CADTH Reimbursement Review

Pembrolizumab (Keytruda)

Sponsor: Merck Canada Inc.

Therapeutic area: Classical Hodgkin lymphoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Introduction

The purpose of this report is to summarize the evidence regarding the use of pembrolizumab as monotherapy in adult and pediatric patients with refractory or relapsed classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or who are not candidates for salvage chemotherapy and ASCT. Pembrolizumab is an immune checkpoint inhibitor dosed at 200 mg every 3 weeks in adults and 2 mg/kg every 3 weeks in pediatrics.

The term Hodgkin lymphoma (HL) refers to a group of lymphoid proliferations that share clinical and morphological features that distinguish them from other types of lymphoma. It is estimated that in 2020, 1,000 Canadians were diagnosed with cHL and 100 died from the disease.¹ Clinically, HL presents most commonly with enlarged cervical lymph nodes, and spread is generally between contiguous nodal areas. Mediastinal masses and B symptoms (fever, weight loss, and night sweats) are common. A bimodal age distribution is appreciated for HL, with most patients diagnosed between the ages of 15 years and 39 years. A second peak is seen in individuals over the age of 70 years.² HL is diagnosed by biopsy of an affected tissue or organ. On histopathology, large, atypical, and malignant cells, termed Reed-Sternberg or Hodgkin cells, are observed in a heterogeneous background consisting of non-neoplastic inflammatory cells.³ Subclassification of HL into cHL (nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted) and nodular lymphocyte-predominant HL is based on the degree of atypia of the malignant cells, their immunophenotype, and the features of the inflammatory background.

Standards of Therapy

The treatment of cHL is guided by careful assessment of stage- and disease-specific risk factors. ¹⁸F-fluorodeoxyglucose PET is considered the gold standard for staging of HL and the Cotswold modification of the Ann Arbor staging system is applied to determine the numerical stage. In 1998, Hasenclever et al. published a prognostic score for adult patients with advanced HL consisting of 7 clinical (sex, age, and stage) and laboratory (anemia, leukocytosis, reduced serum albumin, and lymphopenia) factors. This score predicts freedom from progression (84% for patients with no risk factors to 42% for those with 5 or more factors) and overall survival (OS; 89% for patients with no risk factors to 56% for those with 5 or more factors) at 5 years.⁴ Treatment is risk-adapted, with low-risk patients (stage I to II, few risk factors) receiving a limited number of cycles of ABVD (doxorubicin-bleomycin-vinblastine-dacarbazine) chemotherapy, often with low-dose involved field radiotherapy^5,6 while those with higher-risk disease receiving more extensive chemotherapy. Intensive chemotherapy, in the form of escalated BEACOPP (bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone), is reserved for patients with the highest risk of adverse outcome.⁷ Response-adapted therapy with the use of interim PET restaging is used to de-escalate treatment for patients who are likely cured^8,9 and to escalate treatment of patients who are not responding as expected.^8,10 Risk- and response-adapted combined modality therapies are similarly used in pediatric protocols with some differences in chemotherapy backbones.¹¹ Recognizing the shared clinical-pathological features of HL in the most affected age groups, North American adult and pediatric study groups have amalgamated efforts to study new agents using a common chemotherapy backbone.¹² The outcome of HL has improved significantly over time and today more than 80% of patients with cHL are cured with initial therapy.^2,13

Most patients who do not respond to or who relapse after first-line treatment for HL are treated with high-dose chemotherapy and autologous cell transplantation.¹⁴ This approach is supported by 2 randomized trials,^15,16 several phase II^17-20 and registry²¹ studies, and results in progression-free survival (PFS) in 50% to 60% of patients and OS in 60% to 80% of patients. Careful patient selection is required for successful ASCT as the presence of multiple or severe comorbidities may make the treatment-related mortality of high-dose therapy prohibitive. Patients may also not undergo ASCT if they fail to mobilize sufficient numbers of hematopoietic stem cells to support the use of high-dose chemotherapy, if they fail to respond to salvage chemotherapy, or for reasons of conscience as in the case of Jehovah’s Witnesses. Overall, approximately 85% of patients with relapsed or refractory cHL undergo ASCT.

There is currently no standard of care for patients with cHL who relapse after ASCT or who are ineligible for ASCT for 1 of the reasons noted above. Options to treat these patients include chemotherapy, radiotherapy (for those with localized recurrences), targeted therapy with brentuximab vedotin (BV), and immune checkpoint inhibitors. Although responses to standard-dose chemotherapy occur frequently in later lines of treatment, the use of conventional-dose salvage chemotherapy is unlikely to lead to a cure in these patients.²² Good palliation can be achieved with oral single-agent or combination chemotherapy regimens.^23,24 BV is an antibody-drug conjugate that targets CD30-positive cells, delivering the antimitotic agent MMAE into the cytoplasm of these cells by endocytosis.²⁵ The utility of BV in relapsed or refractory cHL was demonstrated in a pivotal phase II study in 102 patients who failed ASCT. The overall response rate was 75% with complete responses seen in 34% of patients and toxicity was manageable, although peripheral neuropathy was frequently dose limiting.²⁶ After 5 years of follow-up, OS in this cohort of 102 patients was 41% and PFS was 22%; median OS and PFS were higher among those patients who achieved complete remission to BV.²⁷ Real-world experience with BV in transplant-ineligible relapsed or refractory cHL was provided in a phase II study of 136 patients with a median age of 70 years at diagnosis. The most common reasons for transplant ineligibility in this cohort were comorbidities and age. A median of 8 cycles was given and overall and complete responses were observed in 74.3% and 34.6% of patients, respectively, similar to the results seen in patients who had previously undergone ASCT. Median PFS and OS were 15.1 and 17.8 months, respectively.²⁸

Immune checkpoint inhibitors affect the PD1/PD-L1 axis and lead to increased immune reactivity against cancers that have exploited this mechanism to escape immune control. Nivolumab is a human IgG monoclonal antibody that targets PD1. Nivolumab is licensed for treatment of patients with advanced hepatocellular carcinoma, non–small cell lung cancer, advanced renal cell carcinoma, and certain cases of colorectal carcinoma or malignant melanoma. It is also approved for treatment of patients with cHL who have progressed after ASCT and BV or 3 or more lines of systemic therapy including hematopoietic cell transplantation.²⁹ The indication in cHL is based on the results of the CHECKMATE-205 and CHECKMATE-039 studies, which enrolled a total of 95 patients, demonstrating an overall response rate of 66% and complete and partial remission of 6% and 60%, respectively. Median duration of response (DOR) was 13.1 months. Toxicity was manageable, although immune-mediated toxicity was observed.^30,31 A second immune checkpoint inhibitor, pembrolizumab, is the subject of this CADTH review.

Stakeholder Perspectives

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

Patient Input

Lymphoma Canada was the only patient group to provide input and did so after conducting 2 online surveys which yielded 128 responses. Patients often experienced fatigue, trouble breathing, fever/chills, loss of appetite, itching, anxiety, problems concentrating, loss of sexual desire, and memory loss. Many patients had quit working or school due to their diagnosis. Patients sought treatments that would provide disease control or remission with fewer side effects than current treatment options and valued longer survival and remission.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts highlighted that patients with cHL who relapse after ASCT or who are not fit for multi-agent chemotherapy and ASCT have limited treatment options. The available treatments can be associated with significant side effects and are seldom curative. Both pediatric and adult experts expect pembrolizumab to be effective earlier in the treatment paradigm but that it is also appropriate for use in patients who have failed or are ineligible for ASCT. However, patients recently on therapy for autoimmune disease, patients with poor performance status, patients with organ failure, or at high risk of autoimmune side effects may not be suited for pembrolizumab. A response to therapy would be marked by resolution of disease symptoms, radiologic evidence of disease improvement, improved ability to perform activities of daily living, reduction in size of lymph nodes and other disease sites, and in some patients, becoming eligible for an allogeneic or ASCT. Patients receiving pembrolizumab are assessed clinically every 3 weeks and radiologically every 3 to 4 cycles. Treatment should be discontinued if there is disease progression, severe immune-related adverse event (AE), or severe infusion or hypersensitivity reactions.

Clinician Group Input

Twelve clinicians from the Ontario Health Hematology Disease Site Drug Advisory Committee, Lymphoma Canada Scientific Advisory Board, and the Pediatric Oncology Group of Ontario (POGO) all provided feedback for this review. The input provided aligned with the advice provided from the CADTH clinical experts.

Drug Program Input

Some drug plan questions were regarding retreating patients with pembrolizumab who had already received it. The clinical experts identified limited evidence to provide guidance, but there is some evidence of retreating patients with pembrolizumab who have already received 35 cycles if disease progression is observed. The clinical experts were hesitant to treat patients with pembrolizumab if they had already been treated with a PD-1 or PD-L1 inhibitor unsuccessfully, believing pembrolizumab should be stopped if there is evidence of disease progression or intolerable side effects. The clinical experts were also hesitant to switch a patient from BV to pembrolizumab if the patient is responding to BV.

Clinical Evidence

Description of Studies

KEYNOTE-051

The KEYNOTE-051³² study was a nonrandomized, open-label, single-arm trial of pembrolizumab 2 mg/kg administered every 3 weeks in 7 pediatric patients aged 3 years to 18 years with relapsed or refractory cHL. A 28-day screening period was performed before patient enrolment to collect necessary laboratory, diagnostic, and demographic information and assess study eligibility. The KEYNOTE-051 study evaluated safety and efficacy including objective response rate (ORR), DOR, PFS, and OS for 35 cycles of treatment or until discontinuation due to disease progression or AEs. Post-treatment follow-up assessments occurred every 12 weeks. The study was funded by the sponsor and had a data cut-off date of January 2020.

KEYNOTE-087

The KEYNOTE-087³³ study was a nonrandomized, single-arm study of pembrolizumab 200 mg administered every 3 weeks in adult patients with cHL. A 28-day screening period was performed before patient enrolment to collect necessary laboratory, diagnostic, and demographic information and assess study eligibility. The study evaluated ORR, PFS, DOR, health-related quality of life (HRQoL), and OS with a treatment duration up to 2 years, or until discontinuation of treatment due to disease progression, or occurrence of AEs. Post-treatment follow-up assessments occurred every 12 weeks. The study was funded by the sponsor with a data cut-off date of March 2019. The study consisted of 3 cohorts:

• Cohort 1: Patients who failed to respond to or progressed after ASCT and also relapsed after or failed to respond to treatment with BV after ASCT (N = 69)

• Cohort 2: Patients who were ineligible for ASCT and relapsed after or failed to respond to BV (N = 81)

• Cohort 3: Patients who failed to respond to or progressed after ASCT and had not yet received BV (N = 60)

KEYNOTE-204

The KEYNOTE-204³⁴ study was a phase III, randomized (1:1 ratio), active controlled, open-label clinical trial comparing pembrolizumab 200 mg administered intravenously every 3 weeks (N = 151) with BV 1.8 mg/kg (maximum dose of 180 mg) administered intravenously every 3 weeks (N = 153) in adult patients with relapsed or refractory cHL. A 28-day screening period was performed before patient enrolment to collect necessary laboratory, diagnostic, and demographic information and assess study eligibility. The study evaluated PFS, OS, ORR, DOR, time to response, HRQoL, and safety for 35 cycles of treatment or until early discontinuation due to disease progression, unacceptable AEs, or other reasons to withdraw therapy. Post-treatment follow-up assessments occurred every 12 weeks. The study was funded by the sponsor with data cut-off date of February 2020. A diagram of the KEYNOTE-204 study design is provided in Figure 2.

Baseline Characteristics

Patients in the KEYNOTE-051 study had a median age of 15 years while the median age in the KEYNOTE-087 and KEYNOTE-204 studies ranged from 32.0 to 40.0. The proportion of female patients ranged from 41.2% among BV patients in the KEYNOTE-204 study to 47.8% among cohort 1 of the KEYNOTE-087 study. The proportion of patients with an Eastern Cooperative Oncology Group (ECOG) score of 0 ranged from 42.0% in cohort 1 of the KEYNOTE-087 study to 65.4% among BV patients from the KEYNOTE-204 study. The proportion of patients with an ECOG score of 0 was 54.3% and 48.3% in cohorts 2 and 3, respectively, of the KEYNOTE-087 study and 57.0% in the pembrolizumab arm of the KEYNOTE-204 study. Cohorts 1 and 3 of the KEYNOTE-087 study had higher rates of prior radiation use (46.4% and 40.0%, respectively) relative to either arm in the KEYNOTE-204 study (pembrolizumab: 38.4% and BV: 39.9%) while those in cohort 2 had lower rates (25.9%). Patients in either arm of the KEYNOTE-204 study had more bulky disease (pembrolizumab: 23.2% and BV: 16.3%) relative to any cohort in the KEYNOTE-087 study (cohort 1: 2.9%, cohort 2: 6.2%, and cohort 3: 1.7%). Baseline B symptoms were present in 30.4%, 33.3%, and 31.7% of patients in cohort 1, cohort 2, and cohort 3 of the KEYNOTE-087 study. Baseline B symptoms were also present in 28.5% and 23.5% of pembrolizumab and BV patients, respectively, in the KEYNOTE-204 study. The 2 arms within the KEYNOTE-204 study seem relatively balanced except that pembrolizumab patients had higher rates of bulky disease (23.2% versus 16.3%). Patients in the KEYNOTE-204 study were permitted to be treated with a subsequent anticancer medication after pembrolizumab or BV was discontinued.

Efficacy Results

Progression-Free Survival

In KEYNOTE-051, 3 patients (42.9%) experienced an event (disease progression or death). In the KEYNOTE-087 study, there were 43 (62.3%), 54 (66.7%), and 36 (60.0%) events in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, the proportion of patients experiencing an event was similar between the pembrolizumab (53.6%) and BV (57.5%) arms. In the KEYNOTE-051 study, the median PFS was reported to be 11.1 months (95% confidence interval [CI], 2.6 to not reported). In the KEYNOTE-087 study, median survival was reported to be 16.4 months (95% CI, 11.3 to 27.6), 11.1 months (95% CI, 7.3 to 13.5), and 19.4 (95% CI, 8.4 to 22.1) months in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, the median PFS was higher in the pembrolizumab arm (13.2 months; 95% CI, 10.9 to 19.4) than the BV arm (8.3 months; 95% CI, 5.7 to 8.8). In the KEYNOTE-051 study, the PFS rate at 12 months was 27.8% (no 95% CI reported). In the KEYNOTE-087 study, the PFS rate at 12 months was 61.3%, 43.0%, and 53.9% in cohorts 1, 2, and 3, respectively (no 95% CI reported). In the KEYNOTE-204 study, the 12-month PFS rate was higher in the pembrolizumab arm (53.9%; 95% CI, 45.0 to 61.9) than the BV arm (35.6%; 95% CI, 26.9 to 44.4). In the KEYNOTE-087 study, the 24-month PFS rate was 41.6%, 21.9%, and 34.0% in cohorts 1, 2, and 3, respectively (no 95% CI reported). In the KEYNOTE-204 study, the 24-month PFS rate was 35.4% (95% CI, 26.2 to 44.6) in the pembrolizumab arm and 25.4% (95% CI, 17.1 to 34.5) in the BV arm. The hazard ratio for time to progression was 0.65 (95% CI, 0.48 to 0.88), which was statistically significant (P = 0.0027).

Overall Survival

In the KEYNOTE-051 study, minimal information regarding OS was provided. In the KEYNOTE-087 study, 15.9%, 16.0%, and 15.0% of patients in cohorts 1, 2, and 3, respectively, died. In the KEYNOTE-204 study, a smaller proportion of patients receiving pembrolizumab died relative to patients receiving BV (10.6% versus 19.6%). Median survival was not reported in the KEYNOTE-051 study and not reached in the KEYNOTE-087 or KEYNOTE-204 studies. In the KEYNOTE-051 study, 100% of patients were alive at 12 months. In the KEYNOTE-087 study, OS at 12 months was 95.7%, 96.,2% and 96.6% in cohorts 1, 2, and 3, respectively (95% CI not reported). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| At 24 months in the KEYNOTE-087 study, 92.6%, 91.0%, and 89.4% of patients were alive in cohorts 1, 2, and 3, respectively (95% CI not reported). 　|　 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Objective Response Rate

In the KEYNOTE-051 study, 42.9% (95% CI, 9.9 to 81.6) of patients experienced a partial or complete response. In the KEYNOTE-087 study, 78.3% (95% CI, 66.7 to 87.3), 64.2% (95% CI, 52.8 to 74.6), and 71.7% (95% CI, 58.6 to 82.5) of patients experienced a partial or complete response in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, more partial or completes responses were observed in the pembrolizumab arm relative to the BV arm (65.6%; 95% CI, 57.4 to 73.1 versus 54.2; 95% CI, 46.0 to 62.3), which was associated with a statistically insignificant 11.3% (95% CI, 0.2 to 22.1) difference in favour of pembrolizumab.

Complete Response Rate

In the KEYNOTE-051 study, 28.6% of patients (95% CI, 3.7 to 71.0) experienced a complete response. In the KEYNOTE-087 study, 26.1% (95% CI, 16.3 to 38.1), 25.9 (95% CI, 16.8 to 36.9), and 31.7% (95% CI, 20.3 to 45.0) of patients in cohorts 1, 2, and 3, respectively, experienced a complete response. In the KEYNOTE-204 study, the complete response rate was comparable between the pembrolizumab (24.5%; 95% CI, 17.9 to 32.2) and BV arms (24.2; 95% CI, 17.6 to 31.8).

Duration of Response

In the KEYNOTE-051 study, median DOR was not reached. In the KEYNOTE-087 study, the median DOR in cohorts 1, 2, and 3 were 25.0 months (range = 0 to 36.1), 11.1 months (range = 0 to 35.9), and 16.8 months (range = 0 to 39.1), respectively. In the KEYNOTE-204 study, the median DOR was higher among patients in the pembrolizumab arm (20.7 months; range = 0 to 33.2) than in patients in the BV arm (13.8 months; range = 0 to 33.9).

Time to Response

Median time to response in the KEYNOTE-051 study was 2.6 months (range = 2.1 to 2.8). The median time to response in cohort 1, cohort 2, and cohort 3 of the KEYNOTE-087 study were 2.7 months (range = 2.1 to 12.9), 2.8 months (range = 2.2 to 11.0), and 2.8 months (range = 2.6 to 16.5), respectively. Finally, the median time to response in the pembrolizumab arm of the KEYNOTE-204 study was 2.8 months (range = 1.0 to 31.2) and also 2.8 months (range = 1.3 to 7.3) in the BV arm.

Health-Related Quality of Life

HRQoL data were only measured in the KEYNOTE-087 and KEYNOTE-204 studies. In the KEYNOTE-087 study, the least squares mean change in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status between week 24 and baseline was 11.8, 13.9, and 6.6 in cohorts 1, 2, and 3, respectively. No CIs were reported in the KEYNOTE-087 study. In the KEYNOTE-204 study, the least squares mean change in EORTC QLQ-C30 global health status between baseline and week 24 was 8.60 points (95% CI, 3.89 to 13.31) higher in the pembrolizumab arm versus the BV arm. Consistent results were reported for the EORTC QLQ-C30 physical functioning scale (6.24; 95% CI, 1.87 to 10.62), EuroQol 5-Dimensions 3-Levels questionnaire (EQ-5D-3L) utility score (0.09; 95% CI, 0.04 to 0.14), and EQ-5D-3L visual analogue scale (6.12; 95% CI, 1.91 to 10.34).

Harms Results

In the KEYNOTE-051 study, 85.7% of patients experienced at least 1 AE. In the KEYNOTE-087 study, 98.6%, 98.8%, and 95.0% of patients experienced at least 1 AE in cohort 1, cohort 2, and cohort 3, respectively. In the KEYNOTE-204 study, 98.0% of patients in the pembrolizumab arm and 94.1% of those in the BV arm experienced an AE. The most common AEs were pyrexia, vomiting, headache, abdominal pain, anemia, cough, fatigue, diarrhea, and upper respiratory tract infections. In the KEYNOTE-204 study, pembrolizumab patients were more likely than BV patients to experience endocrine disorders (20.3% versus 3.9%); infections (66.2% versus 45.4%); musculoskeletal and connective tissue disorders (37.8% versus 31.6%); neoplasms (7.4% versus 1.3%); renal or urinary disorders (14.9% versus 4.6%); respiratory, thoracic, or mediastinal disorders (45.3% versus 26.3%); and skin and subcutaneous tissue disorders (43.9% versus 36.8%), but less likely to experience blood or lymphatic system disorders (18.2% versus 25.7%), gastrointestinal disorders (43.9% versus 52.0%), and nervous system disorders (26.4% versus 50.7%).

In the KEYNOTE-051 study, 28.6% of patients experienced at least 1 serious AE. In the KEYNOTE-087 study, 21.7%, 22.2,% and 25.0% of patients experienced a serious AE in cohort 1, cohort 2, and cohort 3, respectively. In the KEYNOTE-204 study, 29.7% of pembrolizumab and 21.1% of BV-treated patients experienced a serious AE. The most common serious AEs in the KEYNOTE-051 study were diaphragmatic hernia and pneumonia. The most common serious AEs in cohort 1 of KEYNOTE-087 were pneumonia and pericarditis. The most common serious AE in cohort 2 of the KEYNOTE-087 study was herpes zoster and the most common serious AEs in cohort 3 of the KEYNOTE-087 study were pyrexia and pneumonitis, There were no notable differences in frequency of serious AEs between the pembrolizumab and BV arms in the KEYNOTE-204 study. The most common serious AEs in the pembrolizumab arm of the KEYNOTE-204 study were infections or infestations; respiratory, thoracic, or mediastinal disorders; neoplasms; general disorders or administration site conditions; and hepatobiliary disorders. The most common serious AEs in the BV arm of the KEYNOTE-204 study were infections or infestations; respiratory, thoracic, or mediastinal disorders; nervous system disorders; gastrointestinal disorders; and general disorders or administration site conditions.

No patients in the KEYNOTE-051 study discontinued treatment due to an AE, while 11.6%, 6.2%, and 8.3% of patients in cohort 1, cohort 2, and cohort 3, respectively, of the KEYNOTE-087 study discontinued treatment due to an AE. In the KEYNOTE-204 study, 13.5% and 17.8% of patients receiving pembrolizumab and BV discontinued treatment due to an AE, respectively.

In the KEYNOTE-051 study, 28.6% of patients experienced at least 1 immune-mediated AE. In cohort 1, 2, and 3 of the KEYNOTE-087 study, 31.9%, 32.1%, and 38.3% of patients, respectively, experienced at least 1 immune-mediated AE. In the KEYNOTE-204 study, more patients in the pembrolizumab arm (35.8%) than the BV arm (13.8%) experienced an immune-mediated AE. No patients in the KEYNOTE-051 study experienced a serious immune-mediated AE. In the KEYNOTE-087 study, 4.3%, 2.5%, and 5.0% of patients in cohort 1, cohort 2, and cohort 3, respectively, experienced a serious immune-mediated AE. In the KEYNOTE-204 study, more pembrolizumab- than BV-treated patients experienced a serious immune-mediated AE (8.8% versus 3.3%).

Critical Appraisal

The KEYNOTE-051 and KEYNOTE-087 studies were single-arm, open-label trials, while the KEYNOTE-204 study was an open-label, randomized controlled trial. The single-arm trials will be unable to provide definitive evidence of a medication’s superiority over the standard of care while the open-label design of all trials puts them at risk of bias in either direction. However, some bias from the open-label design would be attenuated by the fact that tumour progression was assessed by an independent and blinded assessor in all 3 trials. Further, the randomized nature of the KEYNOTE-204 study will balance prognostic factors at the beginning of the study. The KEYNOTE-204 study permitted patients to be treated with a subsequent anticancer medication following discontinuation of the trial medication (pembrolizumab or BV) which may obscure the trial medication’s true impact on OS. Patients originally randomized to pembrolizumab were permitted to be subsequently treated with BV and vice versa. Almost all patients randomized to BV (97.4%) received a subsequent anticancer therapy while 70.2% of pembrolizumab-treated patients did so. Those randomized to BV were more likely to cross over and subsequently receive pembrolizumab (17.8% subsequently received pembrolizumab versus 1.4% of patients originally randomized to pembrolizumab retreated with BV). Those originally randomized to BV were also more likely to receive nivolumab (19.7%) relative to those randomized to pembrolizumab (3.4%). Finally, 25.0% of patients originally randomized to pembrolizumab received BV while 4.6% of patients originally randomized to BV were retreated with BV. The KEYNOTE-051 study identified 7 pediatric patients with refractory or relapsed cHL which is insufficient to be representative of the true treatment effect in children with this condition. Moreover, it is unclear if these patients failed or were ineligible for salvage chemotherapy and ASCT which is the population of interest in this review. Due to the methodological limitations of the KEYNOTE-051 study, the evidence base is limited to the KEYNOTE-087 and KEYNOTE-204 studies. While the KEYNOTE-204 study is methodologically superior to the KEYNOTE-087 study due to the randomized active control design of the KEYNOTE-204 study, only 1 active control (BV) was tested. The KEYNOTE-087 and KEYNOTE-204 studies excluded individuals with a ECOG status of 2 or greater which could limit its generalizability. Similarly, the KEYNOTE-204 study only compared pembrolizumab to BV. Notably, CADTH reviewed the use of BV in adults with HL after failure of at least 2 multi-agent chemotherapy regimens who are not candidates for ASCT and did not recommend reimbursement.³⁵ However, the clinical experts consulted by CADTH confirmed that in jurisdictions where it is funded, BV is still standard of care due to the lack of superior alternatives. This is in part supported by more recent evidence suggesting the efficacy of BV as third-line therapy in patients who have not received a stem cell transplant.³⁶

Conclusions

The body of evidence included in this review suggests that, when compared to BV, pembrolizumab provides statistically and clinically significant improvement in PFS as well as clinically significant improvements in || ORR, DOR, and HRQoL. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||| Patients who received BV were generally less likely to experience AEs, serious AEs, or immune-mediated AEs but more likely to discontinue therapy due to an AE. A definitive explanation of this phenomenon cannot be derived from this evidence alone. However, 1 explanation could be that BV-treated patients expected or observed worse health outcomes and thus were less willing to tolerate AEs, even if the rates were lower than in the pembrolizumab arm. Discontinuation would be a viable alternative for these patients as receiving another anticancer medication, including pembrolizumab, was an option. Conversely, pembrolizumab patients may have been willing to tolerate more AEs as the expected benefits were commensurately higher. The body of evidence primarily evaluated pembrolizumab administered 200 mg every 3 weeks in adults but due to the nature of the disease, CADTH’s clinical experts believe that the benefits observed in adults would also be applicable to pediatric patients. However, because of insufficient evidence on the use of pembrolizumab in pediatric patients, it is uncertain what dose should be used to ascertain the benefits observed in adults. No other comparators to pembrolizumab aside from BV were evaluated in the included studies; thus, the comparative effect of pembrolizumab to other relevant treatments in the population under review, beyond BV, remains uncertain. Also, the KEYNOTE-087 and KEYNOTE-204 studies only recruited patients with an ECOG score of 0 or 1 but the CADTH clinical experts did not recommend limiting the use of pembrolizumab only to patients with low ECOG scores. In totality, the evidence suggests that pediatric and adult patients with relapsed or refractory cHL who failed ASCT or are ineligible for multi-agent salvage chemotherapy and ASCT are more likely to benefit from pembrolizumab than from BV; however, the dose required to ascertain these benefits in pediatrics is uncertain.

Introduction

Disease Background

The purpose of this report is to summarize the evidence regarding the use of pembrolizumab monotherapy in adult and pediatric patients with refractory or relapsed cHL who have failed ASCT or who are not candidates for salvage chemotherapy and ASCT. Pembrolizumab is an immune checkpoint inhibitor dosed at 200 mg every 3 weeks in adults and 2 mg/kg every 3 weeks in pediatrics.

The term HL refers to a group of lymphoid proliferations that share clinical and morphological features that distinguish them from other types of lymphoma. It is estimated that in 2020, 1,000 Canadians were diagnosed with cHL and 100 died from the disease.¹ Clinically, HL presents most commonly with enlarged cervical lymph nodes, and spread is generally between contiguous nodal areas. Mediastinal masses and B symptoms (fever, weight loss, and night sweats) are common. A bimodal age distribution is appreciated for HL, with most patients diagnosed between the ages of 15 years to 39 years. A second peak is seen in individuals older than 70 years.² HL is diagnosed by biopsy of an affected tissue or organ. On histopathology large, atypical, and malignant cells, termed Reed-Sternberg or Hodgkin cells, are observed in a heterogeneous background consisting of non-neoplastic inflammatory cells.³ Subclassification of HL into cHL (nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted) and nodular lymphocyte-predominant HL is based on the degree of atypia of the malignant cells, their immunophenotype, and the features of the inflammatory background.

Standards of Therapy

The treatment of cHL is guided by careful assessment of stage- and disease-specific risk factors.¹⁹ F-fluorodeoxyglucose PET is considered the gold standard for staging of HL and the Cotswold modification of the Ann Arbor staging system is applied to determine the numerical stage. In 1998 Hasenclever et al. published a prognostic score for adult patients with advanced HL consisting of 7 clinical (sex, age, and stage) and laboratory (anemia, leukocytosis, reduced serum albumin, and lymphopenia) factors. This score predicts freedom from progression (84% for patients with no risk factors to 42% for those with 5 or more factors) and OS (89% for patients with no risk factors to 56% for those with 5 or more factors) at 5 years.⁴ Treatment is risk-adapted, with low-risk patients (stage I to II, few risk factors) receiving a limited number of cycles of ABVD (doxorubicin-bleomycin-vinblastine-dacarbazine) chemotherapy, often with low-dose involved field radiotherapy^5,6 while those with higher-risk disease receiving more extensive chemotherapy. Intensive chemotherapy, in the form of escalated BEACOPP (bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone), is reserved for patients with the highest risk of adverse outcome.⁷ Response-adapted therapy with the use of interim PET restaging is used to de-escalate treatment for patients who are likely cured^8,9 and to escalate treatment of patients who are not responding as expected.^8,10 Risk- and response-adapted combined modality therapies are similarly used in pediatric protocols with some differences in chemotherapy backbones.¹¹ Recognizing the shared clinic-pathological features of HL in the most affected age groups, North American adult and pediatric study groups have amalgamated efforts to study new agents using a common chemotherapy backbone.¹² The outcome of HL has improved significantly over time and today more than 80% of patients with cHL are cured with initial therapy.^2,13

Most patients who do not respond to or who relapse after first-line treatment for HL are treated with high-dose chemotherapy and autologous cell transplantation.¹⁴ This approach is supported by 2 randomized trials,^15,16 several phase II^17-20 and registry²¹ studies, and results in PFS in 50% to 60% of patients and OS in 60% to 80% of patients. Careful patient selection is required for successful ASCT as the presence of multiple or severe comorbidities may make the treatment-related mortality of high-dose therapy prohibitive. Patients may also not undergo ASCT if they fail to mobilize sufficient numbers of hematopoietic stem cells to support the use of high-dose chemotherapy, if they fail to respond to salvage chemotherapy, or for reasons of conscience as in the case of Jehovah’s Witnesses. Overall, approximately 85% of patients with relapsed or refractory cHL undergo ASCT.

There is currently no standard of care for patients with cHL who relapse after ASCT or who are ineligible for ASCT for 1 of the reasons noted above. Options to treat these patients include chemotherapy, radiotherapy (for those with localized recurrences), targeted therapy with BV, and immune checkpoint inhibitors. Although responses to standard-dose chemotherapy occur frequently in later lines of treatment, the use of conventional-dose salvage chemotherapy is unlikely to lead to cure in these patients.²² Good palliation can be achieved with oral single-agent or combination chemotherapy regimens.^23,24 BV is an antibody-drug conjugate that targets CD30-positive cells, delivering the antimitotic agent MMAE into the cytoplasm of these cells by endocytosis.²⁵ The utility of BV in relapsed or refractory cHL was demonstrated in a pivotal phase II study in 102 patients who failed ASCT. The overall response rate was 75% with complete responses seen in 34% of patients and toxicity was manageable, although peripheral neuropathy was frequently dose limiting.²⁶ After 5 years of follow-up, OS in this cohort of 102 patients was 41% and PFS was 22%: Median OS and PFS were higher among those patients who achieved complete remission to BV.²⁷ Real-world experience with BV in transplant-ineligible relapsed or refractory cHL was provided in a phase II study of 136 patients with a median age of 70 years at diagnosis. The most common reasons for transplant ineligibility in this cohort were comorbidities and age. A median of 8 cycles was given and overall and complete responses were observed in 74.3% and 34.6% of patients, respectively, similar to the results seen in patients who had previously undergone ASCT. Median progression-free and OS were 15.1 and 17.8 months, respectively.²⁸

Immune checkpoint inhibitors affect the PD1/PD-L1 axis and lead to increased immune reactivity against cancers that have exploited this mechanism to escape immune control. Nivolumab is a human IgG monoclonal antibody that targets PD1. Nivolumab is licensed for treatment of patients with advanced hepatocellular carcinoma, non–small cell lung cancer, advanced renal cell carcinoma, and certain cases of colorectal carcinoma or malignant melanoma. It is also approved for treatment of patients with cHL who have progressed after ASCT and BV or 3 or more lines of systemic therapy including hematopoietic cell transplantation.²⁹ The indication in cHL is based on the results of the CHECKMATE-205 and CHECKMATE-039 studies, which enrolled a total of 95 patients, demonstrating an overall response rate of 66% and complete and partial remission of 6% and 60%, respectively. Median DOR was 13.1 months. Toxicity was manageable, although immune-mediated toxicity was observed.^30,31 A second immune checkpoint inhibitor, pembrolizumab, is the subject of this CADTH review.

Drug

The medication under review is pembrolizumab 200 mg in adults or 2 mg/kg in pediatrics, as monotherapy, administered intravenously every 3 weeks for patients with cHL who have failed ASCT or are ineligible for multi-agent salvage chemotherapy and ASCT. This indication is consistent with the Notice of Compliance provided by Health Canada. This medication has not been assessed by CADTH for this indication in the past.

Stakeholder Perspectives

Patient Group Input

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

One patient group, Lymphoma Canada, provided input for the review of pembrolizumab for adult and pediatric patients with refractory or relapsed cHL. The indication under consideration is pembrolizumab as monotherapy, for those who have failed ASCT, or who are not candidates for salvage chemotherapy and ASCT. Lymphoma Canada is a national charity that collaborates with patients, caregivers, health care professionals, and other stakeholders to empower the lymphoma community.

Lymphoma Canada conducted 2 anonymous, online surveys of patients with HL. One survey was conducted from June 5 to 30, 2017, to which 91 patients responded. No caregivers responded. The other survey was conducted from November 6, 2020, to January 13, 2021, to which 37 patients responded. The survey link was provided via email to patients registered with Lymphoma Canada, and made available via social media platforms, HL-specific forums, and social media groups, Canadian and American Cancer Society message boards, and with physicians at Canadian clinical trial sites. The survey included multiple-choice questions, rating questions, and open-ended questions. Three patients with HL in Canada, who had direct experience with pembrolizumab, were interviewed over the phone.

Not all respondents provided demographic information (103 out of 128 provided this information for country, and 94 out of 128 provided age and gender information). Of those that did provide demographic information, the majority (55%) were from Canada. Of the 9 patients with pembrolizumab experience, 7 reside in Canada, and 2 reside in the US. Table 5 details the country of survey respondents. Of those that provided demographic information, most respondents are male (54%). Most patients are between the ages of 20 to 59 years of age (78%). Table 6 details the gender and age of the survey respondents.

Disease Experience

Experience at Diagnosis

Most of the survey respondents were between the ages of 13 years to 39 years when they were diagnosed (63%; 80 of 128 respondents). When asked about their experience receiving their diagnosis, 11% of respondents did not have all their questions answered, and 27% did not know what questions to ask their doctor who did not explain the disease to them (81 respondents). Some patients commented:

• “I was a teenager and was told I had Hodgkins disease – I didn’t know what that was and no one told me.”

• “Who can think of questions to ask when you receive this kind of news, especially when you’re 23…”

At diagnosis, the HL symptoms that most affected respondents’ quality of life were (based on the responses of 97 patients):

• fatigue or lack of energy (77%)

• enlarged lymph nodes (66%)

• drenching night sweats (44%)

• itching (40%)

• persistent cough (40%)

• unexplained weight loss (35%).

Other symptoms affecting the quality of life for greater than 10% of respondents included loss of appetite, trouble breathing, fever and chills, and chest pain.

When asked about the negative mental and emotional impacts of their disease and treatment, which affected their quality of life at diagnosis, most patients had 1 or more negative impacts (based on the responses of 97 patients):

• anxiety/worry (74%)

• stress of diagnosis (64%)

• difficulty sleeping (52%)

• problems concentrating (44%)

• loss of sexual desire (36%)

• depression (28%)

• memory loss (12%).

Current Experience

Thirty-five patients responded to questions about their current symptoms and quality of life. Current symptom experience, for those that responded, included the following:

• fatigue/lack of energy (51%)

• no symptoms (43%)

• trouble breathing (17%)

• fever/chills (14%)

• loss of appetite (14%)

• itching (14%).

In all, 113 patients provided information on current social and psychological impacts. These include the following:

• anxiety/worry (53%)

• problems concentrating (42%)

• loss of sexual desire (33%)

• memory loss (30%).

Table 7 describes the negative impact of HL on the quality of life of patients.

Three patients describe their experience with HL this way:

• “In remission since 2019 but dealing with long-term effects like ‘chemo brain,’ some PTSD and anxiety about recurrence. Plus, because of COVID and increased risk of complications if I catch it, I’m more nervous than most about gathering (when permitted) with even small groups of people.”

• “I immediately lost my job, as I worked in an environment not safe for someone with a compromised immune system. I had to give up my study at university, and both devastated me. I was very fit, but now if I try to exercise at the same level, I become exhausted very easily. It’s very hard.”

• “I experience more fatigue than I used to and although I’m able to work, I'm exhausted at the end of the day. Exercise is difficult to do on a weekday.”

Experiences With Currently Available Treatments

Of the 85 patients who provided information on previous treatments, all had received treatment or are currently undergoing treatment. Most (94%) had received at least 1 line of conventional chemotherapy, and 24% had received 3 or more lines of therapy. Regarding chemotherapy, the most common regimen received was ABVD (85%). GDP (gemcitabine, dexamethasone, cisplatin) was the next most common (11%), followed by BEACOPP (7%), and least common was BV (6%).

Regarding other treatments, 83 patients provided information, of which 49% received radiation therapy, 20% had an ASCT, and 25% had surgery.

In all, 101 patients indicated their current treatment phase. Following their most recent line of therapy, 85% of respondents are in remission, of which 32% have been in remission for longer than 5 years.

Many respondents are concerned with toxicity and side effects of previous treatments. Table 8 details the most common side effects experienced by respondents during their treatments for HL.

When asked which side effects patients found most difficult to tolerate, respondents reported nausea/vomiting (43%), fatigue (41%), hair loss (13%), mouth sores (10%), and bowel obstruction (4%) (68 respondents). Long-lasting side effects of treatments, reported lasting longer than 2 years or appearing 2 years or later after treatment, included fatigue (66%), “chemo brain” (60%), peripheral neuropathy (41%), loss of menstrual periods (18%) and sterility (18%), chest pain or infection (15%), and thyroid problems (20%) (80 respondents).

Table 9 details the impact of treatment on respondents’ quality of life. The question was a scale from 1 to 5, where 1 equals “no impact” and 5 equals “significant negative impact.”

Table 10 details the impact of treatment on respondents’ daily living. The same scale as the question detailed in Table 9 was used.

When discussing treatments and side effects, 3 respondents reported their experience in this way:

• “Treatments were very difficult, and it took everything in me to complete my 6-month protocol. In fact, the last 2 [months] I almost begged not to have [treatment]. I have a lot of fear of recurrence because I feel I could not go through that experience again especially now that my body has changed so drastically since my initial experience with chemo. I felt young and fit prior to treatment and 3 years later I feel physically like an old woman which I was not mentally prepared for.”

• “The chemotherapy I received before and with my bone marrow transplant put me into premature menopause (I’m in my 20s) and that has negatively affected my intimate relations.”

• “I was unable to finish the first semester of nursing school at the time. I was unable to help coach basketball because of low self esteem from hair loss and fatigue. Did not really want to go places and visit friends because of hair loss.”

Access to Treatment

Many patients (83% of the 90 individuals who responded) were able to access treatment in their own communities. For the 15 patients who were unable to access treatment in their own communities, 73% lived in a community without a cancer care centre and for 26%, the treatment was not available at the local cancer care centre.

Table 11 details the financial impact of treatment.

Improved Outcomes

Patients seek individualized treatment options that provide disease control and remission, with fewer side effects than current treatment options available. When asked about important factors of new drugs or treatments for HL, “longer survival” and “longer remission” were the most important outcomes. Table 12 details the responses from the 24 patients who answered this question. The scale for the question ranged from 1 (“not important”) to 5 (“extremely important”).

Of the 89 respondents who were asked if they would be willing to tolerate short-term side effects of a new treatment, 55% would be willing to tolerate potential short-term side effects, while 31% were not; the remaining 14% were unsure. Respondents were also asked if they would choose a treatment with known and potentially serious side effects if their doctor recommended it was the best option for them. Of the 100 patients who answered this question, 53% selected “Yes,” while only 3% selected “No”; the remaining 44% were unsure.

The survey asked respondents how important it is for patients and physicians to have a choice of therapy (a scale of 1 to 10, with 1 being “not important,” and 10 being “very important”). Most participants (79%) rated this a 7, 8, 9, or 10 (weighted average was 8.2).

A scale of 1 (“least important”) to 10 (“most important”) was used to ask survey participants which HL symptoms would be most important for a new treatment to control. One hundred respondents answered this question. Patients rated the most important symptoms for new treatments to control include difficulty breathing (8.1), drenching night sweats (7.2), chest pain (7.6), fatigue/lack of energy (7.4), and enlarged spleen or abdominal discomfort (7.0).

Experience With Drug Under Review

Nine patients had experience with pembrolizumab; 3 of these patients were interviewed for the patient input submission. The reasons for starting treatment with pembrolizumab include: no other treatment options were available (2 patients); HL progressed after autologous transplant and did not want to risk the potential toxicity of an allogeneic transplant (4 patients), hoping for remission to proceed to allogenic transplant (1 patient); did not respond to 3 previous lines of chemotherapy, and did not want to undergo an autologous transplant (2 patients).

Table 13 details the patients with pembrolizumab experience.

All 9 patients had at least 2 prior lines of conventional chemotherapy, and 3 of these patients had received 6 or more lines of therapy. Previous chemotherapy treatments included ABVD (8), GDP (6), GVD (2), COPP (1), DHAP (1), bendamustine (1), lenalidomide (1), and unknown (1). Regarding other therapies, 7 patients had undergone an ASCT, 1 had undergone an allogeneic stem cell transplant and 4 had received treatment with BV before beginning treatment with pembrolizumab. When asked which symptoms pembrolizumab managed, 7 of the 9 patients responded that pembrolizumab managed all their HL symptoms, including fatigue, enlarged lymph nodes, frequent infections, weight loss, night sweats, shortness of breath, and pain. Two patients reported that pembrolizumab did not manage their fatigue.

Regarding the side effects of pembrolizumab, 8 patients tolerated this therapy well. However, 1 patient had to stop treatment with pembrolizumab because of toxicity and side effects, including peripheral neuropathy and inflammatory arthritis for which medication was taken. Table 14 outlines the side effects of pembrolizumab.

Knowing the potential side effects, all 9 patients responded that they would take this drug again if their doctor thought it was the best choice. The patient who had to stop treatment due to toxicity stated, “PFS was worth the side effects.”

When asked how the side effects of pembrolizumab compared to other treatments, 3 patients provided comments:

• “It’s night and day, compared to chemo. It should be the first treatment offered to patients – it is so much better than chemo, no awful side effects, only a 30-minute infusion.”

• “No side effects at all! This is the best drug ever given to me!”

• “Due to this drug, I’m able to go back to work as a nurse part-time. I don't have to take any other meds to manage side effects, which cost a lot when I was taking chemotherapy.”

Regarding quality of life and impact on daily activities, 7 of the 9 patients reported that they did not experience any negative impact on work or school, family obligations, friendships, intimate relations, activities, or travel. One patient reported lasting fatigue that was thought to have been due to the drug, and the fatigue limited aspects of their life. The patient with lasting side effects of peripheral neuropathy and inflammatory arthritis had this negatively impact their family life and personal image.

Overall Experience With Pembrolizumab

All 9 patients said they had a good to excellent experience with pembrolizumab, and all would take this treatment if offered to them again. Based on their own experience, all 9 patients would recommend this therapy to other patients with HL.

When reflecting on their overall health and well-being, 3 patients had this to say:

• “I felt like I was back to normal for the first time since I was diagnosed. I was able to do everything again and not think about my cancer. I could work again and have a normal social life.”

• “I finally feel well enough to start looking forward in life. I still can't work because of side effects from previous treatments, but I’m able to enjoy life again.”

• “Everybody should be able to take this drug instead of going through chemo. It has been so much better for me.”

Companion Diagnostic Test

There is no companion diagnostic testing for pembrolizumab.

Clinician Input

Input From 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 3 clinical specialists with expertise in the diagnosis and management of pediatric and adult cHL.

Unmet Needs

For pediatric patients, the clinical expert highlighted that the current treatment options are aggressive cytotoxic chemotherapy, which can have serious side effects such as infections and organ toxicities. If patients do not respond to these treatments, there are limited remaining treatment options. The goal for pediatrics is cure of disease whenever possible, as well as minimizing AEs and treatment-related morbidities, improving HRQoL, and delaying disease progression.

The experts who treat adult patients stated several unmet needs in this patient population, mainly that none of the currently available treatments are curative. Current treatments are also limited by their means of administration (e.g., IV administration, which requires a hospital visit) and toxicity associated with treatment. There is a need for better tolerated treatments, formulations to improve convenience, and treatments for patients who do not respond or become refractory to current treatments.

Place in Therapy

The pediatric clinical expert highlighted that studies evaluating the addition of pembrolizumab to upfront and first salvage therapies is highly anticipated. The successful application of pembrolizumab in the relapsed and refractory cHL setting could offer a potential cure, prolonged disease control, and improved quality of life for these patients that are highly pre-treated with other drug therapies.

The adult clinical expert stated that pembrolizumab has the potential to be used earlier in the current treatment paradigm. They highlighted findings that support the use of pembrolizumab after failed ASCT, or as a second-line therapy for patients who are not eligible for salvage chemotherapy or ASCT. Pembrolizumab, while used as a single therapy currently, could potentially be combined with other therapies such as chemotherapy for patients who relapse.

Patient Population

For pediatric patients, the clinical expert suggests that patients meeting criteria, and without comorbidities that would make them ineligible, should be considered for treatment with pembrolizumab. For the adult population, patients with relapsed cHL would be identified by their hematologist or oncologist (their disease state may be apparent by patient symptoms, clinical examination, or medical imaging). Relapsed disease would be confirmed by a biopsy.

It was noted that patients with relapsed and refractory cHL are closely monitored for disease progression. If patients relapse, they are generally offered treatment regardless of whether or not their lymphoma is causing them symptoms; otherwise, their disease will continue to progress. None of the experts were aware of biomarkers that can determine which patients will respond to treatment; in early studies for checkpoint inhibitors, evidence of PD1 or PDL1 expression on biopsy samples was required, but this incidence is almost 100% in patients with cHL and no longer a requirement.

Patients least suited to pembrolizumab, as noted by the pediatric clinical expert, are those patients on therapy or recently on therapy for autoimmune disease, patients with poor performance status, or patients with organ failure. The adult experts highlighted that some patients with localized disease may be better suited for radiation therapy and that patients at high risk for autoimmune side effects with pembrolizumab would be least suited to this treatment.

Assessing Response to Treatment

The pediatric expert commented that a clinically meaningful response to treatment would be resolution of disease symptoms and radiologic evidence of disease response. This response would lead to an allogenic stem cell transplant, if eligible, or to ASCT if previously ineligible, along with improved HRQoL outcomes, and improved ability to perform activities of daily living. Treatment response should be assessed after the first 2 to 4 cycles of therapy (corresponding to 6 to 12 weeks), and then every 12 weeks thereafter.

For adult patients, the clinical experts highlighted improvement in symptoms, radiological evidence of disease response, and reduction in the size of lymph nodes and other disease sites. Goals of treatment would be response (either partial or complete); improved survival; improved quality of life, including ability to perform the activities of daily living and a return to work; and improved symptoms, but ideally complete resolution of symptoms. Patients receiving pembrolizumab are assessed clinically at every visit (every 3 weeks) and radiologically every 3 to 4 cycles.

Discontinuing Treatment

Treatment should be discontinued if there is disease progression, severe immune-related AEs, or severe infusion or hypersensitivity reactions. The pediatric expert noted that checkpoint inhibitors, including pembrolizumab, may be associated with a phenomenon called pseudoprogression, an inflammatory response which does not represent disease progression. Disease response should be carefully considered.

Prescribing Conditions

Pediatric oncologists or adult hematologists or oncologists are required to diagnose, treat, and monitor patients with relapsed or refractory cHL who are receiving pembrolizumab. If a patient experiences an immune-related AE, they may be referred to another specialist. Pembrolizumab can be given in the outpatient setting.

Clinician Group Input

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

Three registered clinician groups provided input for this review. One submission was by the Ontario Health Hematology Disease Site Drug Advisory Committee (Cancer Care Ontario; OH-CCO DAC), which included 6 physicians. OH-CCO DAC provides evidence-based clinical and health system guidance for the Provincial Drug Reimbursement Programs and Systemic Treatment Program. The Lymphoma Canada Scientific Advisory Board provided a separate submission; the group consisted of 5 clinicians. Lymphoma Canada is a not-for-profit organization for Canadian patients with lymphoma and chronic lymphocytic leukemia and more information on this organization can be found at www.lymphoma.ca. POGO also completed a submission; this submission was coordinated by 1 physician, with the input from POGO’s Therapeutic and Technology Advisory Committee. Ontario’s 5 specialized childhood cancer centres, and an official advisor to the Ontario Ministry of Health and Long-Term Care, comprise POGO. More information about POGO can be found at www.pogo.ca.

Unmet Needs

Both Lymphoma Canada and OH-CCO DAC identified highest unmet need in patients who have failed ASCT or are ineligible for ASCT. Lymphoma Canada noted that across the country there are “access gaps” for novel therapies (e.g., BV and anti-PD1 antibodies), due to lack of funding. OH-CCO DAC also echoed that BV is not covered for patients who are transplant ineligible. For patients that are not able to receive ASCT because of a lack of disease response, these patients need an effective therapy to position them to receive ASCT. Lymphoma Canada also stated that standard therapies (e.g., salvage chemotherapy) typically are more toxic and less effective than novel therapies; they also are not associated with favourable PFS or OS, or meaningful long-term disease control. They noted that novel therapies with a favourable efficacy to toxicity ratio are needed.

In the submission from POGO, they identified the greatest unmet need to be patients who have relapsed or refractory cHL and who have had previous exposure to BV. Even in the relapsed or refractory cHL child and adolescent population, the goal of therapy is cure and disease response.

Place in Therapy

In the submission from Lymphoma Canada, pembrolizumab, as supported by the KEYNOTE-204 clinical trial, would be used for patients with relapsed or refractory cHL after primary therapy if they are ineligible for ASCT, and in other patients who have received at least 2 prior lines of therapy, or have relapsed after ASCT. This is in-line with using pembrolizumab in second-line or beyond. It is anticipated that clinical practice would change based on the data from the KEYNOTE-204 study; for example, pembrolizumab would be used instead of BV in the post-ASCT population, or for patients who are not eligible for ASCT and have received prior therapy. It is thought that pembrolizumab might replace BV regarding place in therapy, for patients with relapsed or refractory cHL (funding for BV is limited).

The submission from OH-CCO DAC identified that younger patients who failed first-line therapy and do not respond to salvage chemotherapy (i.e., are ineligible for ASCT), would likely receive pembrolizumab. Older patients who fail first-line therapy and are not eligible for ASCT due to comorbidities or age would likely receive pembrolizumab instead of salvage chemotherapy.

For the pediatric population, where many patients have had past exposure to BV, pembrolizumab would be used after BV. Pembrolizumab would be appropriate for patients who have already received an ASCT and BV, or who fail to respond to BV or experience toxicity.

Patient Population

Both OH-CCO DAC and Lymphoma Canada identified patients who met the criteria outlined by the KEYNOTE-204 clinical trial as experiencing the greatest unmet need for patients with relapsed or refractory cHL, and most suited to receive pembrolizumab. Lymphoma Canada specifically noted adult patients who experienced failure of primary treatment, or who have not responded to second-line treatment. They also identified children and adolescents with relapsed or refractory cHL who have experienced failure after ASCT. Lymphoma Canada stated that most patients with relapsed or refractory cHL would be eligible for pembrolizumab. POGO identified patients who have progressive or relapsed disease after BV, or who are unable to tolerate it, but have acceptable performance status (ECOG 0 or 1 or Lansky Performance Scale score > 60) as most in need of and best likely to tolerate pembrolizumab.

Assessing Response to Treatment

To assess treatment response, Lymphoma Canada identified that patients typically undergo serial imaging (i.e., fluorodeoxyglucose PET) to monitor disease progression, regardless of ASCT eligibility. POGO also identified cross-sectional imaging and PET scans as the means for determining disease progression and treatment response. OH-CCO DAC stated that disease response is determined by standard response criteria, including imaging. Frequency of imaging varies across the country, but typically for the ASCT-eligible population it has typically been done at 3 months, and 1 year after ASCT. For the ASCT-ineligible population, imaging could be based on patient symptoms or after treatment. A clinically meaningful response to treatment would include improvement in disease related symptoms, tumour response, and disease control (i.e., PFS or OS). POGO and OH-CCO DAC suggested disease status should be assessed every 12 weeks, at minimum.

Discontinuing Treatment

When deciding to discontinue treatment, Lymphoma Canada and POGO indicated that disease progression and significant toxicities (i.e., AEs, particularly grade 3 or 4 events, and immune-related events) would be important considerations.

Prescribing Conditions

The submission from Lymphoma Canada stated that there is evidence to support the use of anti-PD1 antibodies in a variety of malignancies, with administration of treatment in the community setting, hospitals, and tertiary cancer centres. OH-CCO DAC stated that outpatient clinics would be suitable to administer pembrolizumab. For the pediatric population, POGO suggested that pembrolizumab be administered in specialized pediatric cancer programs only.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 15.

Clinical Evidence

The clinical evidence included in the review of pembrolizumab is presented as a systematic review which 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.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the efficacy and safety of pembrolizumab, as monotherapy, in adult and pediatric patients with refractory or relapsed cHL, who have failed ASCT or who are not candidates for salvage chemotherapy and ASCT.

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 16.

Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

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.⁴¹ Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via 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 classical HL. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register. No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies. The initial search was completed on March 17, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee meeting on July 15, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.⁴² Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

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.

A focused literature search for network meta-analyses dealing with HL was run in MEDLINE All (1946–) on March 17, 2021. No limits were applied to the search.

Findings From the Literature

A total of 359 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 17. Six reports based on 3 unique studies were identified and were all provided by the sponsor; no additional unique studies were identified from the literature search. No network meta-analyses were identified.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

KEYNOTE-051

The KEYNOTE-051³² study was a nonrandomized, open-label, single-arm trial of pembrolizumab 2 mg/kg administered every 3 weeks in 7 pediatric patients with cHL aged 3 years to 18 years. A 28-day screening period was performed before patient enrolment to collect necessary laboratory, diagnostic, and demographic information and assess study eligibility. The KEYNOTE-051 study evaluated safety and efficacy including ORR, DOR, PFS, and OS for 35 cycles of treatment or until discontinuation due to disease progression or AE. Post-treatment follow-up assessments occurred every 12 weeks. The study was funded by the sponsor and had a data cut-off date of January 2020.

KEYNOTE-087

The KEYNOTE-087³³ study was a nonrandomized, single-arm study of pembrolizumab 200 mg administered every 3 weeks in adult patients with cHL. A 28-day screening period was performed before patient enrolment to collect necessary laboratory, diagnostic, and demographic information and assess study eligibility. The study evaluated ORR, PFS, DOR, HRQoL, and OS with a treatment duration up to 2 years, or until discontinuation of treatment due to disease progression, or occurrence of AE. Post-treatment follow-up assessments occurred every 12 weeks. The study was funded by the sponsor with a data cut-off date of March 2019. The study consisted of 3 cohorts:

• Cohort 1: Patients who failed to respond to or progressed after ASCT and also relapsed after or failed to respond to treatment with BV after ASCT (N = 69)

• Cohort 2: Patients who were ineligible for ASCT and relapsed after or failed to respond to BV (N = 81)

• Cohort 3: Patients who failed to respond to or progressed after ASCT and had not yet received BV (N = 60)

KEYNOTE-204

The KEYNOTE-204³⁴ study was a phase III, randomized (1:1 ratio), active controlled, open-label clinical trial comparing pembrolizumab 200 mg administered intravenously every 3 weeks (N = 151) with BV 1.8 mg/kg (maximum dose of 180 mg) administered intravenously every 3 weeks (N = 153) in adult patients with cHL. A 28-day screening period was performed before patient enrolment to collect necessary laboratory, diagnostic, and demographic information and assess study eligibility. The study evaluated PFS, OS, ORR, DOR, time to response, HRQoL, and safety for 35 cycles of treatment or until early discontinuation due to disease progression, unacceptable AEs, or other reasons to withdraw therapy. Post-treatment follow-up assessments occurred every 12 weeks. The study was funded by the sponsor with data cut-off date of February 2020. A diagram of the KEYNOTE-204 study design is provided in Figure 2.

Inclusion and Exclusion Criteria

The KEYNOTE-051 study recruited children and adolescents aged 3 years to 18 years with cHL who were either refractory to front-line therapy, high-risk and relapsed from front-line therapy, or relapsed or refractory to second-line therapy. The KEYNOTE-051 study did not explicitly recruit patients who failed ASCT or were ineligible for salvage chemotherapy and ASCT. The KEYNOTE-051 study recruited those with a Lansky Play-Performance Scale score of 50 or greater for children 16 years and younger or a Karnofsky score of 50 or greater in children 16 years and older. The KEYNOTE-051 study also excluded those who received prior systemic anticancer therapy including investigational agents within 2 weeks of the study’s start date or patients who had not recovered from AEs due to a previously administered agent. The KEYNOTE-087 and KEYNOTE-204 studies recruited adults 18 years or older with an ECOG score of 0 or 1. The KEYNOTE-087 study divided patients into 3 cohorts as follows.

• Cohort 1: Failed to respond to or progressed after ASCT and also relapsed after or failed to respond to treatment with BV after ASCT

• Cohort 2: Ineligible for ASCT and also relapsed after or failed to respond to BV

• Cohort 3: Failed to respond or progressed after ASCT and had not yet received BV

Finally, patients recruited into the KEYNOTE-204 study had relapsed or refractory cHL and met 1 of the following criteria.

• Failed to achieve a response or progressed after ASCT and had not previously been treated with BV

• Were not ASCT candidates due to chemo-resistant disease, advanced age (≥ 65 years), or a condition likely to have a negative impact on the tolerability to ASCT; these patients must have received at least 2 prior multi-agent chemotherapy regimens that did not include BV

Both the KEYNOTE-087 and KEYNOTE-204 studies excluded those who received a prior monoclonal antibody within 4 weeks before the study’s start date or who had not recovered from AEs due to agents administered more than 4 weeks earlier. Both studies also excluded those who had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks before the study’s start date or who had not recovered from AEs due to a previously administered agent.

Figure 2: Study Design of KEYNOTE-204

Source: Clinical Study Reports for KEYNOTE-204

Baseline Characteristics

Patients in the KEYNOTE-051 study had a median age of 15 years while the median age in the KEYNOTE-087 and KEYNOTE-204 studies ranged from 32.0 years to 40.0 years. The proportion of female patients ranged from 41.2% among BV patients in the KEYNOTE-204 study to 47.8% among cohort 1 of the KEYNOTE-087 study. The proportion of patients with an ECOG score of 0 ranged from 42.0% in cohort 1 of KEYNOTE-087 to 65.4% among BV patients from the KEYNOTE-204 study. The proportion of patients with an ECOG score of 0 was 54.3% and 48.3% in cohorts 2 and 3, respectively, of KEYNOTE-087, and 57.0% in the pembrolizumab arm of the KEYNOTE-204 study. Cohorts 1 and 3 of the KEYNOTE-087 study had higher rates of prior radiation use (46.4% and 40.0%, respectively) relative to either arm in the KEYNOTE-204 study (pembrolizumab: 38.4% and BV: 39.9%), while those in cohort 2 had lower rates (25.9%). Patients in either arm of the KEYNOTE-204 study had more bulky disease (pembrolizumab: 23.2% and BV: 16.3%) relative to any cohort in the KEYNOTE-087 study (cohort 1: 2.9%, cohort 2: 6.2%, and cohort 3: 1.7%). Baseline B symptoms were present in 30.4%, 33.3%, and 31.7% of patients in cohort 1, cohort 2, and cohort 3 of the KEYNOTE-087 study, respectively. Baseline B symptoms were also present in 28.5% and 23.5% of pembrolizumab and BV patients, respectively, in the KEYNOTE-204 study. The 2 arms within the KEYNOTE-204 study seem relatively balanced except that pembrolizumab patients had higher rates of bulky disease (23.2% versus 16.3%). A complete summary of baseline characteristics is provided in Table 18. Patients in the KEYNOTE-204 study were permitted to be treated with a subsequent anticancer medication after pembrolizumab or BV was discontinued. Almost all patients randomized to BV (97.4%) received a subsequent anticancer therapy while 70.2% of pembrolizumab-treated patients did so. Those randomized to BV were more likely to cross over and subsequently receive pembrolizumab (17.8% versus 1.4% of patients originally randomized to pembrolizumab and retreated with pembrolizumab). Those originally randomized to BV were also more likely to receive nivolumab (19.7%) relative to those randomized to pembrolizumab (3.4%). Finally, 25.0% of patients originally randomized to pembrolizumab received BV while 4.6% of patients originally randomized to BV were retreated with BV (Table 19 and Appendix 2).

Interventions

KEYNOTE-051

KEYNOTE-051 studied pembrolizumab 2 mg/kg intravenously every 3 weeks until 35 cycles were administered, disease progression, unacceptable AEs, intercurrent illness preventing further administration, investigator decision to withdraw therapy, patient withdrawal, pregnancy, noncompliance, or administrative reasons. Patients were prohibited from concurrently using granulocyte-macrophage colony-stimulating factor, immunotherapy (other than pembrolizumab), chemotherapy, biologic therapy, investigational agents other than pembrolizumab, radiation, live vaccines, and glucocorticoids for any reason other than to treat an AE. Otherwise, patients were permitted to concurrently receive any medication necessary for the patient’s welfare so long as they adhered to standards of medical care and medication use was documented.

KEYNOTE-087

In each of the 3 cohorts of the KEYNOTE-087 study, pembrolizumab 200 mg was administered intravenously every 3 weeks for 2 years or until documented and confirmed disease progression, intolerable toxicity, or patient or investigator decision to withdraw. Patients were prohibited from concurrently using granulocyte-macrophage colony-stimulating factor, immunotherapy (other than pembrolizumab), chemotherapy, biologic therapy, investigational agents other than pembrolizumab, radiation, live vaccines, and glucocorticoids for any reason other than to treat an AE. Otherwise, patients were permitted to concurrently receive any medication necessary for the patient’s welfare so long as they adhered to standards of medical care and medication use was documented.

KEYNOTE-204

Pembrolizumab 200 mg or BV 1.8 mg/kg (maximum dose of 180 mg) was administered intravenously every 3 weeks for 35 cycles or until disease progression, unacceptable AEs, intercurrent illness preventing further administration, investigator decision to withdraw therapy, patient withdrawal, pregnancy, or administrative reasons. Patients in either arm were permitted to receive subsequent anticancer therapy after discontinuing pembrolizumab or BV. Further, those originally randomized to pembrolizumab were able to then receive BV while those originally randomized to BV were permitted to receive pembrolizumab. Patients were prohibited from concurrently using granulocyte-macrophage colony-stimulating factor, immunotherapy (other than pembrolizumab), chemotherapy (other than BV), biologic therapy, investigational agents other than pembrolizumab and BV, radiation, live vaccines, glucocorticoids for any reason other than to treat an AE, and in those receiving BV, potent CYP3A4 inhibitors or inducers or P-glycoprotein inhibitors. Otherwise, patients were permitted to concurrently receive any medication necessary for the patient’s welfare so long as they adhered to standards of medical care and medication use was documented.

In all 3 trials, if a patient experienced an immune-mediated AE, they could be treated with corticosteroids, anti-inflammatory agents if symptoms did not improve following corticosteroid treatment, insulin, non-selective beta blockers, thyroid hormone replacement therapy, antihistamines, nonsteroidal anti-inflammatory drugs, acetaminophen, opioids, vasopressors, and epinephrine. Supportive care was permitted as deemed necessary by the treating physician.

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 20. These end points are further summarized below. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 3.

Progression-Free Survival

In the KEYNOTE-051 and KEYNOTE-087 studies, PFS was defined as time from first dosing date to the first documented progressive disease, death due to any cause, or start of new anticancer medication, whichever came first by blinded independent central radiology assessment and using International Working Group (IWG) response criteria. The IWG guidelines utilize diagnostic imaging, immunohistochemistry, and flow cytometry to define response to treatment in non-Hodgkin and HL.⁴⁴

In the KEYNOTE-204 study, PFS was assessed by blinded independent central review according to the IWG response criteria including clinical and imaging data following autologous or allogenic stem cell transplant. PFS was defined as the time from randomization to the first documentation of progression or death from any cause. Patients were censored at the last disease assessment if they received an ASCT or another anticancer therapy. These analyses considered ASCT or initiation of another anticancer treatment as a censoring event. A sensitivity analysis of PFS considered the use of another anticancer medication as a progression event but otherwise had the same definition of PFS.

Overall Survival

In the KEYNOTE-051 and KEYNOTE-087 studies, OS was defined as time from first dose to the date of death. In KEYNOTE-204, OS was defined as the time from randomization to death from any cause. In the KEYNOTE-204 study, patients without death were censored at the date of the last assessment.

Objective Response Rate

In the KEYNOTE-051, KEYNOTE-087, and KEYNOTE-204 studies, ORR was defined as the proportion of patients who had a complete or partial response. All studies assessed response by blinded independent central review and used the IWG criteria.

Complete Remission Rate

Like ORR, complete remission rate was assessed by blinded independent central review using the IWG criteria in the KEYNOTE-051, KEYNOTE-087, and KEYNOTE-204 studies.

Duration of Response

In the KEYNOTE-051 and KEYNOTE-087 studies, DOR was defined as the time from first response to documented progressive disease or death from any cause in patients who achieved a partial response or better using IWG response criteria and by blinded independent central review. Those without a response were excluded from this analysis. DOR in the KEYNOTE-204 study was also assessed by blinded independent central review using IWG criteria but a clear definition of DOR was not provided.

Time to Response

No information was provided regarding time to response in the KEYNOTE-051, KEYNOTE-087, or KEYNOTE-204 studies.

Health-Related Quality of Life

HRQoL was not measured in the KEYNOTE-051 study. In the KEYNOTE-087 and KEYNOTE-204 studies, HRQoL was measured by the EORTC QLQ-C30 and EQ-5D-3L. The EORTC QLQ-30 is a widely used, cancer-specific HRQoL instrument consisting of 30 items measuring 5 functional dimensions (physical, role, cognitive, emotional, and social), 3 symptoms dimensions (fatigue, nausea/vomiting, and pain), 6 additional items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global HRQoL measure. The minimal important difference for adult cancer patients on the EORTC QLQ-C30 scale is 5 but no minimal important difference was identified specifically for patients with cHL.⁴⁵ EQ-5D-3L is another standard instrument to measure health outcomes and is particularly useful to develop economic models. EQ-5D-3L measures mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a 3-point ordinal scale. These measurements can be pooled into a single utility score. Further, the EQ-5D-3L contains a visual analogue scale ranging from 0 to 100 so that participants may rate their general health state. Each of the HRQoL questionnaires were conducted at baseline and at 24 weeks so that the change could be calculated and compared between groups. The minimal important difference for adult cancer patients on the EQ-5D-3L visual analogue scale is 6 to 10 and the minimal important difference for American patients with cancer on the EQ-5D-3L utility scale is 0.05 to 0.08.⁴⁶ No minimal important difference on the visual analogue scale or utility portion of the EQ-5D-3L scale for patients with cHL was identified.

Harms

All 3 studies assessed AEs, serious AEs, and immune-mediated AEs. An AE was defined as any untoward medical occurrence in a patient which does not necessarily have a causal relationship with the treatment. Serious AEs were defined as those which result in death, are life threatening, result in persistent or significant disability/incapacity, result in or prolong an existing inpatient hospitalization, result in a congenital anomaly/birth defect, is another important medical event, results in the development of a new cancer (different from the cancer under investigation), or is associated with an overdose. Immune-mediated AEs were defined as AEs of unknown etiology associated with drug exposure and consistent with an immune phenomenon. The following are examples: pneumonitis, diarrhea/colitis, elevated aspartate aminotransferase, elevated alanine aminotransferase, elevated bilirubin, type 1 diabetes mellitus, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, renal dysfunction, and myocarditis.

Statistical Analysis

Progression-Free Survival

In KEYNOTE-087, PFS was estimated using the Kaplan-Meier method. In the KEYNOTE-204 study, PFS was analyzed using a stratified log rank test and the Kaplan-Meier method and the hazard ratio was estimated using a stratified Cox regression model using the Efron method to handle ties. The analysis was stratified by prior ASCT and cHL status after front-line therapy (primary refractory, relapsed disease < 12 months after completion of first-line therapy, or relapse 12 months or longer after completing first-line therapy). In the KEYNOTE-204 study, the analysis considered ASCT or initiation of another anticancer treatment as a censoring event. A sensitivity analysis of PFS considered the use of another anticancer medication as a progression event but otherwise had the same definition of PFS.

Overall Survival

In the KEYNOTE-087 study, OS was estimated using the Kaplan-Meier method. In the KEYNOTE-204 study, OS was analyzed in the same manner as the PFS analysis. The study protocol stated that if required to adjust for patients receiving subsequent anticancer therapies (following pembrolizumab or BV) in the OS analysis, the rank-preserving structural failure time and 2-stage analysis methods would be used. Rank-preserving structural failure time assumes all patients would receive equal benefit from identical interventions. This method compares time on and off treatment to estimate survival times without treatment and a treatment effect adjusted for subsequent utilization of anticancer therapy. The 2-stage adjustment assumes subsequent utilization of anticancer therapy only occurs following disease progression and uses this point to establish a “secondary” baseline. Within the control group, the treatment effect is estimated between those who do and do not subsequently use anticancer therapy that adjusts for “secondary” baseline characteristics. The incremental treatment effect between these groups is then used to discount the treatment effect observed in those who subsequently use additional anticancer therapies, which are then compared with the experimental group to estimate the treatment effect adjusted for subsequent use of anticancer therapies.

Objective Response Rate

In the KEYNOTE-087 and KEYNOTE-204 studies, ORR was estimated by a point estimate and 95% 2-sided binomial exact CIs using the Clopper-Pearson method. In the KEYNOTE-204 study, the difference in ORR was analyzed using the Miettinen and Nurminen method, weighted by stratum. In this analysis, data were stratified by previous ASCT and cHL status following front-line therapy (primary refractory, relapsed disease < 12 months after completion of first-line therapy, or relapse 12 months or longer after completing first-line therapy). Patients with missing data were assumed to be non-responders.

Complete Response Rate

In the KEYNOTE-087 study, complete response rate analysis consisted of the point estimate and 95% 2-sided exact CI. In the KEYNOTE-204 study, complete response rate was analyzed as in the ORR analysis.

Duration of Response

In the KEYNOTE-087 study, DOR was estimated using the Kaplan-Meier method. Patients without progression were censored on the date of the most recent assessment. In the KEYNOTE-204 study, no explicit statistical analysis was outlined for DOR.

Time to Response

In the KEYNOTE-087 and 204 studies, no explicit statistical analysis was outlined for time to response.

Health-Related Quality of Life

In the KEYNOTE-087 study, HRQoL data were collected at baseline and 24 weeks later in all individuals. The difference in scores between baseline and week 24 was analyzed using a longitudinal data analysis model adjusting for time and ECOG status and then estimated using a least squares mean score and standard error. In the KEYNOTE-204 study, no explicit statistical analysis was outlined for HRQoL.

Harms

In the KEYNOTE-087 study, only descriptive statistics were provided. In the KEYNOTE-204 study, descriptive statistics including point estimates and 95% CIs were estimated and the unstratified Miettinen and Nurminen method was used to assess between-treatment differences.

Interim Analyses

The KEYNOTE-204 study results presented in this report constitute the second of 4 planned interim analyses. The study protocol planned for 1 interim analysis of PFS and 2 interim analyses of OS. An interim PFS analysis was to be conducted 3 months after all patients had been enrolled and once 110 PFS events had occurred. A final PFS analysis was planned once 221 events had occurred. If the PFS hypothesis was not rejected at the interim, then the first interim OS analysis would occur with the final PFS analysis. This assumes that 91 OS events would have been observed at this point. If the PFS hypothesis was rejected at the interim analysis then the interim OS analysis would occur 1 year from the interim PFS analysis or when 91 OS events occurred, whichever came first. If the OS hypothesis was not rejected at that point, a second interim OS analysis would occur at 119 events and if the OS hypothesis was not rejected at that point, a final OS analysis was planned to occur at 146 events. No interim analysis was planned for ORR. The final ORR analysis will occur with the final PFS analysis (when 221 PFS events have occurred).

Multiplicity

In the KEYNOTE-087 study, no multiplicity adjustments were required as each cohort was evaluated independently. All tests of significance were controlled at a 1-sided alpha of 0.025. In the KEYNOTE-204 study, the Mauer and Bretz method was used to allocate and re-allocate type I error between hypotheses and group sequential methods to allocate alpha between interim and final analyses. If the null hypothesis was rejected, the type I error allocated to that hypothesis would be redistributed to other hypotheses. For example, multiplicity could be controlled at 2.5% (1-sided) with 1.25% originally allocated to PFS and OS and none allocated to the ORR hypothesis. If the PFS null hypothesis was rejected, then 0.625% would be allocated to both the OS and ORR test. If the ORR null hypothesis was rejected, then 0.625% would be allocated to the OS analysis. OS testing was planned to occur at the 1.25% level if the PFS null hypothesis was not rejected, at 1.875% if the PFS but not ORR null hypotheses were rejected, or 2.5% if both the PFS and ORR null hypotheses were rejected.

Power Calculations

In the KEYNOTE-087 study, for cohorts 1 and 3, there is 93% power, at a 1-sided 2.5% alpha, to detect a 35% or higher ORR between pembrolizumab and a fixed control rate of 15% using the exact binomial test. This would require at least 16 responses if 60 patients are recruited. In cohort 2, there is 93% power, at a 1-sided 2.5% alpha, to detect a 20% or higher overall response rate in the pembrolizumab arm versus the fixed control rate of 5% using exact binomial test. This would require at least 8 responses out of 60 patients.

On the basis of 194 PFS events, the study had an 85% power to detect a hazard ratio of 0.622 (pembrolizumab versus BV) at and alpha of 1.2% (1-sided), assuming PFS would follow an exponential distribution with a median of 5·6 months in the control.

Analysis Populations

In the KEYNOTE-051 and KEYNOTE-087 studies, all patients who received at least 1 dose of study medication were analyzed in the efficacy and safety analyses. In the KEYNOTE-204 study, the intention-to-treat population was used in the efficacy analysis and the safety analysis consisted of all patients who received at least 1 dose of a study medication.

Results

Patient Disposition

No patient in the KEYNOTE-051 study discontinued the trial. Of the 7 patients in the KEYNOTE-051 study, 2 are still receiving treatment while 5 others had discontinued therapy at the time of data cut-off. In the KEYNOTE-087 study, 72.5%, 84.0%, and 76.7% of patients discontinued treatment in cohorts 1, 2, and 3, respectively, at the time of data cut-off. In the KEYNOTE-204 study, 338 patients were screened, 151 patients were randomized to pembrolizumab, and 153 were randomized to BV. Fewer patients in the pembrolizumab arm (13.2%) discontinued the trial compared to those in the BV arm (28.1%). A notable difference in trial discontinuation was due to deaths (10.6% in the pembrolizumab arm and 17.6% in the BV arm) and withdrawals (2.0% in the pembrolizumab arm and 8.5% in the BV arm). Similarly, treatment discontinuations were lower in the pembrolizumab arm (74.3%) than in the BV arm (96.1%). Notable differences in the reasons for treatment discontinuations were due to AEs (pembrolizumab: 13.5% versus BV: 19.1%) and progressive disease (pembrolizumab: 39.2% versus BV: 49.3%). Full details regarding patient disposition are available in Table 22.

Exposure to Study Treatments

In the KEYNOTE-051 study the median exposure to pembrolizumab was 344 days. Those in the KEYNOTE-087 study were exposed to pembrolizumab for a median of 506, 254, and 399.5 days in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, the median duration of exposure to pembrolizumab was 305 days and the median duration of exposure to BV was 146.5 days.

Efficacy

Only the efficacy outcomes that were identified in the review protocol are summarized below and in Table 23.

Progression-Free Survival

In the KEYNOTE-051 study, 3 patients (42.9%) experienced an event (disease progression or death). In the KEYNOTE-087 study, there were 43 (62.3%), 54 (66.7%), and 36 (60.0%) events in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, the proportion of patients experiencing an event were similar between the pembrolizumab (53.6%) and BV (57.5%) arms. In the KEYNOTE-051 study, the median PFS was reported to be 11.1 months (95% CI, 2.6 to not reported). In the KEYNOTE-087 study, median survival was reported to be 16.4 months (95% CI, 11.3 to 27.6), 11.1 months (95% CI, 7.3 to 13.5), and 19.4 (95% CI, 8.4 to 22.1) months in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, the median PFS was higher in the pembrolizumab arm (13.2 months; 95% CI, 10.9 to 19.4) than the BV arm (8.3 months; 95% CI, 5.7 to 8.8). In the KEYNOTE-051 study, the PFS rate at 12 months was 27.8% (no 95% CI reported). In the KEYNOTE-087 study, the PFS rate at 12 months was 61.3%, 43.0%, and 53.9% in cohorts 1, 2, and 3, respectively (no 95% CI reported). In the KEYNOTE-204 study, the 12-month PFS rate was higher in the pembrolizumab arm (53.9%; 95% CI, 45.0 to 61.9) than the BV arm (35.6%; 95% CI, 26.9 to 44.4). In the KEYNOTE-087 study, the 24-month PFS rate was 41.6%, 21.9%, and 34.0% in cohorts 1, 2, and 3, respectively (no 95% CI reported). In the KEYNOTE-204 study, the 24-month PFS rate was 35.4% (95% CI, 26.2 to 44.6) in the pembrolizumab arm and 25.4% (95% CI, 17.1 to 34.5) in the BV arm. The hazard ratio for time to progression was 0.65 (95% CI, 0.48 to 0.88), which was statistically significant (P = 0.0027).

In the KEYNOTE-204 study, the primary PFS analysis considered initiation of subsequent anticancer therapy or ASCT as a censoring event. A sensitivity analysis was conducted which treated these events as a progression event instead. In this analysis, 103 (68.2%) and 119 (77.8%) events were observed in the pembrolizumab and BV arms, respectively. The median PFS was higher in the pembrolizumab arm (9.5 months; 95% CI, 8.2 to 12.7) than the BV arm (5.7 months; 95% CI, 5.6 to 8.3). The hazard ratio for time to progression was 0.62 (95% CI, 0.48 to 0.82).

Figure 3: Kaplan-Meier Estimates of PFS in KEYNOTE-204

MK-3475 = pembrolizumab.

Source: Clinical Study Reports for KEYNOTE-204 studies.

Overall Survival

In the KEYNOTE-051 study, minimal information regarding OS was provided. In the KEYNOTE-087 study, 15.9%, 16.0%, and 15.0% of patients in cohorts 1, 2, and 3, respectively, died. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||| Median survival was not reported in the KEYNOTE-051 study and not reached in the KEYNOTE-087 or KEYNOTE-204 studies. In the KEYNOTE-051 study, 100% of patients were alive at 12 months. In the KEYNOTE-087 study, OS at 12 months was 95.7%, 96.2% and 96.6% in cohorts 1, 2, and 3, respectively (95% CI not reported). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| At 24 months in the KEYNOTE-087 study, 92.6%, 91.0%, and 89.4% of patients were alive in cohorts 1, 2, and 3, respectively (95% CI not reported). 　|　 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

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Note: Figure 4 has been redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.

Objective Response Rate

In the KEYNOTE-051 study, 42.9% (95% CI, 9.9 to 81.6) of patients experienced a partial or complete response. In the KEYNOTE-087 study, 78.3% (95% CI, 66.7 to 87.3), 64.2% (95% CI, 52.8 to 74.6), and 71.7% (95% CI, 58.6 to 82.5) of patients experienced a partial or complete response in cohorts 1, 2, and 3, respectively. In the KEYNOTE-204 study, more partial or completes responses were observed in the pembrolizumab arm relative to the BV arm (65.6%; 95% CI, 57.4 to 73.1 versus 54.2; 95% CI, 46.0 to 62.3), which was associated with a statistically insignificant 11.3% (95% CI, 0.2 to 22.1) difference in favour of pembrolizumab.

Complete Response Rate

In the KEYNOTE-051 study, 28.6% of patients (95% CI, 3.7 to 71.0) experienced a complete response. In the KEYNOTE-087 study, 26.1% (95% CI, 16.3 to 38.1), 25.9 (95% CI, 16.8 to 36.9), and 31.7% (95% CI, 20.3 to 45.0) of patients in cohorts 1, 2, and 3, respectively, experienced a complete response. In the KEYNOTE-204 study, the complete response rate was comparable between the pembrolizumab (24.5%; 95% CI, 17.9 to 32.2) and BV arms (24.2; 95% CI, 17.6 to 31.8).

Duration of Response

In the KEYNOTE-051 study, median DOR was not reached. In the KEYNOTE-087 study, the median DOR in cohorts 1, 2, and 3 were 25.0 months (range = 0 to 36.1), 11.1 months (range = 0 to 35.9), and 16.8 months (range = 0 to 39.1), respectively. In the KEYNOTE-204 study, the median DOR was higher among patients in the pembrolizumab arm (20.7 months; range = 0 to 33.2) than in patients in the BV arm (13.8 months; range = 0 to 33.9).

Time to Response

Median time to response in the KEYNOTE-051 study was 2.6 months (range = 2.1 to 2.8). The median time to response in cohort 1, cohort 2, and cohort 3 of the KEYNOTE-087 study were 2.7 months (range = 2.1 to 12.9), 2.8 months (range = 2.2 to 11.0), and 2.8 months (range = 2.6 to 16.5), respectively. Finally, the median time to response in the pembrolizumab arm of the KEYNOTE-204 study was 2.8 months (range = 1.0 to 31.2) and also 2.8 months (range = 1.3 to 7.3) in the BV arm.

Health-Related Quality of Life

HRQoL data were only measured in the KEYNOTE-087 and KEYNOTE-204 studies. In the KEYNOTE-087 study, the least squares mean square change in EORTC QLQ-C30 global health status between week 24 and baseline was 11.8, 13.9 and 6.6, in cohorts 1, 2, and 3, respectively. No CIs were reported in the KEYNOTE-087 study. In the KEYNOTE-204 study, the least squares mean change in EORTC QLQ-C30 global health status between baseline and week 24 was 8.60 points (95% CI, 3.89 to 13.31) higher in the pembrolizumab arm versus the BV arm. Consistent results were reported for the EORTC QLQ-C30 physical functioning scale (6.24; 95% CI, 1.87 to 10.62), EQ-5D-3L utility score (0.09; 95% CI, 0.04 to 0.14), and EQ-5D-3L visual analogue scale (6.12; 95% CI, 1.91 to 10.34).

Harms

The safety outcomes (harms) identified in the review protocol are reported below. See Table 24 for detailed harms data.

Adverse Events

In the KEYNOTE-051 study, 85.7% of patients experienced at least 1 AE. In the KEYNOTE-087 study, 98.6%, 98.8%, and 95.0% of patients experienced at least 1 AE in cohort 1, cohort 2, and cohort 3, respectively. In the KEYNOTE-204 study, 98.0% of patients in the pembrolizumab arm and 94.1% of those in the BV arm experienced an AE. The most common AEs were pyrexia, vomiting, headache, abdominal pain, anemia, cough, fatigue, diarrhea, and upper respiratory tract infections. In the KEYNOTE-204 study, pembrolizumab patients were more likely than BV patients to experience endocrine disorders (20.3% versus 3.9%); infections (66.2% versus 45.4%); musculoskeletal and connective tissue disorders (37.8% versus 31.6%); neoplasms (7.4% versus 1.3%), renal or urinary disorders (14.9% versus 4.6%); respiratory, thoracic, or mediastinal disorders (45.3% versus 26.3%); and skin and subcutaneous tissue disorders (43.9% versus 36.8%), but less likely to experience blood or lymphatic system disorders (18.2% versus 25.7%), gastrointestinal disorders (43.9% versus 52.0%), and nervous system disorders (26.4% versus 50.7%).

Serious Adverse Events

In the KEYNOTE-051 study, 28.6% of patients experienced at least 1 serious AE. In the KEYNOTE-087 study, 21.7%, 22.2%, and 25.0% of patients experienced a serious AE in cohort 1, cohort 2, and cohort 3, respectively. In the KEYNOTE-204 study, 29.7% of pembrolizumab and 21.1% of BV-treated patients experienced a serious AE. The most common serious AEs in the KEYNOTE-051 study were diaphragmatic hernia and pneumonia. The most common serious AEs in cohort 1 of the KEYNOTE-087 study were pneumonia and pericarditis. The most common serious AE in cohort 2 of the KEYNOTE-087 study was herpes zoster and the most common serious AEs in cohort 3 of the KEYNOTE-087 study were pyrexia and pneumonitis, There were no notable differences in frequency of serious AEs between the pembrolizumab and BV arms in the KEYNOTE-204 study. The most common serious AEs in the pembrolizumab arm of the KEYNOTE-204 study were infections or infestations; respiratory, thoracic, or mediastinal disorders; neoplasms; general disorders or administration site conditions; and hepatobiliary disorders. The most common serious AEs in the BV arm of the KEYNOTE-204 study were infections or infestations; respiratory, thoracic, or mediastinal disorders; nervous system disorders; gastrointestinal disorders; and general disorders or administration site conditions.

Treatment Discontinuation Due to AEs

No patients in KEYNOTE-051 discontinued treatment due to an AE while 11.6%, 6.2%, and 8.3% of patients in cohort 1, cohort 2, and cohort 3 of KEYNOTE-087, respectively, discontinued treatment due to an AE. In the KEYNOTE-204 study, 13.5% and 17.8% of patients receiving pembrolizumab and BV, respectively, discontinued treatment due to an AE.

Mortality

No patients in the KEYNOTE-051 study or cohort 1 of the KEYNOTE-087 study died. In the KEYNOTE-087 study, 2.5% and 1.7% of patients in cohort 2 and cohort 3, respectively, died. In the KEYNOTE-204 study, 2.0% and 1.3% of patients receiving pembrolizumab or BV, respectively, died.

Immune-Mediated AEs

In the KEYNOTE-051 study, 28.6% of patients experienced at least 1 immune-mediated AE. In cohort 1, 2, and 3 of the KEYNOTE-087 study, 31.9%, 32.1%, and 38.3% of patients, respectively, experienced at least 1 immune-mediated AE. In the KEYNOTE-204 study, more patients in the pembrolizumab arm (35.8%) than the BV arm (13.8%) experienced an immune-mediated AE.

No patients in the KEYNOTE-051 study experienced a serious immune-mediated AE. In the KEYNOTE-087 study, 4.3%, 2.5% and 5.0% of patients in cohort 1, cohort 2, and cohort 3, respectively, experienced a serious immune-mediated AE. In the KEYNOTE-204 study, more pembrolizumab- than BV-treated patients experienced a serious immune-mediated AE (8.8% versus 3.3%).