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Indication: In combination with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of adult patients with human epidermal growth factor receptor 2–negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma
CADTH recommends that Opdivo be reimbursed by public drug plans for the first-line treatment of human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic gastric adenocarcinoma (GAC), gastroesophageal junction adenocarcinoma (GEJAC), or esophageal adenocarcinoma (EAC) if certain conditions are met.
Opdivo should only be covered to treat patients who have not received previous treatment for advanced or metastatic GAC, GEJAC, or EAC, and who have good performance status. The price of Opdivo must be lowered to be cost-effective and affordable.
Opdivo should only be reimbursed if prescribed in combination with fluoropyrimidine- and platinum-containing chemotherapy by a clinician experienced in treating cancer.
Gastric, gastroesophageal junction, and esophageal cancers are those that occur in the stomach, where the esophagus and stomach join, and in the esophagus, respectively. Most gastric, gastroesophageal junction, and esophageal cancers are adenocarcinomas. There are approximately 6,600 new cases of gastric, gastroesophageal junction, or esophageal cancer every year.
Many patients do not respond to available treatment options. Even in patients who do respond to treatment, the duration of their response is often short, and their survival is quite limited.
Treatment with Opdivo in combination with fluoropyrimidine- and platinum-containing chemotherapy is expected to cost approximately $9,833 to $10,618 per patient per 28 days of treatment.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy be reimbursed for the first-line treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma only if the conditions listed in Table 1 are met.
Evidence from a phase III, open-label randomized controlled trial (RCT), demonstrated that treatment with nivolumab plus chemotherapy (leucovorin, fluorouracil, and oxaliplatin [FOLFOX], or capecitabine and oxaliplatin [XELOX]) resulted in added clinical benefit over chemotherapy alone in patients with previously untreated, HER2-negative advanced or metastatic GAC, GEJAC, or EAC. The CheckMate-649 trial (N = 1,581) demonstrated that, compared with chemotherapy alone, treatment with nivolumab plus chemotherapy was associated with a statistically significant and clinically meaningful improvement in overall survival (OS) in patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) of 5 or greater (hazard ratio [HR] = 0.71; 98.4% confidence interval [CI], 0.59 to 0.86; P < 0.0001), in patients with a PD-L1 CPS of 1 or greater (HR = 0.77; 99.3% CI, 0.64 to 0.92; P < 0.0001), and in all randomized patients regardless of PD-L1 CPS (HR = 0.80; 99.3% CI, 0.68 to 0.94; P = 0.0002). Results for progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) across different PD-L1 cut-offs were supportive of the OS findings. Conclusions on health-related quality of life (HRQoL) outcomes could not be drawn due to the absence of formal statistical testing, the potential for bias in an open-label trial, and the high proportions of missing data, but the results suggested that HRQoL was not worse in the nivolumab plus chemotherapy arm. Although the notable harms associated with nivolumab were appreciable, they were in line with previous experience with nivolumab and considered to be manageable with supportive care. The patient input received for this review indicated that patients need new therapies that prolong survival, reduce risk of disease progression, improve HRQoL, allow for more convenient administration of therapy, and minimize side effects. Given the totality of the evidence, pERC concluded that treatment with nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy met some of the needs identified by patients because it prolongs survival and has a manageable safety profile.
Using the sponsor-submitted price for nivolumab plus FOLFOX or XELOX and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for nivolumab plus FOLFOX or XELOX was $398,312 per QALY when compared with FOLFOX or XELOX. At this incremental cost-effectiveness ratio, nivolumab plus FOLFOX or XELOX is not cost-effective at a $50,000 per QALY WTP threshold for adult patients with HER2-negative advanced or metastatic GAC, GEJAC, or EAC. A reduction in price of at least 95% is required for nivolumab plus FOLFOX or XELOX 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.
Nivolumab, in combination with fluoropyrimidine- and platinum-containing chemotherapy, has a Health Canada indication for the treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma. It is also noted in the Health Canada indication that a positive association was observed between PD-L1 CPS score and the magnitude of the treatment benefit. Nivolumab is an anti–programmed cell death protein 1 antibody. It is available as a 10 mg/mL solution for IV infusion and the Health Canada–approved dosage is 240 mg every 2 weeks or 360 mg every 3 weeks.
To make its recommendation, the committee considered the following information:
Input was provided by 1 patient group for this review (My Gut Feeling – Stomach Cancer Foundation of Canada). My Gut Feeling is the first non-profit organization in Canada dedicated to providing support, awareness, education, information, and advocacy to patients with gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal cancer (EC) as well as survivors and caregivers. My Gut Feeling distributed a survey via email, social media, and online forums to patients with GC, GEJC, or EC as well as their caregivers between August 20, 2021, and September 9, 2021. Among the 62 respondents (half patients and half caregivers), most (79%) were female, resided in Canada or the US (63% and 29%, respectively), and had received or were caring for someone who had received a diagnosis of GC (74.2%) and adenocarcinoma (82.3%). The number of respondents with advanced or metastatic disease was unclear.
Most respondents (90.3%) reported a significant impact of their cancer on HRQoL, with adverse effects on physical health, mental health, ability to eat, ability to work, finances, social life, identity, and self-image. Some of these impacts extended to caregivers and families, as well. Symptoms frequently included weight loss, change in appetite, pain, fatigue, reflux, nausea, vomiting, difficulty swallowing, shortness of breath, bleeding, anemia, ascites, and dumping syndrome. Patients highlighted the limited treatment options for GC, GEJC, and EC and their experiences with prior therapies (surgery, radiation, chemotherapy, and immunotherapy), including variable effectiveness in delaying disease progression and controlling symptoms as well as significant side effects impacting HRQoL (e.g., fatigue, nausea and vomiting, appetite changes exacerbating weight loss). Twelve respondents had experience with nivolumab and felt that the drug controlled their disease, improved HRQoL, and was more convenient and tolerable than surgery or chemotherapy.
According to patients, an ideal therapy for GC, GEJC, and GC would, when compared to standard care, prolong survival while maintaining or improving HRQoL. Delaying recurrence or progression and manageable side effects were also important factors for patients, who identified an unmet need for equitable access to therapies that may prolong life, improve symptoms, reduce risk of recurrence, and have improved tolerability. Such treatment options should be available barrier free for all patients in Canadian with GC, GEJC, or EC who could potentially benefit.
All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of advanced or metastatic GAC, GEJAC, and EAC.
According to the clinical experts consulted by CADTH for this review, all currently used treatment approaches for advanced or metastatic GAC, GEJAC, and EAC are palliative in nature, and survival is typically less than 1 year. Only a minority of patients respond to currently used combination chemotherapy regimens; these responses are usually short-lived and very few patients live beyond 15 to 18 months. There is clearly an unmet need for more effective therapies for advanced or metastatic GAC, GEJAC, and EAC that can be administered with similar or lower toxicity than current chemotherapy options.
According to the clinical experts, prior experience in other cancers has shown that when immunotherapy alone is ineffective, combining it with chemotherapy may lead to better treatment outcomes with no or limited additional toxicity. According to the experts as well as the sponsor, nivolumab would be administered in combination with fluoropyrimidine- and platinum-based chemotherapy for first-line treatment of most patients who are HER2 negative with advanced or metastatic GAC, GEJAC, or EAC who are able to tolerate chemotherapy. It would not be appropriate for patients to receive other treatments before nivolumab plus chemotherapy: according to the clinical experts, the most effective interventions should be used first line as there is significant attrition and many patients do not receive second or subsequent lines of therapy. Nivolumab would not be used in patients who are intolerant to or have failed on chemotherapy. The clinical experts stated that all patients with EAC would be eligible for nivolumab if funded irrespective of the availability of HER2 testing. Nivolumab attempts to address the underlying disease process by potentiating antitumour immune responses but there are many shortcomings to this approach. Reimbursement of nivolumab plus chemotherapy would not shift the treatment paradigm as most patients would receive chemoimmunotherapy rather than fluoropyrimidine- and platinum-based chemotherapy alone in the first line, with second and subsequent lines remaining the same.
Unfortunately, the patients who are most in need of intervention have the most advanced disease, poor PS, and do not generally respond well to immunotherapy and are thus excluded from clinical trials. According to the clinical experts consulted by CADTH for this review, the available data from trials provide evidence regarding the use of nivolumab plus chemotherapy in patients with advanced or metastatic GAC, GEJAC, and EAC and Eastern Cooperative Oncology Group (ECOG) PS of 0 and 1, but administration in additional patients (ECOG PS of 2 or potentially even 3) may be possible if judged appropriate by the treating clinician. In the opinion of the clinical experts, nivolumab plus chemotherapy should be available for all patients with advanced or metastatic GAC, GEJAC, or EAC for whom local or curative treatment is not possible and in whom chemotherapy is a treatment option. The site of metastasis or presence of symptoms would not affect patient selection. Diagnosis and staging (based on biopsy and CT or PET imaging) are standard and misdiagnosis is unlikely.
According to the clinical experts, patients with a good PS (ECOG PS of 0 or 1) are most likely to respond to nivolumab plus chemotherapy. In addition, the clinical experts emphasized that PD-L1 expression is an established biomarker of response and patients with higher PD-L1 CPS are more likely to respond to nivolumab. PD-L1 CPS testing of biopsy specimens is now routinely performed for other cancer types and could easily be adapted for patients with GAC, GEJAC, or EAC, although this is not routinely done at present. According to the clinical experts, the minor proportion of patients (3% to 5%) with high microsatellite instability are also much more likely to respond to immunotherapy including nivolumab. The clinical experts viewed patients with poor PS and PD-L1 CPS of less than 1 as least likely to benefit from nivolumab, and stated that patients with active autoimmune diseases are least suitable for treatment due to safety concerns.
Imaging (e.g., CT and PET scans) is used to evaluate response to therapy. In clinical practice, imaging assessments are performed approximately every 3 months (in contrast with the trial setting in which they were performed every 6 weeks). Survival is the most important indicator of response, with improvement in symptoms and HRQoL also being important parameters in assessing response. Weight and PS may also give an indication of treatment response and are evaluated at each clinic visit.
Treatment should be discontinued in patients with clear objective progressive disease assessed by imaging. Treatment intolerance or significant toxicity may also require discontinuation of therapy.
Diagnosis of GAC, GEJAC, or EAC and initial workup is typically performed by surgeons and gastroenterologists. Patients are then transferred to the care of a medical oncologist for systemic therapy. Palliative and supportive care specialists as well as dietitians would also follow these patients. Treatment would be administered in outpatient centres with professionals experienced in delivering systemic therapy (including chemotherapy and immunotherapy). Most centres already have significant experience with nivolumab and the accompanying chemotherapy regimens.
The clinical experts emphasized that most oncologists already have significant experience with administering nivolumab, including combinations with chemotherapy, for other indications.
Two clinician groups provided input for this review: the Ontario Health (Cancer Care Ontario) Gastrointestinal Cancer Drug Advisory Committee (5 clinicians) and the CGOEN, as well as other physicians treating gastroesophageal cancers (7 clinicians). No major contrary views were presented. Both clinician groups echoed the limited efficacy of available systemic therapies for advanced or metastatic GAC, GEJAC, and EAC and the short DOR in many patients. In contrast with the clinical experts consulted by CADTH for this review, clinicians from the CGOEN felt that patients with PD-L1 CPS lower than 5 (rather than lower than 1) would be least suitable for treatment with nivolumab plus chemotherapy, while those from the Ontario Health (Cancer Care Ontario) Gastrointestinal Cancer Drug Advisory Committee felt that although patients with PD-L1 CPS of 5 or greater and 1 or greater are more likely to respond, all patients with GAC, GEJAC, or EAC can benefit from the addition of nivolumab to chemotherapy.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
CheckMate-649 was a phase III, open-label, multi-centre RCT (N = 1,581)13 whose primary objective was to compare the efficacy of first-line therapy with nivolumab plus FOLFOX or XELOX versus FOLFOX or XELOX alone in prolonging OS and PFS per blinded independent central review (BICR) in patients with advanced or metastatic GAC, GEJAC, or EAC (all with a PD-L1 CPS of ≥ 5). Secondary objectives included comparing OS and PFS by BICR in patients with a PD-L1 CPS of ≥ 1 (OS hierarchically tested), all randomized patients (OS hierarchically tested), and patients with a PD-L1 CPS of 10 or greater and comparing ORRs in patients with a PD-L1 CPS of 5 or greater, patients with a PD-L1 CPS of 1 or greater, all randomized patients, and patients with a PD-L1 CPS of 10 or greater. Changes in HRQoL (measured using the patient-reported EQ-5D-3 Levels [EQ-5D-3L] and functional assessment of cancer therapy – gastric [FACT-Ga] instruments, including the FACT-Ga gastric cancer subscale [GaCS]), were assessed in exploratory fashion. Patients had to be 18 years or older with inoperable advanced or metastatic, HER2-negative or HER2-unreported GAC, GEJAC, or EAC previously untreated in the advanced or metastatic setting and have an ECOG PS of 0 or 1. Patients were enrolled at 175 sites in 29 countries, and were randomized 1:1:1 to receive either nivolumab 360 mg plus XELOX every 3 weeks or nivolumab 240 mg plus FOLFOX every 2 weeks; XELOX (every 3 weeks) or FOLFOX (every 2 weeks); or 4 cycles of nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks followed by nivolumab monotherapy 240 mg every 2 weeks. The nivolumab plus ipilimumab and nivolumab monotherapy arm was closed to recruitment on June 5, 2018 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||| ||||; data for these patients were not relevant to this review and are not included. Patients were treated until disease progression, unacceptable toxicity, study withdrawal, or death, whichever came first. Treatment with nivolumab plus chemotherapy beyond initial, investigator-assessed progressive disease was allowed if the patient had investigator-assessed clinical benefit and was tolerating treatment. Further progression (i.e., increase in tumour burden of ≥ 10%) resulted in discontinuation of nivolumab plus chemotherapy. For patients receiving nivolumab plus chemotherapy, the maximum treatment period was 24 months. Following treatment discontinuation, patients entered survival follow-up (every 3 months until study withdrawal, death, or data cut-off, whichever came first).
The mean ages of study participants were || years and || years in the nivolumab plus chemotherapy and chemotherapy alone arms, respectively. Approximately 70% of patients were male, approximately 70% were White, and approximately 60% were enrolled at sites outside of North America and Asia. Approximately 70% of patients had GAC |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||. Almost all patients (approximately 96%) had metastatic disease while a minority (approximately 4%) had locally advanced or recurrent disease. Only a minority of patients (10% to 20%) had received prior surgery, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Approximately 60% had HER2-negative tumours, while in approximately 40% of patients HER2 status was not reported. Approximately 83%, 61%, and 49% of patients had a PD-L1 CPS of 1 or greater, 5 or greater, and 10 or greater, respectively. Baseline demographic and disease characteristics were generally well balanced between study arms.
At the database lock of July 10, 2020 (minimum follow-up of 12.1 months; mean follow-up of |||| months [standard deviation = || months] in the nivolumab plus chemotherapy arm and |||| months [standard deviation = || months] in the chemotherapy alone arm), the coprimary efficacy analyses of OS and PFS in patients with a PD-L1 CPS of 5 or greater showed that patients in the nivolumab plus chemotherapy arm had longer OS and PFS than those in the chemotherapy alone arm. Median OS was 14.39 months (95% CI, 13.11 months to 16.23 months) in the nivolumab plus chemotherapy arm versus 11.10 months (95% CI, 10.02 months to 12.09 months) in the chemotherapy alone arm (P < 0.0001). The HR for OS comparing nivolumab plus chemotherapy with chemotherapy was 0.71 (98.4% CI, 0.59 to 0.86). Median PFS was 7.69 months (95% CI, 7.03 to 9.17 months) in the nivolumab plus chemotherapy arm versus 6.05 months (95% CI, 5.55 to 6.90 months) in the chemotherapy alone arm (P < 0.0001). The HR for PFS comparing nivolumab plus chemotherapy with chemotherapy was 0.68 (98% CI, 0.56 to 0.81). The hierarchically tested secondary analyses of OS in patients with a PD-L1 CPS of 1 or greater and all randomized patients also showed that patients in the nivolumab plus chemotherapy arm had longer OS than those in the chemotherapy alone arm. Among patients with a PD-L1 CPS of 1 or greater, median OS was 13.96 months (95% CI, 12.55 to 14.98 months) in the nivolumab plus chemotherapy arm versus 11.33 months (95% CI, 10.64 moths to 12.25 months) in the chemotherapy alone arm (P < 0.0001). The HR comparing nivolumab plus chemotherapy with chemotherapy alone was 0.77 (99.3% CI, 0.64 to 0.92). Among all randomized patients, median OS was 13.83 months (95% CI, 12.55 to 14.55 months) in the nivolumab plus chemotherapy arm versus 11.56 months (95% CI, 10.87 to 12.48 months) in the chemotherapy alone arm (P = 0.0002). The HR comparing nivolumab plus chemotherapy with chemotherapy alone was 0.80 (99.3% CI, 0.68 to 0.94). The results of the coprimary and hierarchically tested secondary OS analyses were clinically relevant according to the clinical experts consulted by CADTH for this review, based on their judgment that a 6-week improvement in survival represents a clinically meaningful improvement in this patient population.
OS and PFS analyses were conducted as secondary end points across other PD-L1 CPS cut-offs. Median OS in patients with a PD-L1 CPS of 10 or greater was |||| months (95% CI, |||||||||||||||| months) in the nivolumab plus chemotherapy arm and |||| months (95% CI, || |||||||| months) in the chemotherapy alone arm; the HR for OS comparing nivolumab plus chemotherapy with chemotherapy alone was 0.66 (95% CI, ||||||||||||). Among patients with a PD-L1 CPS of 10 or greater, median PFS was || months (95% CI, |||||||||||| months) in the nivolumab plus chemotherapy arm and || months (95% CI, |||||||||||| months) in the chemotherapy alone arm; the HR for PFS comparing nivolumab plus chemotherapy with chemotherapy alone was || (95% CI, ||||||||||||). Among patients with a PD-L1 CPS of 1 or greater, median PFS was 7.49 months (95% CI, 7.03 to 8.41 months) in the nivolumab plus chemotherapy arm and 6.90 months (95% CI, 6.08 to 7.03 months) in the chemotherapy alone arm; the HR for PFS comparing nivolumab plus chemotherapy with chemotherapy alone was 0.74 (95% CI, 0.65 to 0.85). Among all randomized patients, median PFS was 7.66 months (95% CI, 7.10 months to 8.54 months) in the nivolumab plus chemotherapy arm and 6.93 months (95% CI, 6.60 to 7.13 months) in the chemotherapy alone arm; the HR for PFS comparing nivolumab plus chemotherapy with chemotherapy alone was 0.77 (95% CI, 0.68 to 0.87).
Subgroup analyses of OS by PD-L1 CPS showed decreasing treatment effects with nivolumab plus chemotherapy versus chemotherapy with lower PD-L1 CPS cut-offs as follows: PD-L1 CPS lower than 10: HR = 0.94 (95% CI, 0.80 to 1.10); PD-L1 CPS of 10 or greater: HR = 0.65 (95% CI, 0.55 to 0.78); PD-L1 CPS of lower than 5: HR = 0.94 (95% CI, 0.78 to 1.13); PD-L1 CPS of 5 or greater: HR = 0.70 (95% CI, 0.60 to 0.81); PD-L1 CPS of lower than 1: HR = 0.92 (95% CI, 0.70 to 1.23); and PD-L1 CPS of 1 or greater: HR = 0.76 (95% CI, 0.67 to 0.87). Subgroup analyses of PFS followed a similar pattern.
EQ-5D-3L utility index scores, EQ-5D visual analogue scale (VAS) scores, FACT-Ga total scores, and GaCS scores at baseline were similar among all randomized patients in the 2 treatment arms. Mean values for EQ-5D-3L utility index scores, EQ VAS scores, FACT-Ga total scores, and GaCS scores were numerically higher (improved) at post-baseline assessments during the treatment period compared with the baseline assessment among all randomized patients in both treatment arms.
Comparisons of ORR and DOR also favoured nivolumab plus chemotherapy over chemotherapy alone. According to the clinical experts consulted by CADTH for this review, differences in these outcomes, which were outside the statistical hierarchy, had uncertain clinical significance on their own but were supportive of the clinically meaningful difference in OS in favour of nivolumab plus chemotherapy.
Adverse events (AEs) occurred in almost all patients treated with nivolumab plus chemotherapy and chemotherapy alone (99.2% versus 98.0%). Serious AEs and withdrawals due to AEs occurred in larger proportions of patients receiving nivolumab plus chemotherapy than those receiving chemotherapy alone (54.1% versus 43.7% and 47.4% versus 32.7%, respectively). A total of 68.8% of patients treated with nivolumab plus chemotherapy and 74.6% of patients treated with chemotherapy alone died during the study period.
Select AEs, immune-mediated AEs (IMAEs), and other events of special interest (protocol-defined to capture the expected toxicity profile of nivolumab) occurred more frequently in the nivolumab plus chemotherapy arm than in the chemotherapy alone arm. Select AEs affecting the gastrointestinal system (40.3% in the nivolumab plus chemotherapy arm and 33.9% in the chemotherapy alone arm), select AEs affecting the hepatic system (34.1% and 24.3%), select AEs affecting the skin (33.5% and 17.9%), select AEs affecting the endocrine system (15.0% and 1.8%), and hypersensitivity and infusion reactions (15.1% and 5.9%) were the most common select AEs in the nivolumab plus chemotherapy arm. Hypothyroidism and thyroiditis (9.5% in the nivolumab plus chemotherapy arm and 0.8% in the chemotherapy alone arm), rash (6.5% and 0.5%), pneumonitis (4.2% and 0%), diarrhea and colitis (3.3% and 0%), hyperthyroidism (2.9% and 0.3%), and hepatitis (2.4% and 0%) were the most common immune-mediated AEs in the nivolumab plus chemotherapy arm.
A notable limitation of the CheckMate-649 trial was its open-label design and the potential sources of bias associated with this design. Randomization was stratified by tumour PD-L1 expression (≥ 1% versus < 1%) while the coprimary OS and PFS analyses were conducted in patients with a PD-L1 CPS of 5 or greater, eliminating the protection of stratified randomization. Although outcome assessment of tumour response and progression was performed by BICR using objective Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 criteria, patient-reported HRQoL data and assessment of harms outcomes may have been impacted to some degree by knowledge of treatment allocation. The open-label design may also have resulted in more frequent discontinuation before receiving any study therapy (nivolumab plus chemotherapy arm = 0.9% versus chemotherapy alone arm = 3.2%), discontinuation of therapy during the treatment phase (patient request: nivolumab plus chemotherapy arm = 1.7% versus chemotherapy alone arm = 4.6%; withdrawal of consent: nivolumab plus chemotherapy arm = 2.6% versus chemotherapy alone arm = 5.3%), and discontinuation from the study (withdrawal of consent: nivolumab plus chemotherapy arm = 2.6% versus chemotherapy alone arm = 4.7%) by patients randomized to the chemotherapy alone arm. The open-label design could have altered treatment exposure in either or both study arms due to investigator biases, especially as treatment beyond progression was allowed for nivolumab plus chemotherapy but not chemotherapy alone. According to the clinical experts consulted by CADTH for this review, treatment with nivolumab plus chemotherapy beyond progression is clinically appropriate in some patients; although, in most patients, therapy would be discontinued at the first objective determination of progressive disease. According to the clinical experts consulted for this review, the frequency of treatment beyond progression in the CheckMate-649 trial (|||||||||||||||||||||||||||| ||||||) was higher and the duration of treatment beyond progression was longer than expected based on current clinical practice in Canada; the impact of extended administration of nivolumab on OS was uncertain, although the clinical experts were of the opinion that post-progression treatment was unlikely to significantly influence OS or the interpretation of OS data. The absence of formal statistical comparison and high amounts of missing HRQoL data (due to deaths and low questionnaire completion rates following treatment discontinuation) limited interpretation of these end points. In addition, the GaCS has not been validated as a standalone scale and the degree to which it specifically measures changes in symptomology versus general HRQoL changes was unclear. The study had very high power for the coprimary efficacy analyses and would likely have been capable of detecting smaller treatment effects than originally anticipated with uncertain clinical relevance. The magnitude of OS differences between the nivolumab plus chemotherapy and chemotherapy alone arms in the primary analysis population (PD-L1 CPS of ≥ 5) was statistically and clinically significant according to the clinical experts consulted by CADTH for this review, but smaller differences in PFS were of uncertain clinical relevance.
The demographic and disease characteristics of the CheckMate-649 trial population were broadly reflective of the Canadian population with GAC, GEJAC, or EAC. Of note, there were major unresolved questions of generalizability to some of the patient groups that would be covered by the Health Canada indication and the reimbursement request submitted for CADTH’s review. The CheckMate-649 trial enrolled patients with an ECOG PS of 0 or 1 and no prior systemic therapy in the advanced or metastatic setting. This review identified no evidence regarding administration of nivolumab plus chemotherapy beyond first-line therapy or in patients with an ECOG PS of 2 or greater. Critically, the study was not designed to conclusively identify the PD-L1 expression thresholds required for therapeutic benefit. Analyses of OS and PFS using different PD-L1 CPS cut-offs, as well as subgroup analyses by tumour cell PD-L1 expression, pointed toward potentially important differences in efficacy according to PD-L1 status.
One sponsor-submitted indirect treatment comparison (ITC) contributed evidence to this review. The purpose of the ITC was to compare the efficacy of nivolumab plus chemotherapy to relevant comparators (chemotherapy alone regimens: fluoropyrimidine, fluoropyrimidine plus platinum, taxane plus platinum, fluoropyrimidine plus topoisomerase inhibitor, fluoropyrimidine plus taxane, platinum plus topoisomerase inhibitor, taxane plus topoisomerase inhibitor, fluoropyrimidine plus platinum and taxane, or fluoropyrimidine plus platinum and anthracycline) for first-line treatment of advanced or metastatic GC, GEJC, or EAC. Pembrolizumab plus chemotherapy was not considered a relevant comparator by the ITC authors.
Following a literature search, 31 studies presenting data on OS and PFS and with relevant treatment comparisons were considered for inclusion in the network meta-analysis. Of these, 23 were used in the PFS network and 28 were used in the OS network. The ATTRACTION-4 study was excluded from the main ITC. Studies were connected in drug class–based networks for OS and PFS outcomes to indirectly compare nivolumab plus chemotherapy to other relevant therapies among all-comers (irrespective of PD-L1 status). A Bayesian framework was conducted with non-informative priors. As both fixed- and random-effects models were used, models were compared using the deviance information criterion. Scenario analyses were conducted based on the heterogeneity observed across trials included in the networks.
Pairwise comparisons for OS and PFS did not show differences between nivolumab plus fluoropyrimidine and platinum and the following treatments of interest: fluoropyrimidine plus platinum, fluoropyrimidine plus topoisomerase inhibitor, and fluoropyrimidine plus platinum and anthracycline. Scenario analyses were generally consistent with the primary analyses for PFS and OS for all relevant comparisons.
The sponsor-submitted ITC did not assess harms outcomes.
Studies of pembrolizumab plus chemotherapy were not included in the ITC; while pembrolizumab is currently not funded outside special access programs across Canadian jurisdictions, it was still considered a clinically relevant comparator by the clinical experts consulted for this review. Substantial heterogeneity was observed across patient and trial characteristics. While multiple scenario analyses were conducted to explore the impact of certain effect modifiers, others could not be investigated. A risk of bias assessment conducted by the sponsor revealed that most studies included in the ITC were of low to medium quality, and scenario analyses that excluded low-quality studies produced more precise estimates. The sponsor’s ITC also did not include outcomes other than OS and PFS, such as toxicities or HRQoL, both of which are important outcomes to patients. Overall, the ITC had limitations associated with clinical and statistical heterogeneity that increased the uncertainty of estimates and may have prevented detection of differences between treatments.
No other relevant evidence was identified for this review.
Evidence from the CheckMate-649 trial suggested that compared with FOLFOX or XELOX alone, first-line administration of nivolumab plus FOLFOX or XELOX contributed to statistically significant and clinically meaningful prolongation of OS among patients who were HER2 negative and had GAC, GEJAC, or EAC. This finding was consistent across patients with a PD-L1 CPS of 5 or greater, patients with a PD-L1 CPS of 1 or greater, and all randomized patients. Administration of nivolumab plus FOLFOX or XELOX also resulted in statistically significant prolongation of PFS among patients with a PD-L1 CPS of 5 or greater, though the clinical relevance of the difference in PFS was unclear. Other analyses of PFS, ORR, and DOR across different PD-L1 CPS cut-offs also favoured nivolumab plus chemotherapy and were supportive of the OS results. Results for patient-reported HRQoL and symptom scores (EQ-5D-3L, FACT-Ga) could not be interpreted due to absence of formal statistical testing, potential for bias in an open-label trial, and high rates of missing data at later time points post-baseline. There were signals from the trial that the comparative efficacy of nivolumab plus chemotherapy versus chemotherapy alone in patients with GAC, GEJAC, or EAC was dependent upon PD-L1 status. Despite this, prolongation of OS by nivolumab plus chemotherapy, which was acknowledged as the most important outcome of therapy by both patients and clinicians, was statistically and clinically significant among all randomized patients. A sponsor-submitted ITC did not provide evidence of differences in efficacy between nivolumab plus fluoropyrimidine- and platinum-based chemotherapy and other chemotherapy regimens and did not include pembrolizumab plus chemotherapy as a comparator. Notable harms associated with nivolumab (including immune-mediated AEs) were appreciable but were expected and generally manageable in most patients with supportive care.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis: meaningful uncertainty in estimated population size; inappropriate modelling of drug plan perspective and omission of drug wastage; outdated unit costs and inappropriate dosing; treatment cost of nivolumab was underestimated; the market share of nivolumab and comparators may not reflect likely use; and uncertainty in the treatment duration of nivolumab in combination with chemotherapy.
CADTH conducted reanalysis that included assuming 85% of patients have HER2-negative status, including drug wastage, assuming flat dosing of nivolumab, and excluding fluorouracil plus irinotecan and leucovorin from the market mix.
Based on the CADTH reanalysis, the 3-year budget impact to the public drug plans of introducing nivolumab is expected to be $198,898,038 (year 1: $57,115,126; year 2: $66,231,528; year 3: $75,551,384). The estimated budget impact is sensitive to nivolumab dosing (weight-based versus flat dosing) and recurrence rate of HER2-negative advanced or metastatic GAC, GEJAC, or EAC.
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: January 12, 2022
Regrets: None
Conflicts of interest: None
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Indication: In combination with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of adult patients with human epidermal growth factor receptor 2–negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.
Sponsor: Bristol Myers Squibb Canada
Final recommendation: Reimburse with conditions
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