Summary

Recommendation

The CADTH pCODR Expert Review Committee (pERC) recommends that nivolumab be reimbursed as monotherapy for the adjuvant treatment of adult patients with stage IIB or IIC melanoma following complete resection only if the conditions listed in Table 1 are met.

Rationale for the Recommendation

One phase III, randomized, multicentre, placebo-controlled study (CheckMate-76K; N = 790) demonstrated that adjuvant treatment with nivolumab may result in added clinical benefit for patients with resected stage IIB or IIC cutaneous melanoma. The CheckMate-76K trial showed that administering nivolumab 480 mg every 4 weeks for up to 12 months was associated with statistically significant improvement in recurrence-free survival (RFS) compared to placebo. After a median follow-up of 23.5 months in the nivolumab group and 23.0 months in the placebo group, the median RFS had not been reached in the nivolumab group and was 36.14 months (95% CI, 24.77, not estimable) in the placebo group, corresponding for a hazard ratio (HR) of 0.53 (95% confidence interval [CI], 0.40 to 0.71). The distant metastases-free survival (DMFS) rate at 12 months was 92.0% (95% CI, 89.3 to 94.1) with nivolumab and 88.5% (95% CI, 83.9 to 91.9) with placebo and at 24 months, was 84.0% (95% CI, |||| to ||||) with nivolumab and 76.5% (95% CI, |||| to ||||) with placebo.

The sponsor-submitted indirect treatment comparisons (ITC) suggested no statistically significant differences in efficacy or harm outcomes between nivolumab and pembrolizumab (currently reimbursed adjuvant systemic therapy for patients with stage IIB and IIC melanoma in Canada) when administered as monotherapy in patients with resected stage IIB or IIC cutaneous melanoma.

Patients identified a need for more effective treatment options without significant long-term side effects. They desired therapies that allow patients to function as best as possible and prevent unnecessary surgical and radiation-impacting quality of life. pERC concluded that nivolumab met some patient needs by providing an additional treatment option with manageable side effects and improved RFS and DMFS after 2 years of follow-up. Conclusions regarding health-related quality of life (HRQoL) outcomes could not be drawn from the CheckMate-76K trial due to the lack of statistical testing and higher dropout rates for patients in the nivolumab group at later time points.

At the sponsor-submitted price for nivolumab and publicly listed price for pembrolizumab, nivolumab was less costly than pembrolizumab. As nivolumab is considered similarly effective as pembrolizumab, the total drug cost of nivolumab should not exceed the total drug cost of pembrolizumab.

Table 1

Reimbursement Conditions and Reasons.

Discussion Points

• pERC agreed with the clinical experts that stage IIB and IIC melanoma following complete resection is associated with a high risk of recurrence and a significant impact on patients’ quality of life. Acknowledging that pembrolizumab is the only active adjuvant therapy available in Canada for these patients, pERC agreed with both patients and clinicians that it is important to have an additional drug as an alternative option for this patient population.
• pERC deliberated on the results of the CheckMate-76K trial and noted that 1 year of adjuvant treatment with nivolumab in patients with resected stage IIB or IIC melanoma resulted in a statistically significant improvement in RFS over placebo. The clinical experts consulted by CADTH on this review believed that RFS to be a key outcome in this population. They noted that a between-group difference in RFS of 10% at 1 year would be considered clinically meaningful. They would expect a clinically important effect to increase with time to 15% at 2 years. pERC discussed that the proportion of patients who had not had an RFS event at 12 months was 88.8% (95% CI, 85.6 to 91.2) in the nivolumab group and 81.1% (95% CI, 75.7 to 86.4) in the placebo group, suggesting that the between-group difference at this time point may not be clinically meaningful. At 2 years, this proportion was 76.5% (95% CI, |||| to ||||) in the nivolumab group and 60.6% (95% CI, |||| to ||||) in the placebo group. pERC agreed with the clinical experts that the RFS results after 2 years of follow-up appeared more clinically relevant.
• pERC discussed that the primary goal of adjuvant therapy in melanoma is to reduce the risk of recurrence and improve overall survival (OS) in patients who have undergone complete surgical resection. pERC noted that, at the most recent data cut-off (February 2023), there were not enough events to analyze OS data, therefore the impact of nivolumab on mortality could not be ascertained. The clinical experts consulted by CADTH noted that mortality would not be expected to be high in this population and that the optimal time point to assess OS would be much longer than the length of follow-up available from the pivotal trial.
• pERC deliberated on the validity of RFS as an acceptable surrogate for OS and agreed with the clinical experts that an improvement in RFS has not been shown to predict improvement in OS in this patient population reliably. However, pERC agreed that RFS may be a meaningful clinical outcome for patients in the adjuvant setting. The clinical experts suggested that it might be reasonable to assume that a reduction in recurrence due to adjuvant treatment with nivolumab will ultimately lead to improved OS in the long-term; however, it may be challenging to confirm this in a randomized controlled trial.
• pERC discussed the sponsor-submitted ITC and noted that neither of the ITC analyses provided by the sponsor (including a Bayesian network meta-analysis for the primary efficacy analysis and a frequentist analysis using Bucher method to estimate relative harms) provided evidence to support significant differences in efficacy (i.e., RFS) or harms outcomes for nivolumab compared to pembrolizumab for the indication under review. pERC agreed with the CADTH review team that, despite the limitations of the ITC, the claim of no difference between nivolumab compared to pembrolizumab was justified.
• pERC discussed the toxicity profile observed in the CheckMate-76K trial and agreed that the reported adverse events (AEs) appeared to be consistent with the known safety profile of nivolumab. Differences in notable harms between nivolumab and placebo groups were noted, including diarrhea and/or colitis (5.0% versus 1%), hepatitis (4% versus < 1%), rash (9% versus 2%), hypothyroidism/thyroiditis (13% versus < 1%), and hyperthyroidism (8% versus 1%). pERC discussed that, given that diarrhea is a known side effect of nivolumab, there is a risk that this may have resulted in unblinding for those patients experiencing those events. pERC agreed with the CADTH review team that while potential unblinding was likely to impact patient-reported outcomes such as HRQoL, it was less likely to bias results for key outcomes such as RFS and DMFS. A relatively large number of patients also discontinued study treatment in the trial. pERC noted that the difference in treatment discontinuations between the nivolumab (40%) and placebo (27%) groups mainly was accounted for by a difference in withdrawals due to AEs.
• pERC noted that, although patients aged ≥ 12 years were eligible for inclusion in the CheckMate-76K trial, the trial included no adolescent patients. The study participants’ ages ranged from 19 to 92 years, with a median of 62 years. Acknowledging that the disease characteristics and treatment effects may be similar in adolescent patients with those in adult patients, pERC discussed the appropriateness of generalizing the CheckMate-076 K results to pediatric patients 12 years and older. It acknowledged that the disease characteristics and treatment effects may be similar between adolescent and adult patients. However, both the Health Canada indication and the sponsor's reimbursement request was for adult patients only.

Background

Melanoma originates from melanocytes, the pigment-producing cells of the skin. It is commonly present in cutaneous primary locations (cutaneous melanoma) but can also arise from melanocytes within the mucosal surfaces of the body (mucosal melanoma) and the uvea of the eye (uveal melanoma) or cutaneous locations in nonhair-bearing surfaces (acral melanoma).

In Canada, melanoma is the fourth most common cancer in those aged 30 to 49 years (7% of all cancer cases). The estimated 25-year person-based prevalence of melanoma in Canada is estimated to be 1 in 399 persons (0.3% of the population in Canada). In 2018, 5.5% (93,890 cases) of all 25-year prevalent cancer cases diagnosed between 1993 and 2017 were melanoma. Based on the 25-year prevalence period, melanoma was the fourth and fifth most prevalent cancer among males and females in Canada, respectively. The estimated incidence of melanoma in Canada for 2022 is 23.5 per 100,000 persons.

Surgical excision is the primary curative treatment for most cases of melanoma, which are identified. According to the Canadian Cancer Society, 10.4% of all new melanomas are stage III at diagnosis, and 3.9% are stage IV (metastatic disease). Although there are no stage-specific survival statistics available in Canada for melanoma, the estimated US-based 5-year survival rate for stage IIB melanoma is 87% and decreases to 82% with stage IIC. Stage IIB/C melanoma patients account for approximately half of patients with stage II melanoma and are at high risk of disease recurrence, with approximately one-third of stage IIB and half of stage IIC patients experiencing recurrence within 5 years after surgery. In addition, some patients with stage IIB/C melanoma have worse survival outcomes than those with stage III, where adjuvant therapy is the standard of care. The decision to pursue adjuvant therapy requires assessment of an individual patient’s risk for recurrence. In stage II melanoma specifically, multivariate analysis found that the most relevant prognostic indicators were tumour thickness, presence of ulceration, and anatomic site of the tumour. The primary goal of adjuvant therapy in melanoma is to reduce the risk of recurrence and improve OS in patients who have undergone complete surgical resection but who are considered at high risk for disease recurrence. Currently, pembrolizumab is the only active adjuvant therapy in Canada indicated for patients with stage IIB and IIC melanoma following complete resection, and it is available through restricted benefits with specified criteria in most provinces or territories.

Nivolumab is a humanized IgG4 monoclonal antibody immune checkpoint inhibitor that targets the programmed cell death (PD)-1 receptor, preventing PD-1 from inhibiting the immune response to tumours. Health Canada has approved it for the adjuvant treatment of adult patients with stage IIB or IIC melanoma following complete resection. The Notice of Compliance was received on December 29, 2023. Nivolumab is also indicated for melanoma with regional lymph node involvement or metastatic melanoma, as well as classical Hodgkin Lymphoma and various colorectal, renal, lung, head and neck, esophageal, gastric and urothelial carcinomas. Nivolumab is administered as an IV infusion over 30 minutes. The recommended dosage for adjuvant treatment of adult patients with stage IIB or IIC is 240 mg every 2 weeks or 480 mg every 4 weeks, until disease recurrence or unacceptable toxicity, up to 1 year.

Sources of Information Used by the Committee

To make its recommendation, the committee considered the following information:

• a review of 1 phase III, randomized controlled trial in patients with completely resected stage IIB and IIC melanoma; and ITC conducted for the comparisons of efficacy and safety of nivolumab versus pembrolizumab
• patients’ perspectives gathered by 2 patient group(s), Melanoma Canada and Save Your Skin Foundation
• input from public drug plans and cancer agencies that participate in the CADTH review process
• input from 2 clinical specialists with expertise in diagnosing and treating patients with stage IIB/IIC melanoma
• input from 1 clinician group, Ontario Health - Cancer Care Ontario (OH-CCO) Skin Cancer Drug Advisory Committee
• a review of the pharmacoeconomic model and report submitted by the sponsor.

Stakeholder Perspectives

Drug Program Input

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Table 2

Responses to Questions from the Drug Programs.

Clinical Evidence

Systematic Review

Description of Studies

CheckMate-76K is a phase III, randomized, double-blind, multicentre clinical trial designed to evaluate the efficacy and safety of nivolumab in wholly resected stage IIB and IIC melanoma across 20 countries and 132 locations, including Canada.¹³ Adults and children ≥ 12 years of age were eligible for enrolment. A total of 790 patients were randomly assigned in a 2:1 ratio to receive 480 mg of nivolumab (n = 526) or placebo (n = 264). Patients in the treatment groups were treated with nivolumab 480 mg every 4 weeks via 30-minute IV infusions or a matched-administration placebo. Placebo-treated patients who experienced disease recurrence within 3 years after the last dose of placebo and nivolumab-treated patients who experienced recurrence greater than 6 months and within 3 years after completing treatment were eligible to receive on-study open-label nivolumab treatment. The primary objective of CheckMate-76K was to compare the efficacy, as measured by investigator-assessed RFS, provided by nivolumab monotherapy versus placebo in patients with completely resected stage IIB and IIC melanoma with no evidence of disease who are at high risk for recurrence.¹⁴ The secondary objectives were to compare OS and DMFS between the 2 treatment groups, assess nivolumab's safety and toxicity, and evaluate investigator-assessed outcomes on next-line therapies.

Overall, the enrolled patient population generally represented a stage II melanoma population, with a median age of 62 years and more males (61.2%) than females (38.8%). The majority of patients had stage IIB melanoma (60.1%) (American Joint Committee on Cancer [AJCC], 8th edition). The mean time from local-wide excision surgery to randomization was |||| |||||. Although patients aged ≥ 12 years were eligible for enrolment, no adolescents were randomized. Generally, baseline demographic and disease characteristics were well balanced between the nivolumab and placebo groups.

Efficacy Results

Recurrence-Free Survival

At the data cut-off date of 28 June 2022, the median follow-up for all randomized patients was 15.84 months for the nivolumab arm and 15.93 months for the placebo group. At the data cut-off date of 21 February 2023, the median follow-up for all randomized patients was 23.5 months for the nivolumab group and 23.0 months for the placebo group.

At the first interim analysis 1 (IA1, data cut-off of June 28, 2022), a median RFS had not been reached in either group for an HR of 0.42 (95% CI, 0.30 to 0.59), P < 0.0001. At the most recent data cut-off date of February 21, 2023, 186 RFS events had occurred (complete information fraction). The median RFS had not been reached in the nivolumab group and was 36.14 months (95% CI, 24.77, not estimable) in the placebo group, for an HR of 0.53 (95% CI, 0.40 to 0.71).

At a data cut-off date of June 28, 2022, the RFS rate was 89.0% (95% CI, 85.6 to 91.6) and 79.4% (95% CI, 73.5 to 84.1) in nivolumab and placebo, respectively. At the February 21, 2023, data cut-off, the RFS rate was largely unchanged from IA1, 88.8% (95% CI, 85.6 to 91.2) and 81.1% (95% CI, 75.7 to 86.4) at 12 months, for nivolumab and placebo. At 24 months, which was only reported at IA2, the RFS rates were 76.5% (95% CI, |||| || ||||) and 60.6% (95% CI, |||| || ||||) in the nivolumab and placebo groups, respectively.

Overall Survival

At the time of the most recent February 21, 2023, data cut-off, the prespecified number of events for the OS interim analysis had not been reached, so no data were reported.

Distant Metastases-Free Survival

At IA1, with a data cut-off of June 28, 2022, a median DMFS had not been reached in either group, with 8.0% of patients in the nivolumab group having experienced an event and 15.5% of patients experiencing an event in the placebo group, for an HR of 0.47 (95% CI, 0.30 to 0.72). The DMFS rate at 12 months was ||||| (95% CI, 89.3 to ||||) in the nivolumab group and ||||| (95% CI, |||| to ||||) in the placebo group. At the most recent data cut-off, February 21, 2023, a median DMFS was still not reached in the nivolumab group and was 36.14 months (95% CI, 32.85, N/A) in the placebo group, with 13.1% of patients in the nivolumab group and 19.3% of patients in the placebo group experiencing an event, for an HR of 0.62 (95% CI, 0.43 to 0.89). The DMFS rate at 12 months was 92.0% (95% CI, 89.3 to 94.1) with nivolumab and 88.5% (95% CI, 83.9 to 91.9) with placebo and at 24 months, was 84% (95% CI, |||| to ||||) with nivolumab and was 76% (95% CI, |||| to ||||) with placebo.

Progression-Free Survival 2

A median progression-free survival (PFS) was not reached as of the most recent data, February 21, 2023. In all randomized patients, 40 (7.6%) PFS2 events had occurred in the nivolumab group, and 31 (11.7%) PFS2 events had happened in the placebo group, for an HR of 0.63 (95% CI, 0.40 to 1.01).

Health-Related Quality of Life

HRQoL was an exploratory outcome in CheckMate-76 76K and was assessed using the EORTC QLQ-C30 and EQ-5D-5L instruments. None of the within-group changes from baseline over time in the study exceeded the MID for the instrument.

Harms Results

There were 96% of patients in the nivolumab group and 88% of patients in the placebo group who reported an AE (all-cause), with 23% and 12% of patients, respectively, reporting a grade 3 or 4 AE. The most common AE, nivolumab versus placebo, were fatigue (||| versus |||), diarrhea (||| versus |||) and pruritus (||| versus |||). Hypothyroidism was reported in 12% of patients in the nivolumab group and no patients in the placebo group.

15% of patients in the nivolumab group and 11% of patients in the placebo group reported a serious adverse event (SAE), but no specific SAEs occurred in 1% or more of patients.

There were 18% of patients in the nivolumab group and 4% of patients in the placebo group who discontinued due to an AE, and 7% versus 1% who withdrew due to a grade 3 or 4 AE, respectively. The most common reason for discontinuation was |||||||||| ||||||| ||| ||||||||| |||||| |||| |||| |||||||||

Notable harms identified by the clinical experts consulted by CADTH on this review included diarrhea (particularly grade 3 or 4), diabetes mellitus, and arthritis. Grade 3 or 4 diarrhea/colitis events occurred in 2% of nivolumab patients and less than 1% of placebo patients, while diabetes occurred in less than  1% of nivolumab patients and no placebo patients, and arthritis in |||| of nivolumab and |||| placebo patients.

Critical Appraisal

Concerning internal validity, CHECKMATE-76K appears to have been a reasonably well-conducted trial, with adequate procedures for randomization and blinding. A relatively large number of patients discontinued study treatment, and there was a difference in treatment discontinuations between the nivolumab (40%) and placebo (27%) groups. This difference was mostly accounted for by a difference in withdrawals due to AE, and this may have biased the analysis of efficacy and harms.

Concerning external validity, CheckMate-76K was not of sufficient duration to assess OS, as the clinical experts believed that a follow-up of at least 5 years would be needed for such an analysis to occur. The clinical experts also believed that RFS, the primary outcome, is better assessed at a later time than was reported in the trial. There was also no active comparator in CheckMate-76K, the most appropriate choice being pembrolizumab.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

RFS (1, 2, and 3 years follow-up), OS (5 years follow-up), DMFS (1, 2, and 3 years follow-up)

notable harms: diarrhea (grade 3 or 4), diabetes mellitus, arthritis (all reported within 100 days of last study dose).

Table 3

Summary of Findings for Adjuvant Nivolumab Versus Placebo for Patients With Stage IIB/IIC Resected Melanoma.

Economic Evidence

Cost and Cost-Effectiveness

Table 4

Summary of Economic Information.

pERC Information

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Indication: As monotherapy, for the adjuvant treatment of adult patients with stage IIB or IIC melanoma following complete resection

Sponsor: Bristol Myers Squibb

Final recommendation: Reimburse with conditions