endometrial carcinoma, with up to 2 prior lines of systemic therapy, an ECOG PS of 0 or 1, and life expectancy of ≥ 12 weeks.

Patients (N = 94) received PEM + LEN combination therapy, with PEM 200 mg IV once every 3 weeks (to a maximum of 35 PEM treatments) and LEN 20 mg once daily orally. The primary efficacy outcome was ORR at week 24. Key secondary outcomes were ORR at the data cut-off date, DOR, PFS, and OS.

At the data cut-off date (January 10, 2019), the median duration of treatment with PEM + LEN was 7.38 months (range = 0.03 months to 37.78 months). Overall, the median follow-up time for OS was 18.7 months (95% CI, 14.1 months to 20.9 months).

Efficacy Results

Overall Survival

The median OS was 16.4 months (95% CI, 13.5 to 25.9). The survival probabilities of patients at 12 months, 18 months, and 24 months were 69.5% (95% CI, 58.6 to 78.1%), 43.8% (95% CI, 31.2, 55.7%), and 39.2% (95% CI, 26.7 to 51.5%), respectively.

Progression-Free Survival

The median PFS was 5.4 months (95% CI, 4.4 to 7.6). PFS rates at 6 months, 12 months, and 18 months were 49.4%, 33.2%, and 33.2.0%, respectively.

Objective Response Rate

At the data cut-off date (January 10, 2019), among patients who had been enrolled for at least 26 weeks before the cut-off, 36 patients out of 94 patients achieved an objective response, resulting in an ORR of 38.3% (95% CI, 28.5 to 48.9).

Duration of Response

Based on the product-limit (Kaplan-Meier) method for censored data, the median DOR was not reached (95% CI, 6.3 to not reached; range = 1.2 months to 33.1 months).

Harms Results

At the data cut-off date, all patients had experienced at least 1 TEAE (N = 94, 100%). The most common TEAEs (occurring in ≥ 50% patients) were hypertension (63.8%), diarrhea (62.8%), fatigue (54.3%), and decreased appetite (51.1%). The percentage of patients reporting an SAE was 52.1%. The most frequent SAEs (> 5%) were hypertension and abdominal pain, reported by 7.4% and 5.3% of patients, respectively. The proportion of patients with an AE leading to discontinuation from the treatment was 25.5%. The most common events leading to discontinuation from the treatment were muscular weakness and pancreatitis, both reported in 2.1% patients. Three patients (3.2%) died due to an AE. Overall, the safety profile of PEM + LEN was generally consistent with the known safety profiles of each drug when used as monotherapy, with no new safety signals identified for the combination.

Critical Appraisal

The main limitation of the KEYNOTE-146 study was its single-arm design, with no comparator arm. Such a design, in addition to a lack of consideration of confounding variables, precludes causal inferences (i.e., the outcomes cannot be directly attributed to PEM). Without an active comparator or any statistical hypothesis testing, it is not possible to assess the relative therapeutic benefit or safety of PEM against other available treatments (such as chemotherapy) in this population. As indicated in the Health Canada reviewer’s report,²⁰ due to the nature of the limitation of the single-arm design, the findings observed in the KEYNOTE-146 trial needed to be confirmed in a phase III study (i.e., KEYNOTE-775).

Overall, no apparent generalizability issue was identified.

Conclusions

One sponsor-submitted, phase III, multinational, open-label, randomized, active-controlled trial (KEYNOTE-775) was included in this review. Compared with TPC (doxorubicin or paclitaxel), PEM + LEN combination therapy showed a statistically significant and clinically meaningful benefit in terms of OS, PFS, and ORR in the treatment of adult patients with advanced pMMR (i.e., non-MSI-H or dMMR) endometrial carcinoma who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation. The clinical experts consulted for this review indicated that the safety profile of PEM + LEN observed in this study appeared consistent with the known safety profile of each individual drug (PEM or LEN); no additional safety signals were identified. The AEs observed in the study were generally manageable through dose interruption, dose discontinuation, or LEN dose reduction, with or without concomitant steroid therapy.

Introduction

Disease Background

Endometrial cancer arises from the cells of the uterine lining. It is the most common gynecological cancer in Canada.¹ More than 95% of all uterine cancers are endometrial.³ Uterine cancer is ranked as the 17th leading cause of cancer death in Canada.^3,21 CCS estimated that 8,000 women would be diagnosed with uterine cancer in 2021 and that 1,400 women would die of the disease.^21,22 Endometrial cancer most often occurs in patients over the age of 50 years, with an average age at diagnosis at 60 years.² Diagnosis occurs at an early stage for approximately 80% of patients because uterine bleeding is an early presenting symptom.^1,3,4 The most common method of diagnosis is endometrial biopsy, followed by endometrial curettage and hysterectomy specimen.¹ The International Federation of Gynecology and Obstetrics (FIGO) criteria are commonly used to determine the stage of endometrial cancer, which is based on the size of the tumour and the extent to which the tumour has spread to lymph nodes or distant sites (i.e., metastasis).²³ Generally, the higher the stage number, the more the cancer has spread.²⁴ Tumour stage is fixed regardless of tumour type.¹ The prognosis of endometrial cancer depends primarily on the tumour stage, tumour histology, and grade. Overall survival by FIGO stage is 80% to 90% for stage I, 70% to 80% for stage II, and 20% to 60% for stages III and IV.¹ In terms of histology, there are 2 subtypes. Type I endometrial cancers are low-grade (1 or 2) endometrioid tumours, and represent 80% of patients.^1,3,5 Type II endometrial cancers account for 10% to 20% of cases and include grade 3 endometroid tumours as well as tumours of non-endometroid histology, such as serous clear-cell, mucinous, squamous, transitional cell, mesonephric carcinosarcoma, and undifferentiated.^1,3 The 5-year survival rate for type I endometrial cancer is around 80% to 90%, while the 5-year survival rate for type II endometrial cancer is as low as 20%. Other notable factors that may affect the prognosis for endometrial cancer include race, age, uterine tumour location, peritoneal cytology results, and lymph vascular space invasion.¹

Molecular testing for cancer biomarkers during endometrial biopsy assists in decision-making about treatment options and risk stratification.¹ Two molecular cancer biomarkers are commonly assessed in patients with endometrial cancer. One is MSI, which evaluates DNA hypermutability. The other is MMR protein expression, which evaluates the functional status of the MMR DNA repair pathway.⁷ Tumours can be classified as MSI-H (exhibiting ≥ 30% to 40% microsatellite marker instability), MSI-L (exhibiting instability at <  30% to 40% of loci), and MSS (exhibiting no unstable markers).²⁵ Based on MMR status, endometrial cancer can be classified into dMMR and pMMR. IHC is used to test for dMMR, in which the cells’ ability to repair mistakes during the division process is impaired. The tumour is immunohistochemically assessed for the loss of at least 1 of the following MMR proteins: MLH1, MSH2, MSH6, and/or PMS2.^26-28 MSI statuses are determined by analyzing 5 tumour microsatellite loci using polymerase chain reaction–based assays (either the 5 mononucleotide loci [BAT25, BAT26, NR21, NR24, and Mono27] or the 5 mixed mononucleotide and dinucleotide loci [BAT25, BAT26, Di 5S346, Di 2S123, and Di 17S250]).²⁹ If MMR status cannot be determined from tumour samples, the sample may undergo genetic testing using next-generation sequencing to identify MSI status.

MMR status testing is already widely available and performed routinely in local laboratories. Tumours can be screened by IHC or polymerase chain reaction, and there is a high concordance between the 2 techniques.^30-32 Although MSI and MMR are 2 distinct biomarkers, these are both signs of an altered MMR pathway. In clinical trials, the terms dMMR and MSI-H are often used interchangeably (i.e., termed MSI-H or dMMR or MSI-H/dMMR). Non-MSI-H (including MSS and MSI-L) and pMMR are also interchangeable terms.^7-10 The clinical experts CADTH consulted for this review agreed that dMMR and MSI-H are commonly used interchangeably in clinical practice. The defect or absence of MMR protein causes DNA hypermutation and high levels of MSI-H in sections of the DNA.²⁸ Compared with MSS endometrial cancers, MSI-H or dMMR endometrial cancer is associated with a higher neoantigen load and increased PD-1–expressing, tumour-infiltrating lymphocytes, and programmed death ligand 1 (PD-L1)–expressing intraepithelial and peritumoral immune cells.³³ Thus, MSI-H or dMMR tumour status is predictive of clinical benefit from PD-1 inhibitor monotherapy. For patients with pMMR gynecologic tumours, the combination of a PD-1 inhibitor and another targeted drug may be necessary to achieve the same level of response.³⁴ pMMR represents approximately 69% to 75% of primary endometrial cancers and 70% to 87% of recurrent endometrial cancers.^35-39

Recurrence occurs in approximately 13% to 20% of patients with endometrial cancer, with rates varying greatly by FIGO stage at diagnosis; these are highest (> 65%) among patients with stage IV endometrial cancer.^6,11,40 The prognosis for patients with recurrent endometrial cancer is poor, with a median survival of about 12 months.⁶

Standards of Therapy

Treatment options for endometrial cancer depend on stage and pathologic factors after initial surgery and are based on an estimated risk of disease recurrence. Early-stage endometrial cancer and/or type I tumour endometrial cancers can be cured through surgery alone.^11-13 Individuals diagnosed with advanced or recurrent endometrial cancer may require adjuvant radiotherapy and/or chemotherapy, depending on the extent and location of spread and/or pathologic risk factors. Cancer Care Ontario and Alberta Health Services recommendations favour combination chemotherapy over single-drug chemotherapy for individuals with advanced or recurrent endometrial cancer because it elicits a higher response rate with less toxicity.^11,14 The current standard of care for patients with advanced or recurrent disease is platinum-based chemotherapy as a doublet or single drug,¹⁴ a standard echoed by the European Society of Gynecological Oncology, the European Society of Radiotherapy and Oncology, and the European Society of Pathology.¹⁵ The most common platinum-based therapy is carboplatin plus paclitaxel.^11,14-16 For a subset of patients with low-grade recurrent or metastatic endometrial cancer who are estrogen and/or progesterone receptor–positive, or for patients with poor tolerance to systemic therapy, hormonal therapy — such as megestrol, letrozole, and medroxyprogesterone — may be used.¹⁴

For patients with newly diagnosed advanced or recurrent endometrial cancer, response rates for standard first-line treatment range from 40% to 62%.^41-44 However, for patients with advanced or recurrent endometrial cancer who have progressed on or after platinum-based chemotherapy, there is currently no established, standard effective or curative second-line therapy.^11,15 Patients with recurrent endometrial cancer are typically re-treated with either platinum-based chemotherapy or doxorubicin, but the response is poor. The response rates range from 10% to 15% among all available treatment options.¹⁵ The clinical experts consulted by CADTH noted that median survival rates range from 12 months to 15 months after re-treatment. Various single-drug chemotherapies may be administered to patients who are resistant or refractory to platinum-based chemotherapy, with response rates typically below 15% and no known, clear survival benefit.⁴⁵ Hormonal treatments may also be used for disease control, but are not considered curative.

The clinical experts consulted by CADTH for this review indicated that there is a great unmet need for effective therapies with acceptable toxicity profiles that achieve disease control, reduce disease-related symptoms, improve HRQoL, prevent disease progression, and prolong survival among patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen. There is currently no standard, effective second-line therapy for recurrent or refractory disease, and commonly used therapies are non-curative.

Drug

PEM is a selective, humanized monoclonal antibody that enhances the immune system’s detection of tumours and facilitates tumour regression through the PD-1 pathway. The Health Canada–recommended dose is 200 mg every 3 weeks or 400 mg every 6 weeks administered as an IV infusion for up to 24 months or until disease progression or unacceptable toxicity.

LEN is a targeted antineoplastic drug that belongs to the family of receptor tyrosine kinase inhibitors that selectively inhibit the kinase activities of vascular endothelial growth factor (VEGF) receptors. The Health Canada–recommended dose is 20 mg orally once daily until unacceptable toxicity or disease progression.

The Health Canada–approved indication of interest for this review is PEM + LEN combination therapy for the treatment of adult patients with advanced endometrial carcinoma that is not MSI-H or dMMR who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation.⁸ The CADTH reimbursement request aligns with this Health Canada indication (refer to Table 3).

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

The input from patient advocacy groups for PEM + LEN for the treatment of advanced endometrial cancer was provided by CCRAN in collaboration with CCSN and CCSN. CCRAN is a Canadian not-for-profit patient advocacy group focusing on patients with colorectal cancer, but its mandate extends to support other cancer populations who lack capacity or representative patient groups.

The information provided by CCS was collected through an online survey conducted from October 22 to November 3, 2021, with 22 responders from Canada (20 patients and 2 caregivers). CCSN conducted an outreach survey on December 5, 2021, and provided feedback from 1 patient in Canada with endometrial cancer. CCRAN provided additional feedback from 1 caregiver and 3 patients with advanced endometrial cancer through telephone interviews that took place from December 1 to December 14, 2021, in Canada.

The 3 patient groups reported that individuals with endometrial cancer experience physical symptoms (e.g., vaginal bleeding, pelvic pain, diarrhea, nausea, and fatigue) and psychological symptoms (feeling isolated and lonely). Some of the patients expressed substantial frustration related to their long diagnostic journeys, noting that these might have contributed to their disease progression and advanced stage at diagnosis. Endometrial cancer negatively affects the QoL of patients and their families. Many patients report issues with work, daily chores, and socialization. Caregivers and family members have to take on additional responsibilities and deal with stress and anxiety.

Regarding current treatment, patients reported a variety of options, including surgery, chemotherapy, and hormonal therapy. The CCSN survey and CCRAN interviews captured a general lack of efficacy and debilitating side effects of the standard of care treatments indicated for the management of advanced endometrial cancer.

Three patients in Canada had experience with PEM + LEN combination therapy through a clinical trial or private pay plan. Two of the 3 patients reported significant amelioration of cancer-induced symptoms, disease regression, and superior QoL after 26 months of therapy in 1 case and 4 months of therapy in the other. They reported being able to function at an almost normal level and resume their daily activities. Treatment-induced side effects were reported by 2 of the patients and included diarrhea, fatigue, and urinary tract infection. One patient experienced a dose reduction of LEN (to 10 mg/day from 14 mg/day) due to a headache at the beginning of the treatment. Patients appreciated having access to an oral treatment (LEN) as well as the short infusion time of PEM (30 minutes to 45 minutes every 3 weeks).

Key outcomes identified by the patient advocacy groups as important to patients with endometrial cancer include improved symptoms, cancer control, fewer side effects, good QoL, and extension of survival.

Overall, the CCRAN patient group indicated that there is an urgent, unmet need for the treatment of patients with advanced endometrial cancer. The group emphasized that patients need access to treatments with fewer side effects that would extend and improve their QoL. CCRAN strongly supports the use of PEM + LEN combination therapy as a second-line treatment option for patients who are MSS or pMMR and whose tumours are inoperable, metastatic, and/or recurrent.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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 endometrial cancer.

Unmet Needs

Currently, there is a lack of treatment options and no standard second-line therapy for individuals with metastatic or recurrent EC. Both clinical experts noted that most patients undergoing current therapies show low response rates, short DOR, and progression. This represents a critical unmet need in this patient population.

Place in Therapy

Patients with endometrial cancer who have progressed on platinum chemotherapy currently receive cytotoxic treatments, such as carboplatin and paclitaxel, doxorubicin, or pegylated liposomal doxorubicin. Additional chemotherapeutic drugs that can be taken occasionally include topotecan, gemcitabine, pemetrexed ifosfamide, and hormonal treatments (megestrol acetate, tamoxifen). These treatments are not considered curative and have low expected response rates and short durations.

Both clinical experts indicated that PEM + LEN would become standard second-line therapy for patients with endometrial cancer after recurrence or failure of typical platinum-based regimens. This treatment combination would address the underlying disease process. The clinical experts felt it would be preferable to initiate treatment with the drug under review before other therapies.

Clinical experts also indicated that currently, there is no evidence to support re-treatment with the same drugs in the event of relapse.

Patient Population

Clinical experts agreed that patients with endometrial carcinoma who experience recurrent or progressive disease following platinum-containing chemotherapy and have a good ECOG PS (e.g., 0 or 1) would benefit most from PEM + LEN combination therapy. Although not supported by clinical trial evidence, the experts also indicated that the treatment might be extended to patients with an ECOG PS of 2 if the patient is appropriately informed and motivated. The experts noted that there is currently a lack of data on treatment response among patients with other histologic types of endometrial cancer (e.g., carcinosarcoma, endometrial leiomyosarcoma, and endometrial stromal sarcomas). One expert indicated that unstable CNS metastases should be treated with neurosurgical resection and post-operative cranial irradiation before considering treatment with PEM + LEN combination therapy.

Regarding the identification of patients, 1 clinical expert mentioned that standard practice includes a clinical examination by an oncologist, diagnostic imaging, and biopsies. The other expert noted that biomarker testing for MMR status through IHC staining is used in many centres in Canada.

The clinical experts reported that treatment with PEM + LEN combination therapy would be least suitable in patients with poor a ECOG PS (3 or 4). One expert added that patients with multiple lines of chemotherapy, and those with intolerance of or contraindications to PEM, would be least suited to receive the drug under review.

Assessing Response to Treatment

According to the clinical experts, treatment response in clinical practice is evaluated through imaging (e.g., CT, MRI), assessment of clinical symptoms, and physical exam findings. One expert noted that treatment benefit for most biologics would include the absence of progression and good tolerance of the treatment.

Both experts agreed that improved PFS and OS, maintained or improved QoL, and control of symptoms can be considered clinically meaningful responses to the treatment under review. Treatment response should be assessed every 12 weeks to 16 weeks (3 months to 4 months).

Discontinuing Treatment

According to the clinical experts, treatment with PEM + LEN combination therapy should be discontinued in the case of disease progression (confirmed clinically or on imaging), or the appearance of serious immune AEs or intolerable treatment toxicities.

Both experts noted that, if toxicity or tolerability issues are related to LEN, it would be reasonable to continue treatment with PEM alone if the patient is benefiting from it.

Prescribing Conditions

Clinical experts consulted by CADTH indicated that treatment administration and monitoring of patients with endometrial cancer should be undertaken by a specialist, namely a gynecologic oncologist or a medical oncologist. Treatment monitoring can potentially be conducted by a general practitioner in oncology with supervision by 1 of the specialists.

The experts recommended administering PEM + LEN in an infusion setting with appropriate monitoring capabilities, such as a hospital or oncology clinic. In terms of companion diagnostics, 1 expert noted that detection of MMR status through IHC staining would be required.

In reference to dosing, clinical experts consulted by CADTH noted that fixed dosing would be applied for PEM and anticipated that dose modifications of LEN would be common in clinical practice. One clinical expert indicated that less frequent administrations (i.e., over 6-week periods) would be better for patients, clinicians, and health centres.

Additional Considerations

One clinical expert expressed concerns about the high cost of the treatment under review and indicated that the costs might improve with increased availability of other PD-L1 inhibitors on the market.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

One joint clinician submission was provided by 7 physicians on behalf of the Ontario Health (Cancer Care Ontario) Gynecology Cancer Drug Advisory Committee. The clinician group noted the absence of currently available therapies for patients with recurrent or progressive endometrial cancer. The group recognized the unmet needs of this patient population, indicating that most patients remain unresponsive to available treatments and highlighting a need for better-tolerated treatment options. The clinician group stated that the LEN + PEM combination could be used second-line as a preferred option for all patients with endometrial cancer who experienced a recurrence or progression after platinum-based chemotherapy. Prolonged life, delayed disease progression, symptomatic relief, partial response, full response, and improved HRQoL were identified as the most important treatment goals. In terms of assessing response to treatment, the clinician group stated that imaging, clinical exam, and symptomatic improvement should be assessed in clinical practice. The clinician group also advised that LEN in combination with PEM should be discontinued if a patient experiences disease progression or intolerable side effects related to the treatment. Lastly, outpatient hospital settings were noted as appropriate treatment settings for these patients.

Of note, 5 out of 7 physicians provided CADTH with a conflict of interest declaration within the clinician group input.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may have an impact on 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

CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IHC = immunohistochemistry; LEN = lenvatinib; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = microsatellite instability-high; PCR = polymerase chain reaction; PEM = pembrolizumab; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; pMMR = mismatch repair proficient.

Clinical Evidence

The clinical evidence included in the review of PEM in combination with LEN is presented in 3 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 from the sponsor (if submitted) and indirect evidence selected from the literature that met the selection criteria specified in the review. No indirect treatment comparison (ITC) was submitted by the sponsor or identified in the CADTH literature search. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review (if available). No additional relevant study was identified.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of PEM in combination with LEN for the treatment of adult patients with advanced endometrial carcinoma that is not MSI-H or dMMR who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation.

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 those considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; dMMR = mismatch repair deficient; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HRQoL = health-related quality of life; FIGO = International Federation of Gynecology and Obstetrics; ICU = intensive care unit; LEN = lenvatinib; MSI-H = microsatellite instability-high; ORR = objective response rate; OS = overall survival; PEM = pembrolizumab; PFS = progression-free survival; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

^aPatient-important outcome identified in patient input.

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.⁴⁹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through Ovid. 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 endometrial cancer. Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) 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 January 21, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Review Committee on July 13, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the CADTH Grey Matters: A Practical Tool For Searching Health-Related Grey Literature tool.⁵⁰ Included in this search were the websites of regulatory agencies (US FDA and 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.

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.

Findings From the Literature

A total of 1 study (KEYNOTE-775)¹⁹ was identified from the literature for inclusion in the systematic review (Figure 1). The included study, presented in 2 documents,^19,51 is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

BICR = blinded independent central review; CNS = central nervous system; DCR = disease control rate; dMMR = mismatch repair deficient; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Endometrial Cancer Module; EQ-5D-5L VAS = 5-Level EQ-5D Visual Analogue Scale; HRQoL = health-related quality of life; GHS = Global Health Status; MMR = mismatch repair; ORR = objective response rate; OS = overall survival; PD = progressive disease; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; PD-L2 = programmed cell death ligand 2; PFS = progression-free survival; PFS2 = progression-free survival on next-line therapy; pMMR = mismatch repair proficient; PRO = patient-reported outcome; QoL = quality of life; QTc = heart-rate corrected QT; RCT = randomized controlled trial; RECIST = Response Evaluation Criteria in Solid Tumours; q.3.w. = every 3 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; TPC = treatment of physician’s choice; VEGF = vascular endothelial growth factor.

Note: Only information related to pMMR is reported in the rest of this report, unless otherwise specified. There is no major impact of the protocol amendments on the pMMR population (Table 26 in Appendix 3).

^aThe information reported in Table 6 is for all comers, including pMMR and dMMR. There is no information only for pMMR.

^bThe number of randomized patients is for pMMR only, which is the population of interest in this review. Please note that overall, the KEYNOTE-775 study was conducted in patients with pMMR or dMMR cancer. A total of 827 patients were included (all comers: N = 827; pMMR = 697; dMMR: N = 130). Also note that pMMR was not considered a subgroup in the original study design. The sample size and power calculations were based on pMMR populations. dMMR was designed as a subgroup. In this review, only the pMMR population is of interest, which aligns with Health Canada’s indication and the sponsor’s reimbursement request.^8,19,32

Source: Clinical Study Report¹⁹ and Makker et al. (2022).⁵¹

Description of Studies

The KEYNOTE-775 trial is an ongoing, phase III, randomized, open-label, active-controlled, multi-centre superiority study comparing PEM + LEN to TPC (doxorubicin or paclitaxel) for the treatment of adult patients with advanced endometrial carcinoma who have disease progression following prior platinum-based systemic therapy in any setting and are not candidates for curative surgery or radiation.

The trial was conducted at 167 global sites in 21 countries (Canada, US, and 19 other countries in Europe, South America, Central America, and Asia). Fifty-eight patients in Canada at 11 Canadian research sites participated. The key characteristics of the study design are summarized in Table 6 and Figure 2.

The primary objective of this study was to assess whether PEM + LEN prolongs PFS and OS when compared to TPC. The secondary objectives were to compare the ORR, EORTC QLQ-C30 GHS, and the safety and tolerability of PEM + LEN combination therapy versus TPC. Other objectives (as exploratory) were to assess the DOR and EORTC QLQ-C30 Physical Function scale score, the EORTC QLQ-EN24 Urological Symptoms Score, and the 5-Level EQ-5D Visual Analogue Scale (EQ-5D-5L VAS) score in patients treated with PEM + LEN combination therapy versus TPC.

Figure 2: Study Design Schematic

BICR = blinded independent central review; PD = progressive disease; Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1.

Source: Clinical Study Report.¹⁹

A total of 1,178 patients were screened. In the pMMR population, 697 patients were randomized in a 1:1 ratio to receive PEM + LEN (n = 346) or TPC (n = 351). A total of 346 patients received PEM + LEN and 351 patients received TPC (doxorubicin or paclitaxel). Treatment allocation and randomization were done centrally using an interactive response technology system. Treatment allocation and randomization were stratified according to MMR status; ECOG PS status (0 or 1); geographic region (region 1 [Europe, US, Canada, Australia, New Zealand, and Israel] or region 2 [rest of the world]); and prior history of pelvic radiation (yes or no). The first patient was randomized on June 11, 2018, and the last patient was enrolled on February 03, 2020. The cut-off date for IA1 was October 26, 2020. A total of 667 patients received at least 1 dose of PEM + LEN (N = 342 [98.8%]) or TPC (N = 325 [92.6%]) as assigned. Four patients (1.2%) in the PEM + LEN arm and 26 patients (7.4%) in the TPC arm did not receive treatment. No reasons were provided for this.

Pre-specified interim analysis results (cut-off date of October 26, 2020) for the primary outcomes (PFS and OS), secondary outcomes (ORR and EORTC QLQ-30 GHS), ORR, and other exploratory outcomes (e.g., DOR, HRQoL outcomes, and safety outcomes) were provided in the submission. The sponsor indicated that the PFS and OS results in IA1 were considered final because both the PFS and OS analyses met the pre-specified statistical significance threshold.¹⁸

There is no major impact of protocol amendments on the pMMR population (Table 26 in Appendix 3).

Populations

Inclusion and Exclusion Criteria

Eligible patients were those (≥ 18 years old) with confirmed advanced, recurrent, or metastatic endometrial cancer of any histologic subtype except for carcinosarcoma and sarcoma. Patients had disease progression after receiving 1 previous platinum-based chemotherapy regimen, with no history of exposure to regimens targeting VEGF or PD-1. Patients may have received 2 lines of platinum-based chemotherapy if 1 was given as neoadjuvant or adjuvant therapy. There was no restriction regarding the previous receipt of hormonal therapy. Other criteria included patients who had an ECOG PS score of 0 or 1. The main exclusion criteria were carcinosarcoma, endometrial leiomyosarcoma, and endometrial stromal sarcomas; patients with CNS metastases were also excluded unless they had completed local therapy and discontinued the use of corticosteroids for this indication at least 4 weeks before starting treatment in this study. Patients who had received more than 1 prior systemic chemotherapy regimen (other than adjuvant or neoadjuvant therapy) for endometrial cancer were excluded. Patients with prior treatment with any drug targeting VEGF-directed angiogenesis, or any anti-PD-1, anti-PD-L1, or anti-PD-L2 drug, were excluded. Refer to Table 6.

Baseline Characteristics

The main baseline demographic and disease characteristics of all randomized patients with pMMR tumours are summarized in Table 7, and appeared balanced between the PEM + LEN and TPC arms.

The median age was 65 years (range = 30 years to 86 years). Patients had a baseline ECOG PS of either 0 (60.1%) or 1 (39.7%). One patient (0.3%) in the PEN+LEN arm had an ECOG PS of 3. A total of 431 patients (61.8%) were White and 154 patients (21.4%) were Asian. A total of 19.2% patients had endometrioid carcinoma, while 41.6% of patients reported a history of prior pelvic radiation (refer to Table 7).

Details about prior therapies for endometrial cancer were reported for the pMMR population. Treatment with 1 previous platinum-based therapy was reported for 77.7% of the patients in the PEM + LEN group and for 73.2% of those in the chemotherapy group. Treatment with 2 prior platinum-based therapies (including neoadjuvant or adjuvant therapies) was reported in 21.7% patients in the PEM + LEN arm and in 26.8% of patients in the TPC arm; 1 patient (0.3%) in the PEM + LEN arm had received 3 or more platinum-based therapies. It was reported that 56.9% of patients in the PEM + LEN arm and 62.4% of patients in the TPC arm had previously received systemic treatment as neoadjuvant or adjuvant therapy: 36.1% of patients in the PEM + LEN arm and 37.9% of patients in the TPC arm had previously received only neoadjuvant or adjuvant therapy; 8.7% and 10.0% had received palliative hormonal therapy previously, respectively; and 44.8% and 45.3% had received external beam radiotherapy previously, respectively. History of hysterectomy was reported in 72.8% patients in the PEM + LEN arm and 79.5% of patients in the TPC arm. (Refer to Table 7 in this section and Table 29 in Appendix 3.)

Table 7: Participant Characteristics in Patients With pMMR Tumours (ITT Population)

ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology and Obstetrics; ITT = intention to treat; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; TPC = treatment of physician’s choice (doxorubicin or paclitaxel).

^aRegion 1 = Europe, US, Canada, Australia, New Zealand, Israel; region 2 = rest of world.

^bIncludes reported locations of colon, abdominal cavity, omentum, small intestine, peritoneal cavity, and peritoneum. Does not include lymph nodes or other organs.

^cLesion location as determined by investigator review.

Source: Clinical Study Report.¹⁹

Interventions

The study intervention(s) and comparators are detailed in Table 28 in Appendix 3.

Intervention and comparators: Patients received treatment with either PEM + LEN (N = 342) or TPC (N = 325) (doxorubicin [N = 239] or paclitaxel [N = 86]). Patients in the PEM + LEN arm received IV infusion of PEM 200 mg over 30 minutes every 3 weeks for up to 35 cycles or a total duration of 24 months in combination with 20 mg of LEN once daily, orally. Patients in the TPC arm received either doxorubicin (N = 239) (60 mg/m² by IV every 3 weeks) or paclitaxel (N = 86) (80 mg/m² by IV once a week). Paclitaxel was administered in 28-day cycles (i.e., with weekly administration, 3 weeks on and 1 week off).

Treatment cycles were counted continuously regardless of dose interruptions or missed doses for both treatment arms.

Patients continued to receive the study treatment until disease progression, development of unacceptable toxicity, withdrawal of consent, receipt of 35 administrations of PEM (approximately 2 years), or a cumulative dose of 500 mg/m² of doxorubicin. Discontinuation of PEM treatment was considered for patients who had attained a confirmed complete response (CR), been treated with PEM for at least 8 cycles (at least 24 weeks), and had at least 2 treatments with PEM beyond the date when the initial CR was declared. Patients who stopped the study treatment after receiving 35 administrations of PEM for reasons other than disease progression or intolerability, or who attained a CR and stopped PEM, may be eligible for up to an additional year of treatment with PEM (17 cycles), with or without LEN, upon experiencing disease progression (i.e., second course phase).¹⁹ In the presence of clinical benefit, patients who completed 35 cycles of treatment with PEM (approximately 2 years) could continue on LEN alone beyond this time point.

Patients were permitted to continue the study treatment beyond disease progression if the maximum dosage of the study drugs had not been reached (e.g., 35 administrations of PEM or a cumulative dose of 500 mg/m² of doxorubicin), as long as the treating investigator considered that the participant could experience a clinical benefit from continued treatment and was tolerating the treatment.

Patients who completed PEM continued to receive LEN until disease progression, development of unacceptable toxicity, or withdrawal of consent. Following the demonstration of a survival benefit in the interim analysis, eligible patients in the TPC group who experienced disease progression were allowed to cross over to receive LEN + PEM. PEM dose reductions were not permitted for the management of toxicities of individual patients. However, doses of PEM were allowed to be interrupted, delayed, or discontinued, depending on how well the patient tolerated the treatment.

Lenvatinib

The starting dose of LEN was 20 mg/day for patients enrolled. Dose reductions of LEN occurred in succession based on the previous dose level (14 mg/day, 10 mg/day, and 8 mg/day).

LEN dose reduction and interruption were allowed for patients experiencing toxicity related to PEM + LEN combination therapy. The dose reduction on LEN is presented in Table 13 and Table 39 in Appendix 3. A total of 229 patients (67.0%) treated with PEM + LEN experienced a dose reduction of LEN, and 42 patients (12.9%) treated with TPC (doxorubicin or paclitaxel) experienced a dose reduction (refer to Table 39).

Information about dose interruption and/or delay in pMMR is presented in Table 13 in this section and Table 38 in Appendix 3. A total of 235 patients (68.7%) in the PEM + LEN group and 91 patients (28%) in the TPC group experienced a dose interruption. In the PEM + LEN group, a total of 100 patients (29.2%), 199 patients (58.2%), and 165 patients (48.2%) experienced PEM + LEN, LEN, and PEM dose interruptions, respectively (Table 13).

Information about the administration of PEM, LEN, doxorubicin, and paclitaxel is summarized in Table 41 in Appendix 3.

Concomitant Treatments

Patients were prohibited from receiving the following therapies during the screening and treatment phases of the study: concurrent anticancer therapies (e.g., chemotherapy), targeted therapies (e.g., tyrosine kinase inhibitors), hormonal therapy directed at endometrial carcinoma, radiotherapy (with the exception of palliative radiotherapy, as specified), antitumour interventions (e.g., surgical resection, surgical debulking of tumour), or cancer immunotherapy. Patients were permitted to use the following concomitant medications: hormone replacement therapy; thyroid hormone suppressive therapy; adjuvant hormonal therapy for history of definitely treated breast cancer; anticoagulants, including low molecular weight heparin, warfarin, and anti-Xa drugs; anti-inflammatory drugs; bisphosphonates or denosumab; antihypertensive therapies (including additional antihypertensive treatment as appropriate if blood pressure increased once the participant was enrolled); palliative radiotherapy for up to 2 painful, pre-existing, non-target bone metastases. The details of the potential relevant concomitant medications used in the study are presented in Table 30.

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Subsequent Cancer Therapy During the Trial

Of the 346 patients in the PEM + LEN arm, 109 patients (31.5%) received any subsequent systemic anticancer therapy. Of the 351 patients in the TPC arm, 176 patients (50.1%) received subsequent therapy (Table 31). The most common form of subsequent anticancer therapy was chemotherapy, which was received by 92 patients (26.6%) in the PEM + LEN group and 119 patients (33.9%) in the TPC group; 4 patients (1.2%) in the PEM + LEN group and 42 patients (12.0%) in the TPC group received any subsequent PD-1 or PD-L1 inhibitors. Twenty-four patients (6.9%) in the PEM + LEN group and 51 patients (14.5%) in the TPC group received hormonal therapy.

A total of 6 patients (1.7%) in the PEM + LEN group and 11 patients (3.1%) in the TPC group received 1 line of subsequent systemic therapy; 81 patients (23.4%) in the PEM + LEN group and 134 patients (38.2%) in the TPC group received 2 lines of subsequent systemic therapy; 55 patients (15.9%) in the PEM + LEN group and 78 patients (22.0%) in the TPC group received 3 or more subsequent lines of systemic therapy (Table 31).

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 8. These end points are further summarized in this section. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

The primary outcomes of the KEYNOTE-775 trial were OS and PFS. OS was defined as the time from the date of randomization to the date of death from any cause. PFS was defined as the time from the date of randomization to the date of the first documentation of disease progression, or death from any cause (whichever occurred first). The secondary outcome was ORR, defined as the proportion of patients who achieved either CR or partial response.

DOR was an exploratory outcome. It was defined as the time from the date a response was first documented until the date of the first documentation of disease progression or date of death, whichever occurred first.

Patient-reported and HRQoL outcomes included the EORTC QLQ-C30 GHS scale, the EORTC QLQ-C30 Physical Functioning scale, the EORTC QLQ-EN24 Urological Symptoms Score, and the EQ-5D-5L VAS score (refer to Table 8).

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

BICR = blinded independent central review; DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS: EQ visual analogue scale; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Endometrial Cancer Module; EQ-5D VAS = EQ-5D Visual Analogue Scale; HRQoL = health-related quality of life; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours version 1.1.

Statistical Analysis

Analysis strategies are summarized in Table 32 in Appendix 3.

Primary Outcomes: PFS and OS

Power Calculation

Note that the sample size and power calculations were based on the pMMR population.

With approximately 368, 463, and 526 OS events in the pMMR population at the planned IA1 (at 27 months follow-up), IA2 (at 35 months’ follow-up), and final OS analysis (at 43 months’ follow-up), respectively, the study would have 90% power to detect an HR of 0.75 at the 1-sided 0.0245 significance level.

The study was designed to have 90% power to detect a statistically significant difference in OS at a 1-sided alpha equal to 0.0245. As a result, the study had at least 99% power to detect a statistically significant difference in PFS at a 1-sided alpha equal to 0.0005. Assuming an accrual period of 19 months and a follow-up period of 24 months, a total of 660 patients were required to observe 526 death events by 43 months after the first participant was randomized (i.e., 19 months’ enrolment plus 24 months’ follow-up).

For OS, a total of 526 OS events were required to detect a statistically significant difference at a 0.0245 level with 90% power, assuming that the HR was 0.75 (median OS = 16.4 months in the PEM + LEN arm and 12.3 months in the TPC arm); the IA1 was performed when approximately 368 OS events were observed (i.e., 70% of the total target death events); the IA2 analysis was planned when approximately 463 OS events were observed (i.e., 88% of the total target death events); and the Lan-DeMets spending function with O’Brien-Fleming boundary was used.

The final PFS analysis was planned to be performed at the time of IA1, 27 months after the first participant was randomized. A total of 564 PFS events were estimated to be observed to detect a statistically significant difference at a 0.0005 level with greater than 99% power under the assumption that the HR was 0.55 (median PFS was 7.3 months in the PEM + LEN arm and 4 months in the TPC arm).

It was indicated that the success criteria for the study hypotheses of PFS, OS, and ORR were all met at IA1; consequently, the IA2 was not required.^17,18

Statistical Test or Model

Median PFS and OS for each treatment arm were estimated and plotted using the Kaplan-Meier product-limit method (refer to Table 9). The primary hypotheses were evaluated by comparing PFS and OS using a stratified log-rank test. The HRs were estimated using a stratified Cox regression model. Event rates over time were estimated within each treatment group using the Kaplan-Meier method. The HRs for PFS and OS were assessed based on the Cox regression model with the Efron method of tie handling with treatment as a covariate stratified by ECOG PS, geographic region, and prior history of pelvic radiation in the pMMR population (refer to Table 9).

Subgroup Analyses

The influences of baseline demographics and disease characteristics on the treatment effect among all randomized patients were examined by OS and PFS HRs (along with the 95% Cis). The key subgroups included ECOG PS (0 or 1), histology (endometrioid or non-endometrioid), and the number of lines of prior systemic anticancer therapy (1, 2, and ≥ 3). Only those subgroups identified in the CADTH review protocol are reported in the Efficacy section.

Sensitivity Analyses

Two sensitivity analyses with different sets of censoring rules for PFS were performed. The first sensitivity analysis follows the ITT principle. That is, progressive disease and deaths were counted as events regardless of missed study visits or initiation of new anticancer therapies The second sensitivity analysis considered the initiation of new anticancer treatment or the discontinuation of treatment due to reasons other than CR. If a participant met multiple criteria for censoring, the censoring criterion that occurred earliest was applied (Table 9).

Table 9: Statistical Analysis of Efficacy End Points in the KEYNOTE-775 Trial (pMMR)

ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; MMR = mismatch repair; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; pMMR = mismatch repair proficient.

Source: Clinical Study Report.¹⁹

Secondary Outcomes: ORR and HRQoL

The stratified Miettinen and Nurminen method was used to compare ORR between 2 treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen and Nurminen method with strata weighting by sample size was reported. The stratification factors used for randomization were applied to the analysis. The point estimate of ORR was provided by treatment group, together with 95% CI, using the exact binomial method proposed by Clopper and Pearson.⁵⁹ Cis were not adjusted for multiplicity.

In addition, the EORTC QLQ-C30 GHS was used as a secondary outcome. The HRQoL analyses were based on the HRQoL and patient-reported outcome (PRO) full analysis set (FAS) population. The FAS was defined as all randomized patients who had at least 1 HRQoL assessment available for the specific end point and had received at least 1 dose of the study intervention. Patients were analyzed in the treatment group to which they were randomized. The Clinical Study Report did not report on how the missing data were handled (i.e., last observation carried forward, multiple imputation, or other).

Multiplicity

The total family-wise error rate (type I error) among the dual-primary PFS and OS and the secondary ORR end points was controlled at a 1-sided 0.025 level. A type I error rate of 0.0005 was initially allocated to test PFS, and a type I error rate of 0.0245 was initially allocated to test OS between 2 treatment arms in patients with pMMR tumours. Details about the alpha allocation strategy among the hypotheses for PFS, OS, and ORR are provided in Figure 6, Appendix 3. The secondary outcome, EORTC QLQ-C30 GHS, was not controlled for multiplicity.

Other Exploratory Outcomes

Patient-reported and HRQoL outcomes, including the EORTC QLQ-C30 Physical Functioning scale, the EORTC QLQ-EN24 Urological Symptoms Score, and the EQ-5D-5L VAS score, were assessed using a constrained longitudinal data analysis (cLDA) model, with PRO scores as the response variable with covariates for treatment by study visit interaction, MMR status, ECOG PS, geographic region, and prior history of pelvic radiation. The mean scores and mean changes from baseline to week 12 for these exploratory outcomes were summarized by treatment arm at the week 12 assessment.

Safety Outcomes

Only descriptive statistics of safety were presented.

Analysis Populations

The efficacy populations in the KEYNOTE-775 trial for the analysis of the primary outcomes of OS and PFS and the secondary outcome of DOR were the ITT populations (i.e., all randomized patients; refer to Table 10). The DOR was assessed based on the number of responders. The HRQoL analyses were based on the HRQoL PRO FAS population, defined as all randomized patients with at least 1 HRQoL assessment available for the specific end point who received at least 1 dose of the study intervention. Patients were analyzed in the treatment groups to which they were randomized. The safety analysis was assessed based on all patients as treated.

Results

Patient Disposition

Patient disposition in the KEYNOTE-775 study (for the pMMR population) is presented in Table 10. Of the 1,178 patients with pMMR tumours screened, a total of 697 were randomized to receive PEM + LEN (n = 346) or TPC placebo (n = 351). Of the 697 randomized patients, 4 (1.2%) in the PEM + LEN arm and 26 (7.4%) in the TPC arm did not receive their assigned treatment. No reason was provided for this¹⁹ (Table 10).

At the time of the data cut-off date of October 26, 2020, a total of 485 patients (72.7%) discontinued treatment (n = 247 [72.2%] in the PEM + LEN arm and n = 238 [73.2%] in the TPC arm). The main reasons for discontinuation of treatment were disease progression (N = 156 [45.6%] in the PEM + LEN arm versus N = 144 [44.3%] in TPC arm); AEs (N = 56 [16.4%] in the PEM + LEN arm versus N = 29 [8.9%] in the TPC arm); withdrawal by patient (N = 17 [5.0%] in the PEM + LEN arm versus N = 23 [7.1%] in the TPC arm), clinical progression (N = 13 [3.8%] in the PEM + LEN arm versus N = 19 [5.8%] in the TPC arm); physician decision (N = 3 [0.9%] in the PEM + LEN arm versus N = 17 [5.2%] in the TPC arm); and CR (N = 2 [0.6%] in the PEM + LEN arm versus N = 3 [0.9%] in the TPC arm). A total of 95 patients (27.8%) in the PEM + LEN arm and 9 patients (2.8%) in the TPC arm were still receiving the treatment at the time of data cut-off.

The efficacy population (i.e., ITT population) included 697 patients, while the safety population included 668 patients.

Table 10: Disposition of Patients With pMMR Tumours (ITT Population)

APaT = all patients as treated; ITT = intention to treat; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; NR = not reported; pMMR = mismatch repair proficient; PP = per protocol; TPC = treatment of physician’s choice (doxorubicin or paclitaxel).

Notes: If the overall count of patients is calculated and displayed in a cell in the first row, then it is used as the denominator for the percentage calculation. Otherwise, the numbers of patients in population is used as the denominator for the percentage calculation.

For PEM + LEN, completion of study medication means 35 infusions of pembrolizumab. For TPC of doxorubicin, it indicates having received a lifetime maximum cumulative dose of doxorubicin. For TPC of paclitaxel, it indicates that per the investigator, a maximum tolerable dose was reached.

Source: Clinical Study Report.¹⁹

Exposure to Study Treatments

Information about drug exposures for the pMMR population is presented in Table 36.

The median duration on treatment was longer in the PEM + LEN arm than in the TPC arm. As of the data cut-off date, the median treatment durations were 7.22 months (range = < 0.03 to 26.9, reported as 219.5 days; range = 1 day to 817 days in the Clinical Study Report) and 3.49 months (range = < 0.03 to 25.8, reported as 106.0 days; range = 1 day to 785 days in the Clinical Study Report) in the PEM + LEN arm and TPC arm, respectively (refer to Table 36).

The median follow-up durations for pMMR were 12.2 months (range = 0.3 to 26.9) in the PEM + LEN arm and 10.8 months (range = 0.3 to 26.3) in the TPC arm (refer to Table 43 in Appendix 3).

Efficacy

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

Overall Survival

At the preplanned IA1, a total of 368 death events (165 [47.7%] in the PEM + LEN arm and 203 [57.8%] in the TPC arm) had occurred. The median OS was longer in the PEM + LEN arm (17.4 months; 95% Cl, 14.2 to 19.9) than in the TPC arm (12.0 months; 95% Cl, 10.8 to 13.3). The HR for PEM + LEN versus TPC was 0.68 (95% CI, 0.56 to 0.84; P < 0.0001) (Figure 3 and Table 11).

Figure 3: Kaplan-Meier Estimates of Overall Survival in Patients With pMMR Tumours (ITT Population)

ITT = intention to treat; OS = overall survival; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient.

Source: Clinical Study Report.¹⁹

Table 11: Key Outcomes for the KEYNOTE-775 Trial

CI = confidence interval; cLDA = constrained longitudinal data analysis; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 GHS = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Global Health Status; FAS = full analysis set; ITT = intention to treat; HR = hazard ratio; LSM = least squares mean; ORR = objective response rate; OS = overall survival; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; PFS = progression-free survival; PRO = patient-reported outcome; SD = standard deviation; TPC = treatment of physician’s choice; vs. = versus.

^aFrom the 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 ECOG Performance Status, geographic region, and prior history of pelvic radiation.

^cOne-sided P value based on log-rank test stratified by ECOG Performance Status, geographic region, and prior history of pelvic radiation. The P value has been adjusted for multiple testing.

^dBased on a cLDA model with the PRO scores as the response variable with covariates for treatment by study visit interaction, MMR status, ECOG Performance Status, geographic region, and prior history of pelvic radiation. Note: For baseline and week 12, N is the number of patients in each treatment group with non-missing assessments at the specific time point; for change from baseline, N is the number of patients in the analysis population in each treatment group. The P value has not been adjusted for multiple testing.

^eBased on the Miettinen and Nurminen method stratified by ECOG Performance Status, geographic region, and prior history of pelvic radiation.

^fOne-sided P value for testing. H0 means the difference in percentage equals 0, whereas H1 means the difference in percentage is greater than 0. The P value has been adjusted for multiple testing.

^gFor DOR, “+” indicates there is no progressive disease by the time of the last disease assessment.

Source: Clinical Study Report.¹⁹

The OS rates at 12 months were 61.6% (95% Cl, 56.1% to 66.6%) in the PEM + LEN arm and 49.5% (95% Cl, 43.8% to 55.0%) in the TPC arm, respectively. The OS rates over the time are presented in Table 44 and Table 45. OS is summarized by Kaplan-Meier plot in Figure 3.

The sponsor indicated that the IA1 analysis for OS met the success criteria for the hypothesis of the primary efficacy end point of OS; i.e., the combination of LEN + PEM was superior to TPC with respect to OS in patients with pMMR tumours. Therefore, IA2 and a final analysis were not required.^17,18,60

OS Subgroup Analysis

Pre-specified subgroup analyses for OS are presented in Table 46 in Appendix 3.

For patients with an ECOG PS of 0 and an ECOG PS of 1, the HRs (PEM + LEN versus TPC) were 0.56 (95% CI, 0.42 to 0.75) and 0.87 (95% CI, 0.64 to 1.18), respectively. For patients with endometrioid cancer and non-endometrioid cancer, the HRs (PEM + LEN versus TPC) were 0.78 (95% CI, 0.57 to 1.05) and 0.56 (95% CI, 0.42 to 0.74), respectively. For patients with 1, 2, and greater than or equal to 3 prior lines of systemic therapy, the HRs (PEM + LEN versus TPC) were 0.61 (95% CI, 0.47 to 0.78), 0.88 (95% CI, 0.59 to 1.30), and 0.75 (95% CI, 0.24 to 2.37), respectively.

It should be noted that the prior lines of therapy (1, 2, and ≥ 3) used for the subgroup analysis in pMMR included prior lines of neoadjuvant and/or adjuvant systemic therapy (refer to Table 29).

OS Sensitivity Analysis

No sensitivity analysis for OS was done in this study.

Progression-Free Survival

At the preplanned IA1, a total of 485 events (247 [71.4%] in the PEM + LEN arm and 238 [67.8%] in the TPC arm) had occurred. The median PFS was longer in the PEM + LEN arm (6.6 months; 95% Cl, 5.6 to 7.4) than in the TPC arm (3.8 months; 95% Cl, 3.6 to 5.0). The HR for PEM + LEN versus TPC was 0.60 (95% Cl, 0.50 to 0.72; P < 0.0001) (Table 11 and Figure 4).

The PFS rates at 6 months were 53.5% (95% Cl, 48.4% to 58.3%) in the PEM + LEN arm and 34.4% (95% Cl, 29.2% to 39.4%) in the TPC arm, respectively. The PFS rates over time are presented in Table 47 and Table 48 in Appendix 3. PFS is summarized using a Kaplan-Meier plot in Figure 4.

Figure 4: Kaplan-Meier Estimates of Progression-Free Survival (Primary Censoring Rule) in Patients With pMMR Tumours (ITT Population)

ITT = intention to treat; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; PFS = progression-free survival; pMMR = mismatch repair proficient.

Source: Clinical Study Report.¹⁹

The sponsor indicated that the IA1 analysis for PFS met the success criteria for the hypothesis of the primary efficacy end point of PFS (i.e., the combination of LEN + PEM was superior to TPC with respect to PFS in both pMMR groups). Therefore, no IA2 or final analysis were required.^17,18,60

PFS Subgroup Analysis

Pre-specified subgroup analyses for PFS are presented in Table 49 in Appendix 3. The HRs (PEM + LEN versus TPC) for patients with an ECOG PS of 0 and an ECOG PS of 1 were 0.57 (95% CI, 0.45 to 0.72) and 0.65 (95% CI, 0.49 to 0.86), respectively. The HRs (PEM + LEN versus TPC) for patients with endometrioid cancer and those with non-endometrioid cancer were 0.59 (95% CI, 0.46 to 0.76) and 0.56 (95% CI, 0.43, 0.73), respectively. The HRs (PEM + LEN versus TPC) for patients with 1, 2, and greater than or equal to 3 prior lines of systemic therapy were 0.52 (95% CI, 0.42 to 0.65), 0.74 (95% CI, 0.53 to 1.04), and 0.60 (95% CI, 0.12 to 3.07), respectively.

PFS Sensitivity Analysis

Two sensitivity analyses with different sets of censoring rules were performed to assess PFS in the pMMR population to support the robustness of the primary analysis for PFS. The first sensitivity analysis followed the ITT principle: that is, disease progressions and deaths were counted as events regardless of missed study visits or initiation of new anticancer therapy. The second sensitivity analysis considered the initiation of new anticancer treatments or the discontinuation of treatment for reasons other than CR (whichever occurred later) to be a progressive disease event for patients without documented progressive disease or death. If a participant met multiple criteria for censoring, the censoring criterion that occurred earliest was applied (refer to Table 9).

Both sensitivity analyses for PFS showed results that were consistent with the PFS primary analysis in the pMMR primary analysis population (Table 50 and Table 51 in Appendix 3).

Health-Related Quality of Life

The findings of patient-reported and HRQoL outcomes (i.e., the EORTC QLQ-C30 GHS, the EORTC QLQ-C30 Physical Functioning scale, the EORTC QLQ-EN24 Urological Symptoms Score, and the EQ-5D VAS score) are presented in Table 12. Among patients completing the HRQoL measures, patients in both arms appeared to experience deterioration in HRQoL when assessed at week 12 (Table 12). No obvious between-group differences in change from baseline were observed. These findings suggest that there appeared to be no apparent between-group differences (for PEM + LEN versus TPC) observed in terms of HRQoL during the treatment period at week 12 (refer to Table 52, Table 53, Figure 8, Figure 9, Figure 10, and Figure 11 in Appendix 3).

No subgroup or sensitivity analysis was done for HRQoL outcomes.

Symptom Reduction

Symptom severity reduction was not assessed as a separate outcome in the KEYNOTE-775 trial. However, urological symptoms were assessed using the EORTC QLQ-EN24 Urological Symptoms Score (Table 12).

Objective Response Rate

At IA1, the KEYNOTE-775 trial met the success criteria for the hypothesis of the secondary efficacy end point on ORR; i.e., the combination of LEN + PEM was superior to TPC with respect to ORR in patients with pMMR tumours. The confirmed ORR was higher in the PEM + LEN arm compared to the TPC arm (30.3% versus 15.1%, respectively). The between-group difference in ORR (PEM + LEN versus TPC) was 15.2% (95% Cl, 9.1% to 21.4%; P < 0.0001) (refer to Table 54 in Appendix 3).

ORR subgroup analysis results are presented in Table 55 in Appendix 3. The between-group differences in ORR (PEM + LEN versus TPC) were 14.7% (95% CI, 6.5% to 22.7%) and 16.1% (95% CI, 6.7 to 25.6) for patients with an ECOG PS of 0 and an ECOG PS of 1, respectively. The between-group difference in ORR (PEM + LEN versus TPC) was 11.6% (95% CI, 3.1% to 20.1%) versus 19.9% (95% CI, 11.1 to 228.7) in patients with endometrioid cancer and patients with non-endometrioid cancer, respectively. The between-group differences in ORR (PEM + LEN versus TPC) were 17.9% (95% CI, 10.5% to 25.27%), 10.9% (95% CI, –0.7 to 22.8), and 1.8% (95% CI, 377.7 to 38.2) for patients with 1, 2, and greater than or equal to 3 lines of systemic therapy, respectively (Table 55).

No sensitivity analysis was done for ORR.

Duration of Response

The median DOR was 9.2 months (range = 1.6 to 23.7) in the PEM + LEN arm and 5.7 months (range = 0.0 to 24.2) in the TPC arm (Table 11, Table 56, and Figure 12 in Appendix 3).

No subgroup or sensitivity analysis was done for DOR.

Table 12: Analysis of Change From Baseline to Week 12 in EORTC QLQs and EQ-5D VAS (pMMR, FAS)

CFB = change from baseline; cLDA = constrained longitudinal data analysis; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 GHS = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Global Health Status; EORTC QLQ-EN24 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Endometrial Cancer Module; FAS = full analysis set; LS = least squares; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; PRO = patient-reported outcome; SD = standard deviation; TPC = treatment of physician’s choice; vs. = versus.

Note: For baseline and week 12, N is the number of patients in each treatment group with non-missing assessments at the specific time point; for change from baseline, N is the number of patients in the analysis population in each treatment group with at least 1 measurement.

^aBased on a cLDA model with PRO scores as the response variable with covariates for treatment by study visit interaction, MMR status, ECOG Performance Status, geographic region, and prior history of pelvic radiation.

Source: Clinical Study Report.¹⁹

Harms

Only those harms identified in the review protocol are reported. Refer to Table 13 for detailed harms data.

Adverse Events

A total of 99.7% of patients in both the PEM + LEN arm and TPC arm experienced at least 1 AE (Table 13).

The most common AEs (≥ 40% in either of arm) were hypertension (65.5% for PEM + LEN versus 5.2% for TPC), hypothyroidism (55.3% for PEM + LEN versus 0.9% for TPC), diarrhea (54.7% for PEM + LEN versus 19.7% for TPC), nausea (49.4% for PEM + LEN versus 47.4% for TPC), decreased appetite (4,428% for PEM + LEN versus 20.6% for TPC), and anemia (24.3% for PEM + LEN versus 48.9% for TPC) (refer to Table 57 in Appendix 3). The exposure-adjusted AE rates per 100 person-months are presented in Table 58 in Appendix 3.

Serious Adverse Events

A total of 49.7% of patients in PEM + LEN arm and 28.9% of patients in the TPC arm experienced an SAE (Table 13). The most common SAEs (≥ 2% in either of the arms) were hypertension (4.4% for PEM + LEN versus 0% for TPC), urinary tract infection (3.2% for PEM + LEN versus 0.6% for TPC), acute kidney injury (2.3% for PEM + LEN versus 0.9% for TPC), colitis (2.0% for PEM + LEN versus 0.3% for TPC), pyrexia (2.0% for PEM + LEN versus 0.9% for TPC), decreased appetite (2.0% for PEM + LEN versus 0% for TPC), febrile neutropenia (0.6% for PEM + LEN versus 4.0% for TPC), and neutropenia (0.3% for PEM + LEN versus 2.2% for TPC) (Table 59 in Appendix 3).

Mortality

At the time of the pre-specified IA1 a total of 4.7% of patients in the PEM + LEN arm and 4.6% of patients in the TPC arm had died due to AEs (refer to Table 13 in this section and Table 60 in Appendix 3). The most common AEs (i.e., affecting system organ classes) resulting in death were cardiac disorders (0.6% for PEM + LEN versus 0.9% for TPC), gastrointestinal disorders (1.2% for PEM + LEN versus 0% for TPC), general disorders and administration site conditions (0.9% for PEM + LEN versus 1.2% for TPC), and infections and infestations (0.6% for PEM + LEN versus 1.5% for TPC) (refer to Table 60 in Appendix 3).

Withdrawals Due to Adverse Events

All-cause AEs leading to study drug discontinuation occurred in 31.0% of patients in the PEM + LEN arm and in 8.3% of patients in the TPC arm (Table 13). Among patients in the PEN+LEN arm, 17.5%, 18.4%, and 12.6.0% discontinued PEM, LEN, or both due to AEs, respectively. Although 8.3% of patients in the TPC arm discontinued treatment due to AEs, no specific information was reported for the number of patients who discontinued from doxorubicin versus paclitaxel.

Notable Harms

Hyperthyroidism occurred in 10.8% of patients treated with PEM + LEN and in 1.2% patients treated with TPC. The following notable harms were reported in the study (Table 13): hypothyroidism (55.3% for PEM + LEN versus 0.9% for TPC), pneumonitis (1.2% for PEM + LEN versus 0.3% for TPC), colitis (5.3% for PEM + LEN versus 0.3% for TPC), adrenal insufficiency (0.9% for PEM + LEN versus 0% for TPC), hepatitis (1.8% for PEM + LEN versus 0% for TPC), hypophysitis (0.6% for PEM + LEN versus 0% for TPC), nephritis (0.6% for PEM + LEN versus 0% for TPC), type 1 diabetes mellitus (0.9% for PEM + LEN versus 0% for TPC), and hypertension (65.5 for PEM + LEN versus 5.2% for TPC).

Table 13: Summary of Harms in the KEYNOTE-775 Trial

AE = adverse event; DC = discontinuation; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TPC = treatment of physician’s choice (doxorubicin or paclitaxel); WDAE = withdrawal due to adverse event.

Note: Non-serious AEs were followed for up to 30 days after the last dose. SAEs were followed for up to 90 days after the last dose.

^aDefined as an action taken to reduce the dose or interrupt or withdraw the drug.

^bFor PEM + LEN, the dose interruption of either pembrolizumab or lenvatinib.

^cFor PEM + LEN, the dose reduction for only lenvatinib.

^dFor PEM + LEN, the discontinuation of either pembrolizumab or lenvatinib.

^eDeath due to AE.

Source: Clinical Study Report.¹⁹

Critical Appraisal

Internal Validity

The included pivotal study (KEYNOTE-775) was a relatively well-designed, prospective, multi-centre, open-label, randomized, parallel, active-controlled trial. The study used an appropriate randomization and allocation method (i.e., an interactive response technology system). It should be noted that the pMMR population was not considered a subgroup in the original study design. The sample size and power calculations were based on pMMR populations.¹⁹

Overall, most of the demographic and baseline characteristics were well balanced between arms (Table 7). The key prognostic factors, such as ECOG PS (0 or 1), histology of tumour type (e.g., endometrioid, non-endometrioid), and prior history of pelvic radiation, were well balanced between arms. Minor imbalances between the 2 study arms were observed in the proportion of patients with number of prior systemic therapies, type of prior therapy (such as neoadjuvant or adjuvant), and history of prior hysterectomy (Table 29 in Appendix 3). However, the clinical experts consulted for this review stated that these minor imbalances would have been unlikely to affect the comparative study results between the PEM + LEN and TPC groups.

A total of 4 patients (1.2%) in the PEM + LEN arm and 26 patients (7.4%) in the TPC arm did not receive their assigned treatment. The relatively small percentage of patients who did not received the treatment medication is unlikely to have had a significant impact on the comparative assessment of the efficacy of PFS and OS in the ITT analysis.

A total of 229 patients (67%) experienced a dose reduction of LEN in the PEM + LEN arm and a total of 42 patients (12.9%) experienced a dose reduction in the TPC group (either doxorubicin or paclitaxel) due to AEs (Table 13). The proposed dose regimen of LEN was 20 mg. The actual median dose of LEN was 13.8 mg, ranging from 3 mg to 20 mg in the pMMR population (Table 41); however, detailed dose reduction information was not reported for the pMMR population. The clinical experts consulted for this review indicated that the dose modifications (reductions or interruptions) of LEN, doxorubicin, or paclitaxel reflects clinical practice in Canada; therefore, it was not expected to have an impact on the comparative clinical efficacy of PEM + LEN versus the TPC.

Based on the study design, during the treatment phase, patients were prohibited from receiving concurrent anticancer therapies, such as chemotherapy or targeted therapies (e.g., tyrosine kinase inhibitors). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Based on the concomitant medication information reported, while the reasons for prohibiting these additional concomitant anticancer drugs were not clearly described in the Clinical Study Report, the clinical experts consulted for this review considered that the potential impact of this restriction on the comparative efficacy assessment (of PEM + LEN versus TPC) would be negligible because of the very small numbers of patients using them (e.g., carboplatin, cisplatin, doxorubicin, paclitaxel, LEN, and PEM).

KEYNOTE-775 was an open-label trial. As a result, the study investigators and patients were aware of their treatment status, which increases the risk of detection and performance biases that have the potential to influence outcome reporting. However, OS, PFS, ORR, and DOR are all objective response measurements. These were assessed using the Response Evaluation Criteria in Solid Tumours (version 1.1) through independent central radiologic review. The open-label design is less of a concern for objective responses such as OS, PFS, ORR, and DOR; however, it remains a concern for subjective end points, such as safety and HRQoL. The direction of anticipated bias related to these outcomes is unclear.

The primary outcomes were PFS and OS. PFS was defined as the time between the randomization date and the first date of disease progression (assessed by imaging) or death. Therefore, the efficacy measurement was objective and not likely biased by the subsequent systemic therapy. However, subsequent systemic anticancer treatment (e.g., chemotherapy or PD-1 or PD-L1 inhibitors) may contribute to patients’ OS benefit in both arms. The impact of a subsequent systemic anticancer treatment on comparative OS may introduce potential bias. However, more patients in the TPC group than in PEN + LEN group received subsequent systemic anticancer treatments (Table 31), which would make the between-group differences less pronounced; the direction of bias would likely go against PEM + LEN treatment. Furthermore, the reported OS results are considered final based on IA1, according to pre-specified stopping criteria. A limitation of this study is the relatively short duration of follow-up, which may mean that survival data (e.g., OS) are evolving. Therefore, whether more mature OS efficacy results would be consistent with the interim results is unknown.

EORTC QLQ-C30 GHS scores were assessed as a secondary outcome but not controlled for type I error. The other patient-reported and HRQoL outcomes (the EORTC QLQ-C30 Physical Functioning scale, EORTC QLQ-EN24 Urological Symptoms Score, and EQ-5D VAS score) were assessed as exploratory outcomes using a cLDA model. The cLDA model is most appropriate when data are missing at random or missing completely at random. It is expected to be biased when the missing data are not missing at random, which is likely the case with these data. There is a potential risk of bias because a large number of patients did not have complete measures (there are substantial missing data on these outcomes) as well as due to the open-label nature of the design. How the missing data were handled or imputed was not clearly described in the Clinical Study Report. As well, there may have been differential recall bias. Overall, the magnitude and direction of the impact of these missing data and recall bias on the patient-reported and HRQoL outcomes is unknown. No minimal important difference (MID) was identified for HRQoL measures in the population. Overall, the findings for HRQoL should be viewed as supportive evidence only.

In subgroups that were not part of the randomization scheme, imbalances in characteristics may bias the results observed between the groups.

Symptom reduction was identified an outcome in the CADTH review protocol. Symptom severity was not assessed as a separate outcome in KEYNOTE-775. However, the severity of urological symptoms was assessed using the EORTC QLQ-EN24 Urological Symptoms Score (Table 12).

DOR was assessed as an exploratory outcome. No formal statistical analysis was performed.

Finally, the primary analyses of PFS, OS, and ORR were based on the ITT analysis. In the pMMR population, important protocol deviations were reported for 17 patients: 9 patients (2.7%) in the LEN + PEM arm and 8 patients (2.3%) in the TPC arm. There was no protocol deviation information reported for the pMMR population. No per-protocol analysis was conducted to assess whether the per-protocol analysis was consistent with the ITT analysis. Therefore, it is unknown if the protocol deviation may have had an impact on the findings. However, given that the number of patients with important deviations was relatively low and balanced across both groups, its impact on the comparative efficacy findings (PEM + LEN versus TPC) are expected to be negligible.

External Validity

This study was a multinational, multi-centre trial, with 67 sites in 21 countries. A total of 58 patients living in Canada participated at 11 sites across Canada. According to the clinical experts consulted for this review, the KEYNOTE-775 trial population (i.e., adult patients with advanced pMMR endometrial carcinoma who have disease progression following prior platinum-based systemic therapy in any setting and are not candidates for curative surgery or radiation) is considered reflective of the requested target population. There is no concern about the generalization of findings from the pivotal study to Canadian clinical settings.

The following considerations are of importance regarding the external validity of KEYNOTE-775 trial.

It is uncertain whether the findings can be generalized to patients with an ECOG PS of 2 or greater because no such patients were included in the study. The clinical experts believe that the PEM + LEN combination treatment could be extended to patients with an ECOG PS of 2 who are appropriately informed and motivated. These drugs should likely not be used in patients with an ECOG PS of 3 or 4.

Patients with carcinosarcoma were excluded from the trial. The clinical experts indicated that the evidence to date is in carcinomas; as a result, they are not aware of benefit in pure sarcomas. However, given that carcinosarcomas are a combination, theoretically, PEM + LEN combination therapy could be extended to patients with carcinosarcomas. Nevertheless, it was a reasonable exclusion criterion in the clinical trial, and there is no supporting research evidence at the moment.

The Health Canada–recommended dose of LEN in the PEM + LEN combination treatment is 20 mg orally once daily until unacceptable toxicity or disease progression. However, the median dosage of LEN reported in the trial was 13.8 mg (range = 3 mg to 20 mg). The clinical experts consulted for this review indicated that dose modification is very common in clinical practice. Therefore, there is no concern about the dose reduction of LEN in the routine clinical setting. In the TPC group, 239 patients out of 351 patients (68.1%) received doxorubicin, and 86 patients (24.51%) patients received paclitaxel (Table 35). The clinical experts indicated that the choice would vary based on clinicians’ preference. It is likely irrelevant to the efficacy assessment because there does not seem to be scientific evidence about efficacy differences between doxorubicin and paclitaxel. The clinical experts indicated that the dose of paclitaxel used in the trial is aligned with the clinical standard dosage for this treatment; that is, 60 mg or 80 mg administered through IV once a week, with a cycle of 3 weeks on and 1 week off.

In the KEYNOTE-775 trial, the only dosage of PEM was 200 mg every 3 weeks. The clinical experts indicated that clinically, physicians and patients may prefer dosing 400 mg every 6 weeks. Either dose can be continued in combination with LEN for up to 24 months (i.e., 18 doses of 400 mg or 35 doses of 200 mg) or until unacceptable toxicity disease progression, whichever is longer.

Indirect Evidence

No ITC was identified in this review.

Other Relevant Evidence

This section includes an additional relevant study, KEYNOTE-146,⁶¹ that was included in the sponsor’s submission to CADTH and was considered to provide additional longer-term evidence for this review.

KEYNOTE-146^61,62 is an ongoing, multinational, open-label, single-arm, phase Ib and II study of PEM + LEN in patients with selected solid tumours, including endometrial carcinomas. This section focuses on only the cohort of patients with advanced non-MSI-H or pMMR endometrial cancer.

Table 14: Details of the KEYNOTE-146 Trial

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; DOR = duration of response; irRECIST = immune-related Response Evaluation Criteria in Solid Tumours; MSI-H = microsatellite instability-high; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; PD-L2 = programmed cell death ligand 2; PEM = pembrolizumab; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient.

Note: The sponsor provided an updated analysis for pMMR (cut-off date = August 18, 2020; median follow-up duration = 35.8 months; 95% CI, 31.2 to 41.2). The sponsor indicated that the findings of the updated analysis were largely aligned with those reported in the analysis on January 10, 2019. (Refer to Appendix 5.)

^aThe extracted information focused on patients with endometrial cancer with pMMR or non-MSI-H status in the KEYNOTE-146 trial only where available. Overall, KEYNOTE-146 included 283 patients. Among the 283 patients, 159 patients had non-endometrial carcinoma. A total of 124 patients had endometrial carcinoma. Among the 124 patients with endometrial carcinoma, 16 patients had no prior anticancer treatment; therefore, they did not meet the inclusion criteria for this review. One hundred and eight patients were previously treated with at least 1 systemic anticancer therapy. Among the 108 patients, 94 were non-MSI-H or pMMR, 11 were MSI-H or dMMR, and 3 had unknown MSI and/or MMR status. Therefore, in this report, only information about patients with non-MSI-H or pMMR tumours (N = 94) was extracted, unless otherwise specified. That is, the KEYNOTE-146 trial indicates the endometrial patients with pMMR/non-MSI-H status (N = 94) included unless otherwise specified. Patients with pMMR endometrial cancer are those with histologically confirmed endometrial carcinoma who were previously treated with at least 1 systemic anticancer therapy and had sufficient follow-up to provide a median follow-up of at least 12 months. In addition, for all responders, there was an opportunity for follow-up after initial objective response (as assessed by the investigator) of at least 6 months.

^bPatients with endometrial cancer were enrolled across 20 sites, including 15 sites in the US (N = 101 patients) and 5 sites in Spain (N = 23 patients).⁶¹

^cOverall inclusion and exclusion criteria for all cohorts. No inclusion or exclusion criteria specifically for patients with pMMR endometrial carcinoma were provided in the Clinical Study Report.

Source: Clinical Study Report.⁶¹

Methods

Inclusion and exclusion criteria for the KEYNOTE-146 trial are summarized in Table 14.

Briefly, patients were deemed eligible if they met the following criteria: greater than or equal to 18 years old; histologically and/or cytologically confirmed, advanced pMMR endometrial carcinoma, with up to 2 prior lines of systemic therapy (unless discussed with the sponsor). Patients must have had progressive disease after previous treatment. They also had to have measurable disease (at least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node), an ECOG PS of 0 or 1, and life expectancy of greater than or equal to 12 weeks.

Eligible patients (N = 94) were included to receive PEM + LEN combination treatment, consisting of PEM 200 mg IV once every 3 weeks (to a maximum of 35 PEM treatments) and LEN 20 mg once daily orally.

The primary efficacy measure was ORR at week 24. Key secondary measures were ORR at the data cut-off date, DOR, PFS, and OS.

Populations

Detailed patient baseline disease and demographic characteristics for the KEYNOTE-146 trial are summarized in Table 15 and Table 16. The median age was 66.0 years (range = 40 years to 80 years). Patients had a baseline ECOG PS of either 0 (52.1%) or 1 (47.9%). A total of 81 patients (86.2%) were White; 6 patients (6.4%) were Black or African American. All patients (N = 94, 100%) had received a prior platinum therapy regimen. A total of 48 patients (51.1%) had received 1 line of prior therapy; 36 patients (38.32%) had received 2 lines of prior therapies. Ten patients (10.6%) had received 3 or more lines of prior therapies. The most common histologic subtypes of disease were endometrioid adenocarcinoma (N = 46, 48.9%) and serous adenocarcinoma (N = 33, 35.1%).

Table 15: Participant Characteristics in Patients With pMMR Tumours (FAS Population, KEYNOTE-146 Trial)

ECOG PS = Eastern Cooperative Oncology Group Performance Status; FAS = full analysis set; FIGO = International Federation of Gynecology and Obstetrics; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient.

Source: Clinical Study Report.⁶¹

Table 16: Prior Medications and Therapeutic Setting Treatment (pMMR, KEYNOTE-146 Trial)

PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient.

^aPatients may be counted in multiple categories.

Source: Clinical Study Report.⁶¹

Interventions

Patients received PEM + LEN combination therapy, consisting of LEN 20 mg once daily orally and PEM 200 mg IV once every 3 weeks in 3-week cycles (to a maximum of 35 PEM treatments).

PEM dose reductions were not permitted, per protocol; PEM dose interruptions due to TEAEs were allowed.

LEN reductions and/or interruptions due to TEAEs were allowed.

Concomitant Medications

One patient (1.1%) received antineoplastic and immunomodulating drugs (i.e., methotrexate). A total of 28 patients (29.8%) received corticosteroids for systemic use (Table 61, Appendix 3).

Subsequent Cancer Therapy

Subsequent anticancer treatments were recorded during the follow-up phase.⁶¹

Outcomes

The primary efficacy measure was ORR at week 24. Key secondary measures were ORR at the data cut-off date (January 10, 2019), PFS, OS, and DOR.

Statistical Analysis

There was no statistical analysis information for the non-MSI-H or pMMR cohort.

The efficacy analysis was based on the FAS and included all patients who entered the study treatment period. The safety outcomes analysis included all patients who received any PEM + LEN treatment (i.e., PEM 200 mg plus LEN 20 mg).

Power Calculation

No power calculation was performed. It was indicated that the initial size of the cohort with endometrial cancer could be expanded to approximately 120 evaluable patients. Expansion decisions were based on the results of 2 separate interim analyses that were to occur when 21 patients and 60 patients, respectively, had sufficient follow-up to be evaluated for response. At the first analysis, if there were more than 3 responses, then approximately 40 additional patients could be enrolled. If there were more than 12 responses at the second analysis, then approximately 60 additional patients could be enrolled.

Primary Outcome: ORR at Week 24

The rate (%) and 95% CI for ORR were presented.

Secondary Outcomes: ORR at the Cut-Off Date, DOR, PFS, and OS

The median (95% CI) PFS and OS were estimated. The median (95% CI) DOR was plotted using the Kaplan-Meier method. Event rates over time were also estimated.

Subgroup and Sensitivity Analyses

A subgroup analysis was conducted for ORR. The subgroup analysis of interest defined in the review protocol was based on histologic subtype. No subgroup analyses were conducted for OS and PFS.

No sensitivity analyses were conducted for any outcomes.

Patient Disposition

A total of 94 patients started the PEM + LEN combination therapy. Among them, 47 were still ongoing. Forty-seven patients (50%) discontinued from the trial. The main reason for discontinuation was death (N = 44, 46.8%). (Refer to Table 17.)

Table 17: Disposition of Patients With pMMR Tumours (FAS, KEYNOTE-146 Trial)

FAS = full analysis set; ITT = intention to treat; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; PP = per protocol.

Note: The FAS was the same as the ITT analysis set in this study. It included all patients who entered the study treatment period. The efficacy analyses were based primarily on the full analysis set.

Source: Clinical Study Report.⁶¹

Exposure to Study Treatments

At the data cut-off date (January 10, 2019), the median duration of treatment with PEM + LEN was 7.38 months (range = 0.03 months to 37.78 months) in the non-MSI-H or pMMR cohort (N = 94). The overall treatment duration was defined as the duration between the earliest first-dose start date of either medication and the latest end date of either medication. The duration of the treatment was 12 months or longer in 16 patients (17%), 18 months or longer in 8 patients (8.7%), and 24 months or longer in 5 patients (5.3%). A total of 65 patients (69.1%) experienced a LEN dose reduction. A total of 67 patients (71.3%) experienced a LEN dose interruption. The median number of PEM doses in the pMMR cohort was 9.5 cycles (range = 1 cycle to 35 cycles).

Overall, the median follow-up time for OS was 18.7 months (95% CI, 14.1 months to 20.9 months).

Efficacy

Overall Survival

The results for OS are summarized in Table 18 and Figure 5. There were 44 deaths (46.8%), and the median OS was 16.4 months (95% CI, 13.5 to 25.9). The survival probabilities of patients at 12 months, 18 months, and 24 months were 69.5% (95% CI, 58.6 to 78.1%), 43.8% (95% CI, 31.2, 55.7%), and 39.2% (95% CI, 26.7 to 51.5%), respectively.

Table 18: Summary of Overall Survival in the pMMR Population (FAS, KEYNOTE-146 Trial)

CI = confidence interval; FAS = full analysis set; OS = overall survival; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient.

^aThe median was estimated using Kaplan-Meier methodology; 95% CIs were constructed with a generalized Brookmeyer and Crowley method.

^bPoint estimates for OS were based on Kaplan-Meier methodology; 95% CIs were based on the Greenwood formula using log-log transformation.

Source: Clinical Study Report.⁶¹

Figure 5: Kaplan-Meier Plot of OS (pMMR, KEYNOTE-146 Trial, FAS)

CI = confidence interval; MSI-H = microsatellite instability-high; pMMR = mismatch repair proficient.

Note: The median was estimated using the Kaplan-Meier method; the 95% CI was constructed with a generalized Brookmeyer and Crowley method.

Source: Clinical Study Report.⁶¹

Progression-Free Survival

The results for PFS per independent imaging review (IIR) are summarized in Table 19 and Figure 6. At the data cut-off date, 58 patients (61.7%) had experienced a PFS event. The median PFS was 5.4 months (95% CI, 4.4 months to 7.6 months). PFS rates at 6 months, 12 months, and 18 months were 49.4%, 33.2%, and 33.2.0%, respectively.

Table 19: Summary of Progression-Free Survival by IIR in pMMR (FAS, KEYNOTE-146 Trial)

CI = confidence interval; FAS = full analysis set; IIR = independent imaging review; mTOR = mammalian target of rapamycin; NR = not reported; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; PFS = progression-free survival; PK = protein kinase; pMMR = mismatch repair proficient.

^aThe new anticancer treatments initiated before progressive disease by IIR were doxorubicin, carboplatin, temsirolimus, gemcitabine, leuprorelin, pembrolizumab, LY3023414 (mTOR and DNA-PK inhibitor), letrozole, and paclitaxel-bevacizumab.

^bThe median was estimated using Kaplan-Meier methodology; 95% CIs were constructed with a generalized Brookmeyer and Crowley method.

^cPoint estimates were based on Kaplan-Meier methodology; 95% CIs were based on the Greenwood formula using log-log transformation.

Source: Clinical Study Report.⁶¹

Figure 6: Kaplan-Meier Plot of PFS (pMMR, KEYNOTE-146 Trial, FAS)

CI = confidence interval; FAS = full analysis set; MSI-H = microsatellite instability-high; pMMR = mismatch repair proficient.

Note: The median was estimated using the Kaplan-Meier method, and the 95% CI was constructed with a generalized Brookmeyer and Crowley method. All tumour assessments were considered as long as patients did not start a new anticancer therapy.

Source: Clinical Study Report.⁶¹

Health-Related Quality of Life

HRQoL was not reported.

Symptom Reduction

Symptom reduction was not reported.

Objective Response Rate

At week 24 (the primary outcome), 37 patients (39.4%; 95% CI, 29.4% to 50.0%) had achieved the ORR.

The results for ORR (per IIR) as of the data cut-off date are presented in Table 20. Among patients who had been enrolled for at least 26 weeks before the data cut-off date, 36 patients out of 94 patients achieved an objective response, resulting in an ORR of 38.3% (95% CI, 28.5 to 48.9). Ten patients (10.6%) achieved CR, and 26 patients (27.7%) achieved a partial response.

The subgroup analysis showed that the ORRs were 26.1% (95% CI, 14.3% to 41.1%), 50.0% (95% CI, 35.2% to 64.8%), 42.4% (95% CI, 25.5% to 60.8%), and 80.0% (95% CI, 28.4 to 99.5) in patients with endometrioid adenocarcinoma, non-endometrioid adenocarcinoma, serous adenocarcinoma, and clear-cell adenocarcinoma, respectively (Table 21).

Duration of Response

The results for DOR are presented in Table 22 and Figure 13 in Appendix 3.

Among responders (N = 36), 21 patients (58.3%) were censored, primarily due to lack of progression and no death at the data cut-off date (N = 18, 50%). The probabilities of DOR for 6 months or longer and 12 months or longer were 76% and 51%, respectively (Table 22).

Based on the product-limit (Kaplan–Meier) method for censored data, the median DOR was not estimable (NE) (95% CI, 6.3 to NE; range = 1.2 months and ongoing to 33.1 months and ongoing). The maximum DOR among the 36 responders was 33.1 months and ongoing (refer to Figure 13).

The subgroup analysis showed that the median DORs were NE (95% CI, 4.8 to NE), 11.2 months (95% CI, 6.2 months to NE), NE (95% CI, 5.1 months to NE), and NE (95% CI, 6.3 months to NE) in patients with endometrioid adenocarcinoma, non-endometrioid adenocarcinoma, serous adenocarcinoma, and clear-cell adenocarcinoma, respectively.

Harms

The AEs are presented in Table 23 in this section and Table 62 in Appendix 3. By the data cut-off date, all patients had experienced at least 1 TEAE (N = 94, 100%). The most common TEAEs (occurring in ≥ 50% patients) were hypertension (63.8%), diarrhea (62.8%), fatigue (54.3%), and decreased appetite (51.1%). The proportion of patients reporting an SAE was 52.1%. The most frequent SAEs (> 5%) were hypertension and abdominal pain, reported in 7.4% and 5.3% patients, respectively. The proportion of patients with an AE leading to discontinuation from the treatment was 25.5%. The most common events leading to discontinuation from the treatment were muscular weakness and pancreatitis, each reported in 2.1% patients. Three patients (3.2%) died due to an AE. Overall, the safety profile of PEM + LEN was generally consistent with the known safety profiles of each drug when used as monotherapy, with no new safety signals identified for the combination.⁶¹

Table 20: Summary of Tumour Response in pMMR (FAS, KEYNOTE-146 Trial)

CR = complete response; FAS = full analysis set; ORR = objective response rate; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; PR = partial response.

Source: Clinical Study Report.⁶¹

Table 21: Objective Response by Histologic Subtype in pMMR (FAS, KEYNOTE-146 Trial)

CI = confidence interval; FAS = full analysis set; ORR = objective response rate; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient.

Source: Clinical Study Report.⁶¹

Table 22: Summary of Duration of Response in pMMR (FAS, KEYNOTE-146 Trial)

CI = confidence interval; CR = complete response; DOR = duration of response; FAS = full analysis set; NE = not estimable because not reached; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; PR = partial response.

^aThe median duration was estimated using the Kaplan-Meier method; the 95% CI was constructed with a generalized Brookmeyer and Crowley method.

^b+ indicates the time is censored.

^cProbability and 95% CI were calculated using the Kaplan-Meier product-limit method and Greenwood formula.

Source: Clinical Study Report.⁶¹

Table 23: Summary of Harms (Safety Set, pMMR, KEYNOTE-146 Trial)

AE = adverse event; DC = discontinuation; LEN = lenvatinib; NR = not reported; PEM = pembrolizumab; PEM + LEN = pembrolizumab plus lenvatinib combination therapy; pMMR = mismatch repair proficient; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Source: Clinical Study Report.⁶¹

Critical Appraisal

Internal Validity

The main limitation of the KEYNOTE-146 trial was its single-arm study design (no comparator arm). Such a design, in addition to a lack of consideration for confounding variables, precludes causal inferences (i.e., the outcomes cannot be directly attributed to PEM). Without an active comparator or any statistical hypothesis testing, it is not possible to assess the relative therapeutic benefit or safety of PEM versus other available treatments (such as chemotherapy in this population). Although inclusion and exclusion criteria are stated, selection procedures are not described; therefore, the potential for selection bias cannot be excluded.

In addition, KEYNOTE-146 was an open-label trial. The study investigators and patients were aware of their treatment status — a situation that increases the risk of detection and performance biases that have the potential to influence outcome reporting. The open-label design is a concern for subjective end points, such as safety, but is unlikely to affect objective outcomes, such as OS. The direction of anticipated bias related to these outcomes is unclear.

Based on the study design, during the follow-up phase, other subsequent anticancer treatments appeared to be allowed. Therefore, it is possible that OS data were confounded by the use of subsequent anticancer therapies potentially received by some patients after disease progression; this may result in bias of OS results.

External Validity

Overall, according to the clinical experts consulted by CADTH, the inclusion and exclusion criteria of the KEYNOTE-146 trial were reasonable, and the baseline patient characteristics, concomitant medications, and prohibited medications were reflective of patients seen in clinical practice for the indication under review. Of the 94 patients included, the majority were White (86.2%) and in the US (86.2%). There were no barriers to identifying patients who would most benefit from the treatment, given that testing for MMR and/or MSI status is standard practice in Canada.

Patients with an ECOG PS of greater than 1 were excluded from this study. Therefore, there is uncertainty in whether the findings may be generalized to these populations. The clinical experts consulted by CADTH indicated that it may be reasonable to expect patients with CNS metastases controlled by radiation, those with carcinosarcomas, and patients with higher ECOG PS scores could benefit from treatment with PEM + LEN.

Overall, as indicated in the Health Canada reviewer’s report,²⁰ due to the limitations inherent in the single-arm design, the findings observed in the KEYNOTE-146 trial need to be confirmed in a phase III study (i.e., KEYNOTE-775).

Discussion

Summary of Available Evidence

This CADTH clinical review report included input from patient groups, clinician groups, clinical experts, drug programs, and a single pivotal phase III randomized controlled trial.

Overall, the KEYNOTE-775 trial was conducted in patients who had either pMMR or dMMR endometrial cancer. A total of 827 patients were included (N = 827); 697 patients were pMMR and 130 patients were dMMR. It is important to emphasize that the pMMR population was not considered a subgroup in the original study design. The sample size and power calculations were based on pMMR populations. The dMMR population was designed as a subgroup. In this review, the pMMR population is the only population of interest, which aligns with Health Canada’s indication and the sponsor’s reimbursement request.^8,19,32

The KEYNOTE-775 trial (pMMR population) is a relatively well-designed, ongoing, phase III, multi-centre, randomized, open-label, active-controlled superiority study comparing PEM + LEN to TPC for the treatment of adult patients with advanced endometrial carcinoma that is pMMR (i.e., not MSI-H or dMMR) who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation. A total of 697 patients were randomized in a 1:1 ratio to receive PEM + LEN (n = 346) or TPC (n = 351).

The primary outcomes were PFS and OS. Secondary outcomes included ORR and HRQoL (measured using the EORTC QLQ-C30 GHS scale). Exploratory outcomes included DOR and other HRQoL measurements (i.e., based on the EORTC QLQ-30, EORTC QLQ-EN24 Urological Symptoms Score, and EQ-5D-5L).

This study’s findings were based on IA1 with a data cut-off date of October 26, 2020. It was indicated that the success criteria for the study hypotheses of PFS, OS, and ORR were all met at IA1; consequently, IA2 was not required.^17,18

No ITC or other relevant study was identified for this review.

An additional relevant study (KEYNOTE-146) that was included in the sponsor’s submission to CADTH was considered to provide additional longer-term follow-up evidence for this review.

Interpretation of Results

Efficacy

Based on an interim analysis, the median OS was statistically significantly longer in PEM + LEN (17.4 months) compared with TPC (12.0 months; HR = 0.68; 95% CI, 0.56 to 0.84; P = 0.0001). The subgroup analyses of OS were consistent with the primary analysis.

PFS findings were in line with OS. The median PFS was 6.6 months (95% Cl, 5.6 to 7.4) in the PEM + LEN arm, which was statistically significantly longer compared to TPC (HR = 0.60; 95% CI, 0.50 to 0.72; P = 0.0001). The subgroup analyses of PFS were consistent with the primary analysis.

Patient-reported and HRQoL outcomes were identified as important for patients and assessed as secondary or exploratory outcomes. Although there is no expectation of significant improvement in QoL with treatment for this population, overall, there appeared to be no between-group difference observed for PEM + LEN versus TPC in terms of HRQoL.

The clinical experts indicated that ORR is an important outcome in this patient population because, in their experience, improved ORR (based on radiographic evaluation) is usually correlated with improvement in other important clinical outcomes, such as PFS, OS, slower decline in ECOG PS, and delays in the presentation of clinical symptoms, worsening, or HRQoL deterioration; however, these are not always absolutely proportionally correlated. ORR was assessed as the secondary outcome in this study. It was reported that the response rates ranged between 10% and 15% among all available existing treatment options,¹⁵ which is consistent with the ORR reported in the TPC arm (15.1%) in the KEYNOTE-775 trial. ORR in KEYNOTE-775 was statistically significant greater in favour of PEM + LEN combination therapy over TPC. The results for ORR are in line with the survival benefit seen for OS and PFS. However, it remains uncertain what impact the clinically meaningful ORR has on improvement in cancer symptoms. Given the known toxicities associated with PEM + LEN, improvement in symptoms may be difficult to determine. Regardless, halting the progression of the disease, improving survival, and improving symptoms are important outcomes for patients.

The median follow-up duration was 12.2 months, which is relatively short and may mean that responses (e.g., OS) are evolving; although the protocol-specified criteria were met for the efficacy analyses, monitoring of safety and efficacy are ongoing. The sponsor provided a final descriptive analysis (cut-off date: March 1, 2022. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The results of the final analysis appeared to be consistent with those observed in IA1 (cut-off date = October 26, 2020). (Refer to Appendix 5.) In the KEYNOTE-146 trial, the median follow-up time for OS was 18.7 months (95% CI, 14.1 months to 20.9 months), which was longer than that in KEYNOTE-775 trial. However, the KEYNOTE-146 trial was limited due to its single-arm design. It is noted that the results observed in this trial were consistent with those reported in the KEYNOTE-775 trial.

Overall, the KEYNOTE-775 trial met the predefined criteria for statistical significance for both of its primary end points (OS and PFS) and for its key secondary end point (ORR). The clinical experts consulted by CADTH for this review indicated that the findings for OS, PFS, and ORR reported in the KEYNOTE-775 trial are considered clinically meaningful in this population.

According to the clinical experts consulted by CADTH, patients recruited for the KEYNOTE-775 trial were considered representative of patients in Canadian clinical practice. There were no major concerns about the generalizability of the findings to Canadian practice. The clinical experts anticipated that because of the mechanism of action and acceptable safety profile of PEM + LEN combination therapy, they would expect to experience a benefit of treatment with it for all patients with pMMR endometrial cancer who have received at least 1 previous line of systemic therapy.

Harms

The safety profile of PEM + LEN for the treatment of various cancers, including endometrial cancer, has been well established in previous clinical trials.^8,32,46,65 The proportions of patients experiencing at least 1 TEAE were similar in the PEM + LEN group and the TPC group (i.e., 99.7% in both). The frequency of SAEs was higher than in the TPC arm in the KEYNOTE-775 trial. However, when adjusted for exposure, the incidence of SAEs appeared similar between the 2 treatment groups (i.e., the number of SAEs per 100 person-months were 9.83 versus 9.4 in the PEM + LEN versus TPC groups, respectively) (Table 58). More patients discontinued the study medication due to AEs than did those on TPC (PEM + LEN = 31.0%; TPC = 8.3%). Notable AEs (i.e., the AEs of special interest for this review) were higher in the PEM + LEN group than in the TPC group. The higher incidence of notable harms in the PEM + LEN group was driven primarily by hypothyroidism, hyperthyroidism, and hypertension. Overall, the clinical experts consulted by CADTH for this review agreed that the safety profile of PEM + LEN observed in this study appeared consistent with the known safety profile of each individual drug (PEM or LEN), with no additional safety signals identified. Additionally, the clinical experts indicated that the AEs observed in the study were generally manageable with dose interruption or discontinuation of PEM, LEN, or both, or with LEN dose reduction, with or without concomitant steroid therapy.

Conclusions

One sponsor-submitted, phase III, multinational, open-label, randomized, active-controlled trial (KEYNOTE-775) was included in this review. Compared with TPC (doxorubicin or paclitaxel), PEM + LEN combination therapy showed a statistically significant and clinically meaningful benefit in terms of OS, PFS, and ORR in the treatment of adult patients with advanced pMMR (i.e., non-MSI-H or dMMR) endometrial carcinoma who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation. The clinical experts consulted for this review indicated that the safety profile of PEM + LEN observed in this study appeared consistent with the known safety profile of each individual drug (PEM or LEN), with no additional safety signals identified. The AEs observed in the study were generally manageable with dose interruption, dose discontinuation, or LEN dose reduction, with or without concomitant steroid therapy.

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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: January 21, 2022

Alerts: Bi-weekly search updates until project completion

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

Limits:

• Conference abstracts: excluded

Table 24: Syntax Guide

Multi-Database Strategy

1. (pembrolizumab* or Keytruda* or SCH-900475 or SCH900475 or MK-3475 or MK3475 or lambrolizumab* or HSDB8257 or HSDB 8257 or Merck 3475 or DPT0O3T46P).ti,ab,ot,kf,hw,nm,rn.

2. exp Endometrial neoplasms/

3. ((endometri* or uterus or uterine) adj3 (cancer* or carcinoma* or neoplas* or sarcoma* or tumo?r* or adenocarcinoma* or carcinosarcoma*)).ti,ab,kf.

4. 1 and (2 or 3)

5. 4 use edal

6. *pembrolizumab/

7. (pembrolizumab* or Keytruda* or SCH-900475 or SCH900475 or MK-3475 or MK3475 or lambrolizumab* or HSDB8257 or HSDB 8257 or Merck 3475).ti,ab,kf,dq.

8. 6 or 7

9. exp Endometrium tumor/

10. ((endometri* or uterus or uterine) adj3 (cancer* or carcinoma* or neoplas* or sarcoma* or tumo?r* or adenocarcinoma* or carcinosarcoma*)).ti,ab,kf,dq.

11. 9 or 10

12. 8 and 11

13. 12 use oemezd

14. 12 not (conference abstract or conference review).pt.

15. 5 or 14

16. remove duplicates from 15

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

Search – pembrolizumab | “Endometrial Neoplasms”

WHO ICTRP

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

Search terms – pembrolizumab AND endometrial

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

Search terms – pembrolizumab AND endometrial

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

Search terms – pembrolizumab AND endometrial

Grey Literature

Search dates: January 13-18, 2022

Keywords: Keytruda/pembrolizumab, endometrial cancer

Limits: Conference abstracts excluded

Updated: Search updated prior to the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 25: Excluded Studies

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 26: Protocol Amendments

PFS= progression-free survival; pMMR= mismatch repair proficient; OS = overall survival.

Source: Clinical Study Report.¹⁹

Table 27: Dose Modification Guidelines for Lenvatinib-Related Adverse Events (PEM + LEN Combination Arm)

AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse Events; MSD = Merck Sharp & Dohme Corporation; PEM + LEN = pembrolizumab + lenvatinib combination.

^aAn interruption of study treatment for more than 28 days will require MSD’s approval before treatment can be resumed.

^bInitiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea prior to any lenvatinib interruption or dose reduction.

^cApplicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.

^dObese patients with weight loss do not need to return to the baseline weight or 10% of baseline weight (i.e., Grade 1weight loss). These patients will restart the study drug(s) at a lower dose once their weight remains stable for at least 1 week and they reached the normal BMI (if the weight loss occurred but it is still above normal BMI, they can restart the study treatment at a lower dose once the weight has been stable for at least 1 week). Normal BMI should be used as the new baseline for further dose reductions.

^eFor asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not considered clinically relevant by the investigator, continuation of treatment should be discussed with MSD.

^fExcluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.

Note: For grading, refer to CTCAE version 4.0. Collect all AE grades (i.e., decreasing and increasing CTCAE grade).

Source: Clinical Study Report.¹⁹

Table 28: Study Interventions

q.3.w. = every 3 weeks; q.d. = once daily; q.w. = every week.

^a4 mg capsules provided for successive dose reduction of lenvatinib.

^b28-day cycle with weekly administration; 3 weeks on and 1 week off.

Note: Maximum doses of study drugs: pembrolizumab (35 cycles); doxorubicin (cumulative lifetime dosage of 500 mg/m2 or lower as consistent with site’s standard of care); paclitaxel (per site standard of care); no maximum number of doses for lenvatinib.

Source: Clinical Study Report.¹⁹

Table 29: Prior Therapies for Endometrial Cancer (ITT Population)

ITT = intention to treat; n = number of patients with event; N = total number of patients; TPC = Treatment Physician´s Choice of doxorubicin or paclitaxel.

^aDoes not include the therapeutic setting of palliative hormonal therapy.

Source: Clinical Study Report.¹⁹

Table 30: Patients With Specific Concomitant Medications (Incidence > 0% in 1 or More Treatment Groups) (APaT Population)

APaT = all patients as treated; n = number of patients with event; N = total number of patients; TPC = Treatment Physician´s Choice of doxorubicin or paclitaxel.

Source: Clinical Study Report.¹⁹

Table 31: Summary of Subsequent Systemic Anticancer Treatment Patients (ITT Population)

ITT = intention to treat; n = number of patients with event; N = total number of patients; PEM + LEN = pembrolizumab + lenvatinib combination; pMMR = mismatch repair proficient; TPC = treatment of physician’s choice (doxorubicin or paclitaxel).

Source: Clinical Study Report.¹⁹

Table 32: Summary of Interim and Final Analysis Strategy

FA = final analysis; IA1 = interim analysis 1; IA2 = interim analysis 2; OS = overall survival; PFS = progression-free survival; pMMR = mismatch repair proficient.

^aNote that if events accrue slower than expected for the FA, the sponsor may conduct the analysis up to 3 months after the estimated timing of the FA (i.e., approximately 46 months after first participant randomized).

Source: Clinical Study Report.¹⁹

Figure 7: Multiplicity Graph for Type I Error Control of Study Hypotheses

ORR = objective response rate; OS = overall survival; PFS = progression-free survival; pMMR = mismatch repair proficient.

Source: Clinical Study Report.¹⁹

Table 33: Censoring Rules for Primary Analysis of Progression-Free Survival Based on RECIST 1.1

PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumours.

Source: Clinical Study Report.¹⁹

Table 34: Summary of Important Protocol Deviations (ITT Population)