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Indication: 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 esophagogastric junction (tumour centre 1 cm to 5 cm above the gastric cardia)
CADTH recommends that Keytruda should be reimbursed by public drug plans for the treatment of esophageal or human epidermal growth factor receptor 2 (HER2)-negative esophagogastric junction (EGJ) cancer that cannot be removed by surgery or is metastatic, if certain conditions are met.
Keytruda should only be covered to treat adult patients who have not received previous treatment for advanced or metastatic esophageal or EGJ cancer and who have good performance status.
Keytruda should only be reimbursed if prescribed in combination with platinum and fluoropyrimidine–based chemotherapy and given by a clinician who is experienced in treating cancer. The price of Keytruda must be lowered to be cost-effective and affordable.
Evidence from a clinical trial demonstrated that Keytruda combined with cisplatin and 5-fluorouracil (5-FU) improved survival compared with cisplatin and 5-FU alone. Keytruda also had manageable side effects, which is an outcome identified as important by patients.
Based on public list prices, Keytruda is not considered cost-effective at a willingness-to-pay threshold of $50,000 per quality-adjusted life-year (QALY) for patients included in the indication approved by Health Canada, relative to cisplatin plus 5-FU. Economic evidence suggests that the price of Keytruda needs to be reduced by 75% for it to be cost-effective at a $50,000 per QALY threshold.
Based on public list prices, Keytruda is expected to cost the public drug plans $91 million over 3 years.
Esophageal cancer occurs in the esophagus — a muscular tube that connects the throat to the stomach — and EGJ cancer occurs where the esophagus and the stomach join. The cancer is considered locally advanced if it spreads in the esophagus or GEJ or metastatic if it spreads to another part of the body. Approximately 5% of patients diagnosed with advanced esophageal cancer are expected to be alive in 5 years.
Many patients do not respond to available treatment options. Even in patients who do respond, the duration of response is often short, and their survival is quite limited.
Treatment with Keytruda is expected to cost approximately $8,472.27 per cycle of pembrolizumab in combination with 5-FU and cisplatin at the sponsor’s assumed relative dose intensities.
The CADTH pCODR Expert Review Committee (pERC) recommends that pembrolizumab in combination with platinum and fluoropyrimidine–based chemotherapy be reimbursed 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) only if the conditions listed in Table 1 are met.
Evidence from 1 phase III, randomized, double-blind, placebo-controlled trial demonstrated that treatment with pembrolizumab plus cisplatin and 5-fluorouracil (5-FU) resulted in added survival benefit when used for the first-line treatment of patients with locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced or metastatic Siewert type I adenocarcinoma of the EGJ. The KEYNOTE-590 trial (N = 749) demonstrated that, when compared with placebo plus cisplatin and 5-FU, treatment with pembrolizumab plus cisplatin and 5-FU was associated with a statistically significant improvement in progression-free survival (PFS) (hazard ratio [HR] = 0.65; 95% confidence interval [CI], 0.55 to 0.76; P < 0.0001) and a statistically and clinically significant improvement in overall survival (OS) (HR = 0.73; 95% CI, 0.62 to 0.86; P < 0.0001). Input from patient groups indicated that patients desire new effective therapies that prolong OS, improve quality of life (QoL), reduce disease symptoms, and have tolerable side effects. Given all the evidence, pERC concluded that pembrolizumab plus cisplatin and 5-FU met some of the needs identified by patients because it provides an additional treatment option with improved OS and a manageable safety profile.
Using the sponsor-submitted price for pembrolizumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for pembrolizumab in combination with 5-FU and cisplatin was $170,819 per quality-adjusted life-year (QALY) compared with 5-FU plus cisplatin alone. At this ICER, pembrolizumab is not cost-effective at a $50,000 per QALY willingness-to-pay (WTP) threshold for first-line treatment of patients with locally advanced unresectable or metastatic cancer of the esophagus or HER2-negative adenocarcinoma of the EGJ. A reduction in price of at least 75% is required for pembrolizumab to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
Issues that may impact the drug plan’s ability to implement a recommendation as identified by pERC and the drug plans are summarized in Table 2.
Implementation Guidance from pERC.
Pembrolizumab in combination with platinum and fluoropyrimidine–based chemotherapy has a Health Canada indication 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). Pembrolizumab is an IgG4 monoclonal anti–programmed cell death 1 (PD-1) antibody. The Health Canada–approved dose is 200 mg every 3 weeks or 400 mg every 6 weeks administered as an IV infusion until disease progression, unacceptable toxicity, or up to 24 months.
To make their recommendation, the Committee considered the following information:
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient and from clinical expert(s) 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.
Three patient groups co-created 1 patient input for this review: CCC, the GI Society, and My Gut Feeling – Stomach Cancer Foundation of Canada.
According to the patient and caregiver respondents (N = 33), most patients were diagnosed with esophageal adenocarcinoma (77.42%); 12.90% of patients were diagnosed with esophageal squamous cell carcinoma (ESCC). All patient and caregiver respondents (except 1 patient) reported patients experienced 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 treatment-related side effects. One patient reported abdominal pain, diarrhea, rash, shortness of breath, and constipation; the other patient reported fatigue, itching, and some allergic reactions. 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. One patient reported pain behind the breastbone or in the throat, black stool, and weight loss (1 patient); the other patient reported fatigue and vomiting. Both patients indicated that they expected the following key outcomes to be improved by pembrolizumab: prolonging OS, delaying the need for chemotherapy, and having a convenient route of administration.
Patient and caregiver respondents highlighted that given the poor and short survival rates 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 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.
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 a PD-L1 CPS > 10). The clinical experts identified patients with autoimmune diseases are at increased risk of autoimmune disease flares and immune-related adverse events when treated with immunotherapy. However, the clinical experts agreed that for patients with well-controlled autoimmune disease, 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 EGJ 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, would be an appropriate treatment option for Siewert type I HER2-negative adenocarcinoma of EGJ and for tumours with CPS less than 10.
The clinical experts identified prolonged life and improved health-related QoL 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 a manageable safety profile.
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 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 did not cause a detriment to QoL and improved survival, that would also be considered a clinically meaningful response to treatment.
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 Gastrointestinal 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 Gastrointestinal 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 EGJ adenocarcinoma have poor prognosis and 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 health-related QoL as the goals of treatment. Additional goals of treatment identified by the Ontario Health-Cancer Care Ontario Gastrointestinal Drug Advisory clinicians were delay disease progression and ensure adequate nutritional intake.
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 or 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, although the clinician groups and clinical experts noted that patients with a PD-L1 CPS of 10 or higher, and patients with ESCC and a PD-L1 CPS of 10 or higher are more likely to respond to pembrolizumab than the intention-to-treat population (any PD-L1 CPS and esophageal cancer or EGJ Siewert type I), all patients with esophageal cancers and esophagogastric junction adenocarcinomas (Siewert type I) would benefit from pembrolizumab. As a result, both the clinician groups and clinical experts expressed that the full patient population in the indication submitted for reimbursement (i.e., esophageal cancer and HER2-negative EGJ Siewert type I) should be eligible for treatment with pembrolizumab.
Input from the Provincial Advisory Group (PAG) identified factors pertaining to relevant comparators, consideration for initiation of therapy, consideration for discontinuation of therapy, generalizability, care provision, system issues, and economic considerations. pERC weighed evidence from the KEYNOTE-590 trial and other clinical considerations, including input from clinical experts consulted by CADTH, to provide responses which are presented in Table 3.
Responses to Questions From the Drug Programs.
Keynote 590 is a phase III, randomized, double-blind, placebo-controlled, multicentre, superiority study comparing pembrolizumab plus cisplatin and 5-FU to placebo plus cisplatin and 5-FU for the first-line treatment of patients with locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced or metastatic Siewert type I adenocarcinoma of the EGJ. A total of 749 patients were randomized in a 1:1 ratio to receive pembrolizumab plus cisplatin and 5-FU (373 patients) or placebo plus cisplatin and 5-FU (376 patients). The first patient was randomized on July 25, 2017, and the last patient was randomized on July 2, 2020. This is an ongoing study with interim (primary analysis) results using a Global Study Population which included both the Global Cohort and the China Extension Study. These interim results represent the final analysis, with a data cut-off date of July 2, 2020, because the study end points were met for both PFS and OS.
The co-primary outcomes were:
Secondary and exploratory outcomes included objective response rate, duration of response, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Module (EORTC QLQ-OES18), safety and EuroQol 5-Dimensions 5-Levels (EQ-5D-5L).
The demographic and baseline characteristics were well-balanced between groups, except for age (65 years or older) and stage IV B (distant lymph nodes and/or other organs) disease. There were more patients aged 65 years or older in the pembrolizumab plus cisplatin and 5-FU group (46.1%) compared with the placebo plus cisplatin and 5-FU group (39.9%). There were more patients with a current disease stage of IV B in the pembrolizumab plus cisplatin and 5-FU group (17.4%) compared with the placebo plus cisplatin and 5-FU group (10.9%). The majority had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 (99.7%: ECOG PS 0% to 39.9% and ECOG PS 1% to 59.8%, respectively) and had metastatic disease (91.2%). Most patients were male (83.4%), had an ESCC primary diagnosis (73.2%), and approximately half were Asian (53.4%), enrolled in Asia (52.5%), and had tumour-expressed PD-L1 CPS of 10 or higher (51.1%).
The results for both PFS and OS are deemed final based on interim analysis because both primary end points met the prespecified 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.
As of the data cut-off date (July 2, 2020), the median follow-up duration for patients in the pembrolizumab plus 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 combined with cisplatin and 5-FU group was 9.8 months (range = 0.1 to 33.6).
In all patients, there was a 27% reduction in the risk of death in favour of pembrolizumab plus cisplatin and 5-FU. The OS HR was 0.73 (95% CI, 0.62 to 0.86; P < 0.0001), which met the statistical significance threshold in the analysis. The median OS was 12.4 months (95% CI, 10.5 to 14.0) for the pembrolizumab plus cisplatin and 5-FU group compared with 9.8 months (95% CI, 8.8 to 10.8) for the placebo plus cisplatin and 5-FU group. A statistically significant OS benefit in favour of pembrolizumab plus cisplatin and 5-FU was also observed in the following subgroups: patients with ESCC whose tumours expressed PD-L1 CPS of 10 or higher, patients with ESCC, and patients whose tumours expressed PD-L1 CPS of 10 or higher.
In all patients, there was a 35% reduction in risk of death and disease progression in favour of pembrolizumab plus cisplatin and 5-FU. The PFS HR was 0.65 (95% CI, 0.55 to 0.76; P < 0.0001), which met the statistical significance for statistical significance. The median PFS was 6.3 months (95% CI, 6.2 to 6.9) for the pembrolizumab plus cisplatin and 5-FU group compared with 5.8 months (95% CI, 5.0 to 6.0) for the placebo plus cisplatin and 5-FU group. A statistically significant PFS benefit in favour of pembrolizumab plus cisplatin and 5-FU was also observed in subgroups of patients with ESCC and patients whose tumours expressed PD-L1 CPS of 10 or higher.
In the patient-reported outcome (PRO) full set analysis 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 for EQ-5D VAS score was similar between the 2 groups. The mean change from baseline in global health status or QoL (using the EORTC QLQ-C30 scale) remained stable over time for the pembrolizumab plus cisplatin and 5-FU group compared with the placebo plus cisplatin and 5-FU group, and the median time to deterioration for global health status or QoL was not reached for both groups.
Overall, any adverse events, treatment-related adverse events, grade 3 to 5 adverse events, and any serious adverse events were comparable between the pembrolizumab plus cisplatin and 5-FU group and the placebo plus cisplatin and 5-FU group. The most commonly reported adverse events reported in each group, respectively, 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%).
The number of deaths due to an adverse event and deaths due to a treatment-related adverse events were low and similar between the 2 groups.
Immune-mediated adverse events 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 higher treatment-related adverse events (71.9% versus 67.6%), serious treatment-related adverse events (31.6% versus 26.2%), and discontinuation due to treatment-related adverse events (19.5% versus 11.6%) were higher among the pembrolizumab plus cisplatin and 5-FU group versus the placebo plus cisplatin and 5-FU group.
Notable limitations of the KEYNOTE-590 trial are highlighted below:
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.
The submitted feasibility assessment was summarized and critically appraised by the CADTH clinical review team. Ultimately, the CADTH clinical review team concluded that a standard network meta-analysis was not feasible due to a lack of network connectivity and an unanchored MAIC would likely be biased, and it would not be possible to quantify or identify the direction of the bias.
Two studies (KEYNOTE-062 and KEYNOTE-859) were identified as relevant. However, the study populations of these trials were slightly different from the population of interest in this review. Both the KEYNOTE-062 and KEYNOTE-859 trials enrolled patients with HER2-negative EGJ cancer without any Siewert classification, whereas only patients with HER2-negative Siewert type I EGJ cancer are of relevance to the reimbursement request. The trials also did not include patients with ESCC or adenocarcinoma of the esophagus, which are relevant populations for the reimbursement request. For the KEYNOTE-062 trial, patients had to be PD-L1 positive (i.e., CPS ≥ 1), whereas PD-L1 status is not an eligibility criterion for reimbursement for this submission. Both trials used alternative platinum and fluoropyrimidine–based chemotherapy backbones for the intervention and comparator compared with the KEYNOTE-590 trial. In the KEYNOTE-062 trial, cisplatin and 5-FU or cisplatin and capecitabine were offered as the chemotherapy backbone for the intervention and comparator, whereas in the KEYNOTE-859 trial, cisplatin and 5-FU or oxaliplatin and capecitabine were offered.
KEYNOTE-062 is a phase III, randomized, partially blinded, multicentre study comparing pembrolizumab as monotherapy and pembrolizumab in combination with cisplatin plus 5-FU or cisplatin plus capecitabine versus placebo, in combination with cisplatin plus 5-FU or cisplatin plus capecitabine, as first-line treatment for patients with advanced gastric or EGJ adenocarcinoma. The results from the prespecified subgroup analysis of the primary location (EGJ) were only available for OS, and safety data were reported for the entire study population (gastric and EGJ adenocarcinoma).In the overall study population (patients with gastric and EGJ adenocarcinoma), there was no difference in OS between the pembrolizumab combination and chemotherapy groups for patients with a PD-L1 CPS of 1 or higher (OS HR = 0.85; 95% CI, 0.7 to 1.03). The prespecified OS subgroup analyses of the primary location for EGJ were consistent with the overall study population results (OS HR = 0.96; 95% CI, 0.67 to 1.36). The EGJ subgroup OS results were exploratory, underpowered, and not reflective of the entire reimbursement population; therefore, these results should be interpreted with caution. Results for the primary location (EGJ adenocarcinoma) subgroup for other important efficacy outcomes were not available. In the overall population (patients with gastric and EGJ adenocarcinoma), more adverse events leading to discontinuation and immune-mediated adverse events and infusion reactions were reported in the pembrolizumab combination group compared with the chemotherapy group (27.6% versus 18.0% and 24.0% versus 7.8%, respectively).
KEYNOTE-859 is a phase III, multicentre study comparing pembrolizumab plus chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) versus placebo plus chemotherapy (cisplatin and 5-FU or oxaliplatin and capecitabine) as first-line treatment for patients with advanced gastric or EGJ adenocarcinoma. Currently, only study design details are available. The study is still ongoing, and no results are available at this time.
Summary of Economic Evaluation.
CADTH identified uncertainty in the assumed referral rate to a medical oncologist and the HER2-negative oncology treatment rate.
CADTH reanalysis included aligning market share assumptions with the economic evaluation, assuming lower rate of transitioning to second-line treatments, assuming higher referral rate to medical oncologists, and assuming a higher HER2-negative treatment rate.
Based on CADTH reanalyses, the budget impact to the public drug plans of introducing pembrolizumab, in combination with platinum and fluoropyrimidine–based chemotherapy, is expected to be $7,281,922 in year 1, $33,335,288 in year 2, and $50,440,428 in year 3 (a 3-year total of $91,057,638).
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: October 13, 2021
Regrets: One expert committee member did not attend.
Conflicts of interest: One expert committee member did not participate due to considerations of conflict of interest.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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