CADTH Reimbursement Review

Pembrolizumab (Keytruda)

Sponsor: Merck Canada Inc.

Therapeutic area: Esophageal carcinoma, gastroesophageal junction adenocarcinoma

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

In Canada, esophageal cancer is ranked 19th among all cancer types based on incidence and 10th based on mortality.⁸ There are 2 distinct histological subtypes: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC).^9,10 EAC typically occurs in the distal esophagus and gastroesophageal junction (GEJ).¹¹ Adenocarcinoma of the GEJ is further classified into Siewert type I (1 cm to 5 cm above the GEJ), Siewert type II (1 cm above and up to 2 cm below the GEJ), and Siewert type III (2 cm to 5 cm below the GEJ).¹²

Signs and symptoms of esophageal cancer include dysphagia (difficulty swallowing), frequent chocking on food, unexplained weight loss, indigestion or heartburn, coughing or hoarseness, nausea or vomiting, fatigue, and chest pain, pressure, or burning.^8,13,14

The current standard treatment for locally advanced and unresectable or metastatic cancer of the esophagus and GEJ is systemic chemotherapy. Standard first-line chemotherapy regimens typically include a fluoropyrimidine and a platinum (usually cisplatin or oxaliplatin).^15-18 Examples of fluoropyrimidine- and platinum-based chemotherapy used in the first-line setting include: cisplatin and 5-fluorouracil [5-FU], capecitabine and cisplatin, capecitabine and oxaliplatin (CAPOX), and 5-FU, oxaliplatin, and leucovorin (FOLFOX). Patients with advanced cancer of the EAC or GEJ may be treated with irinotecan, 5-FU, and oxaliplatin (FOLFIRI),^;9 however, this is not commonly used in the first-line setting. Other less common first-line treatments include paclitaxel or docetaxel doublet regimens, paclitaxel or docetaxel triplet regimens, and epirubicin.

Pembrolizumab is a selective humanized monoclonal antibody that enhances immune system detection of tumours and facilitates tumour regression via the programmed cell death protein 1 (PD-1) pathway. The recommended dose for pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks administered as an IV infusion until disease progression, unacceptable toxicity, or to a maximum of 24 months. The Health Canada–approved indication of interest is pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the esophagogastric junction (EGJ; tumour centre 1 cm to 5 cm above the gastric cardia). The CADTH reimbursement request aligns with this Health Canada indication. Refer to the Introduction of the main body of this report for more details.

The objective of this clinical review is to review the beneficial and harmful effects of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy as per the indication previously highlighted.

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. As well, issues identified by the Provincial Advisory Group that may impact their ability to implement a recommendation are summarized. Refer to the Stakeholder Perspectives Section of the main body of this report for more details.

Patient Input

Three patient groups, including Colorectal Cancer Canada (CCC), the Gastrointestinal (GI) Society, and My Gut Feeling (Stomach Cancer Foundation of Canada), co-created 1 patient input for this review.

According to the patient and caregiver respondents (N = 33), most patients were diagnosed with EAC (77.42%) and 12.90% of patients were diagnosed with ESCC. All patient and caregiver respondents, except 1 patient, reported experiencing the following symptoms before diagnosis: trouble swallowing, heartburn, weight loss, fatigue, worsening indigestion, frequent choking on food, hiccups, and indigestion.

Two patient respondents had experience with the drug under review (pembrolizumab) and reported the following treatment-related side effects: abdominal pain, diarrhea, rash, shortness of breath, and constipation (1 patient); fatigue, itching and some allergic reactions (the other patient). One patient respondent noted that pembrolizumab manages coughing, back pain, hoarseness, and vomiting less effectively than existing therapies. However, both respondents reported that pembrolizumab did manage certain symptoms better than existing therapies including pain behind the breastbone or in the throat, black stool, and weight loss (1 patient); fatigue and vomiting (the other patient). Both patients indicated that they expected the following key outcomes to be improved by pembrolizumab: prolonged overall survival (OS), delayed need for chemotherapy, and convenient route of administration.

Patient and caregiver respondents highlighted that given the poor and short survival rate for most patients with esophageal cancer, it is necessary for patients to have access to new effective therapies that prolong OS, improve quality of life (QoL), reduce disease symptoms, and have tolerable side effects. It was also noted that given the severity of disease symptoms, improved QoL is an important outcome to consider in this setting. Additionally, when asked to indicate trade-offs in respect to treatment outcomes in choosing a new therapy, almost all patient and caregiver respondents indicated that they were willing to take a drug that has been proven to improve QoL even if it would not prolong OS.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts agreed that the full patient population included in the indication (adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ [tumour centre 1 cm to 5 cm above the gastric cardia]) should be eligible for treatment with pembrolizumab. However, the clinical experts noted that some patients are more likely to respond to treatment with pembrolizumab than others (e.g., ESCC histology and programmed cell death ligand 1 [PD-L1] with a combined positive score [CPS] ≥ 10). The clinical experts identified patients with autoimmune diseases are at increased risk of autoimmune disease flares and immune-related adverse events (AEs) when treated with immunotherapy. However, the clinical experts agreed that for patients with well-controlled autoimmune diseases, immunotherapy may still represent an appropriate treatment option for these patients after a discussion of the risks and benefits between clinician and patient. The clinical experts reiterated that the full patient population included in the indication should be eligible for treatment with pembrolizumab.

According to the clinical experts, pembrolizumab added to chemotherapy has the potential to represent a standard of care for patients with esophageal cancer or GEJ Siewert type I. The clinical experts felt that pembrolizumab added to chemotherapy would certainly be a standard of care for patients with ESCC and for patients with a CPS of 10 or greater. The clinical experts also felt that pembrolizumab added to chemotherapy was an appropriate treatment option for patients with GEJ Siewert type I who are HER2 negative, EAC, and tumours with a CPS of less than 10.

The clinical experts identified prolonged life and improved health-related quality of life (HRQoL) to be important outcomes and goals for treatment. The clinical experts noted that not all patients respond to available treatment options and patients ultimately become refractory to current therapies. As a result, there is a need for more effective treatment options with manageable safety profile.

To the clinical experts, a clinically meaningful response to treatment would be an improved OS and a reduction in the frequency or severity of symptoms (improved QoL). The clinical experts expressed that for patients treated with immunotherapy, a long-term plateau of the survival curve would also be considered a significant benefit since current median survival for this patient population is less than 12 months. As well, the clinical experts stated that if the addition of an agent to an established regimen was not detrimental to QoL and improved survival, that would also be considered a clinically meaningful response to treatment.

Clinician Group Input

Overall, 2 clinician group inputs were provided for the review: 1 joint submission by 6 clinicians on behalf of the medical advisory board of My Gut Feeling, the Canadian GI Oncology Evidence Network, and the medical advisory board of CCC; and 1 joint submission from 4 clinicians on behalf of the Ontario Health-Cancer Care Ontario GI Drug Advisory.

Both clinician groups emphasized that all patients with esophageal cancers and EGJ adenocarcinomas (Siewert type I) would greatly benefit from this treatment. The clinician group emphasized that all patients with locally advanced unresectable or metastatic esophageal carcinoma or HER2-negative GEJ adenocarcinoma have a poor prognosis; therefore, all patients should be eligible for the addition of pembrolizumab to first-line platinum and fluoropyrimidine chemotherapy.

The clinician groups identified prolonged life and improved or maintained HRQoL as the goals of treatment. Delaying progression of disease and ensuring adequate nutritional intake were additional goals of treatment identified by the Ontario Health-Cancer Care Ontario GI Drug Advisory clinicians.

To the clinician groups, a clinically meaningful response to treatments would be a reduction in symptoms or at minimum, a stabilization of symptoms (e.g., less pain, weight gain/cessation of weight loss, less fatigue). Additionally, an overall improvement in the ability to perform daily activities and a reduction in the caregiver burden would also be considered clinically meaningful responses to treatment.

In summary, while the clinician groups and clinical experts noted that patients with PD-L1 with a CPS of 10 or greater, and ESCC patients with PD-L1 with a CPS of 10 or greater are more likely to respond to pembrolizumab than the intention-to-treat (ITT) population (any PD-L1 CPS and esophageal cancer or GEJ Siewert type I), all patients with esophageal cancers and EGJ adenocarcinomas (Siewert type I) would benefit from pembrolizumab, and as a result, both the clinician groups and the clinical experts expressed that the full patient population in the indication submitted for reimbursement (i.e., esophageal cancer and HER2-negative GEJ Siewert type I) should be eligible for treatment with pembrolizumab.

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: relevant comparators, consideration for initiation of therapy, consideration for discontinuation of therapy, generalizability, care provision, system issues, and economic considerations. The clinical experts consulted by CADTH weighed evidence from the KEYNOTE-590 trial and other clinical considerations to provide responses to the Provincial Advisory Group’s drug program implementation questions. Refer to Table 4: Summary of Drug Plan Input and Clinical Expert Response for more details.

Clinical Evidence

Pivotal Study and Protocol Selected Study (KEYNOTE-590)

Description of Study

The KEYNOTE-590 study is an ongoing phase III, randomized, double-blind, placebo-controlled, multi-centre, superiority study comparing pembrolizumab in combination with cisplatin and 5-FU to placebo in combination with cisplatin and 5-FU for the first-line treatment of patients with locally advanced unresectable or metastatic adenocarcinoma or ESCC or advanced or metastatic Siewert type I adenocarcinoma of the GEJ. Refer to Table 6: Details of Included Study.¹

One co-primary outcome is OS among patients with ESCC whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), patients with ESCC, patients whose tumours are PD-L1 with a CPS of 10 or greater, and all patients. The second co-primary outcome is progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) among patients with ESCC, patients whose tumours are PD-L1 with a CPS of 10 or greater, and all patients. Secondary and exploratory outcomes included: objective response rate (ORR), duration of response (DOR), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module (EORTC QLQ-OES18), safety, and EQ5D-5 Levels questionnaire (EQ-5D-5L).¹

The demographic and baseline characteristics were well-balanced between groups, except for age (65 years or older) and stage IVB (distant lymph nodes and/or other organs) disease. There were more patients 65 years or older in the pembrolizumab in combination with cisplatin and 5-FU group (46.1%) compared with the placebo in combination with cisplatin and 5-FU group (39.9%). There were more patients with a current disease stage of iv B in the pembrolizumab in combination with cisplatin and 5-FU group (17.4%) compared with the placebo in combination with cisplatin and 5-FU group (10.9%). The majority (99.7%) had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 (39.9% and 59.8%, respectively) and had metastatic disease (91.2%). Most patients were male (83.4%), had an ESCC primary diagnosis (73.2%), and about half were Asian (53.4%), enrolled in Asia (52.5%), and had tumour expressed PD-L1 with a CPS of 10 or greater (51.1%). Refer to Table 7: Summary of Baseline Characteristics, ITT Population.¹

The results for both PFS and OS are deemed final based on interim analysis since both primary end points were met with a pre-specified stopping boundary for statistical significance. However, the study is ongoing; therefore, long-term efficacy and safety data are anticipated to be available in the future.³

Efficacy Results

As of the data cut-off date (July 2, 2020), the median follow-up duration for patients in the pembrolizumab in combination with cisplatin and 5-FU group was 12.6 months (range = 0.1 to 33.6) and the median follow-up duration for patients in the placebo combination with cisplatin and 5-FU group was 9.8 months (range = 0.1 to 33.6).¹

In all patients, there was a 27% reduction in the risk of death in favour of pembrolizumab in combination with cisplatin and 5-FU. The OS hazard ratio (HR) was 0.73 (95% confidence interval [CI]:, 0.62 to 0.86) with P < 0.0001, crossing the boundary for statistical significance. The median OS was 12.4 months (95% CI, 10.5 to 14.0) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 9.8 months (95% CI, 8.8 to 10.8) for the placebo in combination with cisplatin and 5-FU group. A statistically significant OS benefit in favour of pembrolizumab in combination with cisplatin and 5-FU was also observed in patients with ESCC whose tumours express PD-L1 with a CPS of 10 or greater, patients with ESCC, and patients whose tumours express PD-L1 with a CPS of 10 or greater.¹

In all patients, there was a 35% reduction in risk of death and disease progression in favour of pembrolizumab in combination with cisplatin and 5-FU. The PFS HR was 0.65 (95% CI, 0.55 to 0.76) with P < 0.0001, crossing the boundary for statistical significance. The median PFS was 6.3 months (95% CI, 6.2 to 6.9) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 5.8 months (95% CI, 5.0 to 6.0) for the placebo in combination with cisplatin and 5-FU group. A statistically significant PFS benefit in favour of pembrolizumab in combination with cisplatin and 5-FU was also observed in patients with ESCC and patients whose tumours express PD-L1 with a CPS of 10 or greater.¹

In the patient-reported outcome (PRO) full analysis set (FAS) population (i.e., all randomized patients who have at least 1 PRO assessment available for the specific end point and have received at least 1 dose of the study intervention), the least squares mean change from baseline to week 18 in EQ-5D visual analogue scale (VAS) was similar between the 2 groups. The mean change from baseline in global health status/QoL (using the EORTC QLQ-C30 scale) remained stable over time for the pembrolizumab in combination with cisplatin and 5-FU group compared with the placebo in combination with cisplatin and 5-FU group, and the median time to deterioration for global health status/QoL was not reached for both groups.¹

Refer to Table 2 and Table 14.

Harms Results

Overall, any AEs, treatment-related AEs, grade 3 to 5 AEs, and any serious AEs were comparable between the pembrolizumab in combination with cisplatin and 5-FU group and the placebo in combination with cisplatin and 5-FU (Table 2) group. The most commonly reported AEs were nausea (67.3% versus 62.7%), anemia (50.5% versus 56.2%), decreased appetite (44.3% versus 38.1%), fatigue (40.3% versus 34.1%), and constipation (40.0% versus 40.3%).

Although the number of events was infrequent, deaths due to AEs and deaths due to treatment-related AEs were similar between the 2 groups.

Of note, immune-mediated AEs and infusion reactions (25.7% versus 11.6%), hypothyroidism (10.8% versus 6.5%) and hyperthyroidism (5.7% versus 0.8%), pneumonitis (6.2% versus 0.5%), grade 3 or greater treatment-related AEs (71.9% versus 67.6%), serious treatment-related AEs (31.6% versus 26.2%), and discontinuation due to treatment-related AEs (19.5% versus 11.6%) were higher among the pembrolizumab in combination with cisplatin and 5-FU group.¹

Refer to Table 2: Summary of Key Results from Pivotal and Protocol Selected and Table 27 Additional Harms Outcomes.

Critical Appraisal

Notable limitations of the KEYNOTE-590 trial are highlighted in the following text. For a complete list of critical appraisal points, refer to Clinical Evidence Section, Critical Appraisal.

There is a potential risk of bias because of missing data on secondary and exploratory end points (e.g., DOR, EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L), particularly on the QoL measures. In addition, for subjective outcomes (e.g., in PROs), patients may also have differential recall bias. For example, drug-related AEs, such as immune-mediated events (25.7% versus 11.6%), and particularly, hypothyroidism (symptoms including fatigue, increased sensitivity to cold, muscle weakness) and hyperthyroidism (symptoms including nervousness, anxiety, fatigue, and weight loss) might have led to unblinding and the patients’ awareness of their treatment assignment, potentially leading to biased assessment of the PROs. Overall, the magnitude and direction of the impact of missing data and imbalances is unknown.

The platinum- and fluoropyrimidine-based chemotherapy used in the KEYNOTE-590 study (i.e., cisplatin and 5-FU) represents 1 of the standard first-line chemotherapies regimens, other relevant treatment regimens (listed in the systematic review protocol) are not considered in the KEYNOTE-590 study. The overall beneficial effect of the combination therapy with pembrolizumab was present. However, it would remain uncertain if such benefit could be generalizable to different combinations of chemotherapies regimens. Moreover, the study excluded patients with poor ECOG PS scores (> 1). This further compromised the generalizability of the findings on efficacy and particularly, safety to those patients who may receive this first-line combination therapy in practice.

The reported OS and PFS results are deemed final based on interim analysis according to pre-specified stopping criteria. However, whether the “actual” final efficacy results would conform with these interim results is unknown. There are case reports that discuss the early stop of a trial to claim statistical significance according to pre-specified stopping rule that had suffered type I error with the interim results and the estimates of effects could not be the repeated at the final analysis after the trial was completed.^20-22

Indirect Comparisons

No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search. The sponsor conducted a feasibility assessment³ estimating the comparative efficacy and safety of pembrolizumab plus cisplatin and 5-FU versus other competing interventions using data obtained from a systematic literature review.

The submitted feasibility assessment was summarized and critically appraised by the CADTH clinical review team and can be found in Appendix 5. Ultimately, the CADTH clinical review team concluded that a standard network meta-analysis was not feasible due to lack of network connectivity, and that an unanchored matching-adjusted indirect comparison (MAIC) would likely be biased, and it would not be possible to quantify or identify the direction of the bias.

Other Relevant Evidence

The following 2 studies (KEYNOTE-062 and KEYNOTE-859) were identified as relevant because they met the systematic review protocol; however, were a mixed population (i.e., all HER2-negative GEJ patients were enrolled without any Siewert classification, whereas only patients with HER2-negative Siewert type I GEJ are of relevance to the reimbursement request).

It is also important to note that the trials did not include patients with ESCC or adenocarcinoma of the esophagus, which is a relevant population for the reimbursement request. For the KEYNOTE-062 study, patients must be PD-L1 positive (i.e., CPS ≥ 1), whereas PD-L1 status is not an eligibility criterion for reimbursement in for this submission. Both trials used alternative platinum- and fluoropyrimidine-based chemotherapy backbones for the intervention and comparator compared to the KEYNOTE-590 study. In the KEYNOTE-062 study, cisplatin and 5-FU or cisplatin and capecitabine were offered as the chemotherapy backbone for the intervention and comparator, while in the KEYNOTE-859 study, cisplatin and 5-FU or oxaliplatin and capecitabine were offered.

The KEYNOTE-062 study is a phase III, randomized, partially blinded, multi-centre study comparing pembrolizumab as monotherapy and in combination with cisplatin and 5-FU or cisplatin and capecitabine versus placebo in combination with cisplatin and 5-FU or cisplatin and capecitabine as first-line treatment for patients with advanced gastric or GEJ adenocarcinoma. The results from the pre-specified subgroup analysis of the primary location (GEJ) were only available for OS and safety data were reported for the entire study population (gastric and GEJ adenocarcinoma).

In the overall study population (patients with gastric and GEJ adenocarcinoma), there is no difference in OS between the pembrolizumab combination and chemotherapy groups for patients with PD-L1 a CPS of 1 or greater (OS HR = 0.85; 95% CI, 0.7 to 1.03). The pre-specified OS subgroup analysis of the primary location for GEJ were consistent with the overall study population results (OS HR = 0.96; 95% CI, 0.67 to 1.36). The GEJ subgroup OS results were exploratory, underpowered, and not reflective of the entire reimbursement population, and therefore should be interpreted with caution. Results for the primary location (GEJ adenocarcinoma) subgroup for other important efficacy outcomes were not available. In the overall population (patients with gastric and GEJ adenocarcinoma), more AEs leading to discontinuation and immune-mediated AEs and infusion reactions were reported in the pembrolizumab combination group compared to the chemotherapy group (27.6% versus 18.0%, and 24.0% versus 7.8%, respectively).²³

KEYNOTE-859 is a phase III, multi-centre study comparing pembrolizumab in combination with chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) versus placebo in combination with chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) as first-line treatment for patients with advanced gastric or GEJ adenocarcinoma. Currently, only study design details are available.²⁴ The study is still ongoing, and no results are available at this time.³

Refer to Clinical Evidence Section, Other Relevant Evidence for more details.

Conclusions

Compared to placebo in combination with cisplatin and 5-FU, first-line treatment with pembrolizumab in combination with cisplatin and 5-FU showed a clinically meaningful and statistically significant overall and PFS benefit in adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ (tumour centre 1 cm to 5 cm above the gastric cardia). While patients with PD-L1 with a CPS of 10 or greater, and patients with ESCC with PD-L1 with a CPS of 10 or greater are more likely to respond to pembrolizumab than the ITT population (any PD-L1 CPS and esophageal cancer or GEJ Siewert type I), all patients with esophageal cancers and EGJ adenocarcinomas (Siewert type I) would benefit from pembrolizumab, and as a result, clinicians expressed that the full patient population in the indication (adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ [tumour centre 1 cm to 5 cm above the gastric cardia]) should be eligible for treatment with pembrolizumab. Discontinuation due to treatment-related AEs, serious treatment-related AEs, and immune-mediated AEs and infusion reactions were more frequently reported in patients treated with pembrolizumab in combination with cisplatin and 5-FU compared to patients treated with placebo in combination with cisplatin and 5-FU. Although there was no clinically meaningful deterioration in QoL, there remains uncertainty in PROs and QoL due to the limitations discussed (i.e., missing data, recall bias). The study is ongoing; therefore, long-term efficacy and safety data are anticipated to be available in the future. In addition, study eligibility included only patients with ECOG PS 0 or 1. Therefore, the benefit and safety profile are unknown in those patients with an ECOG PS greater than 1 in real-world clinical practice, who are also likely to receive this combination therapy.

The platinum- and fluoropyrimidine-based chemotherapy used in the KEYNOTE-590 study (i.e., cisplatin and 5-FU) represents 1 of the standard of first-line chemotherapies regimens. The KEYNOTE-062 and KEYNOTE-859 studies used alternative platinum- and fluoropyrimidine-based chemotherapy backbones for the intervention and comparator compared to the KEYNOTE-590 study (cisplatin and 5-FU or cisplatin and capecitabine for the KEYNOTE-062 study and cisplatin and 5-FU or oxaliplatin and capecitabine for the KEYNOTE-859 study). However, both trials had a mixed population (i.e., all HER2-negative GEJ patients were enrolled without any Siewert classification, whereas only patients with HER2-negative Siewert type I GEJ are of relevance to the reimbursement request) and both trials did not include patients with ESCC or adenocarcinoma of the esophagus, which is a relevant population for the reimbursement request. Based on clinical expert opinion, it would be reasonable to use other platinum- and fluoropyrimidine-based chemotherapy backbones apart from cisplatin and 5-FU.

Introduction

Disease Background

Esophageal cancer initiates in the cells of the esophagus. In Canada, esophageal cancer is ranked 19th among all cancer types based on incidence and 10th based on mortality.⁸ In 2020, it was estimated that a total of 2,400 Canadians would be diagnosed with esophageal cancer and 2,300 Canadians would die from esophageal cancer.²⁵ Esophageal cancer is among 1 of the cancers with a high proportion of metastatic disease (stage IV) at first diagnosis (39.9%),⁸ with a relative 5-year survival rate for metastatic esophageal cancer of 5%.²⁶

There are 2 distinct histological subtypes: EAC which begins in the glandular cells and ESCC which begins in the squamous (flat, thin) cells.^9,10 EAC typically occurs in the distal esophagus and GEJ.¹¹ Adenocarcinoma of the GEJ is further classified into: Siewert type I (1 cm to 5 cm above the GEJ), Siewert type II (1 cm above and up to 2 cm below the GEJ), and Siewert type III (2 cm to 5 cm below the GEJ).¹²

Although ESCC is the most common subtype diagnosed globally, EAC has become more predominant across the Western countries.¹⁰ In Canada, the incidence of EAC has been increasing (10.9 cases per million in 1992 compared to 26.8 cases per million in 2010), while the incidence of ESCC has been declining (18.2 cases per million in 1992 compared to 14.7 cases per million in 2010).¹⁰ It is estimated that by 2026, the incidence of EAC would be 4.8 per 100,000 in men and 0.8 per 100,000 in women and the incidence of ESCC would be 1.3 per 100,000 in men and 0.6 per 100 women.²⁷

Signs and symptoms of esophageal cancer include dysphagia (difficulty swallowing), frequent chocking on food, unexplained weight loss, indigestion or heartburn, coughing or hoarseness, nausea or vomiting, fatigue, and chest pain, pressure, or burning.^4,8,13 As a result, patients’ QoL is negatively affected.²⁸

The recommended diagnostic work-up includes an esophagogastroduodenoscopy with biopsy to establish the tumour’s location and histology, followed by a CT scan of the thorax, abdomen, and pelvis to establish the tumour’s location, depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph node, and metastatic disease. Blood work is also recommended to identify end-organ dysfunction.¹⁵

Standards of Therapy

The current standard treatment for locally advanced and unresectable or metastatic cancer of the esophagus and GEJ is systemic chemotherapy. Patients with advanced or metastatic EAC and GEJ are treated similarly to gastric adenocarcinoma.^15-18 In fact, phase III clinical trials for metastatic gastric cancer include patients with GEJ.^15-18,23,24 HER2 status is evaluated for patients with EAC or GEJ, as targeted therapy (trastuzumab-based treatment) is recommended for patients who are HER2 positive.²⁹

As noted by the clinical experts, standard first-line chemotherapy regimens include a fluoropyrimidine and a platinum (usually cisplatin or oxaliplatin)^15-18 for patients with advanced ESCC and patients with HER2-negative EAC or GEJ. Examples of fluoropyrimidine- and platinum-based chemotherapy used in the first-line setting include: cisplatin and 5-FU, capecitabine and cisplatin, CAPOX, and FOLFOX. Patients with advanced cancer of the EAC or GEJ may be treated with FOLFIRI¹⁹; however, this is not commonly used in the first-line setting. Other less common first-line treatments include paclitaxel or docetaxel doublet regimens, paclitaxel or docetaxel triplet regimens, and epirubicin.

The clinical experts identified prolonged life and improved HRQoL as the goals of treatment. Similarly, the clinician groups identified prolonged life and improved or maintained HRQoL as the goals of treatment. Delaying progression of disease and ensuring adequate nutritional intake were additional goals of treatment identified by a clinical group, while access to new effective therapies that prolong OS, improve QoL, reduce disease symptoms, and have tolerable side effects were noted as important for patient and caregiver respondents.

Drug

Pembrolizumab is a selective humanized monoclonal antibody that enhances immune system detection of tumours and facilitates tumour regression via the PD-1 pathway. The Health Canada recommended dose is 200 mg every 3 weeks or 400 mg every 6 weeks administered as an IV infusion until disease progression, unacceptable toxicity, or to a maximum of 24 months. Health Canada has issued market authorization for pembrolizumab in various indications such as classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, urothelial carcinoma, endometrial carcinoma, melanoma, non–small cell lung carcinoma, renal cell carcinoma, head and neck squamous cell carcinoma, and colorectal cancer.⁵

The Health Canada–approved indication of interest is pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ (tumour centre 1 cm to 5 cm above the gastric cardia).⁵ The CADTH reimbursement request aligns with this Health Canada indication. Refer to Table 3.

Stakeholder Perspectives

Patient Group Input

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

About the Patient Groups and Information Gathered

Three patient groups, CCC, the GI Society, and My Gut Feeling (Stomach Cancer Foundation of Canada), co-created 1 patient input for this review. CCC drafted the patient group input which was reviewed by the GI Society and My Gut Feeling (Stomach Cancer Foundation of Canada) before its submission to CADTH. All 3 patient groups collected survey data.

CCC is a charitable not-for-profit organization which is dedicated to colorectal cancer awareness and education, supports patients and caregivers, and advocates on their behalf. It aims to reduce the incidence and mortality of colorectal cancer in Canada while improving the QoL of patients, their families, and their caregivers.

The GI Society is committed to improving the lives of people with GI and liver conditions, supporting research, advocating for appropriate patient access to health care, promoting GI and liver health, and providing trusted, evidence-based information for all areas of the GI tract.

My Gut Feeling (Stomach Cancer Foundation of Canada) is a non-profit organization, founded by 2 survivors, dedicated to providing support, awareness, education, information, and advocacy to patients with stomach cancer, survivors, and caregivers. It aims to dispel misconceptions about stomach cancer and to provide information every step of the way from the time of diagnosis to living with and surviving stomach cancer. It strives to improve patients’ and caregivers’ QoL, offer a voice to patients and caregivers, and provide a peer mentorship based on personal experience with stomach cancer.

Patient input was collected through an online patient and caregiver survey co-created by the 3 patient groups (CCC, GI Society, and My Gut Feeling [Stomach Cancer Foundation of Canada)] during the period of April 23, 2021, to May 16, 2021. A total of 25 patients and 8 caregivers responded to the survey, 62.50% of respondents were male (1 respondent’s gender was unknown). Most survey respondents were from the UK and Northern Ireland (45.45%), followed by the US (36.36%), Canada (9.09%), New Zealand (3.03%), Ireland (3.03%), and Belgium (3.03%). According to the survey respondents, at the time of diagnosis, patients’ ages ranged from 20 years to 29 years (6.06%) to 70 to 79 years (3.03%); most patients (39.39%) were 50 to 59 years old at the time of their cancer diagnoses. Of all survey respondents (N = 33), 30.30% were previously treated, 24.24% were in remission, 21.21% were undergoing treatment, 6.06% were caregivers participating in the survey on behalf of a patient undergoing treatment, and 18.18% were caregivers participating on behalf of a patient who had been previously treated.

Disease Experience

According to the patient and caregiver respondents, most patients were diagnosed with adenocarcinoma (77.42%) and 12.90% of patients were diagnosed with squamous cell carcinoma. The percentage of patients diagnosed with stage III esophageal cancer was 38.71%, followed by 25.81%, 22.58%, and 3.23% of patients diagnosed with stage IV, II, and I disease, respectively. Of those patients diagnosed with stage IV disease (n = 7), 3 patients were in stage IV disease, 2 patients were clear of metastases, 1 patient had passed away, and 1 patient was in the neoadjuvant stage at the time of completing the survey. Two patients who were diagnosed with stage III disease were experiencing stage IV disease at the time of participating in the survey. According to the survey responses, patients whose cancer had spread beyond the initial diagnosis had metastases mostly in the lymph nodes (37.93%), liver (20.69%), lung (17.24%), and stomach (14.29%).

When asked if any esophageal cancer-induced symptoms were experienced before diagnosis, all patient and caregiver respondents, except 1 patient, reported experiencing symptoms including (presented here in order of most frequently reported) trouble swallowing, heartburn, weight loss, fatigue, worsening indigestion, frequent choking on food, hiccups, and indigestion.

Experiences With Currently Available Treatments

According to the patient and caregiver respondents, most patients had received chemotherapy (96.70%) followed by surgery (66.70%), radiation therapy (50.0%), endoscopic therapy (16.70%), and other targeted therapies (10.0%); more than half of the survey respondents (58.62%) felt that therapies were effective at controlling symptoms of esophageal cancer. According to the survey, the most reported side effects from therapies included fatigue (88.89%), nausea (62.96%), loss of appetite (62.96%), and low white blood cell count (51.85%). One patient respondent reported being currently on nivolumab.

Most patient and caregiver respondents (75.86%) indicated that most of their needs were being met by therapies currently available; however, 24.14% of respondents believe otherwise. The following quotes illustrate areas of unmet need.

“Short survival rates.”

“[Ability of the cancer] to continue to spread.”

“[The lack of] “metabolism of food.”

“Inability to eat enough to constitute a healthy diet.”

“It is not possible for [current drugs] to stop the growth, only prolong life.”

“The chemotherapy was tolerable but did not improve quality of life as the side effects in addition to the side effects from the surgery and need for a feeding tube really impacted my brother-in-law’s ability to go out, eat, carry on a conversation, or enjoy his family.”

Experience With Drug Under Review

Two patient respondents had experience with the drug under review; 1 patient with stage III esophageal cancer was previously treated with pembrolizumab, and another patient with stage IV esophageal cancer is currently undergoing treatment with pembrolizumab. One patient respondent noted that in addition to pembrolizumab, treatment also involved cryotherapy, radiation, and targeted therapy. The other patient respondent indicated having access to pembrolizumab via a clinical trial with no other therapy included.

The following treatment-associated side effects were reported by the 2 patient respondents: abdominal pain, diarrhea, rash, shortness of breath, and constipation (I patient); fatigue, itching, and some allergic reactions (the other patient). One patient respondent noted that pembrolizumab manages some symptoms less effectively than existing therapies including coughing, back pain, hoarseness, and vomiting. However, both respondents reported that pembrolizumab did manage certain symptoms better than existing therapies including pain behind the breastbone or in the throat, black stool, and weight loss (1 patient); fatigue and vomiting (the other patient).

While 1 patient respondent did not mention any difficulties taking pembrolizumab, the other patient respondent indicated that social issues, lifestyle changes, and anxiety were difficult to manage while taking pembrolizumab. Both patient respondents rated their overall experience with pembrolizumab as a 6 on a scale of 1 to 10 (1 being much worse and 10 being much better) compared to other treatments.

Both patient respondents did not identify any particular gap or unmet patient need associated with current therapies that pembrolizumab could help address. However, both patients indicated that they believe pembrolizumab will change their long-term health and well-being for the better.

The following quotes illustrate the importance that patient and caregiver respondents place on having access to pembrolizumab and other future immunotherapies.

“Any treatment that helps someone with esophageal cancer is a chance.”

“Many people have had a very successful story with Keytruda.”

“I would like access to anything that would extend my life.”

“I was one of the lucky ones to survive so I know how important access to new treatments are to all patients.”

Improved Outcomes

The authors of the patient input highlighted that given the poor and short survival rate for most patients with esophageal cancer, it is necessary for patients to have access to new effective therapies that prolong OS, improve QoL, reduce disease symptoms, and have tolerable side effects. It was also noted by the authors that given the severity of disease symptoms, improved QoL is an important outcome to consider in this setting. Additionally, when asked to indicate trade-offs in respect to treatment outcomes in choosing a new therapy, almost all patient and caregiver respondents (92.0%) indicated that they were willing to take a drug that has been proven to improve QoL even if it would not prolong OS. Furthermore, on a scale of 1 to 10 (1 being no side effects and 10 being severe side effects), patients and caregivers rated on average 5 for the severity of side effects to extend survival by 2 months, 6 months, and 1 year. One caregiver and 1 patient respondent indicated that they were willing to tolerate significant side effects to extend survival by 2 months. However, 2 patient respondents indicated that they were not willing to tolerate any side effects to extend their survival by 1 year. When asked about how important it is for patients along with their physicians to have a choice in deciding which drug to take on a scale of 1 to 10 (1 being not important and 10 being very important), patient and caregiver respondents rated on average 8 for the level of importance.

Two patient respondents who had experience with pembrolizumab reported that they expected the following key outcomes to be improved by pembrolizumab, including prolonging OS, delaying the need of chemotherapy, and having a convenient route of administration.

The following quote illustrates the importance of QoL and the potential impact a new therapy (pembrolizumab) can have on improving QoL.

“A good quality of life is essential for esophageal patients. Even if overall survival is not dramatically improved, the quality of life improvement from this drug can bring significant advantages enabling them to spend more time with their families with the side effects of existing treatments.”

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 esophageal carcinoma and GEJ adenocarcinoma.

Current Treatment Options

The current standard treatment for locally advanced and unresectable or metastatic cancer of the esophagus and GEJ is systemic chemotherapy. Patients with advanced or metastatic EAC and GEJ are treated similarly to gastric adenocarcinoma.^15-18 Rare types of esophageal cancer such as GI stromal tumour, leiomyosarcoma, and neuroendocrine tumours are treated differently than patients with adenocarcinoma and squamous cell histology, whom comprise the focus of this review.

Palliative radiation, endoscopic dilatation, or stenting can improve local symptoms of dysphagia or bleeding.^15-18 Early interdisciplinary care with the addition of psychologists and dieticians has been shown to improve survival compared to standard oncology care.³⁰ Many patients derive benefit from formal palliative care consultation.³¹

Systemic therapy improves survival compared to best supportive care for patients with advanced cancer of the esophagus and GEJ.³² With respect to systemic therapy, HER2 is evaluated for patients with EAC or GEJ and anti-HER2 therapy is included in their treatment if positive. Palliative chemotherapy is recommended for patients with good performance status. Standard first-line chemotherapy regimens include a fluoropyrimidine and a platinum (usually cisplatin or oxaliplatin)^15-18 for patients with advanced ESCC and patients with HER2-negative EAC or GEJ. Examples of fluoropyrimidine- and platinum-based chemotherapy used in the first-line setting include cisplatin and 5-FU, capecitabine and cisplatin, CAPOX, and FOLFOX. Patients with advanced cancer of the EAC or GEJ may be treated with FOLFIRI¹⁹; however, this is not commonly used in the first-line setting. Other less common first-line treatments include paclitaxel or docetaxel doublet regimens, paclitaxel or docetaxel triplet regimens, and epirubicin.

With respect to second-line therapy, patients with advanced cancer of the EAC or GEJ may be treated with irinotecan or FOLFIRI. The combination of paclitaxel ramucirumab is also a therapeutic option for patients with cancer of the GEJ in the absence of contraindications to ramucirumab. Single agent docetaxel and paclitaxel can also be used for ESCC, EAC, or GEJ in the absence of significant neuropathy.^15-18

Unmet Needs

The most important goals of treatment are to prolong life and improve HRQoL.

There is a need for more effective treatment options with manageable safety profile. Patients ultimately become refractory to current therapies and not all patients respond to available options. This patient population can be frail, and nutrition is often a challenge due to dysphagia; thus, treatments are needed that are better tolerated.

Place in Therapy

In the current treatment paradigm, pembrolizumab would be used in combination with a platinum- and a fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced or unresectable cancer of the esophagus or HER2-negative adenocarcinoma of the GEJ (tumour epicentre 1 cm to 5 cm above the gastric cardia). Pembrolizumab added to chemotherapy is not currently a standard of care in Canada in this patient population. However, pembrolizumab added to chemotherapy has the potential to represent a standard of care for patients with esophageal cancer or GEJ Siewert type I. The clinical experts felt that pembrolizumab added to chemotherapy would certainly be a standard of care for patients with ESCC and for patients with a CPS of 10 or greater. The clinical experts also felt that pembrolizumab added to chemotherapy was an appropriate treatment option for patients with GEJ Siewert type I who are HER2 negative, EAC, and for tumours with a CPS of less than 10.

Patient Population

The clinical experts agreed that the full patient population in the indication should be eligible for treatment with pembrolizumab (i.e., esophageal cancer and HER2-negative GEJ Siewert type I). However, the clinical expert noted that some patients are more likely to respond to treatment with pembrolizumab than others. For instance, characteristics associated with increased survival benefit to the addition of pembrolizumab to cisplatin and 5-FU include ESCC histology and a CPS of 10 or greater.

The clinical experts noted that clinician judgment would be used to identify suitable patients and that access to PD-L1 CPS testing (though not required for eligibility and is not currently available), would also be useful in identifying patients who are most likely to benefit from the addition of pembrolizumab to systemic therapy.

Clinical experts identified patients with autoimmune diseases are at increased risk of autoimmune disease flares and immune-related AEs when treated with immunotherapy. However, the clinical experts agreed that for patients with well-controlled autoimmune diseases, immunotherapy may still represent an appropriate treatment option for these patients after a discussion of the risks and benefits between clinician and patient. As well, patients requiring prednisone 10 mg per day or higher may derive less benefit from pembrolizumab. Immunotherapy is generally not started until a patient’s steroid requirement is less than the equivalent of 10 mg of prednisone per day.

Nonetheless, the clinical experts reiterated that full patient population included in the indication should be eligible for treatment with pembrolizumab.

Assessing Response to Treatment

In clinical practice, imaging (CT scan) is used to assess response and is done every 3 months as standard of care. PROs (formal and informal report of symptoms) are used as an early indication of benefit and for monitoring toxicity.

According to the clinical experts, a clinically meaningful response to treatment would be improved OS and a reduction in the frequency or severity of symptoms (improved QoL). The clinical experts noted that the definition of a clinically meaningful response may vary across physicians. For patients treated with immunotherapy, a long-term plateau of the survival curve would also be considered a significant benefit since current median survival for this patient population is less than 12 months. If the addition of an agent to an established regimen did not cause a detriment to QoL, and improved survival, that would also be considered a clinically meaningful response to treatment.

Discontinuing Treatment

Treatment of pembrolizumab is discontinued in the presence of death, disease progression on CT, deterioration in clinical status precluding continuation of treatment, withdrawal of patient consent, severe AEs, or grade 3 or higher immune-related AEs.

Prescribing Conditions

The clinical experts noted that pembrolizumab is commonly used in other tumour sites; thus, all settings in which it is currently administered would be appropriate for administration. Patients should have access to the following specialists: medical oncology, hepatology, gastroenterology, endocrinology, respirology, nephrology, and dermatology. Access to rheumatology and ophthalmology would also be ideal.

The clinical experts highlighted that some patients will be treated at community cancer centres and have therapy given by nurse practitioners or general practitioners.

Clinician Group Input

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

Two clinician group inputs were provided for the review of pembrolizumab for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative GEJ adenocarcinoma in combination with platinum- and fluoropyrimidine-based chemotherapy, in adult patients. One joint clinician input was provided by 6 clinicians on behalf of the medical advisory board of My Gut Feeling, the Canadian GI Oncology Evidence Network and the medical advisory board of CCC. For ease of reference, this group of clinicians will be referred to throughout the input as “clinicians from the medical advisory boards.” Two of the clinicians from the medical advisory boards practice in British Columbia, 2 clinicians practice in Alberta, 1 clinician practices in Ontario, and 1 clinician practices in Nova Scotia The medical advisory board of CCC works with patient groups to ensure their activities and health information are relevant and valuable for patients and caregivers. The medical advisory board of My Gut Feeling works with patient organizations to advise on education and awareness initiatives and issues regarding access to treatment. The Canadian GI Oncology Evidence Network is a virtual and inclusive network of Canadian GI oncology clinicians who contribute to the knowledge of GI cancer and its treatments, including participating in clinical trials, conducting observational research, and assisting with local, provincial, and national clinical guideline developments and health technology assessments.

The second joint input was provided by 4 clinicians on behalf of the Ontario Health-Cancer Care Ontario GI Drug Advisory. Ontario Health-Cancer Care Ontario Drug Advisory Committees provide evidence-based clinical and health system guidance on drug-related issues including The provincial drug reimbursement programs and the systemic treatment program.

Current Treatments

The clinicians from the medical advisory boards explained that the goal of current treatments for patients with locally advanced unresectable or metastatic esophageal or GEJ cancers is to manage symptoms and prolong survival. Patients often have symptoms such as dysphagia, odynophagia, early satiety, nausea, and vomiting. These symptoms can limit their ability to maintain adequate nutritional intake. Additionally, the tumours can lead to both acute and chronic bleeding which can be life-threatening. The clinicians advised that these symptoms often need to be addressed before patients can start therapy. Systemic therapy can be considered for patients with an adequate ECOG PS, of which the most common is cytotoxic chemotherapy. The clinician group noted the following treatment sequence:

1. Platinum- and fluoropyrimidine-based doublet chemotherapy (with the addition of trastuzumab if the patient has HER-2 positive adenocarcinoma)

2. Taxane (with the addition of ramucirumab if primary tumour is GEJ adenocarcinoma)

3. Irinotecan-based therapy

4. Trifluridine or tipiracil (if the primary tumour is GEJ adenocarcinoma)

Additionally, the clinician group stated that local therapies such as radiation therapy or endoscopic stents are also often used to help mitigate some of the symptoms. Some patients are also treated with IV iron replacement to address iron deficiency. Although there is some phase III evidence that supports the use of immunotherapy checkpoint inhibitors in later lines of therapy, Canadian patients currently do not have access through funded indications or access programs. Patients with esophageal and gastroesophageal cancers have had access to immunotherapy through clinical trials, private insurance, or out-of-pocket expenses.

The clinicians from the Ontario Health-Cancer Care Ontario noted the following treatments options in each line of therapy:

1. First-line therapy: FOLFOX or FOLFIRI

2. Second-line therapy: paclitaxel with or without ramucirumab for GEJ adenocarcinoma; FOLFOX or single agent capecitabine or weekly Taxol or radiation for ESCC

3. Third-line therapy: trifluridine or tipiracil for GEJ adenocarcinoma

Unmet Needs

Clinicians from the Ontario Health-Cancer Care Ontario explained that the goals of treatments are to prolong patients’ survival, delay the progression of disease, maintain QoL, and ensure adequate nutritional intake. The clinician group also noted that currently many patients do not respond to all available systemic treatments. Their DOR is very short, and they often become refractory. Even among patients who demonstrate a response, survival is quite limited. Therefore, there exists a significant unmet need for therapies that not only improve QoL, but also significantly prolong survival.

Similarly, clinicians form the medical advisory boards stated that the aim of treatments is to maintain or improve patients’ QoL and prolong survival. The clinician group emphasized that the disease presents patients with a significant symptom burden that impairs their QoL. Patients often struggle with both local symptoms such as adequate nutrition, nausea and vomiting, pain, and blood loss, and constitutional symptoms such as weight loss, weakness, and fatigue. Without therapy, patients have poor survival, which is often less than 6 months. Although current systemic therapy can prolong survival compared to best supportive care, the average survival with systemic therapy is still very modest, (approximately 11 months) as patients often experience a rapid clinical deterioration at the time of progression. This can lead to significant attrition rates between lines of therapy and only a small number of patients end up receiving systemic therapy beyond first or second line. The clinician group emphasized the importance of having access to the best therapies earlier during the course of treatment to maximize survival, reduce symptom burden, and improve overall QoL. The clinicians asserted that pembrolizumab therapy addresses this unmet need. In the KEYNOTE-590 trial, the improvement in survival was statistically and clinically significant and was maintained throughout key time points with a 12% absolute improvement in OS rates at both 12 months and 24 months from randomization.

The clinician groups were asked to identify the patient populations that have the greatest unmet need for a therapy like pembrolizumab. Both clinician groups emphasized that all patients with esophageal cancers and EGJ adenocarcinomas (Siewert type I) would greatly benefit from this treatment. The clinicians from the medical advisory boards noted that in the KEYNOTE-590 trial, patients with PD-L1 with a CPS of 10 or greater received the greatest benefit with pembrolizumab and chemotherapy. The clinicians from the Ontario Health-Cancer Care Ontario did not specify any additional subgroups but noted that patients with adenocarcinoma that is HER-2 positive would be excluded from this treatment as these patients would receive trastuzumab along with platinum- and fluoropyrimidine-based doublet chemotherapy.

Place in Therapy

Both clinician groups stated that pembrolizumab would be added to treatments in the first-line setting. Clinicians from the medical advisory boards specified that it would be added to platinum- and fluoropyrimidine-based doublet chemotherapy. The clinician group further commented that there are many studies in other solid tumours that have demonstrated the benefit of adding checkpoint inhibitor immunotherapy to cytotoxic chemotherapy. Similarly, the KEYNOTE-590 trial demonstrated that compared to chemotherapy alone, adding pembrolizumab improved OS, PFS, and response rates without deteriorating QoL. Adding pembrolizumab as first-line therapy would have no impact on the treatment options used in subsequent lines of therapy.

Both clinician groups advised against recommending patients to try other treatments before initiating treatment with pembrolizumab. The clinicians from the Ontario Health-Cancer Care Ontario reiterated that pembrolizumab is an addition to first-line treatment to improve overall patient outcomes. The clinicians from the medical advisory boards further commented that there is no indication in Canada for immunotherapy checkpoint inhibitors in subsequent lines of therapy. Additionally, the rapid deterioration of patients at the time of progression makes patients ineligible for further therapy beyond first line, due to decreased performance status. Therefore, the clinicians emphasized that it is important to offer the therapies during the start of treatment.

Clinicians were asked to identify how the drug might affect the sequencing of therapies for esophageal cancer. The clinicians from the medical advisory boards stated that if patients remain well enough to consider further therapy beyond first line, the subsequent lines of therapy would apply as stated above. Both groups of clinicians explained that if pembrolizumab is used as first-line therapy, immunotherapy will not be used in subsequent lines of therapy. The clinicians from the medical advisory boards further commented that there are no opportunities to treat patients with pembrolizumab or any other immunotherapy checkpoint inhibitor in subsequent lines of therapy.

Patient Population

The clinicians from the medical advisory boards stated that all patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative GEJ adenocarcinoma would benefit from pembrolizumab and platinum- and fluoropyrimidine-based doublet chemotherapy, assuming they have no contraindications to immune checkpoint inhibition such as solid tumour transplant recipient, severe and active autoimmune disease.

Both clinician groups noted that although the greatest benefit in the KEYNOTE-590 trial was observed for patients with PD-L1 with a CPS of 10 or greater and an ECOG PS of 0 to 1, OS for the entire study population was clinically and statistically significant, regardless of their histology or PD-L1 CPS status. Clinicians from the medical advisory boards therefore concluded that no population subgroup should be excluded on the basis of either histology or PD-L1 subtype. Furthermore, the clinician group re-emphasized that all patients with locally advanced unresectable or metastatic esophageal carcinoma or HER2-negative GEJ adenocarcinoma have grim prognosis and therefore all should be eligible for the addition of pembrolizumab to first-line platinum and fluoropyrimidine chemotherapy.

Clinicians were asked to explain how eligible patients would be identified. The clinicians form the medical advisory boards stated that since there is currently no indication to treat based on PD-L1 status or histology, no additional testing is required beyond what is routinely done (i.e., histological confirmation of carcinoma, radiographic work-up to determine locally advanced unresectable or metastatic staging, and HER-2 results of gastro-EAC to ensure patients are not HER-2 positive). Similarity the clinicians from Ontario Health-Cancer Care Ontario noted that although the greatest benefit is observed in patients who have PD-L1 with a CPS of 10 or greater, there is currently no routine testing conducted for this, nor is any testing expected in the future.

Furthermore, the clinicians from the medical advisory boards commented that it is very unlikely that the disease will be undiagnosed. The symptoms of the disease for new patients are often quite extreme, which leads them to immediately seek medical attention and confirm a diagnosis. For patients that have been treated with curative intent, the majority of locally advanced or metastatic recurrences occur within the first 5 years after treatment, during which is it routine for the patients to be monitored for clinical and radiographic changes.

Clinicians were asked to identify which group of patients would be least suited for pembrolizumab. The clinicians form the medical advisory boards stated that patients with a poor performance status that cannot be improved with best supportive care (e.g., nutritional support, pain control or iron replacement) would not be suited for platinum- and fluoropyrimidine-based doublet chemotherapy. Additionally, patients who are ineligible for either platinum- and fluoropyrimidine-based doublet chemotherapy or immunotherapy checkpoint inhibitors due to comorbidities would not be suitable for treatment with pembrolizumab. Pembrolizumab is also not well suited for patients with contraindications to immunotherapy such as autoimmune diseases.

Clinicians were asked to advise if it is possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review. Both groups of clinicians stated that patients with ESCC and a PD-L1 with a CPS of 10 or greater would be most likely to exhibit a response to pembrolizumab. However, clinicians from the medical advisory boards noted that when pembrolizumab was added to platinum- and fluoropyrimidine-based doublet chemotherapy in the full ITT population in KEYNOTE-590 trial, the outcomes were superior in all subgroups regardless of histology and PD-L1 status. Therefore, although histology and PD-L1 status are good biomarkers that can help predict a greater benefit, they should not be used to exclude eligible patients from receiving pembrolizumab.

Assessing Response to Treatment

Clinicians were asked to report which outcomes are used to determine whether a patient is responding to treatment in clinical practice. Clinicians from the medical advisory boards responded that clinical assessments are conducted by the clinicians every 3 to 4 weeks and as needed, if a change in clinical status is observed between the formal assessments. The clinical assessments consist of an assessment of the presence and severity of symptoms, as well as an overall assessment of health and functioning. A reduction or stabilization of symptoms and improved functioning are good indicators to determine patients’ response to therapy. Additionally, radiographic assessments are conducted every 8 to 12 weeks to objectively assess for response to treatment. The clinicians further noted that in the KEYNOTE-590 trial, key trial end points included PFS, response rates, and QoL. These assessments are also conducted in routine clinical practice. Similarly, the clinicians from Ontario Health-Cancer Care Ontario stated that an improvement in symptoms and objective response on radiographic imaging are good indicators to determine patient response to treatment.

Both clinician groups responded that a clinically meaningful response to treatments would be a reduction in symptoms or at minimum, a stabilization of symptoms (e.g., less pain, weight gain or cessation of weight loss, and less fatigue). Additionally, an overall improvement in the ability to perform daily activities and a reduction in the caregiver burden would also be considered clinically meaningful responses to treatment.

Clinicians were asked to advise on how often the response to treatment should be assessed. Both groups of clinicians responded that radiographic imaging would occur every 2 to 3 months. The clinicians from the medical advisory board further noted that clinical assessments would be done every 3 to 4 weeks.

Discontinuing Treatment

Both groups of clinicians stated that treatment with pembrolizumab should be discontinued if there is evidence of disease progression or if the patient develops AEs and/or toxicities that cannot be treated with best supportive care. Additionally, the clinicians from the medical advisory board stated that treatment may also be discontinued if the patient no longer wishes to continue with the treatment.

Prescribing Conditions

Both clinician groups advised that the treatment would be administered on an outpatient basis. The clinicians from the medical advisory boards further stated that treatment would mostly likely be in a specialized cancer hospital that has expertise in chemotherapy and immunotherapy. This is standard practice in most regions in Canada.

Additional Considerations

Both clinician groups provided some additional comments for consideration. Reflecting on the results of the KEYNOTE-590 trial, the clinicians form the medical advisory groups concluded that they highly support the reimbursement of pembrolizumab. The clinicians emphasized that the results of the KEYNOTE-590 trial are very notable, as OS was quite significant and was maintained at key time points. Almost 38% of patients in the ITT population were alive at 24 months, which the clinicians commented is quite remarkable for this type of cancer. Additionally, all patients, regardless of PD-L1 status, benefited from the addition of pembrolizumab, and the control arms were representative of the current standard of care in Canada. Toxicity did not increase significantly by adding pembrolizumab and QoL was comparable among the treatment arms.

The clinicians from Ontario Health-Cancer Care Ontario advised that peer review publication and final analyses are still needed, and the publication should be based on the planned duration of the study. The clinicians asserted that PD-L1 CPS testing should be made available to identify which patient subgroup will experience the greatest benefits from pembrolizumab. Additionally, the clinicians advised that further speculation and discussions are needed to determine if FOLFOX or FOLFIRI would be an approximate chemotherapy substitute for pembrolizumab. Consideration should be given to patients treated by adjuvant nivolumab and in their subsequent lines of therapy in the metastatic setting.

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. Their implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

As well, the Patient Advisory Group noted that uptake of pembrolizumab in this setting versus existing systemic therapies is likely to be immediate leading to a considerable increase in budget impact in a reimbursement scenario and also noted that reimbursement of pembrolizumab in the first-line setting would likely shift other systemic therapies to later lines of therapy, representing an added cost. However, the clinical experts expressed that it would not cause a shift in the current treatment paradigm as pembrolizumab is not standard of care in Canada. Similarly, the clinician group highlighted that adding pembrolizumab as a first-line therapy would have no impact on the treatment options used in subsequent lines of therapy.

Clinical Evidence Selection

The clinical evidence included in the review of pembrolizumab is presented in 3 sections. The first section, the systematic review, includes the pivotal study provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section refers to a summary and appraisal of the feasibility assessment for indirect evidence from the sponsor found in Appendix 5. The third section includes sponsor-submitted additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review: Pivotal and Protocol Selected Studies

Objective

To perform a systematic review of the beneficial and harmful effects of pembrolizumab (200 mg every 3 weeks or 400 mg every 6 weeks) in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ (tumour centre 1 cm to 5 cm above the gastric cardia).

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5: Inclusion Criteria for the Systematic Review. 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.³³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were pembrolizumab and esophageal or GEJ cancer. 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 June 18, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on October 10, 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.³⁴ 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.

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 will independently make the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 296 studies were identified from the literature for inclusion in the systematic review (Figure 1: Flow Diagram for Inclusion and Exclusion of Studies). The included study (KEYNOTE-590) is summarized in Table 6. A list of excluded studies and reason for exclusion is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Study (KEYNOTE-590)

The KEYNOTE-590 study is an ongoing, phase III, randomized, double-blind, placebo-controlled, multi-centre, superiority study comparing pembrolizumab in combination with cisplatin and 5-FU to placebo in combination with cisplatin and 5-FU for the first-line treatment of patients with locally advanced unresectable or metastatic EAC or ESCC or advanced or metastatic Siewert type I adenocarcinoma of the EGJ. The trial was conducted in 168 sites in the Americas including Canada and the US, Asia, Europe, Africa, and Australia. Trial characteristics are summarized in Table 6.

The co-primary objectives were to evaluate if pembrolizumab in combination with cisplatin and 5-FU, compared to placebo in combination with cisplatin and 5-FU, would improve:

• OS among patients with ESCC whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), patients with ESCC, patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), and all patients, and

• PFS per RECIST 1.1 among patients with ESCC, patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), and all patients.

A key secondary objective was to evaluate if pembrolizumab in combination with cisplatin and 5-FU, compared to placebo in combination with cisplatin and 5-FU, would improve ORR in all randomized participants. Other evaluated secondary outcomes included:

• ORR among patients with ESCC whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), patients with ESCC, patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10)

• DOR: patients with ESCC whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), patients with ESCC, patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), and all patients

• Safety and tolerability profile

• HRQoL using EORTC QLQ-C30 and EORTC QLQ-OES18 in all patients, patients with ESCC whose tumours have a CPS of 10 or greater, patients with ESCC, and patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10)

Exploratory objectives included:

• Characterizing PRO utilities using the EQ-5D-5L questionnaire in all patients, patients with ESCC whose tumours have a CPS of 10 or greater, patients with ESCC, and patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10)

• Evaluating PFS per immune-related RECIST in all patients, patients whose tumours are PD-L1 biomarker-positive (CPS ≥ 10), patients with ESCC, and patients with ESCC whose tumours have a CPS of 10 or greater

• Studying biomarkers predictive of clinical response and resistance, safety, pharmacodynamic activity, and/or the mechanism of action of pembrolizumab and other treatments

A total of 1,020 patients were screened, and 749 patients were randomized in a 1:1 ratio to receive pembrolizumab in combination with cisplatin and 5-FU (n = 373 patients) or placebo in combination with cisplatin and 5-FU (n = 376 patients). Randomization occurred centrally using an interactive voice response/system/integrated web response system. Randomization was stratified for geographic region (Asia, rest of the world), histology (adenocarcinoma, ESCC), and ECOG PS (0, 1). The first patient was randomized on July 25, 2017, and the last patient on July 2, 2020.

This is an ongoing study with interim results using a Global Study Population, whereby the 2 enrolment periods (Global Cohort and China Extension Study) were merged. These interim results represent the final analysis, with a data cut-off date of July 2, 2020.

Populations (KEYNOTE-590)

Inclusion and Exclusion Criteria

Eligible patients had to be at least 18 years of age with histologically or cytologically confirmed locally advanced unresectable or metastatic adenocarcinoma or ESCC or advanced or metastatic Siewert type I adenocarcinoma of the GEJ. Patients had to have an ECOG PS of 0 or 1.

Patients were ineligible if they received previous therapy for advanced or metastatic adenocarcinoma or squamous cell cancer of the esophagus or advanced or metastatic Siewert type I adenocarcinoma of the EGJ, had active central nervous system metastases and/or carcinomatous meningitis, or active infection or autoimmune disease that required systemic therapy in the past 2 years. Inclusion and exclusion criteria are further described in Table 6.

Baseline Characteristics

The demographic and baseline characteristics were well-balanced between groups, except for age (65 years or older) and stage IVB disease. There were more patients 65 years or older in the pembrolizumab in combination with cisplatin and 5-FU group (46.1%) compared with the placebo in combination with cisplatin and 5-FU group (39.9%). There were more patients with a current disease stage of iv B (distant lymph nodes and/or other organs) in the pembrolizumab in combination with cisplatin and 5-FU group (17.4%) compared with the placebo in combination with cisplatin and 5-FU group (10.9%; data not reported in Table 7). The majority (99.7%) had an ECOG PS of 0 or 1 (39.9% and 59.8%, respectively) and had metastatic disease (91.2%). Most patients were male (83.4%), had an ESCC primary diagnosis (73.2%), and about half were Asian (53.4%), enrolled in Asia (52.5%), and had tumour expressed PD-L1 with a CPS of 10 or greater (51.1%).¹ Refer to Table 7: Summary of Baseline Characteristics, ITT Population.

Most patients had been treated with 1 or more prior medications (94.9% in the pembrolizumab in combination with cisplatin and 5-FU group and 94.1% in the placebo in combination with cisplatin and 5-FU group); the types of prior medication were balanced between the 2 treatment groups. Refer to Table 21 for more details.

With regards to concomitant medication, a greater proportion of patients in the pembrolizumab in combination with cisplatin and 5-FU group compared with patients in the placebo in combination with cisplatin and 5-FU group had taken the following concomitant medications: drugs for constipation (55.9% versus 49.2%), antithrombotic agents (31.4% versus 25.9%), corticosteroids in dermatological preparations (17.8% versus 11.6%), anesthetics (24.3% versus 18.1%), and psychoanaleptics (15.1% versus 9.5%). Refer to Table 22 for more details on types of concomitant medication.

Interventions (KEYNOTE-590)

Pembrolizumab in combination with cisplatin and 5-FU group was dosed at 200 mg intravenously, every 3 weeks on day 1 of each cycle to a maximum of 35 administrations (2 years). Along with pembrolizumab, patients in the pembrolizumab in combination with cisplatin and 5-FU group generally received cisplatin at a dose of 80 mg/m² intravenously every 3 weeks on day 1 of each cycle for a maximum of 6 doses and 5-FU at a dose of 800 mg/m² per day for 5 days every 3 weeks on day 1 to day 5 of each cycle. Although administration of cisplatin and/or 5-FU could begin 1 to 2 days following pembrolizumab or placebo, and administration of 5-FU could vary (as per local standard for 5-FU administration duration) provided that the total dose was 4,000 mg/m² per cycle (e.g., 1,000 mg/m² per day on each of days 1 to 4 was permitted).

Normal saline in the placebo in combination with cisplatin and 5-FU group was given every 3 weeks on day 1 of each cycle. Along with placebo, patients in the placebo in combination with cisplatin and 5-FU group generally received cisplatin at a dose of 80 mg/m² intravenously every 3 weeks on day 1 of each cycle for a maximum of 6 doses and 5-FU at a dose of 800 mg/m² per day for 5 days every 3 weeks on day 1 to day 5 of each cycle. Administration of cisplatin and/or 5-FU could begin 1 to 2 days following pembrolizumab or placebo, and administration of 5-FU could vary (as per local standard for 5-FU administration duration) provided that the total dose was 4,000 mg/m² per cycle (e.g., 1,000 mg/m² per day on each of days 1 to 4 was permitted).

Treatment was continued until confirmed progressive disease, unacceptable toxicity, intercurrent illness that prevented further administration of treatment, investigator’s decision to withdraw patient, patient withdrawal of consent, pregnancy of patient, noncompliance with trial treatment or procedure requirements, completion of 35 administrations (approximately 2 years) of treatment with study medication or achievement of a complete response, or administrative reasons. Crossover from placebo to pembrolizumab was not permitted.

Pembrolizumab or placebo dose reduction were not permitted, rather treatment could be interrupted or discontinued due to toxicity.

Outcomes (KEYNOTE-590)

Co-primary outcomes were OS (in patients with ESCC whose tumours are PD-L1 CPS ≥ 10, in patients with ESCC, in patients whose tumours are PD-L1 CPS ≥ 10, and all patients) and PFS (in patients with ESCC, in patients whose tumours are PD-L1 biomarker-positive [CPS ≥ 10] and all patients). Secondary outcomes included: ORR, DOR, EORTC QLQ-C30, EORTC QLQ-OES18, and safety. PFS, ORR, and DOR are based on RECIST 1.1 and assessed by the investigator. EQ-5D-5L was an exploratory outcome. Refer to Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol for more details. A description and critical appraisal of PROs can be found in Appendix 4.

Statistical Analysis (KEYNOTE-590)

In the final protocol, there was 1 efficacy interim analysis in addition to the final analysis planned. The purpose of the interim analysis was to perform the main efficacy analysis for PFS and the interim analysis of OS, while the purpose of the final analysis was to perform the main efficacy analysis for OS. Refer to Table 23 for more details.

Interim data were reviewed by an independent data monitoring committee which could make recommendations for the ongoing conduct of the trial. It was noted that the independent data monitoring committee confirmed that the KEYNOTE-590 study met the specified efficacy and safety end points after the review of the interim analysis results performed by an unmasked independent statistician.⁷ As a result, the interim results in this report represent the final analysis, with a data cut-off date of July 2, 2020.

Important protocol deviations were similar between the 2 groups (7.8% in the pembrolizumab in combination with cisplatin and 5-FU group and 8.2% in placebo in combination with cisplatin and 5-FU group). The majority of important protocol deviations were related to safety reporting (reportable events and/or follow-up safety event information not reported as per timelines outlines in the protocol). None of the important protocol deviations were considered clinically important.

Protocol deviations associated with COVID-19 were reported in 4.0% of patients in the pembrolizumab in combination with cisplatin and 5-FU group and 1.9% in placebo in combination with cisplatin and 5-FU group. The majority of protocol deviations associated with COVID-19 were related to trial procedure and deemed not important. None of the protocol deviations associated with COVID-19 were considered clinically important.

All amendments to the statistical analysis plan occurred before the data lock for the planned interim analysis (July 30, 2020). Of note, changes to the primary end points were made based on results from the KEYNOTE-181 study, an open-label, phase III randomized controlled trial of patients with advanced or metastatic ESCC or adenocarcinoma of the esophagus that progressed after 1 prior therapy³⁵ (e.g., the addition of OS in ESCC; OS in ESCC whose tumours are PD-L1 with a CPS or 10 or greater, and PFS in ESCC). As well, based on input from the US regulatory agency, PFS analysis was changed from blinded independent central review (BICR) to investigator-assessed due to the higher expected discordance rate in the assessment of disease response between investigator and BICR.

Non-parametric Kaplan–Meier method was used to estimate OS, PFS, DOR, and time to deterioration (for PROs: EORTC QLQ-C30, QLQ-OES18, and EQ-5D-5L). A stratified log-rank test was used to assess the difference in OS, PFS, and time to deterioration between the 2 groups. The stratified Miettman and Nurminen method was used to assess the difference in response rate, overall improvement, and overall improvement or stability (for PROs: EORTC QLQ-C30, QLQ-OES18, and EQ-5D-5L). Refer to Table 24 for details on statistical model, adjustment factors, censoring, and sensitivity or exploratory analysis.

If at least 1 of the hypotheses regarding superiority of pembrolizumab in combination with cisplatin and 5-FU compared with placebo in combination with cisplatin and 5-FU was significant, then the KEYNOTE-590 study was considered to have met its primary objective. Overall type I error was controlled at 2.5% (1-sided): 1.2% initially allocated to OS in patients with ESCC and PD-L1 with a CPS of 10 or greater, 1.1% to OS in patients with ESCC, 0 to OS in patients with PD-L1 with a CPS of 10 or greater, 0 to OS in all patients, 0.2% to PFS in patients with ESCC, 0 to PFS in patients with PD-L1 with a CPS of 10 or greater, and 0 to PFS in all patients. Figure 2 illustrates the reallocation of type I error and describes each hypothesis.

Figure 2: Multiplicity Diagram for Type I Error Control

Source: Clinical Study Report, Keytruda submission.¹

The sample size and PFS and OS power calculations were based on the following assumptions: PFS follows an exponential distribution with a median of 6 months in the placebo in combination with cisplatin and 5-FU group; OS follows an exponential distribution with a median of 12 months in the placebo in combination with cisplatin and 5-FU group; an enrolment period of 28 months; and a 5% annual dropout rate for PFS and OS.

For PFS with a targeted number of 460 investigator-assessed events in ESCC at the interim analysis (final for PFS), the study had 82.8% power to detect an HR of 0.7 at an overall alpha level of 0.002 (1-sided). If the PFS hypothesis was rejected in ESCC, the PFS test has 62.2% power to detect an HR of 0.7 at an alpha level of 0.002 in patients with PD-L1 with a CPS of 10 or greater. If both PFS hypotheses in ESCC and in PD-L1 with a CPS of 10 or greater are rejected, the PFS test has 76.8% power to detect an HR of 0.75 at an alpha level of 0.002 in all patients. If the PFS null hypotheses in all populations and all OS null hypotheses are rejected, the PFS test has 95.1% power to detect an HR of 0.75 at an alpha level of 0.025 in all patients.

For OS with a targeted number of 233 events and 1 interim analysis at 86% of target number of events, the study has 84.5% power at final analysis to detect an HR of 0.65 at an overall alpha level of 0.012 (1-sided) in ESCC patients with PD-L1 with a CPS of 10 or greater, and based on a target number of 455 events, the study has 88.3% power at final analysis to detect an HR of 0.72 at an overall alpha level of 0.011 (1-sided) in ESCC patients. If the OS hypothesis is rejected in ESCC with PD-L1 with a CPS of 10 or greater and is not, however, rejected in ESCC, the OS test has 89.5% power at final analysis to detect an HR of 0.65 at an overall alpha level of 0.006 (1-sided) in PD-L1 with a CPS of 10 or greater. If the OS hypothesis is rejected in ESCC and is not, however, rejected in ESCC with PD-L1 with a CPS of 10 or greater, the OS test has 92.9% power at final analysis to detect an HR of 0.65 at an overall alpha level of 0.011 (1-sided) in PD-L1 with a CPS of 10 or greater. If the OS hypotheses in ESCC with PD-L1 with a CPS of 10 or greater and in ESCC are both rejected, the OS test has 96.0% power at final analysis to detect an HR of 0.65 at an overall alpha level of 0.023 (1-sided) in PD-L1 with a CPS of 10 or greater. If OS hypotheses in ESCC with PD-L1 with a CPS of 10 or greater, in ESCC, and in PD-L1 with a CPS of 10 or greater are all rejected, the OS test has 94.1% power at final analysis to detect an HR of 0.75 at an overall alpha level of 0.023 (1-sided) in all patients. If the OS hypotheses in all populations and all PFS null hypotheses are rejected, the OS test has approximately 94.5% power at final analysis to detect an HR of 0.75 at an overall alpha level of 0.025 (1-sided) in all patients.

For ORR, based on 749 patients with at least 10 months of follow-up, the study had a 98.7% power to detect a 15%-point difference in ORR (at an alpha of 0.025) between an underlying 35% response rate in the placebo in combination with cisplatin and 5-FU group and a 50% response rate in the pembrolizumab in combination with cisplatin and 5-FU.

Results

Patient Disposition

Patient Disposition shows the patient disposition for the KEYNOTE-590 study. Of the 1,020 patients screened, a total of 749 patients were randomized and 271 patients were excluded upon screening primarily because they did not have a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic adenocarcinoma or ESCC or advanced or metastatic Siewert type I.¹

Of the 749 patients that were randomized to receive either pembrolizumab in combination with cisplatin and 5-FU (n = 373) or placebo in combination with cisplatin and 5-FU (n = 376), 740 received treatment (n = 370 and n = 370, respectively) and 9 did not receive treatment (n = 3 and n = 6, respectively).¹

At the time of the data cut-off date of July 2, 2020, a total of 687 patients discontinued treatment (n = 328 in the pembrolizumab in combination with cisplatin and 5-FU group; n = 359 in the placebo in combination with cisplatin and 5-FU group). The main reasons for discontinuation in the pembrolizumab in combination with cisplatin and 5-FU group and in the placebo in combination with cisplatin and 5-FU group were progressive disease (55.1% and 64.6%, respectively), followed by AEs (13.2% and 11.9%, respectively), and then clinical progression (9.7% and 11.1%, respectively). A total of 15 patients in the pembrolizumab in combination with cisplatin and 5-FU group completed treatment while 1 patient in the placebo in combination with cisplatin and 5-FU group completed treatment.¹

The efficacy population (ITT population) included 749 patients, while the safety population included 740 patients.¹

As of the data cut-off date, the median follow-up duration for patients in the pembrolizumab in combination with cisplatin and 5-FU group was 12.6 months (range = 0.1 to 33.6) and the median follow-up duration for patients in the placebo combination with cisplatin and 5-FU group was 9.8 months (range = 0.1 to 33.6).¹

Exposure to Study Treatments

The median duration on therapy was similar between groups (5.7 months [range = 0.0 to 26.0] versus 5.1 months [range = 0.1 to 26.6]), while the median number of cycles was 8.0 months (range = 1.0 to 35.0) for the pembrolizumab in combination with cisplatin and 5-FU group compared with 7.0 months (range = 1.0 to 35.0) for the placebo in combination with cisplatin and 5-FU group. AEs leading to dose interruption was similar between the groups (66.8% versus 63.2%). Dose reduction of pembrolizumab was not permitted. Refer to Table 10 and Table 20 for more details.

Efficacy

Overall Survival

In patients with ESCC and PD-L1 with a CPS of 10 or greater, OS HR was 0.57 (95% CI, 0.43 to 0.75; P < 0.0001). The median OS was 13.9 months (95% CI, 11.1 to 17.7) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 8.8 months (95% CI, 7.8 to 10.5) for the placebo in combination with cisplatin and 5-FU group.

In patients with ESCC, OS HR was 0.72 (95% CI, 0.60 to 0.88; P = 0.0006). The median OS was 12.6 months (95% CI, 10.2 to 14.3) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 9.8 months (95% CI, 8.6 to 11.1) for the placebo in combination with cisplatin and 5-FU group.

In patients whose tumour express PD-L1 with a CPS of 10 or greater, OS HR was 0.62 (95% CI, 0.49 to 0.78; P < 0.0001). The median OS was 13.5 months (95% CI, 11.1 to 15.6) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 9.4 months (95% CI, 8.0 to 10.7) for the placebo in combination with cisplatin and 5-FU group.

In all patients, OS HR was 0.73 (95% CI, 0.62 to 0.86; P < 0.0001). The median OS was 12.4 months (95% CI, 10.5 to 14.0) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 9.8 months (95% CI, 8.8 to 10.8) for the placebo in combination with cisplatin and 5-FU group.

In all 4 OS analyses, the HRs were statistically significant. Refer to Table 11: Summary of Efficacy Co-Primary Outcomes, Efficacy (ITT) Population for more details.

Kaplan–Meier Curves for OS are presented in Figure 3, Figure 4, Figure 5, and Figure 6.

Progression-Free Survival

In patients with ESCC, PFS HR was 0.65 (95% CI, 0.54 to 0.78; P < 0.0001). The median PFS was 6.3 months (95% CI, 6.2 to 6.9) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 5.8 months (95% CI, 5.0 to 6.1) for the placebo in combination with cisplatin and 5-FU group.

In patients whose tumour express PD-L1 with a CPS of 10 or greater, PFS HR was 0.51 (95% CI, 0.41 to 0.65; P < 0.0001). The median PFS was 7.5 months (95% CI, 6.2 to 8.2) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 5.5 months (95% CI, 4.3 to 6.0) for the placebo in combination with cisplatin and 5-FU group.

In all patients, PFS HR was 0.65 (95% CI, 0.55 to 0.76; P < 0.0001). The median PFS was 6.3 months (95% CI, 6.2 to 6.9) for the pembrolizumab in combination with cisplatin and 5-FU group compared to 5.8 months (95% CI, 5.0 to 6.0) for the placebo in combination with cisplatin and 5-FU group.

In all 3 PFS analyses, the HRs were statistically significant. Refer to Table 11: Summary of Efficacy Co-Primary Outcomes, Efficacy (ITT) Population for more details.

Kaplan–Meier curves for PFS are presented in Figure 7, Figure 8, and Figure 9.

Figure 3: Kaplan–Meier Estimates of Overall Survival, Patients With ESCC, and PD-L1 CPS ≥ 10 — ITT Population

5-FU = 5-fluorouracil; CPS- = combined positive score; ESCC = esophageal squamous cell carcinoma; ITT = intent to treat; PD-L1 = programmed cell death ligand 1; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 4: Kaplan–Meier Estimates of Overall Survival in Patients With ESCC — ITT Population

5-FU = 5-fluorouracil; ESCC = esophageal squamous cell carcinoma; ITT = intent to treat; PD-L1 = programmed cell death ligand 1; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 5: Kaplan–Meier Estimates of Overall Survival in Patients With PD-L1 CPS of 10 or Greater — ITT Population

5-FU = 5-fluorouracil; CPS = combined positive score; ESCC = esophageal squamous cell carcinoma; ITT = intent to treat; PD-L1 = programmed cell death ligand 1; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 6: Kaplan–Meier Estimates of Overall Survival (All Patients)

5-FU = 5-fluorouracil; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 7: Kaplan–Meier Estimates of PFS Based on Investigator Assessment per RECIST 1.1. in Patients With ESCC — ITT Population

5-FU = 5-fluorouracil; ESCC = esophageal squamous cell carcinoma; ITT = intention to treat; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 8: Kaplan–Meier Estimates of PFS Based on Investigator Assessment per RECIST 1.1. in Patients With PD-L1 CPS of 10 or Greater — ITT Population

5-FU = 5-fluorouracil; CPS = combined positive score; ITT = intention to treat; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 9: Kaplan–Meier Estimates of PFS Based on Investigator Assessment per RECIST 1.1 in All Patients — ITT Population

5-FU = 5-fluorouracil; ITT = intention to treat; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; SOC = cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

In general, pre-specified subgroup analyses for OS and PFS were consistent with the co-primary analysis results, with the exception of sex (female), histology (adenocarcinoma [OS only]), primary tumour site (adenocarcinoma of esophagus [OS only]), and Siewert type I. Refer to Table 12: Summary of Subgroup Analyses, All Patients, ITT Population Forrest plots of OS and PFS HRs by subgroups can be found in Figure 18 and Figure 19.

Objective Response Rate

In all patients, confirmed ORR was higher with the pembrolizumab in combination with cisplatin and 5-FU group compared to the placebo in combination with cisplatin and 5-FU group (45.0% and 29.3% respectively). Refer to Table 13 Objective Response Rate and Duration of Response, All Patients, ITT Population .

For ORR of patients with ESCC, ESCC and a CPS of 10 or greater, and ESCC and CPS refer to Table 25.

Duration of Response

In all patients, the median DOR in the pembrolizumab in combination with cisplatin and 5-FU group was 8.3 months (range = 1.2 to 31.0) compared with the placebo in combination with cisplatin and 5-FU group (6.0 months; 1.5 to 25.0, respectively). Refer to Table 13 Objective Response Rate and Duration of Response, All Patients, ITT Population .

For DOR of patients with ESCC, ESCC and a CPS of 10 or greater, and ESCC and CPS refer to Table 25.

EQ-5D Questionnaire

In the FAS population, the compliance and completion for the EQ-5D at baseline was similar at the baseline (98.1% for both groups). Over time, compliance and completion rates declined as missing data by design (e.g., discontinued due to AE, clinical progression, physician decision, progressive disease, withdrawal by patient) increased.

Based on blinded data review, week 18 was used for the mean change from baseline analysis. At week 18, imbalances (≥ 5% differences) in missing data (i.e., discontinued due to AE, clinical progression, physician decision, progressive disease, protocol violation, withdrawal by patient, patient died) were observed between the pembrolizumab in combination with cisplatin and 5-FU group compared to the placebo in combination with cisplatin and 5-FU group (31.9% versus 38.9%, respectively). At week 18, patients not completing the questionnaire due to disease under study or to site staff error were similar (6.5% versus 4.4%, respectively).

In the FAS population, the least squares mean change from baseline to week 18 in EQ-5D VAS was similar between the 2 groups. EQ-5D was an exploratory end point, with no MID reported by the sponsor. Refer to Table 14.

For EQ-5D VAS of patients with (i) ESCC, (ii) ESCC and a CPS of 10 or greater, and (iii) ESCC and a CPS of 10 or greater refer to Table 26.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

Based on blinded data review, week 18 was used for the mean change from baseline analysis. In the FAS population, the least squares mean change from baseline to week 18 in in global health status/QoL remained was similar between the 2 groups. The mean change from baseline in global health status/QoL remained stable over time for the pembrolizumab in combination with cisplatin and 5-FU group compared with the placebo in combination with cisplatin and 5-FU group and the median time to deterioration for global health status/QoL was not reached for both groups. Refer to Figure 10, Figure 11, and Table 14.

Imbalances (≥ 5% differences) in missing data (e.g., discontinued due to AE, clinical progression, complete response, physician decision, progressive disease, protocol violation, withdrawal by patient, completed study treatment, translation not available in patient’s language, patient died) were observed at week 18 between the pembrolizumab in combination with cisplatin and 5-FU group compared to the placebo in combination with cisplatin and 5-FU group (31.7% versus 38.7%, respectively). At week 18, patients not completing the questionnaire (e.g., did not complete due to disease under study, site staff error, patient in hospital, physically unable to complete, patient refused for other reasons, with visit no record, or other) were similar (6.8% versus 4.7%, respectively).

For global health status/QoL of patients with ESCC, ESCC and a CPS of 10 or greater, and ESCC refer to Table 26, Figure 20, Figure 21, Figure 22, Figure 23, Figure 24 and Figure 25.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module

Based on blinded data review, week 18 was used for the mean change from baseline analysis. In the FAS population, the mean change from baseline in pain was in favour of the pembrolizumab in combination with cisplatin and 5-FU, the mean change from baseline in dysphagia and reflux were similar between the 2 groups, and the median time to deterioration for dysphagia, pain, and reflux was not reached for both groups. Refer to Figure 12, Figure 13, Figure 14, Figure 15, Figure 16, Figure 17, and Table 14.

For dysphagia, pain, and reflux of patients with ESCC, ESCC and a CPS of 10 or greater, and ESCC refer to Table 26, Figure 26, Figure 27, Figure 28,Figure 29, Figure 30, Figure 31, Figure 32, Figure 33,Figure 34, Figure 35, Figure 36, Figure 37, Figure 38, Figure 39, Figure 40, Figure 41, Figure 42, and Figure 43.

Figure 10: Empirical Mean Change From Baseline and 95% CI for the EORTC QLQ-C30 Global Health Status/QoL Over Time by Treatment Group — FAS Population

5-FU = 5-fluorouracil; CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 11: Kaplan–Meier Estimates of Time to Deterioration for EORTC QLQ-C30 Global Health Status and QoL — FAS Population With Baseline

5-FU = 5-fluorouracil; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 12: Empirical Mean Change From Baseline and 95% CI for the EORTC QLQ OES-18 Dysphagia Over Time by Treatment Group — FAS Population

5-FU = 5-fluorouracil; CI = confidence interval; EORTC QLQ-OES18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module; FAS = full analysis set; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 13: Empirical Mean Change From Baseline and 95% CI for the EORTC QLQ OES-18 Pain Over Time by Treatment Group — FAS Population

5-FU = 5-fluorouracil; CI = confidence interval; EORTC QLQ-OES18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module; FAS = full analysis set; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 14: Empirical Mean Change From Baseline and 95% CI for the EORTC QLQ OES-18 Reflux Over Time by Treatment Group — FAS Population

5-FU = 5-fluorouracil; CI = confidence interval; EORTC QLQ-OES18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module; FAS = full analysis set; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 15: Kaplan–Meier Estimates of Time to Deterioration for EORTC QLQ-OES18 Dysphagia — FAS Population With Baseline

5-FU = 5-fluorouracil; EORTC QLQ-OES18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module; FAS = full analysis set; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 16: Kaplan–Meier Estimates of Time to Deterioration for EORTC QLQ-OES18 Pain — FAS Population With Baseline

5-FU = 5-fluorouracil; EORTC QLQ-OES18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module; FAS = full analysis set; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Figure 17: Kaplan–Meier Estimates of Time to Deterioration for EORTC QLQ-OES18 Reflux — FAS Population With Baseline

5-FU = 5-fluorouracil; EORTC QLQ-OES18 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Esophageal Cancer Module; FAS = full analysis set; Pembrolizumab + SOC = pembrolizumab in combination with cisplatin and 5-FU; SOC = placebo in combination with cisplatin and 5-FU.

Note: The data cut-off date was July 2, 2020.

Source: Clinical Study Report, Keytruda submission.¹

Harms (KEYNOTE-590)

Any AEs, treatment-related AEs, grade 3 to 5 AEs, and any serious AEs were comparable between pembrolizumab in combination with cisplatin and 5-FU versus placebo in combination with cisplatin and 5-FU (Table 15).

Although the number of events was infrequent, death due to AEs, and death due to treatment-related AEs were similar between the 2 groups.

The most commonly reported AEs in the pembrolizumab in combination with cisplatin and 5-FU group and the placebo in combination with cisplatin and 5-FU group were nausea (67.3% versus 62.7%, respectively), anemia (50.5% versus 56.2%, respectively), decreased appetite (44.3% versus 38.1%, respectively), fatigue (40.3% versus 34.1%, respectively), and constipation (40.0% versus 40.3%, respectively). The most frequently reported treatment-related AEs were nausea (63.0% versus 59.5%, respectively), decreased appetite (39.2% versus 32.2%, respectively), and anemia (38.6% versus 43.8%, respectively); most of which were grade 1 or 2.

Of note, immune-mediated AEs and infusion reactions were higher among the pembrolizumab in combination with cisplatin and 5-FU group (25.7% versus 11.6%, respectively), hypothyroidism (10.8% versus 6.5%, respectively) and hyperthyroidism (5.7% versus 0.8%, respectively), pneumonitis (6.2% versus 0.5%, respectively), grade 3 or higher treatment-related AE (71.9% versus 67.6%, respectively), serious treatment-related AEs (31.6% versus 26.2%, respectively), and discontinuation due to treatment-related AEs (19.5% versus 11.6%, respectively).¹

Refer to Table 15: Summary of Harms and Table 27: Additional Harms Outcomes.

Critical Appraisal

Internal Validity

Overall, the demographic and baseline characteristics were well-balanced between groups, with the exception of age (65 years or older) and stage IVB disease. There was a greater proportion of patients in the pembrolizumab in combination with cisplatin and 5-FU group who were 65 years of age or older compared with patients in the placebo in combination with cisplatin and 5-FU group (46.1% and 39.9%, respectively). As well, there was a greater proportion of patients in pembrolizumab in combination with cisplatin and 5-FU group with stage IVB compared with patients in the placebo in combination with cisplatin and 5-FU group (17.4% and 10.9%, respectively). These imbalances resulted in more patients who were elderly with severe disease stage in the pembrolizumab than in the placebo combination arm, which rendered the study results more likely against the study drug.

There is a potential risk of bias because of substantial missing data (ORR, DOR, EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L) particularly on the QoL measures. A total of 8.3% of proportion of patients in the pembrolizumab in combination with cisplatin and 5-FU group compared with 8.2% of patients in the placebo in combination with cisplatin and 5-FU had no post-baseline assessment available for response evaluation.

In addition, for subjective outcomes (e.g., PROs), there may have been differential recall bias. For example, drug-related AEs, such as immune-intermediate events (25.7 versus 11.6%, respectively), and particularly, hypothyroidism (i.e., symptoms including fatigue, increased sensitivity to cold, muscle weakness) and hyperthyroidism (i.e., symptoms including nervousness, anxiety, fatigue, weight loss) might have led to unblinding and the patients’ awareness of their treatment assignment, potentially leading to biased assessment of the PROs. In addition, a total of 11 inadvertent unblinding events and a total of 21 premature “emergency” unblinding events were reported by the site due to emergency safety reasons and for further medical management; these patients were not excluded from the efficacy and safety analyses. Overall, the magnitude and direction of the impact of these missing data and recall bias on QoL is unknown.

The clinical experts agreed that the OS interim results represent a clinically meaningful benefit for patients. The reported OS and PFS results are deemed final based on interim analysis according to pre-specified stopping criteria. However, whether the “actual” final efficacy results would conform with the interim results is unknown. There are case reports that discuss the early stop of a trial that claimed statistical significance according to pre-specified stopping rule that had suffered type I error with the interim results and the estimates of effects could not be repeated at the final analysis after the trial was completed.^20-22 Such potential impacts, including the depletion of susceptible subjects, on OS could be more likely to occur toward the end of the trial. Therefore, the magnitude of OS benefit at final analysis may not be as large as what had been obtained at interim analysis.

The majority of patients had been treated with 1 or more prior medications (94.9% in the pembrolizumab in combination with cisplatin and 5-FU group and 94.1% in the placebo in combination with cisplatin and 5-FU group); the types of prior mediation were balanced between the 2 treatment groups.

With regards to concomitant medication, a greater proportion of patients in the pembrolizumab in combination with cisplatin and 5-FU group compared with patients in the placebo in combination with cisplatin and 5-FU group had taken the following concomitant medications: drugs for constipation (55.9% versus 49.2%, respectively), antithrombotic agents (31.4% versus 25.9%, respectively), corticosteroids in dermatological preparations (17.8% versus 11.6%, respectively), anesthetics (24.3% versus 18.1%, respectively), and psychoanaleptics (15.1% versus 9.5%, respectively). The impact of concomitant medications for the control of side effects may also have complicated the assessment of benefit on QoL.

The proportion of new anticancer medication received appeared a little higher in the placebo group (43.5% for patients in the pembrolizumab in combination with cisplatin and 5-FU group compared with 47.8% of patients in the placebo in combination with cisplatin and 5-FU group). The protocol stated that exploratory analysis to adjust for the effect of other PD-L1 therapies on OS could be performed; however, no analysis on the interim OS data were performed. Therefore, impact of other PD-L1 therapies on OS is unknown.

Approximately 1.3% of patients in the pembrolizumab in combination with cisplatin and 5-FU group and 0.8% of patients in the placebo in combination with cisplatin and 5-FU group of withdrew their participation from the trial. At total of 8.1% patients in the pembrolizumab group and 6.2% in the placebo group withdrew study medication.

Early withdrawal of the study medications and significant protocol deviations were also noted. Significant protocol deviations were similar between the pembrolizumab in combination with cisplatin and 5-FU group and the placebo in combination with cisplatin and 5-FU group (7.8% and 8.2%, respectively). Of note, protocol deviations associated with COVID-19 were higher (4.0% versus 1.9%) in the pembrolizumab than placebo combination group.

External Validity

The KEYNOTE-590 study population (first-line patients with locally advanced unresectable or metastatic adenocarcinoma or ESCC or advanced or metastatic Siewert type I adenocarcinoma of the EGJ) is considered reflective of the requested reimbursement population. The following considerations are of importance regarding the external validity of the KEYNOTE-590 study:

Population: The requested reimbursement population is carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ (tumour centre 1 cm to 5 cm above the gastric cardia). Siewert type I adenocarcinoma of the EGJ (in KEYNOTE-590) is synonymous with adenocarcinoma of the EGJ (tumour centre 1 cm to 5 cm above the gastric cardia). The reimbursement request specifies that these patients must be HER2 negative. Patient populations such as patients with active CNS metastases, patients with ECOG PS 2 or greater, and patients with rare forms of esophageal cancer such as GI stromal tumour, leiomyosarcoma, and neuroendocrine tumours were excluded from the KEYNOTE-590 study. Therefore, the magnitude of benefit in these unstudied populations is uncertain. This further compromised the generalizability of the findings on efficacy and particularly, safety, to those patients who may also receive this first-line combination therapy in practice.

Intervention: The requested reimbursement population is more inclusive in terms of the pembrolizumab combination. The KEYNOTE-590 study evaluated pembrolizumab in combination with cisplatin and 5-FU compared with cisplatin and 5-FU, whereas the reimbursement request is pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy and is not limited to the chemotherapy backbone used in the KEYNOTE-590 study.

Comparator: The platinum- and fluoropyrimidine-based chemotherapy (i.e., cisplatin and 5-FU) represents 1 of the standard first-line chemotherapies regimens and is an appropriate comparator in Canada. However, other relevant treatment regimens (listed in the systematic review protocol) are not studied. It would remain uncertain if the observed benefit could be generalizable to different combinations of chemotherapies regimens.

Outcome: The follow-up duration for the pembrolizumab in combination with cisplatin and 5-FU group was 12.6 months (range = 0.1 to 33.6) and the median follow-up duration for the placebo combination with cisplatin and 5-FU group was 9.8 months (range = 0.1 to 33.6).¹ The clinical experts agreed that the OS interim results represent a clinically meaningful benefit for patients.

Setting: This study is a multinational, multi-centre trial. Among the 26 countries that participated, there were 6 Canadians sites that recruited patients. Half of the patient population were enrolled in Asia (52.5%).¹

Table 16 details the assessment of generalizability of evidence for pembrolizumab.

Indirect Evidence

No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search. The sponsor conducted a feasibility assessment³ of estimating the comparative efficacy and safety of pembrolizumab plus cisplatin and 5-FU versus other competing interventions using data obtained from a systematic literature review. Refer to Appendix 5 for the CADTH’s summary and critical appraisal of the feasibility assessment.

Other Relevant Evidence

The following 2 studies (KEYNOTE-062 and KEYNOTE-859) were identified as relevant because they met the systematic review protocol; however, they included a mixed population (i.e., all HER2-negative GEJ patients were enrolled without any Siewert classification, whereas only patients with HER2-negative Siewert type I GEJ are of relevance to the reimbursement request).

It is also important to note that the trials did not include patients with ESCC or adenocarcinoma of the esophagus, which is a relevant population for the reimbursement request. For the KEYNOTE-062 study, patients must be PD-L1 positive (i.e., CPS ≥ 1), whereas PD-L1 status is not an eligibility criterion for reimbursement for this submission. The results from the pre-specified subgroup analysis of the primary location (GEJ) were only available for OS and safety data are reported for the entire study population (gastric and GEJ adenocarcinoma). For the KEYNOTE-859 study, only study design details are available, and no results are available at this time. Both trials used alternative platinum- and fluoropyrimidine-based chemotherapy backbones for the intervention and comparator. In the KEYNOTE-062 study, cisplatin and 5-FU or cisplatin and capecitabine were offered as the chemotherapy backbone for the intervention and comparator, while in the KEYNOTE-859 study, cisplatin and 5-FU or oxaliplatin and capecitabine were offered.

KEYNOTE-062^23,38,39

The KEYNOTE-062 study is a phase III, randomized, partially blinded, multi-centre study comparing pembrolizumab as monotherapy and in combination with cisplatin and 5-FU or cisplatin and capecitabine versus placebo in combination with cisplatin and 5-FU or cisplatin and capecitabine as first-line treatment for patients with advanced gastric or GEJ adenocarcinoma. Patients were enrolled into the trial in 200 centres in 29 countries across the Americas (not including Canada), Asia, Africa, Europe, and Oceania.²³ Refer to Table 17 for more details.

A total of 1,787 patients were screened, and 763 patients were randomized in a 1:1:1 ratio to receive pembrolizumab as monotherapy (n = 256), pembrolizumab in combination with cisplatin and 5-FU or capecitabine (n = 257), or placebo in combination with cisplatin and 5-FU or capecitabine (n = 250). There were slightly more GEJ patients in the pembrolizumab combination group than the chemotherapy group (33.1% versus 26.8%). It is unknown how many patients overall and in each group were classified as Siewert type I. With regard to the fluoropyrimidine-based chemotherapy, more patients received capecitabine than 5-FU in the pembrolizumab combination group (61.9% versus 38.1%) and the chemotherapy group (62.0% versus 38.0%).²³ Refer to Table 1 of the KEYNOTE-062 publication.²³ The results represent the final analysis, with a data cut-off date of March 26, 2019. In the overall study population (patients with gastric and GEJ adenocarcinoma), there was no difference in OS between the pembrolizumab combination and chemotherapy groups for patients with PD-L1 with a CPS of 1 or greater (OS HR = 0.85; 95% CI 0.7 to 1.03). The pre-specified OS subgroup analysis of the primary location for GEJ were consistent with the overall study population results (OS HR = 0.96; 95% CI 0.67 to 1.36). It is important to note that the pre-specified OS subgroup analysis of the primary location for GEJ was exploratory, underpowered, and not reflective of the entire reimbursement population, and therefore should be interpreted with caution. In the overall population (patients with gastric and GEJ adenocarcinoma), more AEs leading to discontinuation and immune-mediated AEs and infusion reactions were reported in the pembrolizumab combination group compared to the chemotherapy group (27.6% versus 18.0%, and 24.0% versus 7.8%, respectively).²³

Refer to Figure 2C of the KEYNOTE-062 publication²³ and Table 2 of the KEYNOTE-062 publication²³ for more details.

KEYNOTE-859^24,40

The KEYNOTE-859 study is an ongoing phase III, multi-centre study comparing pembrolizumab in combination with chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) versus placebo in combination with chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) as first-line treatment for patients with advanced gastric or GEJ adenocarcinoma. Patients must be HER2 negative.⁴⁰ The trial did not include patients with ESCC or adenocarcinoma of the esophagus which is a relevant population for the reimbursement request. Enrolment is ongoing in 33 countries, with 215 study locations in the Americas (including Canada), Asia, Europe, Africa, and Oceania.^40,41 Currently, only study design details are available.²⁴ The study is still ongoing, and no results are available at this time.³ Refer to Table 17 for more details.

Discussion

Summary of Available Evidence

The CADTH clinical review report included input from patient groups, clinical experts, and drug programs, 1pivotal phase III randomized controlled trial, 2 supporting phase III randomized controlled trials, and 1 indirect treatment comparison feasibility assessment report.

The KEYNOTE-590 study is an ongoing phase III, randomized, double-blind, placebo-controlled, multi-centre, superiority study comparing pembrolizumab in combination with cisplatin and 5-FU to placebo in combination with cisplatin and 5-FU for the first-line treatment of patients with locally advanced unresectable or metastatic adenocarcinoma or ESCC or advanced or metastatic Siewert type I adenocarcinoma of the GEJ.

The KEYNOTE-062 study is a phase III, randomized, partially blinded, multi-centre study comparing pembrolizumab as monotherapy and in combination with cisplatin and 5-FU or cisplatin and capecitabine versus placebo in combination with cisplatin and 5-FU or cisplatin and capecitabine as first-line treatment for patients with advanced gastric or GEJ adenocarcinoma.

The KEYNOTE-859 study is an ongoing phase III, multi-centre study comparing pembrolizumab in combination with chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) versus placebo in combination with chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) as first-line treatment for patients with advanced gastric or GEJ adenocarcinoma.

No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search; however, the sponsor conducted a feasibility assessment³ of estimating the comparative efficacy and safety of pembrolizumab plus cisplatin and 5-FU versus other competing interventions using data obtained from a systematic literature review.

Interpretation of Results

Efficacy

In Canada, esophageal cancer is ranked 19th among all cancer types based on incidence and 10th based on mortality.⁸ Esophageal cancer is among 1 of the cancers with a high proportion of metastatic disease (stage IV) at first diagnosis (39.9%),⁸ with a relative 5-year survival rate for metastatic esophageal cancer of 5%.²⁶ Patient and caregiver respondents expressed the need for have access to new effective therapies that prolong OS, improve QoL, reduce disease symptoms, and have tolerable side effects given the poor and short survival rate for most patients with esophageal cancer.

The clinical experts identified prolonged life and improved HRQoL as the goals of treatment. Similarly, the clinician groups identified prolonged life and improved or maintained HRQoL as the goals of treatment. Delaying progression of disease and ensuring adequate nutritional intake were additional goals of treatment identified by a clinical group.

Both the clinical groups and clinical experts agreed that a clinically meaningful and statistically significant survival benefit in favour of pembrolizumab in combination with cisplatin and 5-FU was observed in the KEYNOTE-590 study for the entire study population, ESCC histology, and PD-L1 with a CPS of 10 or greater. The reported OS and PFS results are deemed “final” based on interim analysis according to pre-specified stopping criteria. However, whether the ”actual” final efficacy results would conform with the interim results is unknown.

Both the clinical groups and clinical experts acknowledged that while patients with PD-L1 with a CPS of 10 or greater, and patients with ESCC with PD-L1 with a CPS of 10 or greater are more likely to respond to pembrolizumab than the ITT population (any PD-L1 CPS and esophageal cancer or GEJ Siewert type I), all patients with esophageal cancers and EGJ adenocarcinomas (Siewert type I) would benefit from pembrolizumab. They agreed that the full patient population in the indication should be eligible for treatment with pembrolizumab (i.e., esophageal cancer and HER2-negative GEJ Siewert type I).

With regards to PROs for the FAS population, the mean change from baseline in global health status/QoL (using the EORTC QLQ-C30 scale) remained stable over time for the pembrolizumab in combination with cisplatin and 5-FU group compared with the placebo in combination with cisplatin and 5-FU group, and the median time to deterioration for global health status/QoL was not reached for both groups. EQ-5D was an exploratory outcome with no minimal important difference reported. Similar least squares mean change from baseline to week 18 in EQ-5D VAS was reported between the 2 groups. Although there was no clinically meaningful deterioration in QoL, there remains uncertainty in PROs and QoL due to the limitations discussed (i.e., missing data, recall bias). However, the magnitude and direction of the impact of these issues on the QoL assessment is unknown. As well, there is a potential risk of bias because of missing data, concomitant medication use, and differential recall bias due to patients’ awareness of treatment assignments as a consequence of drug-related AEs. The clinical experts noted, among other clinically meaningful responses (e.g., improved survival, reduction in severity of symptom, improved QoL), that if the addition of an agent to an established regimen improved survival and was not detrimental to QoL, that would also be considered a clinically meaningful response to treatment. In contrast, clinician groups expressed that a clinically meaningful response to treatments would be a reduction in symptoms or at minimum, a stabilization of symptoms (e.g., less pain, weight gain or cessation of weight loss, less fatigue), as well as an overall improvement in the ability to perform daily activities and a reduction in the caregiver burden.

With regards to investigator-assessed PFS and the protocol amendment to change PFS analysis from BICR to investigator-assessed due to the higher expected discordance rate in the assessment of disease response between investigator and BICR, the clinical experts noted that it is common to see discordance between BICR and investigator assessments in outcomes that have some subjectivity. The clinical experts acknowledged that while it is generally viewed that BICR as the more reliable measurement of response because the trial is blinded, the independent investigators response is still an adequate measure.

Although OS and PFS subgroup analysis results were pre-specified, they are considered exploratory and not powered to detect a difference, except for ESCC (histology and primary tumour site because ESCC was included in the statistical analysis plan); and therefore, should be interpretated with caution. The clinical experts acknowledged that although the possibility of sex differences in immunotherapy response has been highlighted in numerous previous publications,⁴² they discouraged different treatment recommendations based on sex.

The clinical experts agreed that while it is preferred to have a longer DOR, the 15.8% difference in ORR is a relatively large and a 6.4% complete response rate for the pembrolizumab in combination with cisplatin and 5-FU group was considered to be impressive for metastatic disease.

Of note, the study eligibility included only patients with ECOG 0 or 1, as a result, the benefit and safety profile are unknown in those patients with ECOG greater than 1, in real-world clinical practice who are also likely to receive this combination therapy.

As noted by the clinical experts, standard first-line chemotherapy regimens include a fluoropyrimidine and a platinum (usually cisplatin or oxaliplatin)^15-18 for patients with advanced ESCC and HER2-negative patients with EAC or GEJ. Examples of fluoropyrimidine- and platinum-based chemotherapy used in the first-line setting include: cisplatin and 5-FU, capecitabine and cisplatin, CAPOX, and FOLFOX. While the platinum- and fluoropyrimidine-based chemotherapy used in the KEYNOTE-590 study (i.e., cisplatin and 5-FU) represents 1 of the standard of first-line chemotherapies regimens, the clinical experts agreed that CAPOX and FOLFOX should be interchangeable chemotherapy backbones with cisplatin and 5-FU. If the patient is not eligible for cisplatin, carboplatin would be a reasonable substitute, which is consistent with standard practice in multiple cancer sites. The KEYNOTE-062 and KEYNOTE-859 studies used alternative platinum- and fluoropyrimidine-based chemotherapy backbones for the intervention and comparator compared to the KEYNOTE-590 study (cisplatin and 5-FU or cisplatin and capecitabine for KEYNOTE-062 and cisplatin and 5-FU or oxaliplatin and capecitabine for KEYNOTE-859). However, both trials had a mixed population (i.e., all HER2-negative GEJ patients were enrolled without any Siewert classification, whereas only patients with HER2-negative Siewert type I GEJ are of relevance to the reimbursement request) and both trials did not include patients with ESCC or adenocarcinoma of the esophagus, which is a relevant population for the reimbursement request. As well, for KEYNOTE-062, patients must be PD-L1 positive (i.e., CPS ≥ 1), whereas PD-L1 status is not an eligibility criterion for reimbursement in for this submission. Although GEJ subgroup OS analysis results were available for KEYNOTE-062, the results should be interpreted with caution because the GEJ subgroup OS analysis was exploratory, underpowered, and not reflective of the entire reimbursement population.

No indirect treatment comparisons comparing pembrolizumab to other relevant treatments were included in the sponsor’s submission to CADTH or identified in the literature search. The sponsor submitted an indirect treatment comparison feasibility assessment. A critical appraisal of the sponsor’s feasibility study was conducted by CADTH acknowledged that a standard network meta-analysis was not feasible due to lack of network connectivity, and that an unanchored MAIC would likely be biased, and it would not be possible to quantify or identify the direction of the bias.

Harms

The majority of patients in the trial reported treatment-related AEs; however, more discontinuation due to treatment-related AEs was reported in patients in the pembrolizumab in combination with cisplatin and 5-FU group. Many patients experienced grade 3 or greater AEs, and approximately half of the patients in the trial reported a serious AE; however, more serious treatment-related AEs were reported in patients in the pembrolizumab in combination with cisplatin and 5-FU group. More immune-mediated AEs and infusion reactions were reported in the pembrolizumab in combination with cisplatin and 5-FU group and among the AEs of special interest, there were more hypothyroidism, hyperthyroidism, and pneumonitis events reported in the pembrolizumab in combination with cisplatin and 5-FU group.

Overall, the clinical experts agreed that the pembrolizumab in combination with cisplatin and 5-FU toxicity profile appeared to be manageable. The clinical experts noted that monitoring and management of immune-related AEs is required. However, the clinical experts highlighted that serious side effects from PD-1 monotherapy are rare and are well described in previous clinical trials^23,35,43; therefore, they felt that the vast majority of patients tolerate these agents well. Although pembrolizumab in combination with cisplatin and 5-FU is a novel combination for the treatment of the indication under review, pembrolizumab is not a novel agent in oncology (i.e., there are various Health Canada–approved indications in oncology) and therefore, AEs and immune-mediated AEs (such as hypothyroidism, hyperthyroidism, pneumonitis, colitis, adrenal insufficiency, hepatitis, hypophysitis, nephritis, and type 1 diabetes mellitus) specific to pembrolizumab are known to clinicians and therefore can be better managed.

Other Considerations

The clinical experts highlighted that pembrolizumab added to chemotherapy is not currently a standard of care in Canada in this patient population. However, they expressed that pembrolizumab added to chemotherapy has the potential to represent a standard of care for patients with esophageal cancer or GEJ Siewert type I. The clinical experts felt that pembrolizumab added to chemotherapy would certainly be a standard of care for patients with ESCC and for patients with a CPS of 10 or greater. The clinical experts also felt that pembrolizumab added to chemotherapy was an appropriate treatment option for patients with GEJ Siewert type I who are HER2 negative, EAC, and for tumours with a CPS of less than 10.

Although ESCC is the most common subtype diagnosed globally, EAC has become more predominant across the Western countries including Canada.^10,27 The clinical experts acknowledged that even though EAC is seen more than ESCC in Canada, the KEYNOTE-590 study included both EAC and ESCC, and the benefit of pembrolizumab is seen in the entire population. As a result, the clinical experts emphasized that the full patient population (i.e., esophageal cancer and HER2-negative GEJ Siewert type I) should be eligible for pembrolizumab.

The clinical experts agreed it would be reasonable to permit the addition of pembrolizumab as a time-limited option for patients who have not progressed on first-line therapy. Applicable first-line chemotherapy regimens would include first-line platinum plus fluoropyrimidine, or alternate doublet chemotherapy (e.g., FOLFOX or CAPOX or FOLFIRI) and patients who had completed treatment without progression would also be suitable. The clinical experts agreed that there is no time frame specified as long as there is lack of progression; however, patients should otherwise meet the inclusion criteria for the KEYNOTE-590 study. The clinical experts noted that the population of patients who would fall into this category will be quite small. The clinical experts suggested that as these patients would be started later in therapy, consideration could be made to limit this to patients with tumours that have a PD-L1 with a CPS of 10 or greater.

The clinical experts noted that PD-L1 IHC 22C3 pharmDx is currently the only commercially available PD-L1 test validated for pembrolizumab and that PD-L1 status is not a requirement for reimbursement eligibility.³ While the clinical experts and clinician groups expressed that the full patient population in the indication should be eligible for treatment with the drug under review (i.e., esophageal cancer and HER2-negative GEJ Siewert type I), the clinical experts highlighted that access to PD-L1 CPS testing would be ideal as testing results provide meaningful information for the clinician to discuss the anticipated benefits of treatment with patients and families. The clinician group highlighted, however, that there is currently no routine testing conducted for this, nor is any testing expected in the future.

Reported OS and PFS results are final based on interim analysis. However, the long-term efficacy and safety of pembrolizumab in combination with cisplatin and 5-FU compared to placebo combination with cisplatin and 5-FU is unknown. The study is ongoing and therefore long-term efficacy and safety data are anticipated to be available in the future.

Conclusions

Compared to placebo in combination with cisplatin and 5-FU, first-line treatment with pembrolizumab in combination with cisplatin and 5-FU showed a clinically meaningful and statistically significant overall and PFS benefit in adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ (tumour centre 1 cm to 5 cm above the gastric cardia). While patients with PD-L1 with a CPS of 10 or greater, and ESCC patients with PD-L1 with a CPS of 10 or greater are more likely to respond to pembrolizumab than the ITT population (any PD-L1 CPS and esophageal cancer or GEJ Siewert type I), all patients with esophageal cancers and EGJ adenocarcinomas (Siewert type I) would benefit from pembrolizumab, and as a result, clinicians expressed that the full patient population in the indication (adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the EGJ [tumour centre 1 cm to 5 cm above the gastric cardia]) should be eligible for treatment with pembrolizumab. Discontinuation due to treatment-related AEs, serious treatment-related AEs, and immune-mediated AEs and infusion reactions were more frequently reported in patients treated with pembrolizumab in combination with cisplatin and 5-FU compared to patients treated with placebo in combination with cisplatin and 5-FU. Although there was no clinically meaningful deterioration in QoL, there remains uncertainty in PROs and QoL due to the limitations discussed (i.e., missing data, recall bias). The study is ongoing and therefore long-term efficacy and safety data are anticipated to be available in the future. In addition, study eligibility included only patients with ECOG PS 0 or 1. Therefore, the benefit and safety profile are unknown in those patients with ECOG greater than 1, who, in real-world clinical practice, are also likely to receive this combination therapy.

The platinum- and fluoropyrimidine-based chemotherapy used in the KEYNOTE-590 study (i.e., cisplatin and 5-FU) represents 1 of the standard of first-line chemotherapies regimens. The KEYNOTE-062 and KEYNOTE-859 studies used alternative platinum- and fluoropyrimidine-based chemotherapy backbones for the intervention and comparator compared to the KEYNOTE-590 study (cisplatin and 5-FU or cisplatin and capecitabine for KEYNOTE-062 and cisplatin and 5-FU or oxaliplatin and capecitabine for KEYNOTE-859). However, both trials had a mixed population (i.e., all patients with HER2-negative GEJ were enrolled without any Siewert classification, whereas only patients with HER2-negative Siewert type I GEJ are of relevance to the reimbursement request) and neither trials did included patients with ESCC or adenocarcinoma of the esophagus, which is a relevant population for the reimbursement request. Based on clinical expert opinion, it would be reasonable to use other platinum- and fluoropyrimidine-based chemotherapy backbones apart from cisplatin and 5-FU.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

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

Date of search: June 21, 2021

Alerts: Biweekly search updates until project completion

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

Limits: Conference abstracts: excluded

Table 18: Syntax Guide

Multi-Database Strategy

1. (Keytruda* or pembrolizumab* or lambrolizumab* or MK 3475 or MK3475 or Merck 3475 or HSDB 8257 or HSDB8257 or Sch 900475 or Sch900475 or DPT0O3T46P).ti,ab,ot,kf,hw,rn,nm.

2. exp Esophageal Neoplasms/

3. ((esophag* or oesophag* or gastroesophag* or GE junction* or EG junction* or GEJ or EGJ or upper gastr* or upper GI or gastric*) adj5 (cancer* or neoplas* or tumo?r* or carcinoma* or adenocarcinoma* or squamous or malignan* or metast*)).ti,ab,kf.

4. 2 or 3

5. 1 and 4

6. 5 use medall

7. *pembrolizumab/

8. (Keytruda* or pembrolizumab* or lambrolizumab* or MK 3475 or MK3475 or Merck 3475 or HSDB 8257 or HSDB8257 or Sch 900475 or Sch900475).ti,ab,kw,dq.

9. 7 or 8

10. esophagus tumour/ or exp esophagus cancer/

11. ((esophag* or oesophag* or gastroesophag* or GE junction* or EG junction* or GEJ or EGJ or upper gastr* or upper GI or gastric*) adj5 (cancer* or neoplas* or tumo?r* or carcinoma* or adenocarcinoma* or squamous or malignan* or metast*)).ti,ab,kw,dq.

12. 10 or 11

13. 9 and 12

14. 13 not (conference abstract or conference review).pt.

15. 14 use oemezd

16. 6 or 15

17. remove duplicates from 16

Clinical Trials Registries

ClinicalTrials.gov

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

[Search -- Keytruda OR pembrolizumab OR lambrolizumab | esophageal OR gastroesophageal OR oesophageal OR esophagogastric]

WHO ICTRP

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

[Search terms – Keytruda, pembrolizumab, esophageal, oesophageal, gastroesophageal, esophagogastric]

Health Canada’s Clinical Trials Database

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

[Search terms – Keytruda, pembrolizumab]

EU Clinical Trials Register

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

[Search terms -- Keytruda, pembrolizumab, esophageal, oesophageal, gastroesophageal, esophagogastric]

Grey Literature

Search dates: June 17, 2021 – June 22, 2021

Keywords: Keytruda, pembrolizumab, lambrolizumab, esophageal, oesophageal, gastroesophageal, esophagogastric, oesophagogastric

Limits: None

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

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

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals

Appendix 2: Excluded Studies

Table 19: Excluded Studies

Note: This table has not been copy-edited.

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 20: Summary of Exposure to Treatment by Regimen Component, Safety Population

5-FU = 5-fluorouracil, SD = standard deviation.

Note: Data cut-off date was July 2, 2020.

Source: Clinical Study Report.¹

Table 21: Prior Types of Medication

A5-FU = 5-fluorouracil.

Note: Data cut-off date was July 2, 2020.

Source: Clinical Study Report.¹

Table 22: Concomitant Medication