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Indication: For the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer in patients who have residual pathologic disease following prior neoadjuvant chemoradiotherapy
What is the CADTH Reimbursement Recommendation for Opdivo?
CADTH recommends that Opdivo be reimbursed by public drug plans for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer in patients who have residual pathologic disease following prior neoadjuvant chemoradiotherapy (CRT) if certain conditions are met.
Which Patients Are Eligible for Coverage?
Opdivo should only be covered to treat adult patients who have esophageal or GEJ cancer; who have been treated with chemoradiation followed by surgery to remove the cancer, but still have some cancer cells present; and who have a good performance status.
What Are the Conditions for Reimbursement?
Opdivo should only be reimbursed if it is prescribed by a clinician who is experienced in treating cancer. Opdivo should not be used in combination with other adjuvant anti-cancer drugs. The price of Opdivo must be lowered to be cost-effective and affordable.
Why Did CADTH Make This Recommendation?
Evidence from a clinical trial demonstrated that Opdivo was better than placebo in allowing patients to remain free of esophageal or GEJ cancer from returning.
Based on public list prices, Opdivo is not considered cost-effective at a willingness-to-pay threshold of $50,000 per quality-adjusted life-year (QALY) for the indicated population, relative to surveillance. A price reduction is therefore required. Economic evidence suggests that at least a 36% price reduction is needed to ensure Opdivo is cost-effective at a $50,000 per QALY threshold.
Based on public list prices, the 3-year budget impact is $122,873,802.
What Are Esophageal and GEJ Cancers?
Esophageal cancer occurs in the esophagus — a muscular tube that connects the throat to the stomach — and GEJ cancer occurs where the esophagus and the stomach join. About 70% to 75% of patients with esophagus or GEJ cancer still have some cancer cells present even after having been treated with chemoradiation followed by surgery, and do not live as long as patients who have no cancer cells present after chemoradiation and surgery.
Unmet Needs in Patients With Esophageal and GEJ Cancers
Currently, there are no drugs available to treat patients who have esophageal or GEJ cancer that have been treated with chemoradiation followed by surgery, but still have some cancer cells present. The only treatment option after surgery is surveillance. For many of these patients, the cancer will return and spread in the esophagus or GEJ or to another part of the body.
How Much Does the Opdivo Adjuvant Treatment Cost?
Treatment with Opdivo is expected to cost approximately $9,387 per patient per 28-day cycle.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that nivolumab be reimbursed for the adjuvant treatment of completely resected esophageal or GEJ cancer in patients who have residual pathologic disease following prior neoadjuvant CRT only if the conditions listed in Table 1 are met.
One ongoing, phase III, double-blind, randomized controlled trial (CheckMate 577; N = 794) comparing nivolumab with placebo for the adjuvant treatment of completely resected esophageal or GEJ cancer in patients who had residual pathologic disease following prior neoadjuvant chemoradiotherapy demonstrated that treatment with nivolumab (240 mg given every 2 weeks by IV infusion for 16 weeks, followed by 480 mg every 4 weeks for a total duration of 1 year) resulted in added clinical benefit with a statistically significant and clinically meaningful improvement in disease-free survival (DFS; hazard ratio [HR] = 0.69; 96.4% confidence interval, 0.56 to 0.86; P = 0.0003) compared to placebo. No mature overall survival (OS) data were available; however, pERC agreed with the clinical experts that DFS was a meaningful outcome for patients on its own and is likely to be correlated with OS in the adjuvant setting. pERC also noted that nivolumab was associated with a manageable toxicity profile.
pERC agreed that there was a significant unmet need for this rare patient population in this setting given the poor prognosis of patients with residual pathologic disease after neoadjuvant therapy and complete resection, as well as the high risk of recurrence, and the lack of effective therapies for patients after neoadjuvant CRT and surgical resection. Patients identified a need for effective and convenient treatment options that could result in longer survival, improved quality of life, and fewer side effects. Given the totality of the evidence, pERC concluded that adjuvant therapy with nivolumab meets some of the needs identified by patients, including a need for effective treatments with manageable side effects and DFS benefit.
Results of the CheckMate 577 trial suggested no deterioration in health-related quality of life (HRQoL) during the treatment period with nivolumab; however, pERC was unable to draw any conclusions on the effect of nivolumab on HRQoL due to the exploratory nature of patient-reported outcomes in the trial.
Using the sponsor-submitted price for nivolumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for nivolumab was $79,241 per QALY compared with active surveillance. At this incremental cost-effectiveness ratio, nivolumab is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for completely resected patients with esophageal or gastroesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy. A reduction in price of at least 36% is required for nivolumab 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 has a Health Canada indication for the adjuvant treatment of completely resected esophageal or GEJ cancer in patients who have residual pathologic disease following prior neoadjuvant CRT. Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to a PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, therefore blocking PD-1 pathway-mediated inhibition of T-cell antitumour immune response and reactivating T-cell antitumour immune response. It is available as 40 mg/4mL and 100 mg/10 mL (10 mg nivolumab/mL) single-use vials. The Health Canada–approved dose is 240 mg every 2 weeks or 480 mg every 4 weeks administered as IV infusion over 30 minutes. After completing 16 weeks of therapy, nivolumab is administered as 480 mg every 4 weeks until disease progression or unacceptable toxicity for a total treatment duration of 1 year.
To make their recommendation, the committee considered the following information:
The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for patient and clinician input and from the clinical experts consulted by CADTH for the purpose of this review. As well, issues identified by the Provincial Advisory Group (PAG) that may impact its ability to implement a recommendation are summarized in the Stakeholder Perspectives section.
One patient group, My Gut Feeling – Stomach Cancer Foundation of Canada, provided input for this review. The patient group, which includes patients with esophageal or GEJ cancer, aims to support patients and caregivers by providing them with information, mentorship, and a platform to voice their opinions. The information collected in this input was based on an international survey, which was conducted between June 29, 2021, and July 16, 2021, with 11 patients and 4 caregivers (total of 15 respondents). Of the 15 participants, 1 patient who had surgically resected cancer and chemoradiation had been treated with nivolumab.
Regarding clinical symptoms, patient respondents with esophageal or GEJ cancer and caregiver respondents indicated that before diagnosis, most symptoms experienced were changes in appetite and pain. Other significant symptoms included weight loss, difficulty swallowing, nausea and vomiting, dumping syndrome, and reflux. Less frequently reported symptoms included bleeding, feeling a mass, ascites, bowel obstruction, food regurgitation, and shortness of breath. Respondents commented that these symptoms impacted their day-to-day life.
Regarding current treatment, more than half of patient respondents (60%) agreed to some degree that current treatment helped them manage their cancer symptoms. The remainder of patient respondents (40%) were neutral or dissatisfied with their treatments. The patient group noted that many aspects of patients’ and caregivers’ lives, such as physical, mental, social, financial, and occupational, have deteriorated as a result of diagnosis and treatment. All patients experienced at least 1 side effect from their therapies. Some side effects were well tolerated, but some led to hospitalization and/or delay in the subsequent treatment.
One patient respondent accessed nivolumab through a hospital special access program. The patient respondent indicated that no evidence of disease was confirmed by PET scan at 3 months following the nivolumab therapy. The respondent did not experience any new side effects or exacerbation of side effects from surgery or chemoradiation, and they expressed strong satisfaction on improvement of quality of life.
Overall, the patient group indicated that there is an unmet need for the treatment of patients with esophageal or GEJ cancer. The patient group strongly supports the use of nivolumab for the adjuvant treatment of completely resected esophageal or GEJ cancer in patients who have residual pathologic disease following prior neoadjuvant chemoradiotherapy. The patient group expressed that patients and caregivers should have equitable access to treatment options that have the potential to improve quality and duration of life.
The clinical experts consulted for this review indicated that the treatment goals include improving DFS, reducing the adverse effects, improving or maintaining HRQoL, and improving OS. There is currently no adjuvant therapy for patients with completely resected esophageal or GEJ cancer who do not achieve a pathologic complete response to neoadjuvant CRT. Nivolumab is the first adjuvant therapy based on phase III evidence that has demonstrated a significant DFS benefit. The clinical experts agreed that nivolumab would represent the new standard of care for adjuvant therapy for patients who do not achieve a pathologic complete response following neoadjuvant CRT. Given that no other treatment is available for this population, it would not be appropriate to recommend that patients try other treatments before initiating treatment with nivolumab adjuvant therapy.
The clinical experts indicated that all patients who receive neoadjuvant CRT and an esophagectomy with pathology showing no pathological complete response should be assessed for adjuvant nivolumab. Patients would need to have an Eastern Cooperative Oncology Group Performance (ECOG PS) of 0 or 1. Although not supported by clinical trial evidence, the experts also indicated that the treatment can be extended to patients with an ECOG PS of 2. Patient should have no contraindication to nivolumab. The clinical experts indicated that nivolumab is contraindicated for patients with an ECOG PS of 3 or 4. According to the clinical experts, it is not possible to identify those patients who are most likely to benefit from treatment with nivolumab. The clinical experts noted that based on the CheckMate 577 trial criteria, patients with R1 resection (e.g., patients with positive circumferential, distal, or proximal margins) would be excluded, and highlighted that the clinical management of patients with R1 resection may be similar to patients with R0 resection given the lack of available effective treatment options for patients with R1 resection. The clinical experts indicated that in clinical practice, clinicians may wish to use nivolumab for patients with R1 resection.
The clinical experts indicated that the goal of adjuvant treatment is primarily to improve the cure rate (i.e., reduce the risk of relapse), and believed that DFS would be a relevant and clinically meaningful outcome for the purpose of this review. The clinical experts indicated that an improved DFS was likely to correlate with an improvement in OS and, therefore, DFS may be considered as a surrogate for OS in adjuvant treatment. CT scans every 3 to 6 months, while on treatment, can be used to determine if a patient has disease recurrence and thus is no longer benefiting from nivolumab.
The clinical experts indicated that nivolumab should continue for 17 cycles or a total duration of 1 year (with a maximum dose delay of 10 weeks, as per the trial protocol) and may be discontinued early if confirmed evidence of disease recurrence or unacceptable toxicity occurs.
The clinical experts indicated that nivolumab should be prescribed at an outpatient oncology clinic. Treatment should be supervised and delivered in institutions trained in chemotherapy delivery and administration.
According to the clinical experts, adjuvant treatment with nivolumab for this population represents a huge advance in the care of patients with esophageal and GEJ cancers. There is no adjuvant treatment for this population and nivolumab fulfills a major unmet need.
The Ontario Health – Cancer Care Ontario Gastrointestinal Drug Advisory Committee recognized the unmet needs in the current treatment algorithm for completely resected esophageal or GEJ cancer in patients who have residual pathologic disease following prior neoadjuvant CRT where the only option is post-operative surveillance. The clinician group indicated that this patient population has a high risk of recurrence associated with an increased mortality rate and poor quality of life. The clinician group expressed that patients should be offered nivolumab if they meet the eligibility criteria of the clinical trial and noted that outpatient chemotherapy suite settings were appropriate treatment settings for patients. The most important treatment goals identified by patients were to prolong life, delay disease progression, reduce the severity of symptoms, minimize adverse effects, and improve quality of life. The clinician group also highlighted that drug toxicity and disease recurrence are factors that should be considered when deciding to discontinue treatment. Finally, the clinician group expressed that nivolumab sets a new standard of care for this patient population.
Input from PAG identified factors pertaining to relevant comparators, considerations for initiation of therapy, discontinuation of therapy, generalizability, care provision, system issues, and economic impacts. pERC weighed evidence from the CheckMate 577 trial and other clinical considerations, including input from the clinical experts consulted by CADTH, to provide responses that are presented in Table 3.
Summary of Implementation Questions From the Drug Plan and Clinical Expert Responses.
The CheckMate 577 trial is an ongoing, phase III, randomized, double-blind, placebo-controlled, multicenter superiority study comparing nivolumab with placebo for the adjuvant treatment of completely resected esophageal or GEJ cancer in adult patients who have residual pathologic disease following prior neoadjuvant CRT. Patients were required to be rendered free of disease (defined as no vital tumour present within 1 mm of the proximal, distal, or circumferential resection margins) with a complete resection performed within 4 to 16 weeks before randomization.
The trial was conducted in 170 sites in 29 countries (including Canada, US, UK, Australia, and other European, South American, and Asian countries).
The primary objective of the CheckMate 577 trial was to compare DFS of nivolumab versus placebo in patients with completely resected esophageal or GEJ cancer. The secondary objective was to compare OS of nivolumab versus placebo. The main exploratory objectives included assessment of overall safety and tolerability, distant metastasis-free survival (DMFS), EQ-5D 3-Levels and Visual Analogue Scale, and patient’s cancer-related quality of life using the Functional Assessment of Cancer Therapy – Esophageal (FACT-E) questionnaire and selected components such as the esophageal cancer subscale (ECS), Functional Assessment of Cancer Therapy – General (FACT-G), and Functional Assessment of Cancer Therapy – General 7 (FACT-G7).
A total of 1,085 patients were screened, and 794 patients were randomized in a 2:1 ratio to receive nivolumab (n = 532) or placebo (n = 262). Randomization was done centrally using the Interactive Web Response System. Randomization was stratified by the following 3 factors: histology (squamous versus adenocarcinoma), pathologic lymph node status (positive [ ≥ ypN1] versus negative [ypN0]) and tumour cell PD-L1 status (≥ 1% versus < 1% or indeterminate or non-evaluable). The first patient was randomized on July 14, 2016, and the last patient was enrolled in August 2019. A total of 792 patients received at least 1 dose of nivolumab or placebo, as assigned. While all patients in the nivolumab arm received at least 1 dose, 2 patients in the placebo arm did not receive the treatment.
Prespecified interim analysis results (cut-off date of July 3, 2020) for the primary outcome, DFS, were provided in the sponsor’s submission. The sponsor indicated that the interim DFS result was considered as the final result because the DFS interim analysis met the prespecified statistical significance criteria.3 The study is ongoing, with an estimated study completion date of October 11, 2025.
At the interim analysis as of database lock (July 3, 2020), nivolumab demonstrated a statistically significant and clinical meaningful improvement in DFS compared with placebo (HR = 0.69; 96.4% CI, 0.56 to 0.86; P value = 0.0003), which implies a 31% reduction in the risk of recurrence or death with the nivolumab adjuvant treatment compared with placebo (the current standard of care is active surveillance). The observed median DFS was twice as long in the nivolumab arm compared with the placebo arm (22.41 months versus 11.04 months in the nivolumab and placebo arms, respectively). DFS rates at 6 months were higher in the nivolumab arm compared with the placebo arm (72.3% versus 63.4%). In addition, the results from various subgroup analyses and sensitivity analyses were consistent with the primary analysis.
As the secondary outcome, the OS was not mature at the data-cut-off; therefore, OS is not available for this review.
Patient-reported and HRQoL outcomes were assessed as exploratory outcomes. Overall, the study demonstrated no deterioration or maintenance from baseline in HRQoL with the treatment of nivolumab or placebo.
The improved benefit of nivolumab over placebo was also supported by the DMFS results, as the median DMFS was numerically longer in the nivolumab arm than the placebo arm (28.32 months versus 17.61 months), with an HR of 0.74 (95% CI, 0.60 to 0.92). However, DMFS was an exploratory outcome in the CheckMate 577 study.
Overall, the frequency of any grade adverse events and serious adverse events were similar in both nivolumab and placebo arms. The most common adverse events (≥ 20% in either of the arms) were “investigations” including |||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, diarrhea (29.1% versus 29.2%), fatigue (27.1% versus 24.2%), and nausea (22.7% versus 21.2%). More patients treated with nivolumab experienced treatment-related adverse events and serious adverse events than patients treated with placebo. Numerically, more patients discontinued from treatment due to adverse events or treatment-related adverse events in the nivolumab arm compared with the placebo arm. Notable adverse events, including pneumonitis and myocarditis, were less than 5% in any arms |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Of note, pneumonitis and myocarditis were all-causality adverse events ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Overall, the clinical experts indicated that the nivolumab safety profile in this study was acceptable, manageable, and consistent with the known safety profile of nivolumab, and no additional safety signals were identified with adjuvant nivolumab monotherapy.
The included pivotal study (CheckMate 577) was a double-blind, randomized, placebo-controlled study. Overall, it was well-designed. OS data were not mature at the time of the data-cut-off; however, according to the clinical experts consulted by CADTH, DFS is a relevant and clinically important primary outcome for the adjuvant treatment in this population and is likely to be correlated with OS in the adjuvant setting.
The patient-reported and HRQoL outcomes (i.e., ECS, FACT-E, FACT-G7, FACT-G, and ED-5D-3L) were assessed as exploratory outcomes. No formal statistical analysis was performed to compare the patient-reported and HRQoL outcomes between the 2 treatment arms. In addition, there is a potential risk of bias because of substantial missing data on these outcomes. As well, there may have been differential recall bias. Overall, the magnitude and direction of the impact of these missing data and recall bias on the patient-reported and HRQoL outcomes is unknown. Therefore, these patient-reported outcomes and HRQoL findings were inconclusive.
No major generalizability issue was noted regarding the findings from the pivotal study.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis: the number of individuals eligible for nivolumab treatment was underestimated; treatment acquisition costs of nivolumab and subsequent chemotherapies were underestimated, with some missing regimens and errors in cost calculations; and there was significant uncertainty in the market share of nivolumab.
CADTH conducted reanalyses that included: including patients with stage I esophageal or GEJ cancer, aligning assumptions made in estimating nivolumab’s treatment cost with the product monograph, assuming a higher market share of nivolumab, and assuming no difference in the distribution of patients on subsequent chemotherapies.
Although the sponsor suggested that nivolumab would be associated with a budget impact of $53,674,419 over the 3-year time horizon, based on the CADTH reanalysis, the budget impact of introducing nivolumab to the public drug plans is expected to be $33,999,272 in year 1; $44,194,197 in year 2; and $44,680,333 in year 3; for a 3-year total of $122,873,802.
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: December 1, 2021
Regrets: None
Conflicts of interest: None
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Indication: For the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer in patients who have residual pathologic disease following prior neoadjuvant chemoradiotherapy
Sponsor: Bristol Myers Squibb Canada
Final recommendation: Reimburse with conditions
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