CADTH Reimbursement Review

Nivolumab and Relatlimab (Opdualag)

Sponsor: Bristol Myers Squibb Canada

Therapeutic area: Unresectable or metastatic melanoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

FDC = fixed-dose combination; NOC = Notice of Compliance.

Introduction

Melanoma is a neoplasm originating from melanocytes or the pigment-producing cells of the skin. The clinical symptoms of advanced melanoma include swollen lymph nodes, a hard lump on the skin, unexplained pain, feeling very tired or unwell, and unexplained weight loss.¹ The mean age at diagnosis of advanced metastatic melanoma is approximately 59 years in Canada.^2,3 The diagnosis of melanoma is based on skin examination, physical examination, skin and/or lymph node biopsy, and diagnostic imaging (i.e., CT).^4-7 According to the Canadian Cancer Society, 10.4% of all new melanomas are stage III at diagnosis and 3.9% are stage IV (i.e., metastatic disease). Poor prognostic factors include an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 or higher, elevated lactate dehydrogenase (LDH), nodal involvement and metastases, increased tumour thickness, ulceration, and mitoses of 1/mm² or greater in thin T1 melanomas.^3,5 Approximately 70% of metastatic melanomas have mutually exclusive mutations in the BRAF oncogene, NRAS homologue oncogene, and c-KIT, and GNAQ or GNA11 genes, which activate the mitogen-activated protein kinase pathway, leading to promotion of cell proliferation, prevention of apoptosis, and angiogenesis.⁸ About 38% to 51% of patients with stage III or IV melanoma had a mutation in the BRAF gene.^9,10 An Australian study of patients with advanced melanoma reported a similar rate, with 48% of tumours testing positive for a V600 BRAF mutation.¹¹ In Canada, melanoma accounted for 3.8% of new cancer cases and 1.5% of cancer deaths in 2021.¹² An estimated 9,000 people in Canada were diagnosed with melanoma in 2022,¹³ with an age-standardized incidence rate of 23.5 per 100,000 in 2018 (excluding Quebec) based on data from Statistics Canada.¹⁴ The incidence is slightly higher in men than in women (25.9 versus 21.2 per 100,000, respectively).^2,14 An estimated 1,200 persons died from melanoma in 2022 in Canada, with an age-standardized mortality rate of 2.7 per 100,000.¹³ In Canada, stage IV distant metastatic disease is associated with a 5-year survival rate of 18%.⁴ However, consistent with the observed decline in mortality rates, melanoma survival rates have improved in recent years with the introduction of novel immunotherapies and BRAF-targeted therapies (TT) based on inhibitors of the BRAF gene and mitogen-activated protein kinase enzyme (MEK) protein.

Important treatment goals of systemic therapy in metastatic advanced melanoma include prolonging survival, generating durable responses, providing symptom relief, minimizing treatment toxicities, and maintaining quality of life.¹⁵ According to the clinical experts consulted by CADTH for this review, immunotherapy is the first line of choice for melanoma regardless BRAF status.^16,17 The immune checkpoint inhibitor (ICI) immunotherapies routinely used for the first-line treatment of metastatic melanoma in Canada include ipilimumab-nivolumab combination therapy,^18-20 nivolumab (anti–programmed cell death protein 1 [PD-1]) monotherapy,^19,21 ipilimumab (anti–cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) monotherapy,^20,22 and pembrolizumab (anti–PD-1) monotherapy.^23,24 However, the use of ipilimumab has been increasing.²⁵ According to the clinical experts consulted for this review, ipilimumab-nivolumab is the first line of choice among the ICIs. After the first line, the treatment decisions are largely determined by BRAF mutation status.¹⁷ Patients with no BRAF mutation are treated with immunotherapies and patients with BRAF mutations are eligible for treatment with a TT.¹⁷ Among the TT regimens that have been approved by Health Canada and recommended for reimbursement by the CADTH pan-Canadian Oncology Drug Review Expert Review Committee are encorafenib (a BRAF inhibitor) combined with binimetinib (a mitogen-activated protein kinase enzyme [MEK] inhibitor),^26-28 vemurafenib (a BRAF inhibitor) combined with cobimetinib (a MEK inhibitor),^29-31 and dabrafenib (a BRAF inhibitor) combined with trametinib (a MEK inhibitor).^32-34 The clinical experts CADTH consulted for this review indicated that TT use as a monotherapy is negligible and not reflective of clinical practice in Canada. It was reported that less than 5% of patients with advanced melanoma rarely receive a TT as a single drug.³⁵ According to the clinical experts CADTH consulted for this review, there is an unmet medical need for an additional novel ICI combination therapy that can be used to treat metastatic melanoma regardless of BRAF mutation status. The novel therapy should offer increased efficacy relative to anti–PD-1 monotherapy and should have a favourable safety profile that does not result in the additive toxicities seen with conventional dual immunotherapy involving an ICI combined with a drug with a different mechanism of action.

Nivolumab is a humanized immunoglobin G4 (IgG4) monoclonal antibody ICI that binds to the PD-1 receptor and blocks its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2, triggering PD-1 pathway–mediated inhibition of the immune response, including the antitumour immune response.^36,37 Relatlimab is a novel, first-in-class ICI that targets the lymphocyte activation gene 3 (LAG-3) receptor.^38,39 Relatlimab is a humanized IgG4 monoclonal antibody that binds to the LAG-3 receptor and prevents LAG-3–mediated inhibition of the immune response by blocking its interaction with ligands, ultimately leading to an antitumour response.^37,40 LAG-3 and PD-1 are distinct ICI pathways, often co-expressed on tumour-infiltrating lymphocytes.⁴⁰ They act synergistically on effector T-cells, leading to the development of T-cell exhaustion and impaired cytotoxic function. The recommended dosages of nivolumab-relatlimab for adult patients are 480 mg of nivolumab and 160 mg of relatlimab, every 4 weeks.

The recommended dosage of nivolumab-relatlimab for pediatric patients who are at least 12 years old and weigh at least 40 kg is the same as for adults. A recommended dosage has not been established for pediatric patients who are 12 years or older and weigh less than 40 kg. Nivolumab-relatlimab is supplied as fixed-dose combination (FDC) concentrate for solution for infusion: 240 mg of nivolumab per 20 mL (12 mg/mL) and 80 mg of relatlimab per 20 mL (4 mg/mL) in a single-dose vial.⁴⁰

The Health Canada–approved indication of interest for this review is nivolumab-relatlimab FDC for the treatment of adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma.⁴⁰ The CADTH reimbursement request aligns with this Health Canada indication. The nivolumab-relatlimab FDC was reviewed by Health Canada through the Standard Review Pathway. It has not been reviewed previously by CADTH.

The objective of this clinical review is to review the beneficial and harmful effects of nivolumab-relatlimab FDC for the treatment of adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from 2 clinical experts consulted by CADTH for the purpose of this review.

Patient Input

CADTH received patient-group submissions from Melanoma Canada and the Save Your Skin Foundation (SYSF). Data were gathered by Melanoma Canada via an online survey. A total of 119 individual patient responses combined with 84 caregiver responses were received. Among the patient respondents, 35 indicated they had no caregiver. Of the patient respondents, 81 were female and 38 were male. Regarding tumour staging, 26 patients had been diagnosed with stage 0 melanoma, 17 had stage I, 10 had stage II, 18 had stage III, 29 had stage IV, and 19 did not know their stage. Two patients in this survey were treated with nivolumab-relatlimab FDC.

Information was obtained by the SYSF through online surveys, virtual patient-roundtables and one-on-one conversations, which included 60 melanoma patients, of whom 12 had experience with the drug under review (nivolumab-relatlimab), that took place over the past 6 months. There were 37 females and 23 males aged between 18 and 89 years. A total of 18 (out of 60) respondents were from outside of Canada (US, Australia, and France).

Most patients reported that pain, scarring, lymphedema, fatigue, anxiety, fear, and depression are common impacts of the disease itself that affect the quality of life for patients and their families. Caregivers reported that the greatest impact of dealing with the diagnosis is the mental stress, followed by the negative financial impact on the family due to the loss of income from a working partner, and the additional responsibilities associated with taking care of the home, family, and loved one. Some of the respondents described the impact of melanoma using the terms scared, disbelief, unsettled, anxious, teary, disrupted life, and totally life changing.

In terms of current therapy options, based on input from 119 of the respondents who took part in Melanoma Canada’s survey, 55% had been treated with some form of drug therapy. Nine patients had been treated with multiple therapies. A total of 92% of the patients treated with available drug therapies indicated that they felt the side effects were worth tolerating for the anticipated results. Moreover, about 20% of patients experienced issues accessing treatment. The SYSF survey also found the same issues, as patients in remote areas of Canada have problems getting to treatment sites, paying for travel costs, taking time off from work, and dealing with the added concern of being treated far from home and their support system, all of which puts extra stress on patients, caregivers, and their families. Access to the drug under review is limited to Ontario and Quebec, and a number of patients in Canada could not obtain the drug under review, although it might have been their only option.

Both patient groups identified a vast opportunity for improvement if a wider variety of more-effective treatment options with minimal side effects and longer responses were made available.

Two respondents from Melanoma Canada’s survey and 12 respondents from the SYSF’s survey indicated that they had experience with the drug under review, the primary method of access to which was a clinical trial. Twelve respondents stated that the benefits outweighed the burdens of side effects, which were mainly rash and fatigue and were somewhat manageable.

Melanoma Canada reported that there is an ongoing need for superior options, and options when 1 therapy does not work or stops working. Melanoma Canada also noted that melanoma is difficult to treat once it has spread. Effective treatments, biomarkers, and earlier-stage treatments are needed to prevent some of the quality-of-life impacts from surgery, loss of income, duration of illness, and the impact on the mental health of both the patient and caregiver. According to Melanoma Canada, the drug under review is an improvement in treatment options for a cancer that continues to be on the rise and is complex to treat.

Clinician Input

The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of adult and pediatric patients (aged 12 years and older and weighing at least 40 kg) with unresectable or metastatic melanoma.

The clinical experts indicated that the goal is to increase overall rates, slow down progression, lessen symptoms, improve quality and quantity of life, and minimize toxicity, particularly long-term significant toxicities. The clinical experts indicated that formulations are needed to improve convenience. Currently the standard of care for metastatic melanoma in Ontario is ipilimumab-nivolumab if the patient is able to tolerate the potential toxicities of the drugs. Failure to respond to ipilimumab-nivolumab may prompt switching to a BRAF inhibitor plus a MEK inhibitor in patient who were BRAF positive. Pembrolizumab or nivolumab may be attempted as monotherapy if a patient experiences too many adverse events (AEs) due to ipilimumab-nivolumab combination treatment. The clinical experts indicated that immunotherapy is not 100% effective. The response rates of combination ipilimumab-nivolumab is approximately 56%. Patients may initially respond and eventually progress. After progression, new treatments are needed. Sometimes treatments are effective but accompanied by AEs that are not tolerable; treatment therefore has to be aborted despite efficacy, creating a need for less-toxic treatments that are more tolerable and less dangerous. This is an unmet need. According to the clinical experts, no beneficial second-line therapy superior to ipilimumab-nivolumab is currently available. New therapy is needed to increase response rates and reduce AEs. According to the clinical experts, the current standard practice is to discuss dual-drug versus single-drug immunotherapy if there are no contraindications. Factors that would be considered when determining the most suitable treatment include patient goals, age, comorbidities, bulk of disease, sites of disease, and pace of disease. Patients who choose a dual-drug therapy may de-escalate to a single drug to manage toxicity. If the patient progresses on dual therapy and has a BRAF mutation, a BRAF or MEK inhibitor would be offered. According to the clinical expert, dual immunotherapy has been recognized as a potentially curative regimen. In addition, many trials are based on fixed dosing and limited vial sizes. The clinical experts noted that many provinces reimburse these therapies based on weight, and that clinics are challenged to cohort patients to minimize drug wastage.

One clinical expert indicated that, given its equivalency to ipilimumab-nivolumab and fewer toxicities, the new treatment under review (nivolumab-relatlimab FDC) could be a first-line treatment for patients. The clinical experts emphasized that fewer AEs may mean improved patient compliance and superior outcomes overall, and that less toxicity may mean fewer hospital admissions, which is better for patients but also more cost-effective and would offset the extra cost of the drug. Nivolumab-relatlimab FDC could also be an alternative to ipilimumab-nivolumab, which is the current first-line treatment in Ontario. The other clinical expert indicated that, if this regimen is approved, then the options (ipilimumab-nivolumab versus nivolumab-relatlimab FDC), the outcomes of overall survival (OS), progression-free survival (PFS), and toxicities would be discussed with patients. The clinical expert also noted that nivolumab-relatlimab FDC is directly compared to nivolumab monotherapy in the RELATIVITY-047 trial; nivolumab-relatlimab FDC is the first-class drug; nivolumab-relatlimab FDC may be used as first or second line of ICIs; nivolumab-relatlimab FDC would not be reserved for those patients who are intolerant, but rather those who would benefit from an effective regimen with less toxicity; nivolumab-relatlimab FDC is expected to cause a shift in treatment paradigms; those candidates for single-drug immunotherapy would be offered nivolumab-relatlimab FDC; and those candidates considered for ipilimumab-nivolumab may be offered or choose nivolumab-relatlimab FDC. The clinical expert stated that this nivolumab-relatlimab FDC regimen may replace ipilimumab-nivolumab for less-robust patients.

The clinical experts indicated that all metastatic patients can be offered this treatment as it was beneficial regardless of BRAF status, PD-L1 and LAG-3 percentage, or stage. It is similar to other immunotherapy combinations and could be offered to all patients. The experts also stated that it will be important to follow OS data as they mature, to determine the efficacy in brain metastases, and whether the combination decreases or delays the occurrence of brain metastases.

The clinical experts indicated that an assessment of improvements in patient symptoms and the modified immunotherapy Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) are needed as pseudoprogression can occur at the beginning of treatment. Usually, it can take up to 2 or 3 months to evaluate the true response. Initially, responses are assessed at 3-month intervals. As patients respond, the response assessment can be tailored and increased to every 6 months. Improved survival is the goal. The clinical experts noted that clinical outcomes assessments align with the clinical trial outcomes; physicians and patients review toxicities, symptom control, and objective evidence of disease response in an ongoing manner during active treatment.

Regarding discontinuation, the clinical experts indicated the nivolumab-relatlimab FDC should be discontinued when disease progression on imaging is obvious with no improvement in symptoms. According to the clinical experts, when harmful grade 3 or 4 AEs occur, patient should at the very least pause treatment of the disease in favour of treating the AE, then determine if disease treatment can be restarted at a lower dose.

The clinical experts noted that, ideally, treatments for metastatic melanoma should be provided by specialist oncologists and pharmacists in a Canadian cancer centre or, if at a community centre, treatment should be supervised or somehow connected to a cancer centre and experts who can be consulted for advice. According to the clinical experts, centres that administer and manage patients on ipilimumab-nivolumab are well equipped to manage this regimen.

Clinician Group Input

CADTH received 1 clinician-group submission from the Ontario Health (Cancer Care Ontario) (OH-CCO) Skin Cancer Drug Advisory Committee (DAC). At the time OH-CCO input, the proposed Health Canada indication was not line-specific (i.e., indicated for the treatment of adult and pediatric patients aged 12 years or older and weighing at least 40 kg with unresectable or metastatic melanoma). However, after the input was received, the indication was approved for the first line (i.e., for the treatment of adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma). In the metastatic or unresectable settings, first-line treatments can include single-drug nivolumab or pembrolizumab, ipilimumab-nivolumab, and TTs (for patients with BRAF mutations). The TT options are dabrafenib-trametinib, cobimetinib-vemurafenib, and binimetinib-encorafenib. If patients received pembrolizumab or nivolumab in the first line, the subsequent-line options are ipilimumab alone, or a TT (for patients with a BRAF mutation). If ipilimumab-nivolumab followed by nivolumab maintenance is used in the first line, only patients with a BRAF mutation have a second-line option to use a TT. Patients who received a first-line TT may be eligible for pembrolizumab, nivolumab, or ipilimumab-nivolumab in the second-line setting. If treated with pembrolizumab or nivolumab, the patient may be eligible to receive ipilimumab further downstream.

According to OH-CCO’s Skin Cancer DAC, the drug under review has a higher response rate compared with single-drug nivolumab in patients with unresectable or metastatic melanoma as shown by the RELATIVITY-047 trial. Although there was no head-to-head comparison trial, this combination also has less toxicity than ipilimumab-nivolumab, the treatment-related AEs for which are reported in the CheckMate 067 trial, and this combination may fill some of the unmet needs of the standard treatment.

The OH-CCO DAC reported that the algorithm in the first-line metastatic or unresectable setting should be: Patients who are not able to tolerate ipilimumab-nivolumab or who would be treated with a single-drug PD-1 inhibitor would be suitable for receiving the drug under review in the first-line metastatic or unresectable setting.

The DAC stated that a clinically meaningful response would be improved survival, reduction in the frequency and/or severity of symptoms, attainment of major motor milestones, ability to perform activities of daily living, improvement of symptoms, and stabilization (no deterioration) of symptoms. Treatment response will be routinely assessed clinically, and by CT and/or PET scans approximately every 3 months.

The DAC mentioned confirmed disease progression and/or unmanageable toxicities would be the most likely reasons to discontinue treatment. It also noted that the drug under review should be administered in an outpatient cancer clinic and prescribed by a oncologist.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Clinical Evidence

Systematic Review

Description of Studies

One pivotal, phase II and III, double-blinded, randomized controlled and ongoing trial (RELATIVITY-047, N = 714)⁴¹ is included in the systematic review. The RELATIVITY-047 trial evaluated the comparative efficacy and safety of nivolumab-relatlimab FDC versus nivolumab monotherapy administered as a first-line therapy in the treatment of adult and pediatric patients aged 12 years or older with previously untreated, unresectable or metastatic melanoma. However, no adolescents (aged 12 to < 18 years) were enrolled. A total of 714 patients were randomized 1:1 to receive nivolumab-relatlimab FDC (N = 355) or nivolumab monotherapy (N = 359). The median age was 63 years (range = 20 to 94). The majority (N = 655, 91.7%) of patients had metastatic stage IV melanoma at study entry. The median duration from diagnosis to study treatment was 1.26 years. A total of 62 patients (8.7%) had received previous adjuvant or neoadjuvant treatment. A total of 275 patients (38.5%) were BRAF-positive. A total of 16 patients (2.2%) from Canada and 63 patients (8.8%) from the US were included. The primary outcome was PFS. The 2 secondary outcomes were OS and overall response rate (ORR). Tertiary and/or exploratory outcomes included duration of response (DoR), time to response (TTR) and health-related quality of life (HRQoL) measurements (Functional Assessment of Cancer Therapy–Melanoma [FACT-M] and EQ-5D-3L questionnaires). The sample size for the study was based on a primary end point of PFS using a blinded independent central review (BICR) for both the phase II and phase III studies. Results presented in this submission reflect the phase III component of the RELATIVITY-047 trial. The final analysis for PFS was conducted after a median follow-up of 13.2 months. The final analysis for OS and ORR were conducted after a median follow-up of 19.3 months. Results for median DoR and TTR were based on the updated descriptive analysis conducted after a median follow-up of 25.3 months. HRQoL measurements (FACT-M and, EQ-5D-3L) were recorded after a median follow-up of 19.3 months. The objective of the safety outcomes was to assess the overall safety and tolerability of nivolumab-relatlimab and nivolumab. Safety data reported in this review were based on a median follow-up of 25.3 months.

Efficacy Results

Based on the final analysis after a median follow-up of 13.2 months, the median PFS was 10.12 months (95% confidence interval [CI], 6.37 to 15.74) in the nivolumab-relatlimab FDC group, which was statistically significant and clinically meaningfully longer than the 4.63 months in the nivolumab monotherapy group (hazard ratio [HR] for nivolumab-relatlimab FDC versus nivolumab = 0.75; 95% CI, 0.62 to 0.92; P = 0.0055). The observed PFS benefit of nivolumab-relatlimab FDC compared with nivolumab monotherapy was shown in an updated descriptive analysis after a median follow-up of 25.3 months. Subgroup and sensitivity analyses of PFS were largely consistent with those of the primary analysis.

After a median follow-up of 19.3 months, the median OS was not reached in the nivolumab-relatlimab group compared to 34.10 months in the nivolumab group. The between-group difference (nivolumab-relatlimab FDC versus nivolumab) for median OS did not reach statistical significance at the final analysis of OS after a median follow-up of 19.3 months (HR = 0.80; 95% CI, 0.64 to 1.01; P = 0.0593). Similarly, after a median follow-up of 25.3 months, the median OS was not reached in the nivolumab-relatlimab group compared to 33.18 months in the nivolumab group in an updated descriptive analysis. The comparative OS of nivolumab-relatlimab FDC and nivolumab monotherapy was therefore uncertain.

Based on the descriptive final analyses, a total of 10.3% (95% CI, 3.4% to 17.3%) more patients in the nivolumab-relatlimab FDC group achieved an objective response compared with the nivolumab group after a median follow-up of 19.3 months. A consistent ORR benefit was also observed in the updated descriptive analysis after a median follow-up of 25.3 months. A total of 9.8% (95% CI, 2.8% to 16.8%) more patients in the nivolumab-relatlimab FDC group achieved an objective response compared with the nivolumab group.

In terms of complete response (CR) and progressive disease, no formal statistical or descriptive analysis was undertaken to report the between-group difference (or 95% CI). No HR (or 95% CI) was provided. The comparative rates of CR and progressive disease of nivolumab-relatlimab FDC compared with nivolumab monotherapy remain inconclusive.

After a median follow-up of 25.3 months, no statistical and clinical meaningful between-group difference was observed for DoR. The TTR appeared to be the same after a median follow-up of 25.3 months. However, no between-group difference and no HR were reported for TTR. The DoR and TTR of nivolumab-relatlimab FDC compared with nivolumab monotherapy remain uncertain.

After a median follow-up of 19.3 months, HRQoL (FACT-M and EQ-5D-3L utility index scores and EQ visual analogue scale [VAS] results) in the nivolumab-relatlimab FDC and nivolumab groups remained generally stable (no clinical meaningful improvement or deterioration) during the treatment period. There were little to no differences between nivolumab-relatlimab FDC and nivolumab monotherapy in FACT-M, EQ-5D-3L utility index scores, and EQ VAS.

No adolescents (aged ≥ 12 to 18 years) were enrolled in the pivotal study. However, in the Health Canada product monograph,⁴⁰ the indication of nivolumab-relatlimab FDC includes pediatric patients aged 12 years or older and weighing at least 40 kg. The product monograph indicates that use of nivolumab-relatlimab FDC in pediatric patients is supported by predicted drug exposures at the recommended nivolumab-relatlimab FDC dose that is expected to result in safety and efficacy similar to those of adults. The safety and efficacy of nivolumab-relatlimab FDC have not been established in pediatric patients under the age of 12 years or in patients aged 12 years or older weighing less than 40 kg.⁴⁰

Harms

The proportion of patients with at least 1 treatment-emergent AE appeared similar in the nivolumab-relatlimab FDC group compared with the nivolumab monotherapy group (99.2% in the nivolumab-relatlimab FDC group and 95.8% in the NIVO monotherapy group). However, the most common any-grade AEs (occurring in > 20% patients in either of the 2 groups) |||||||| || ||||| || |||| |||||||| || ||| ||||||||| |||| |||||||||| ||| ||||| |||| ||| ||||||||| ||||||||||| |||||| |||| || ||||||| |||||||||| ||| ||| ||||| ||||| ||| |||||| The frequency of serious adverse events (SAEs) appeared to be similar in both groups and individual SAEs were relatively rare. With the exception of malignant neoplasm progression, which occurred in 3.9% of patients receiving nivolumab-relatlimab FDC and in 5.6% of those receiving nivolumab monotherapy, no SAEs were reported in more than 2% of patients in either group. The frequency of withdrawal due to AEs also |||||||| ||||||||||| |||||| || ||| ||||||||| |||| |||||||||| ||| ||||| |||| || ||| ||||||||| ||||||||||| ||||| |||||||||| ||| ||| ||||| ||||| ||| ||||||| Discontinuation treatment due to specific AEs occurred in less than 2% patients in either of the groups, with the exception of malignant neoplasm progression, which occurred in 17% of patients receiving nivolumab-relatlimab FDC and 2.8% of those receiving nivolumab monotherapy. The frequency of death due to AEs (i.e., study drug toxicity) was rare in both groups (1.1% of the nivolumab-relatlimab FDC group and 0.6% of the nivolumab monotherapy group). ||||||| ||||||||||||| ||| |||||||||| || |||||||||| ||||||| ||||||||||||||| ||||||| ||||| ||||||| ||||| |||||||| ||||||||||| |||||| || ||| ||||||||| |||| |||||||||| ||| ||||| |||| || ||| ||||||||| ||||| ||||| ||||||||| The other particular notable harm, myocarditis, was rare, occurring in just 1.7% and 0.6% of patients, respectively). Grade 3 or 4 all-cause AEs were numerically more frequent with nivolumab-relatlimab FDC (44.8%) versus nivolumab (36.8%). Overall, the safety profile of nivolumab-relatlimab FDC was considered manageable and consistent with the known mechanisms of action of relatlimab or nivolumab. No new safety signal was identified.

Critical Appraisal

Appropriate methods of randomization, blinding and allocation concealment were reported. Objective outcomes and validated health-related outcomes were assessed. However, the minimally important between-group difference, which is the threshold used for all outcomes of the Grading of Recommendations Assessment, Development and Evaluation (GRADE), is not available. Clinical expert opinion therefore was used to inform the thresholds for determining whether the between-group difference observed for each outcome was clinically meaningful.

The proportion of patients with metastatic stage M1c was higher in the nivolumab-relatlimab FDC group (N = 151 [42.5%]) than in the nivolumab monotherapy group (N = 127 [35.4%]); however, the clinical experts consulted for this review stated that minor between-group imbalances of metastatic stage M1c would have been unlikely to affect the comparative results between the nivolumab-relatlimab FDC and nivolumab monotherapy groups.

Overall survival was assessed as a secondary outcome, and the study was not powered to assess the between-group difference in OS at the prespecified final analysis (after a median follow-up of 19.3 months) and updated analysis (after a follow-up of 25.3 months). The comparative efficacy on OS of nivolumab-relatlimab FDC compared with nivolumab therefore remains uncertain.

The statistical significance of ORR (according to BICR) could not be formally tested due to its position in the statistical hierarchy (the OS final analysis did not reach statistical significance). As a result, ORR, as well as CR and progressive disease (which were part of the overall response analysis), are based on only descriptive analyses after a median follow-up of 19.3 months. Only descriptive analyses without a between-group difference or HR were reported. Results for ORR, CR, and progressive disease should therefore be interpreted with caution.

The DoR and TTR were assessed as tertiary or exploratory outcomes but not subjected to the hierarchical testing procedure to control for type I error. Analyses of DoR and TTR were not statistically powered and were reported using descriptive statistics only. No between-group differences were reported for DoR or TTR, although an HR was reported for DoR. Overall, the findings of DoR and TTR should be viewed as supportive evidence only.

Similarly, FACT-M and EQ-5D-3L data were assessed as tertiary and/or exploratory outcomes but were not subjected to the hierarchical testing procedure to control for type I error. For these patients with reported HRQoL outcomes (FACT-M and EQ-5D-3L), there may have been differential recall bias. Overall, the magnitude and direction of the impact of recall bias on the patient-reported HRQoL outcomes are unknown. The HRQoL analyses were not statistically powered and were reported using descriptive statistics.⁴² Overall, the HRQoL findings should be viewed as supportive evidence only.

All subgroup analysis were excluded from the randomization scheme, and imbalances in characteristics may bias the results observed between the subgroups. In addition, the subgroup analysis may be not powered to detect the between-group difference in each subgroup. The findings of the subgroup analysis should therefore be viewed as supportive evidence only.

In addition, among the limitations of the RELATIVITY-047 trial is the lack of a comparison with current standard-of-care therapy, except for nivolumab monotherapy. The efficacy and safety of nivolumab-relatlimab FDC compared with ipilimumab-nivolumab, encorafenib-binimetinib, dabrafenib-trametinib, vemurafenib-cobimetinib, ipilimumab, pembrolizumab, dabrafenib, and trametinib are unknown.

It is uncertain whether the findings can be generalized to patients with central nervous system (CNS) metastases or those with an ECOG PS greater than 1 as no such patients were included in the study. Only 17 patients (2.4%) with brain metastasis were included (1.7% and 3.1% in the nivolumab-relatlimab FDC and nivolumab monotherapy groups, respectively). Patients with active CNS metastases were excluded. The clinical experts CADTH consulted for this review indicated that, while a higher ECOG PS (> 1) usually indicates more severe disease and is more likely to be accompanied by an unfavourable prognosis, the nivolumab-relatlimab FDC combination treatment could be extended to patients with an ECOG PS greater than 1. In terms of patients with CNS metastasis, the clinical experts CADTH consulted for this review indicated that additional studies are needed to understand the comparative efficacy and safety of nivolumab-relatlimab FDC versus nivolumab monotherapy in patients with CNS metastasis.

Finally, it should be noted that, although an age of 12 years or older was an inclusion criterion, no adolescents (aged ≥ 12 to < 18 years) were enrolled in the pivotal study. The comparative efficacy and safety profile of nivolumab-relatlimab FDC versus nivolumab monotherapy is therefore unknown, and whether the findings from the RELATIVITY-047 trial can be generalized to adolescent patients remains unknown. However, the Health Canada product monograph indicates that the use of nivolumab-relatlimab FDC in pediatric patients aged 12 years or older and weighing at least 40 kg is supported by predicted drug exposures at the recommended nivolumab-relatlimab FDC dosage, which is expected to result in safety and efficacy outcomes similar to those of adults. One clinical expert CADTH consulted for this review indicated that pediatric patients with unresectable or metastatic melanoma should be enrolled in clinical trials, if available, to assess the efficacy and safety profile of nivolumab-relatlimab FDC. The other clinical expert indicated that, because of the potential unfeasibility of the trials on pediatric patients, use of nivolumab-relatlimab FDC in adolescents should be considered on a case-by-case basis, particularly if body habitus is comparable or close to that of an adult. The clinical expert noted that immuno-oncology (IO) drugs are now given to the pediatric population, and they are well tolerated.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to informing the deliberations of CADTH’s expert committee, and a final certainty rating was determined as outlined by the GRADE Working Group.^43,44 Following the GRADE approach, evidence from RCTs was initially treated as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

The selection of outcomes for 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: PFS, OS, ORR, DoR, HRQoL (i.e., FACT-M, EQ-5D-3L utility index, and EQ VAS), and change from cycle baseline after a median follow-up of 19.3 months and at a fixed-landmark time point of 24 months, as well as notable harms (i.e., myocarditis and adrenal insufficiency).

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or relative to the null. For this review, the target of the certainty of evidence assessment was based on the presence of absence of a clinically important effect, as informed by minimally important differences (MIDs) and thresholds suggested by the clinical experts (for all outcomes).

Results of GRADE Assessments

Table 2: Summary of Findings for Nivolumab-Relatlimab FDC Versus Nivolumab Monotherapy for the Treatment of Adult and Pediatric Patients (Aged 12 Years and Older and Weighing at Least 40 kg) With Unresectable or Metastatic Melanoma Who Have not Received Prior Systemic Therapy for Unresectable or Metastatic Melanoma

AE = adverse event; BICR = blinded independent central review; CI = confidence interval; CR = complete response; DMC = data-monitoring committee; DoR = duration of response; EQ VAS = EQ visual analogue scale; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; HR = hazard ratio; HRQoL = health-related quality of life; NA = not available (or not reached); NR = not reported; OR = odds ratio; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; RCT = randomized controlled trial; RECIST = Response Evaluation Criteria in Solid Tumors Version 1.1; vs. = versus.

Note: The analysis of ORR, DoR, and HRQoL (FACT-M total score and EQ-5D-3L) were not adjusted for multiple comparisons.

^aIn the absence of available data for the between-group differences in event probabilities at clinically relevant time points, the judgment of imprecision was based on a 95% CI for the HR using the null as the threshold. The clinical importance of the between-group difference was judged based on the input of the clinical experts consulted by CADTH for the review.

^bRated down 1 level for serious imprecision. In the absence of available data for the between-group difference in event probabilities at clinically relevant time points, the judgment of imprecision was based on the 95% CI for the HR using the null as the threshold. The 95% CI for the HR included the possibility of little to no difference (i.e., included the null). The clinical importance of the between-group difference was judged based on the input of the clinical experts consulted by CADTH for the review. Rated down 1 level for serious indirectness. The follow-up time was not sufficient to assess OS in this population.

^cRated down 1 level for serious imprecision. Based on the threshold for a clinically important between-group difference suggested by the clinical experts of 50 to 100 events per 1,000 patients, the point estimate suggests a benefit; however, the lower bound of the 95% CI suggests little to no difference.

^dRated down 2 levels for very serious imprecision. In the absence of available data for the between-group difference in event probabilities at clinically relevant time points, the judgment of imprecision was based on the 95% CI for the HR using the null as the threshold. The 95% CI for the HR included the possibility of both benefit and harm for nivolumab-relatlimab compared with nivolumab monotherapy.

^eRated down 2 levels for a very serious risk of bias due to missing outcome data. Data were available for 21% of randomized patients. In the absence of a known threshold for a clinically important between-group difference, the null was used as the threshold.

^fRated down 2 levels for very serious imprecision. The results are based on very few events in each group (6 of 355 vs. 2 of 359 for myocarditis and 20 of 355 vs. 4 of 359 for adrenal insufficiency in the nivolumab-relatlimab and nivolumab groups, respectively).

Long-Term Extension Studies

No long-term extensions studies are available.

Indirect Treatment Comparisons

Description of Studies

Two indirect treatment comparison (ITC) reports were submitted. Indirect treatment comparison 1 (ITC1), a Bayesian network meta-analysis (NMA), assessed the safety and efficacy of nivolumab-relatlimab relative to other IO drugs for adult patients in the first-line management of patients with advanced melanoma. Indirect treatment comparison 2 (ITC2), a patient-level propensity-weighted comparison, assessed nivolumab-relatlimab relative to ipilimumab-nivolumab among patients with advanced melanoma treated in the first line.

Efficacy Results

The first ITC, a Bayesian NMA, assessed nivolumab-relatlimab relative to nivolumab monotherapy, ipilimumab monotherapy, nivolumab (1 mg/kg) combined with ipilimumab (3 mg/kg), nivolumab (3 mg/kg) combined with ipilimumab (1 mg/kg), pembrolizumab, and cobimetinib-atezolizumab.

The results of ITC1 indicated that nivolumab-relatlimab is associated with improvements to OS relative || |||||||||| ||||||||||| ||||||||| ||| |||| ||||| |||||| For PFS, nivolumab-relatlimab is associated with improvements relative || |||||||||| |||| ||||| ||| |||| ||||| |||||| pembrolizumab (HR = 0.59; 95% credible interval [CrI], 0.35 to 0.97), and ||||||||||||||||||||||| |||| ||||| ||| |||| ||||| ||||||

For ITC2, the sponsor did not identify any association of the relative efficacy with respect to PFS or OS of nivolumab-relatlimab relative to ipilimumab (3 mg/kg) combined with nivolumab (1 mg/kg).

No data were available in either ITC with respect to ORR, time to progression, or any patient-reported outcome.

Harms Results

In ITC1, nivolumab-relatlimab was associated with higher proportions of patients having grade 3 or 4 treatment-related AEs when compared to nivolumab (odds ratio [OR] = 2.08; 95% CrI, 1.39 to 3.14 || |||||||||| |||| ||||| ||| ||||||||| ||||| and pembrolizumab (OR = 1.99; 95% CrI, 1.01 to 3.87), and was associated with lower proportions of patients experiencing these events relative to nivolumab (1 mg/kg) combined with ipilimumab (3 mg/kg) (OR = 0.43; 95% CrI, 0.25 to 0.73). For discontinuations due to AEs, nivolumab-relatlimab was associated with higher proportions of patients experiencing these events relative to nivolumab (OR = 1.59; 95% CrI, 1.10 to 2.32), and lower proportions of patients experiencing these events relative to nivolumab (1 mg/kg) combined with ipilimumab (3 mg/kg) (OR = 0.29; 95% CrI, 0.17 to 0.48). For discontinuations due to treatment-related AEs, nivolumab-relatlimab was associated with higher proportions of patients experiencing these events relative to nivolumab (OR = 2.21; 95% CrI, 1.41 to 3.56) and |||||||||| |||| ||||| ||| |||| ||||| |||||, and lower proportions of patients experiencing these events relative to nivolumab (1 mg/kg) combined with ipilimumab (3 mg/kg) (OR = 0.89; 95% CrI, 0.50 to 1.59).

No comparative data were presented from ITC2 with respect to safety outcomes, as no formal statistical comparison of the differences in safety events were conducted.

Critical Appraisal

Sponsor-submitted evidence from ITC1 was provided with comparisons to non-IO interventions of interest, such as BRAF and MEK inhibitors but, due to several challenges associated with mixed mutation status and the evidence from treatment nodes connecting to this network of evidence, no clear conclusions could be drawn about comparative efficacy and safety within this population. Several trials reporting on OS for the IO network of evidence still had ongoing observations for survival data at the time of analysis, and additional uncertainty may accompany these comparisons.

Studies Addressing Gaps in the Evidence from the Systematic Review

No studies addressing gaps in the evidence from the systematic review were available.

Conclusions

Evidence from the RELATIVITY-047 trial showed that nivolumab-relatlimab FDC therapy compared with nivolumab monotherapy results in a clinically meaningful benefit in terms of PFS (high certainty) in the treatment of adult patients with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma. Nivolumab-relatlimab FDC may result in a clinically important increase in OS when compared with nivolumab monotherapy (low certainty). However, uncertainty remains in the OS results due to the inadequate length of follow-up for this outcome, and the results are imprecise (the CI included no difference between the nivolumab-relatlimab FDC and nivolumab monotherapy). Nivolumab-relatlimab FDC likely results in a clinically important increase in ORR when compared with nivolumab monotherapy (moderate certainty). However, the results were uncertain for the DoR of nivolumab-relatlimab FDC compared with nivolumab monotherapy after a median follow-up of 25.3 months (low certainty). Nivolumab-relatlimab FDC may result in little to no difference (either improvement or deterioration) when compared with nivolumab monotherapy in HRQoL as measured by FACT-M, EQ-5D-3L utility index, and EQ VAS (low certainty). Numerically more patients appeared to experience AEs (e.g., grade 3 or 4) in the nivolumab-relatlimab FDC group than in the nivolumab monotherapy group. However, the clinical experts CADTH consulted for this review indicated that the safety profile of nivolumab-relatlimab FDC appeared to be consistent with the known safety profile of each component drug (nivolumab and relatlimab) and was generally manageable. No additional safety signals were identified. It should be emphasized that the efficacy and safety profile of nivolumab-relatlimab FDC compared with nivolumab monotherapy is not available for pediatric patients (aged ≥ 12 to < 18 years). In addition, the efficacy and safety profile of nivolumab-relatlimab FDC compared with existing standard therapies except nivolumab monotherapy is not addressed in the RELATIVITY-047 trial. The sponsor-submitted ITCs were inconclusive with respect to nivolumab-relatlimab FDC relative to combination IO (ipilimumab [3 mg/kg] combined with nivolumab [1 mg/kg], ipilimumab [1 mg/kg] combined with nivolumab [3 mg/kg], and cobimetinib-atezolizumab) for PFS and OS but was associated with prolonged OS and PFS relative to ipilimumab monotherapy and prolonged PFS relative to pembrolizumab monotherapy. In the sponsor-submitted ITCs, nivolumab-relatlimab FDC demonstrated a favourable safety profile compared to a combination of nivolumab (1 mg/kg) and ipilimumab (3 mg/kg); however, compared to pembrolizumab, ipilimumab, and nivolumab monotherapy, the safety profile of nivolumab-relatlimab FDC was unfavourable.

Introduction

Disease Background

Contents within this section were informed by materials submitted by the sponsor and clinical expert input. The following summary was validated by the CADTH review team.

Melanoma is a neoplasm originating from melanocytes, the pigment-producing cells of the skin. It is 1 of the 3 main types of skin cancer, along with basal cell carcinoma and squamous cell carcinoma. Melanoma commonly arises in cutaneous primary locations (i.e., cutaneous melanoma).Other forms include mucosal, uveal, and acral melanoma.^45,46 There are 4 main types of cutaneous melanoma: superficial spreading, nodular, lentigo maligna, and acral lentiginous.^46,47 The majority of cases are superficial spreading or nodular, each accounting for approximately 37% of cases (73% combined) and each typically diagnosed at mean ages of 55 and 62 years, respectively.^2,9 The clinical symptoms of advanced melanoma include hard or swollen lymph nodes, a hard lump on the skin, unexplained pain, feeling very tired or unwell, and unexplained weight loss.¹ Melanoma is a debilitating disease that negatively affects patients’ physical, mental, and emotional well-being.^48,49 The diagnosis tool of melanoma includes a skin examination, physical examination, skin and/or lymph node biopsy, and diagnostic imaging (i.e., CT).^4-7 According the clinical experts CADTH consulted for this review, determining the molecular signature of a melanoma is critical. A blood test to assess serum LDH levels is an important prognostic marker of stage IV metastatic disease Most cases of melanoma are clinically identified early and can be cured with surgical excision alone.^4,5,9

According to the Canadian Cancer Society, 10.4% of all new melanomas are stage III at diagnosis and 3.9% are stage IV (i.e., metastatic disease). Poor prognostic factors include an ECOG PS of 2 or higher, elevated LDH, nodal involvement and metastases, increased tumour thickness, ulceration, and mitoses measuring 1/mm² or larger in thin T1 melanomas.^3,5 Approximately 70% of metastatic melanomas have mutually exclusive mutations in BRAF, NRAS viral oncogene homologue, c-KIT, and GNAQ or GNA11 genes, which activate the MEK pathway, leading to promotion of cell proliferation, prevention of apoptosis, and angiogenesis.⁸ In a global systematic review, 38.5% of patients presented with genetic mutations in BRAF, 16.4% in NRAS, and 10% in c-KIT.¹⁰ However, a higher proportion of BRAF mutation-positive melanoma was reported in an analysis, in which 51% of patients with stage III or IV melanoma had a mutation in the BRAF gene.⁹ An Australian study of patients with advanced melanoma reported a similar rate, with 48% of tumours testing positive for a BRAF V600 mutation.¹¹

In Canada, melanoma accounted for 3.8% of new cancer cases, approximately 4% of all diagnosed skin cancers in Canada,^46,50 and 1.5% of cancer deaths in 2021.¹² An estimated 9,000 people were diagnosed with melanoma in 2022 in Canada,¹³ with an age-standardized incidence rate of 23.5 per 100,000 in 2018 (excluding Quebec) based on data from Statistics Canada.¹⁴ The incidence was slightly higher in men than in women (25.9 versus 21.2 per 100,000).^2,14 The mean age at diagnosis of advanced metastatic melanoma is approximately 59 years in Canada.^2,3 The incidence of melanoma in Canada has continued to rise over the past 4 decades.¹² Malignant cutaneous melanoma is responsible for 90% of all skin cancer–related deaths annually.⁴ An estimated 1,200 persons died from melanoma in 2022 in Canada, with an age-standardized mortality rate of 2.7 per 100,000.¹³ In contrast to incidence trends, mortality rates have declined over the past 4 decades.¹² In Canada, stage IV distant metastatic disease is associated with a 5-year survival rate of 18%.⁴ However, consistent with the observed decline in mortality rates, melanoma survival rates have successively improved in recent years with the introduction of novel immunotherapies and TTs based on BRAF and MEK inhibitors. The advent of TTs and immunotherapies has resulted in a paradigm shift in outcomes for patients with advanced melanoma.

Standards of Therapy

Contents within this section were informed by materials submitted by the sponsor and clinical expert input. The following summary was validated by the CADTH review team.

Important treatment goals of systemic therapy in metastatic advanced melanoma include prolonging survival, generating durable responses, providing symptom relief, minimizing treatment toxicities, and maintaining quality of life.¹⁵ The current treatment paradigm in Canada for the first-line treatment of unresectable and/or metastatic advanced melanoma is based on the use of systemic therapies, which includes immunotherapy with ICIs as either monotherapy, dual therapy, or combination treatment with targeted BRAF or MEK inhibitors in BRAF mutation disease.^16,51,52 These immunotherapies and TTs are funded with restrictions across the majority of Canadian provincial and territorial drug programs (excluding Quebec). According to the clinical experts CADTH consulted for this review, immunotherapy is the first line of choice for melanoma regardless BRAF status.^16,17 The ICI immunotherapies that are approved by Health Canada and routinely used for the first-line treatment of metastatic melanoma in Canada include nivolumab (anti–PD-1) monotherapy,^21,19 ipilimumab (anti–CTLA-4) monotherapy,^20,22 pembrolizumab (anti–PD-1) monotherapy^23,24 and ipilimumab-nivolumab combination therapy^18-20 However, the use of nivolumab-ipilimumab has been increasing in patients with BRAF mutation melanoma,²⁵ which is the treatment of choice among the ICIs. After the first line, the treatment decisions are largely determined by BRAF mutation status.¹⁷ Patients with no BRAF mutation are treated with immunotherapies and patients with BRAF mutations are eligible for treatment with a TT¹⁷ that has been approved by Health Canada and recommended for reimbursement by the CADTH pan-Canadian Oncology Drug Review Expert Review Committee, including encorafenib (a BRAF inhibitor) plus binimetinib (a MEK inhibitor),^26-28 vemurafenib (a BRAF inhibitor) plus cobimetinib (MEK inhibitor),^29-31 and dabrafenib (a BRAF inhibitor) combined with trametinib (a MEK inhibitor).^32-34 TT use as a monotherapy is not reflective of typical clinical practice in Canada. Consultation with clinical experts in Canada revealed that patients with advanced melanoma rarely receive TT as a single drug (< 5%);³⁵ standard chemotherapy (e.g., dacarbazine), surgery, and radiation therapy are not typically or commonly used in Canada for metastatic melanoma and have been displaced by either ICIs or TTs.^4,52,53 There is an unmet medical need for an additional novel ICI combination therapy to treat metastatic melanoma, including a new therapy that can be used regardless of BRAF mutation status, offers increased efficacy in relation to anti–PD-1 monotherapy, and has a favourable safety profile that does not result in the additive toxicities seen with conventional dual immunotherapy combinations. A novel combination treatment regimen involving an ICI combined with a drug with a different mechanism of action would be preferred.

Drug Under Review

Key characteristics of nivolumab-relatlimab FDC and other relevant standard treatments available for patients with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma are summarized in Table 3 and Table 4. Nivolumab is a humanized IgG4 monoclonal antibody ICI that binds to the PD-1 receptor and blocks its interaction with PD-L1 and programmed cell death ligand 2, triggering PD-1 pathway–mediated inhibition of the immune response, including the antitumour immune response.^36,37 Relatlimab is a novel, first-in-class ICI that targets the LAG-3 receptor.^38,39 Relatlimab is a humanized IgG4 monoclonal antibody that binds to the LAG-3 receptor and prevents LAG-3–mediated inhibition of the immune response by blocking its interaction with ligands, ultimately leading to an antitumour response.^37,40 LAG-3 and PD-1 are distinct inhibitory immune checkpoint pathways, often co-expressed on tumour-infiltrating lymphocytes.⁴⁰ They act synergistically on effector T-cells, leading to T-cell exhaustion and impaired cytotoxic function. Combined relatlimab (anti–LAG-3) and nivolumab (anti–PD-1)–mediated inhibition enables T-cell activation and restores effector function of exhausted T-cells, an effect that is greater than that of either antibody alone, leading to the initiation of an improved antitumour immune response.^37,40

The recommended dosage of nivolumab-relatlimab FDC for adult patients is 480 mg of nivolumab and 160 mg of relatlimab, every 4 weeks. The recommended dosage for pediatric patients who are aged 12 years or older and weigh at least 40 kg is the same as for adults. A recommended dosage has not been established for pediatric patients aged 12 years or older and weighing less than 40 kg. Nivolumab-relatlimab FDC is supplied as a concentrate for solution for infusion: 240 mg of nivolumab per 20 mL (12 mg/mL) and 80 mg of relatlimab per 20 mL (4 mg/mL) in a single-dose vial (FDC).⁴⁰ The Health Canada–approved indication of interest for this review is nivolumab-relatlimab FDC for the treatment of adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma.⁴⁰ The CADTH reimbursement request aligns with the Health Canada indication.

Health Canada reviewed nivolumab-relatlimab FDC through the Standard Review Pathway. The treatment has not been reviewed previously by CADTH.

Table 3: Key Characteristics of Nivolumab-Relatlimab Encorafenib-Binimetinib, Dabrafenib-Trametinib, Vemurafenib-Cobimetinib, Dabrafenib, and Trametinib

ALA = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate transaminase; BRAF = B-Raf kinase protein; CPK = creative phosphokinase; IgG4 = immunoglobin G4; LAG-3 = lymphocyte activation gene 3; mAb = monoclonal antibody; MEK = mitogen-activated protein kinase enzyme; PD-1 = programmed cell death protein 1.

^aHealth Canada–approved indication.

Sources: Nivolumab-relatlimab product monograph,⁴⁰ Encorafenib in combination with binimetinib drug monographs,^26,27 Clinical Guidance Report for dabrafenib and tramaetinib,⁵⁴ and Clinical Guidance Report for vemurafenib and cobimetinib.⁵⁵

Table 4: Key Characteristics of Ipilimumab-Nivolumab, Nivolumab, Ipilimumab, and Pembrolizumab

BRAF = B-Raf kinase protein; CTLA-4 = cytotoxic T-lymphocyte-associated antigen; mAb = monoclonal antibody; PD-1 = programmed cell death protein 1.

^aHealth Canada–approved indication.

Sources: Keytruda product monograph,²³ Opdivo product monograph,¹⁹ and Yervoy product monograph.²⁰

Stakeholder Perspectives

Patient-Group Input

This section was prepared by the CADTH review team based on input provided by patient groups. The full original patient input received by CADTH is included in the Stakeholder section of this report.

CADTH received patient-group submissions from Melanoma Canada and the SYSF. Melanoma Canada is a national patient focused organization focused on the prevention and elimination of melanoma and skin cancers. Melanoma Canada provides patient support, advocacy, awareness, and education to the public and for health care professionals. The SYSF is a national patient-led not-for-profit group dedicated to the fight against nonmelanoma skin cancers, melanoma, and ocular melanoma through nationwide education, advocacy, and awareness initiatives. The SYSF provides a community of oncology-patient and caregiver support throughout the entire continuum of care, from prevention and diagnosis to survivorship.

Data were gathered by Melanoma Canada via an online survey. The survey link was emailed to a database of patients. Any patients and caregivers, regardless of stage or familiarity with the drug therapy in question, were asked to participate. Melanoma Canada also used its website and social media (e.g., Facebook) to promote the survey. The survey was made available June 15 to July 14, 2023. A total of 119 individual patient responses combined with 84 caregiver responses were received. Among the patients, 35 indicated they had no caregiver. Of the patient respondents, 81 were female and 38 were male. The survey was open to all patients, regardless of stage or whether they had been on the drug under review. There were 26 patients who had stage 0 melanoma, 17 were at stage I, 10 were at stage II, 18 were at stage III, 29 were at stage IV, and a further 19 did not know their stage. A total of 73 respondents were from Ontario, 15 were from Alberta, 11 from British Columbia, 8 from Quebec, 6 from Manitoba, and the remainder from other provinces. Two patients in this survey had been treated with the drug under review. Information was obtained by the SYSF through online surveys, virtual patient-roundtables, and one-on-one conversations with 60 melanoma patients, of whom 12 had experience with the drug under review, over the past 6 months. There were 37 females and 23 males aged between 18 and 89 years. There were 14 respondents from British Columbia, 6 from Alberta, 11 from Ontario, 1 from Nova Scotia, 7 from Quebec, 1 from Newfoundland and Labrador, and 2 from Prince Edward Island. A total of 18 respondents lived outside of Canada (in the US, Australia, and France).

Most patients reported that pain, scarring, lymphedema, fatigue, anxiety, fear, and depression are common impacts of the disease that affect the quality of life of patients and their families. Caregivers reported that the greatest impact associated with dealing with the diagnosis is the mental stress, followed by the negative financial impacts on the family due to the loss of income from a working partner, and the additional responsibilities of taking care of a home, family, and their loved one. Some of the respondents described the impact of melanoma using the following phrases: scared, disbelief, unsettled, anxious, teary, disrupted life, totally life changing, the diagnosis has taken a huge mental toll on me as I have always had a very large fear of cancer and I ended up living my worst nightmare, anxiety not knowing when disease may reoccur, had to stop working, disease affected my heart, general fatigue, less interest in activities, need to manage through therapy to address posttraumatic stress disorder, and fear.

In terms of current therapy options, based on 119 responses to the Melanoma Canada survey, 55% of patients had been treated with some form of drug therapy, and 9 had been treated with multiple therapies. A total of 92% of patients treated with available drug therapies indicated that they felt the side effects were worth tolerating, given the anticipated results. Moreover, about 20% of patients experienced trouble accessing treatment. The SYSF survey also mentioned that, for patients in remote areas of Canada, getting to treatment sites, paying for travel costs, and taking time off from work put extra stress on patients, caregivers, and their family, all of which was compounded by the added concern of being treated far from home and their support system. Access to the drug under review was limited to Ontario and Quebec, and a number of patients in Canada could not get access to the drug under review, even though it may have been their only option.

Regarding the improved outcomes, both patient groups identified a large opportunity for improvement if treatments with a wider variety of effective options with minimal side effects and longer responses were available.

Two respondents from Melanoma Canada’s survey and 12 respondents from SYSF’s survey indicated that they had experience with the drug under review, and the primary method of access to the drug was through a clinical trial. A total of 12 respondents explained that benefits of treatment outweighed the drawbacks of the side effects, which were mainly rash and fatigue and were somewhat manageable.

Melanoma Canada’s input did not mention a companion diagnostic test, while the SYSF asked all participants, not just those who received the drug under review, about their experiences with companion diagnostic testing. Respondents said they had received companion diagnostic testing, but 46 were unsure if they had received it. All patients were unsure how and when their companion diagnostic tests were conducted. For 1 patient, the testing process caused delays in starting treatment. All patients responded that there were no adverse effects associated with the testing procedure. Three patients had their testing expenses covered by private payer, 2 paid out of pocket, 1 received compassionate treatment, and 54 were not sure how treatment costs were covered, with most assuming health insurance was involved.

Melanoma Canada stated that there is an ongoing need for better options, and options for when 1 therapy does not work or stops working. Melanoma Canada also noted that melanoma is a complicated cancer with the highest level of mutations among cancers. It is difficult to treat once it has spread. Effective treatments, biomarkers, and earlier-stage treatments are needed to prevent some of the quality-of-life impacts from surgery, loss of income, duration of illness, and the impact on mental health for the patient and caregiver. According to Melanoma Canada, the drug under review represents an improvement and an option for the treatment of a cancer that continues to be increasingly prevalent and is complex to treat.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in 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 adult and pediatric patients aged 12 years and older and weighing at least 40 kg with unresectable or metastatic melanoma.

Unmet Needs

The clinical experts indicated that the goal of the treatment is to increase OS rates, slow down progression, hopefully achieve a complete objective response, improve symptoms, and minimize toxicity, particularly long-term significant toxicities. They added that formulations are also needed to improve convenience. Currently the standard of care for metastatic melanoma in Ontario is ipilimumab-nivolumab (if the patient is able to tolerate potential toxicities).The general approach is that failure to respond to ipilimumab-nivolumab may prompt switching to a BRAF inhibitor plus a MEK inhibitor in BRAF-positive patients. Pembrolizumab or nivolumab may be attempted as monotherapy if too many AEs occur due to ipilimumab-nivolumab treatment. The clinical experts indicated that immunotherapy is not 100% effective, with response rates to ipilimumab-nivolumab of approximately 56%. Patients may initially achieve a response and then progress. After progression, new treatments are needed. Treatments may sometime be effective but accompanied by AEs that are not tolerable, necessitating discontinuing treatment despite efficacy. Less-toxic treatments that are more easily tolerable are therefore needed. According to the clinical experts, no currently available second-line therapy is more beneficial than ipilimumab-nivolumab combination therapy. A new therapy is needed to increase response rates with fewer AEs. According to the clinical expert, the current standard practice is to discuss dual-drug versus single-drug immunotherapy in the absence of contraindications. Factors that would be considered in determining the most suitable treatment include patient goals, age, comorbidities, bulk of disease, sites of disease, and pace of disease. A patient who chose a dual-drug therapy may de-escalate to a single drug to manage toxicity. If the patient progresses on dual therapy and has a BRAF mutation, BRAF and MEK inhibitors would be offered. According to the clinical experts, dual immunotherapy has been recognized as a potentially curative regimen. In addition, many trials are based on fixed dosing and limited vial sizes. The clinical experts noted that many provinces reimburse these therapies based on weight, and that clinics are challenged to cohort patients to minimize drug wastage.

Place in Therapy

One clinical expert indicated that, given its equivalency to ipilimumab-nivolumab and fewer toxicities, nivolumab-relatlimab FDC to be a first-line treatment for patients. The clinical experts emphasized that fewer AEs may mean more patient compliance and therefore superior outcomes overall, and that less toxicity may mean fewer hospital admissions, which would reduce burdens on patients and offset the extra cost of the drug. Nivolumab-relatlimab FDC could also be an alternative to ipilimumab-nivolumab, which is current first line of therapy in Ontario. The other clinical expert indicated that, if this regimen approved, then the choice between ipilimumab-nivolumab and nivolumab-relatlimab FDC with respect to OS, PFS, and toxicities would be discussed with patients. The clinical expert also noted that nivolumab-relatlimab FDC was directly compared with nivolumab monotherapy in the RELATIVITY-047 trial; nivolumab-relatlimab FDC is a first-class drug that may be used as a first- or second-line ICI. In addition, nivolumab-relatlimab FDC would not be reserved for those patients who are intolerant to ipilimumab-nivolumab, but made available to all those who would benefit from an effective regimen with reduced toxicity. Nivolumab-relatlimab FDC is expected to cause a shift in treatment paradigms; candidates for receiving a single-drug immunotherapy would be offered nivolumab-relatlimab FDC; and those considered for ipilimumab-nivolumab may also be offered nivolumab-relatlimab FDC. The clinical expert stated that the nivolumab-relatlimab FDC regimen may replace ipilimumab-nivolumab for less-robust patients.

Patient Population

The clinical experts indicated that all metastatic patients can be offered this treatment as it was beneficial regardless of BRAF status and PD-L1 and LAG-3 percentage or stage. It is similar to other immunotherapy combinations and could be offered to all patients. In addition, the experts stated that it will be important to follow OS data as they mature to determine the efficacy in brain metastases, and to know if the combination decreases or delays the occurrence of brain metastases.

Assessing the Response Treatment

The clinical experts indicated that it is necessary to assess responses in terms of improved patient symptoms and the modified immunotherapy RECIST criteria, as pseudoprogression can occur at the beginning of treatment. In most cases, it can take up to 2 or 3 months to evaluate a true response. Initially, responses should be assessed at 3-month intervals. As patients respond, the response assessment can be tailored and increased to every 6 months. Improved survival is the goal. The clinical experts noted that clinical-outcome assessments align with clinical trial outcomes; physicians and patients review toxicities, symptom control, and objective evidence of disease response in an ongoing fashion during active treatment.

Discontinuing Treatment

The clinical experts indicated that obvious disease progression on imaging with no improvement in symptoms will lead to discontinuation. When harmful grade 3 or 4 AEs occur, the patient should pause treatment in favour of treating the AE, after which the treatment can be restarted at a lower dose.

Prescribing Considerations

The clinical experts noted that these treatments for metastatic melanoma should be provided by specialist oncologists and pharmacists in a Canadian cancer centre or, if at a community centre, treatment should be supervised or connected to a cancer centre and experts who can dispense advice. According to the clinical experts, a centre administering or managing patients receiving ipilimumab-nivolumab are well equipped to manage this regimen.

Clinician-Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician-group inputs received by CADTH are included in the Stakeholder section of this report. At the time of OH-CCO input, the proposed Health Canada indication was not line-specific (i.e., indicated for the treatment of adult and pediatric patients aged 12 years and older and weighing at least 40 kg with unresectable or metastatic melanoma). However, after the input was received, the indication was amended to first-line treatment of adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma.

CADTH received 1 clinician-group submission from the OH-CCO Skin Cancer DAC. The OH-CCO DACs provide timely evidence-based clinical and health system guidance on drug-related issues in support of OH-CCO mandate, which includes supporting the Provincial Drug Reimbursement Programs and the Systemic Treatment Program.

The OH-CCO DAC gathered data and information via videoconferencing and email. It stated that the indication for the drug under review is broad and can fit in all lines of therapy. In the first-line metastatic or unresectable setting, the current treatments can include single-drug nivolumab or pembrolizumab, combination ipilimumab-nivolumab and TTs (for patients with a BRAF mutation). The TT options are dabrafenib-trametinib, cobimetinib-vemurafenib, and binimetinib-encorafenib. For patients who received pembrolizumab or nivolumab in the first line, the subsequent-line options are ipilimumab alone, or a TT (for patients with a BRAF mutation). If ipilimumab-nivolumab followed by nivolumab maintenance is used in the first line, only patients with a BRAF mutation have a second-line option to use a TT. Patients who received a first-line TT may be eligible for pembrolizumab, nivolumab, or ipilimumab-nivolumab in the second-line setting. If treated with pembrolizumab or nivolumab, the patient may be eligible to use ipilimumab further downstream.

According to OH-CCO’s DAC, the drug under review has a higher response rate compared with single-drug nivolumab in patients with unresectable or metastatic melanoma, as demonstrated by the RELATIVITY-047 trial. Although the trial did not include a head-to-head comparison, this combination is also less toxic than ipilimumab-nivolumab, for which treatment-related AEs are reported in the CheckMate-067 trial, and this combination may fill some of the needs that are not met by the standard treatment.

OH-CCO’s DAC reported that following algorithm in the first-line metastatic and unresectable setting should be: Patients who are not able to tolerate ipilimumab-nivolumab or who would be treated with a single-drug PD-1 inhibitor would be suitable for receiving the drug under review in the first-line metastatic or unresectable setting.

For patients pretreated with ipilimumab-nivolumab, ipilimumab alone, or a PD-1 inhibitor alone: Patients who failed immunotherapy in the second line or beyond setting would also be suitable for this treatment.

In patients who are BRAF-negative:

• If treatment with a PD-1 inhibitor failed, then ipilimumab would be next, followed by the drug under review.

• If treatment with ipilimumab-nivolumab failed, then the patient can receive the drug under review.

In patients who are BRAF-positive:

• If treated with PD-1 with or without cytotoxic CTLA-4 immunotherapy, the patient could then receive a BRAF and MEK inhibitor. The next line could be ipilimumab alone (if not previously treated with ipilimumab) in combination with PD-1 or the drug under review, which could also be used following all prior therapies (PD-1, CTLA-4, BRAF and MEK inhibitors).

According to the OH-CCO’s DAC, a clinically meaningful response would be improved survival and reduction in the frequency and/or severity of symptoms. Treatment response will be routinely assessed clinically, and by CT and/or PET scans approximately every 3 months. The DAC mentioned that the most likely reason to discontinue treatment would be confirmed disease progression and/or unmanageable toxicities. The DAC also noted that the drug under review should be administered in an outpatient cancer clinic and prescribed by an oncologist.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ICI = Immune checkpoint inhibitor; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; FDC = fixed-dose combination; LAG-3 = lymphocyte activation gene 3; MEK = mitogen-activated protein kinase enzyme; PD-1 = programmed cell death protein; PD-L1 = programmed cell death ligand 1.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of nivolumab-relatlimab FDC (nivolumab 12 mg/mL and relatlimab 4 mg/mL) in a single-dose vial FDC), administered as an IV infusion over 30 minutes, in the treatment of adult and pediatric patients (aged 12 years and older and weighing at least 40 kg) with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma. This review focuses on comparing nivolumab-relatlimab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of nivolumab-relatlimab is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The third section includes indirect evidence from the sponsor. Of note, no evidence for long-term extension studies (second section) or studies addressing gaps in the systematic review evidence (fourth section) were submitted by the sponsor for this review.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 1 pivotal and ongoing RCT (multinational, phase II and II RELATIVITY-047) identified in the systematic review

• 2 indirect treatment comparisons.

Systematic Review

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the CADTH review team.

Description of Studies

Key characteristics of the included study are summarized in Table 6. A summary of its design is shown in Figure 1. The RELATIVITY-047 trial is a multinational, phase II and III, randomized, double-blind, and ongoing study of the efficacy and safety of nivolumab-relatlimab FDC relative to nivolumab monotherapy when administered as a first-line therapy in patients with previously untreated, unresectable, or metastatic melanoma. Interactive response technology (IRT) was used to randomize patients. The sponsor (Bristol Myers Squibb [BMS]), patients, investigators, and site staff were blinded to the assignment. The study was conducted in 114 sites across 25 countries, including 4 Canadian sites (Table 10).^41,56 No adolescent patients (aged ≥ 12 to < 18 years) were enrolled. The median age was 63 years (range = 20 to 94). The majority (N = 655; 91.7%) of patients had metastatic stage IV melanoma at study entry. The median duration from diagnosis to study treatment was 1.26 years. A total of 62 patients (8.7%) had received previous adjuvant or neoadjuvant treatment. A total of 275 patients (38.5%) were BRAF-positive. A total of 16 patients (2.2%) from Canada and 63 patients (8.8%) from the US were included in the trial.

Table 6: Details of Study Included in the Systematic Review

AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; BMS = Bristol Myers Squibb; BRAF = B-Raf kinase protein; CTLA = cytotoxic T-lymphocyte-associated protein 4; DBL = database lock; DoR = duration of response; DoR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FACIT-M GP5 = Functional Assessment of Chronic Illness Therapy Item GP5; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; FDC = fixed-dose combination; IMAE = immune-mediated adverse event; MEK = mitogen-activated protein kinase enzyme; OESI = other event of special interest; ORR = overall response rate; OS = overall survival; PD-1 = programmed cell death 1 protein; PD-L1 = programmed cell death ligand 1; PD-L2 = programmed cell death ligand 2; PFS = progression-free survival; PFS2 = progression-free survival after the next line of subsequent therapy; RCT = randomized controlled trial; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; TTR = time to response; ULN = upper limit of normal; vs. = versus; WPAI:GH = Work Productivity and Activity Impairment Questionnaire: General Health.

^aThe final PFS analysis was conducted after a median follow-up of 13.2 months (March 9, 2021, DBL), with supportive data presented after a longer median follow-up of 25.3 months (October 27, 2022, DBL).

^bThe final analysis of both secondary end points of OS and ORR was conducted after a median follow-up of 19.3 months (October 28, 2021, DBL), with supportive data presented after a longer median follow-up of 25.3 months (October 27, 2022, DBL).

^cSafety data are based on the most recent data cut, representing a median follow-up of 25.3 months (October 27, 2022, DBL).

^dThe list of tertiary and/or exploratory end points in Table 10 (T13) is comprehensive. Results are only reported in this submission for DoR and TTR; subgroup analyses of PFS, OS, and ORR; PFS2; FACT-M and the FACIT GP5 individual item; EQ-5D-3L visual analogue scale and utility index scores; and the WPAI:GH:

• DOR, TTR, and PFS2 results are based on a median follow-up of 25.3 months (October 27, 2022, DBL).

• Subgroup analyses of the primary and secondary end points are presented based on their respective final analysis time points, with supportive data presented after a longer median follow-up of 25.3 months (October 27, 2022, DBL).

• Results for patient-reported outcome measures (FACT-M, EQ-5D-3L, and WPAI:GH) are based on a median follow-up of 19.3 months (October 28, 2021, DBL), which reflects the most recent assessment time point.

^ePrimary and secondary end points were tested using a statistical hierarchical procedure with group sequential testing, starting with PFS, followed by OS and ORR.

Sources: BMS (2021) Primary Clinical Study Report,⁴¹ BMS (2022), Addendum 01 – Primary Clinical Study Report,⁶¹ BMS (2023), Addendum 02 – Primary Clinical Study Report,⁶² BMS (2020), Clinical Protocol,⁶³ BMS (2022), Statistical Analysis Plan,⁴² Clinicaltrials.gov (2022),⁵⁶ Tawbi et al. (2022)⁵⁷ Schadendorf et al. (2023).⁵⁸

The primary outcome was PFS with OS and ORR as secondary outcomes. Tertiary and/or exploratory outcomes were DoR, TTR, and HRQoL measurements (i.e., FACT-M and EQ-5D-3L). Adults and adolescents aged 12 years and older were eligible for enrolment. A total of 714 patients were randomized 1:1 to receive nivolumab-relatlimab (N = 355) or nivolumab monotherapy (N = 359). All randomized patients received at least 1 dose of the study drug. Randomization was stratified according to the following factors:

• LAG-3 expression status (≥ 1% versus < 1%)

• Tumour cell PD-L1 expression status (≥ 1% versus < 1%)

• BRAF V600 mutation status (mutation-positive versus wild-type)

• American Joint Committee on Cancer (AJCC) 8th edition metastatic (M) stage.

The RELATIVITY-047 trial was designed as an adaptive and seamless phase II and III trial. A prespecified interim analysis (IA) of PFS was planned after a minimum of 400 patients were enrolled into phase II, or after at least 150 PFS events were observed by BICR, whichever came first. The IA of PFS at phase II was used to decide whether the trial should proceed to phase III or complete the study in phase II. Enrolment was paused until the final phase II analysis was conducted. On August 26, 2019, the IA of PFS in phase II met the prespecified threshold of an HR equal to or lower than 0.8, and therefore the study proceeded seamlessly to phase III enrolment in a double-blinded manner. Both the sponsor and site investigators were blinded to the results of the IA of PFS. In addition, an initial safety lead-in was performed on the first 18 patients randomized to assess potential grade 3 or 4 infusion reactions with nivolumab-relatlimab. This followed a 6 + 6 + 6 design, with 6 patients treated in each sequential set. As no safety risks were identified, enrolment in phase II continued as planned. Patients enrolled in phase II of the study continued on treatment and are part of the phase III analyses. The study design is presented in Figure 1. Results presented in this submission reflect phase III of the RELATIVITY-047 trial, which is still ongoing.

Figure 1: Study Design of RELATIVITY-047

AE = adverse event; AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; BMS = Bristol Myers Squibb; DoR = duration of response; BRAF = B-Raf kinase protein; EQ VAS = EQ visual analogue scale; FACIT-M GP5 = Functional Assessment of Chronic Illness Therapy Item GP5; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; FDC = fixed-dose combination; HRQoL = health-related quality of life; IA = interim analysis; IMAE = immune-mediated adverse event; incl = including; LAG-3 = lymphocyte activation gene 3; M = presence of metastases; OESI = other event of special interest; ORR = overall response rate; OS = overall survival; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival; PFS2 = progression-free survival after the next line of subsequent therapy; Q4W = every 4 weeks; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; TTR = time to response; Tx = treatment; WPAI:GH = Work Productivity and Activity Impairment Questionnaire: General Health.

Notes: LAG-3 expression on immune cells (1%) determined by analytically validated immunohistochemistry assay (LabCorp Clinical Trials, Research Triangle Park, NC, US). PD-L1 expression on tumour cells (1%) determined by validated Agilent/Dako PD-L1 immunohistochemistry 28-8 pharmDx test (Agilent, Santa Clara, CA, US). The first tumour assessment (RECIST 1.1) was performed 12 weeks after randomization, every 8 weeks up to 52 weeks, and then every 12 weeks. HRQoL measures included FACT-M and the FACIT GP5 item, EQ VAS and utility index scores, and WPAI:GH.

Sources: BMS (2021), Primary Clinical Study Report⁴¹ and BMS (2020), Clinical Protocol.⁶³

Populations

Inclusion and Exclusion Criteria

Patients were eligible for inclusion if they were aged 12 years or older with histologically confirmed, previously untreated, unresectable stage III or IV melanoma. Patients must have had measurable disease according to RECIST 1.1, expression of LAG-3 and PD-L1 that could be evaluated in tumour tissue, and an ECOG PS of 0 or 1. Patients must not have had prior systemic anticancer therapy for unresectable or metastatic melanoma, although they may have received prior neoadjuvant or adjuvant treatment if the final dose of therapy was administered at least 6 months before disease recurrence for anti–PD-1, anti–CTLA-4, or anti-BRAF or anti-MEK therapies, and at least 6 weeks before randomization for interferon. Patients were excluded if they had active brain metastases or leptomeningeal metastases, uveal melanoma, or an active, known, or suspected autoimmune disease (Table 6 provides more detail).

Interventions

Patients were randomized 1:1 to receive either nivolumab (480 mg) and relatlimab (160 mg) FDC or nivolumab monotherapy (480 mg). Both treatments were administered as an IV infusion every 4 weeks over 60 minutes in a clinic or hospital setting. Adolescents weighing less than 40 kg were to receive weight-based therapy (relatlimab 2 mg/kg and nivolumab 6 mg/kg), but no adolescents were enrolled in the study. Treatment continued until disease progression, treatment discontinuation, unacceptable toxicity, withdrawal of consent, or end of study.

Dose reductions were not permitted for either treatment group. Administration of study treatment could be delayed but not skipped.

Outcomes

A list of efficacy outcomes assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized outcomes are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review by the clinical experts consulted by CADTH and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected outcomes that were considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of outcomes in consultation with members of the expert committee. All summarized efficacy outcomes were assessed using GRADE. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Table 7: Outcomes Summarized From the Study Included in the Systematic Review

BICR = blinded independent central review; BMS = Bristol Myers Squibb; DBL = database lock; DoR = duration of response; FACIT GP5 = Functional Assessment of Chronic Illness Therapy Item GP5; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; HRQoL = health-related quality of life; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; TTR = time to response; VAS = visual analogue scale.

^aA statistical hierarchical testing procedure was used to control for type I error in the primary and secondary end points. The hierarchy started with the primary analysis of PFS. If this was statistically significant at the applicable 2-sided alpha level (0.05), then the secondary end points would be tested in the order of OS followed by ORR. Other end points were not formally tested. Due to the position of ORR in the statistical testing hierarchy (after OS), ORR according to BICR was not formally tested for statistical significance as there was no significant difference in OS between the 2 treatment groups in the final OS analysis.

^bSafety and tertiary/exploratory end points were assessed using descriptive analyses.

^cThe most recent time point for analysis of HRQoL measures (exploratory) was the October 28, 2021, DBL. HRQoL was not assessed at the October 27, 2022, DBL.

Sources: BMS (2021), Primary Clinical Study Report;⁴¹ BMS (2022), Addendum 01 – Primary Clinical Study Report,⁶¹ BMS (2023), Addendum 02 – Primary Clinical Study Report,⁶² BMS (2022), Statistical Analysis Plan, and sponsor’s summary of clinical evidence.⁴²

Progression-Free Survival

The primary end point was PFS as assessed by BICR using the RECIST 1.1 criteria with modifications by BMS, as presented in Table 9). Two definitions were used to assess PFS. The primary definition of PFS accounted for subsequent therapy (PFS truncated at subsequent therapy) by censoring at the last evaluable tumour assessment on or before the date of subsequent therapy. It was defined as the time between the date of randomization and the date of first documented tumour progression according to BICR, or death due to any cause, whichever occurred first. The secondary definition of PFS (intention-to-treat [ITT]) was irrespective of subsequent therapy and did not account for subsequent therapy. It was defined as the time between the date of randomization and the date of first documented tumour progression according to BICR, or death due to any cause, whichever occurred first.

Overall Survival

A secondary end point in the trial, OS was defined as the time between the date of randomization and the date of death due to any cause.

Overall Response Rate

The ORR was a secondary end point in the trial and was assessed by BICR and defined as the number of patients with a best overall response (BOR) of CR or partial response (PR) divided by the number of randomized patients in each treatment group (Table 9).⁶¹ As indicated previously, tumour assessments were conducted at 12 weeks, followed by every 8 weeks (through to week 52), and then every 12 weeks thereafter until disease progression or treatment discontinuation.

Tertiary and/or Exploratory End Points

While several tertiary and/or exploratory end points were assessed in the RELATIVITY-047 trial (Table 5), results presented in this submission focus on the key relevant exploratory end points of DoR, TTR, and HRQoL as assessed using the FACT-M and EQ-5D-3L.

Duration of Response

The DoR was defined as the time between the date of first response to the date of first documented tumour progression, as, assessed by BICR using RECIST 1.1 or death due to any cause, whichever occurred first.

The TTR was defined as the time from randomization to the date of the first documented response (CR or PR), assessed by BICR.

The DoR and TTR were only evaluated in responders (CR or PR).

Health-Related Quality of Life

The FACT-M and EQ-5D-3L (patient-reported outcomes) are validated instruments to assess the impact of treatment on HRQoL. Patient-reported outcome measures were assessed on day 1 of each cycle during the study, with 1 cycle lasting 4 weeks.

EQ-5D-3L

The EQ-5D-3L measure assessed patient-reported overall health status and consisted of a utility index score and the EQ VAS. The EQ-5D-3L descriptive system involves 5 domains (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression), each with 3 levels (no problems, some problems, and severe problems). In the RELATIVITY-047 trial, utility index scores were calculated from self-reported health states based on a UK set of population-based preference weights; the scoring algorithm used was based on the UK MVH-A1 time trade-off value set.⁴²

The EQ VAS assessed general health on a vertical scale, with scores ranging from 0 (worst health imaginable) to 100 (best health imaginable).^42,64 The MID for the EQ-5D-3L was predefined as a change from baseline of 0.08 in health utility index scores, and a change of 7 for the EQ VAS.^42,65

FACT-M

The FACT-M is a patient-reported measure used to evaluate the effects of disease symptoms on patient function and well-being.⁶⁶ It includes 27 items from the Functional Assessment of Cancer Therapy–General (FACT-G) to assess physical well-being (PWB), social and/or family well-being (SWB), emotional well-being (EWB), and functional well-being (FWB). In addition, the FACT-M includes a 16-item disease-specific melanoma subscale (MS) and an 8-item melanoma surgery scale.⁴² Each item on the FACT-M is rated on a 5-point scale ranging from 0 (not at all) to 4 (very much).⁴² The FACT-G total score is generated by combining scores for the PWB, FWB, SWB, and EWB subscales, which reflects general quality of life. The FACT-M total score is generated by combining FACT-G and MS scores and provides a composite measure of general and targeted HRQoL. Scores are scaled so that higher scores indicate better functioning and lower symptom burden.⁴² The MID for the FACT-M 16-item MS has been estimated as a change of 2 to 4 points.⁶⁷ In the RELATIVITY-047 trial, the midpoint of the range reported in the literature was used to define the MID (change ≥ 3 points). This has been applied in previous melanoma clinical trials.⁶⁸ Using this approach, the MID for the FACT-M subscales was 5 for FACT-G and FACT-M total scores, 7 for trial outcome index, 2.5 for PWB and FWB, 2 for EWB, 3 for MS, and 1.5 for the melanoma surgery scale.^41,67 The FACT scale is an acceptable indicator of patient HRQoL if the overall item response rate is greater than 80%.⁴²

Safety

Safety assessments included the rate of AEs, SAEs, select AEs, AEs leading to study treatment discontinuation, immune-mediated adverse events (IMAEs), other events of special interest (OESIs), abnormalities in clinical laboratory assessments, and death.⁴¹ IMAEs were assessed to further evaluate AEs of clinical interest.⁴² They were defined as specific events or groups of preferred terms describing specific events and considered by the investigator as being potentially immune-mediated that met the following criteria:⁴² occurred within 100 days of the last dose; regardless of causality; treated with immune-modulating medication, and had no clear alternate etiology or an immune-mediated component. OESIs comprised a list of preferred terms grouped by specific category; for example, a myocarditis event and troponin elevation.⁴²

Table 8: Summary of Outcome Measures and Their Measurement Properties

BMS = Bristol Myers Squibb; EWB = emotional well-being; FACT-G = Functional Assessment of Cancer Therapy–General; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; FWB = functional well-being; HRQoL = health-related quality of life; MID = minimal important difference; MS = melanoma subscale; MSS = melanoma surgery scale; PS = performance status; PWB = physical well-being; SWB = social well-being; VAS = visual analogue scale.

Sources: Cormier et al. (2008);⁶⁶ BMS (2022), Statistical Analysis Plan;⁴² and The EuroQol Group (1990).⁶⁴

Table 9: Modified RECIST 1.1 for Evaluation of Target Lesions

BMS = Bristol Myers Squibb; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1.

Source: BMS (2020), Clinical Protocol.⁶³

Statistical Analysis

A summary of the statistical analyses of the outcomes reported in this submission is provided in Table 13.

Primary Outcomes: Progression-Free Survival

Sample Size and Power Calculation

The study sample size for the RELATIVITY-047 trial was based on the primary outcome of PFS according to BICR for the phase II or III part of the study.⁴² As the IA of PFS at phase II met the prespecified HR threshold and the study transitioned to phase III, the sample-size justification was based on the phase III part of the study. The number of events required was simulated based on results from the CheckMate 067 (CA209067) study, with an estimated median PFS of 6.9 months for nivolumab monotherapy and 11.8 months for nivolumab-relatlimab, incorporating 35% of patients with durable response in the combined groups, and a piecewise HR, resulting in an effective HR of approximately 0.73.⁴² At least 365 PFS events were required to ensure approximately 85% power to detect an HR of 0.73, with an overall type I error of 0.05. The target HR was obtained via simulation modelling.⁴² The planned sample size for the phase III study was 700 patients, randomized to the 2 groups in a 1:1 ratio. This population comprised the phase II patient population plus enrolment of an additional 300 patients.⁴² The final analysis of PFS was planned to occur when 365 participants had a PFS event. Based on an anticipated screen failure rate of 30%, approximately 1,000 patients were required to be screened to randomize 700 patients meeting the eligibility criteria.⁴²

Statistical Test or Model

The schedule of analyses of the primary end point and secondary outcomes are presented in Table 10.

The prespecified final analysis of the primary end point of PFS was conducted after a median follow-up of 13.2 months (March 9, 2021, database lock [DBL]). The prespecified final analysis of the secondary end points of OS and ORR were conducted after a median follow-up of 19.3 months (October 28, 2021, DBL).^41,61 Updated efficacy and safety data are available after an additional 12 months of follow-up from the final OS and ORR analysis (October 27, 2022, DBL). Results from this most recent data cut are descriptive only and reflect a median follow-up of 25.3 months.⁶² The main results presented for the primary and secondary end points, as well as respective subgroup analyses, focus on the final analysis time points as prespecified in the statistical hierarchy (based on the March 9, 2021, DBL and October 28, 2021, DBL,⁶¹ respectively). Results for exploratory and/or descriptive end points of DoR, TTR, and safety are based on the most recent October 2022 DBL, reflecting the longest duration of follow-up.⁶² Results for exploratory HRQoL measures are based on the October 2021 DBL, which is the latest available data cut-off point (HRQoL was not assessed at the October 2022 DBL).⁶¹ The interim PFS analysis to determine whether the study continued onto phase III was performed once approximately 400 randomized patients had been followed up for a minimum of 12 weeks (or at least 150 PFS events according to BICR were observed).⁴² An administrative alpha penalty of 0.001 was used for the IA of PFS as the prespecified threshold was met and the study proceeded to phase III. The final PFS analysis was performed when at least 365 PFS events occurred to ensure approximately 85% power to detect an HR of 0.73 with an overall type I error of 0.05; all of the remaining unspent alpha was used (Table 10). At the March 9, 2021, DBL (median follow-up of 13.2 months) the results of the final analysis of PFS were statistically significant, which led to unblinding at the patient level, as prespecified in the statistical analysis plan.

Table 10: Schedule of Analyses of the Primary Outcome (PFS According to BICR)

BMS = Bristol Myers Squibb; BICR = blinded independent central review; HR = hazard ratio; PFS = progression-free survival.

^aNot formally tested (administrative alpha); had to pass this boundary for the study to continue to phase III.

Sources: BMS (2022), Statistical Analysis Plan and sponsor's summary of clinical evidence.⁴²

When a stratified analysis is specified, the following stratifications factors are used: PD-L1 expression (≥ 1% versus < 1% or nonquantifiable immune cell surface expression); LAG-3 expression: (≥ 1% versus < 1% or nonquantifiable immune cell surface expression) (from IRT); BRAF mutation status: mutation-positive versus wild-type (from IRT); and AJCC (8th edition) M stage: M0/M1any[0] versus M1any[1]) (from lab value and electronic case report form). Each of the 4 stratification factors has 2 levels, with 16 strata in total. When there are fewer than 10 patients in a stratum, or in the case of unexpected model convergence issues due to small strata with too small event numbers, stratification factors are removed 1 at a time from the model until convergence is achieved. The CIs for the reported efficacy end points were not adjusted for multiplicity.

Subgroup Analyses

Exploratory subgroup analyses were conducted for PFS, OS, and ORR according to BICR among all randomized patients to assess the consistency of treatment effect across patient subgroups. Analyses of median PFS across subgroups were based on the Kaplan-Meier product-limit method with 2-sided 95% CIs. Unstratified HRs were produced for OS with 95% CIs, and unweighted differences in ORR and corresponding 95% 2-sided CIs used the Newcombe method. Subgroup analyses were not calculated for categories with fewer than 10 patients per treatment group (i.e., there must have been more than 10 patients in each subgroup category for the analysis to be conducted). Figure 4 and Figure 6 describe the subgroup analyses performed.

The RELATIVITY-047 trial was designed to assess the benefit of nivolumab-relatlimab FDC in all populations and was not powered to formally compare outcomes by any subgroups. Subgroup analyses were exploratory and may be limited by small sample sizes.

Sensitivity Analyses

In addition, prespecified sensitivity analyses to assess the robustness of the primary PFS analysis were conducted, as follows: censoring for subsequent therapy, constant hazards assumption, crossover of treatment effect across strata, adjustment for potentially important covariates, censoring for 2 missing images in a row, any differences between stratification values in IRT versus Medidata Rave RTSM Agile Randomization and Trial Supply Management, and an unstratified analysis.

A sensitivity analysis was planned of patients with no relevant protocol deviations greater than 10% of patients had relevant protocol deviations. A sensitivity analysis was planned if 10% of all PFS events were due to COVID-19; patients with a COVID-19 PFS event (i.e., death) would be censored on the previous evaluable image.

The potential effect of missing data (images) was assessed by performing a PFS analysis accounting for 2 or more consecutively missing disease assessments before the PFS event. Patients with 2 or more consecutive missing disease assessments were censored at the last disease assessment date before the 2 missing assessments.

Overall Survival

The analysis scheduled for OS is presented in Table 11. OS, the first key secondary end point in the hierarchical testing procedure, was formally assessed using a Lan-DeMets alpha-spending function with the O’Brien-Fleming type of boundary in East v6 for each end point. Initially, 2 interim analyses of OS were planned before the final analysis of OS. The first IA was performed by the data-monitoring committee at the time of the final PFS analysis, after 227 OS events (i.e., deaths) were observed (March 9, 2021, DBL). The first OS assessment was not statistically significant. However, it was decided that the second IA was no longer needed. The final analysis was conducted after approximately 300 OS events had occurred at the October 28, 2021, DBL (median follow-up of 19.3 months). The OS of nivolumab-relatlimab FDC versus nivolumab monotherapy at the first IA and final analysis was assessed using a 2-sided log-rank test, stratified by LAG-3 expression (≥ 1% versus < 1%), BRAF mutation status, and AJCC (8th edition) M stage. An O’Brien and Fleming alpha-spending function was used to determine the nominal significance levels for the interim and final OS analyses. In the final OS analysis, the O’Brien-Fleming boundary for significance was a P value less than 0.04302 (2-sided), with a cumulative design power of 69%, for a target HR of 0.75.

A sensitivity analysis was planned to assess the impact of COVID-19. This was to be performed if 10% of all OS events were due to COVID-19. Patients who died due to COVID-19 were censored on the start date of their COVID-19 AE.

The schedule of analyses for OS with the second IA removed is presented in Table 11.

Table 11: Schedule of Analyses of the Secondary End Point of Overall Survival (Without IA2)

BMS = Bristol Myers Squibb; HR = hazard ratio; IA2 = interim analysis 2; OS = overall survival; PFS = progression-free survival.

Sources: BMS (2022), Statistical Analysis Plan and sponsor's summary of clinical evidence.⁴²

Overall Response Rate

ORR was assessed as the second key secondary outcome. As the final analysis of OS was not statistically significant, ORR was not formally tested for statistical significance given its position in the hierarchical testing procedure. ORR was only considered mature once all patients had had the potential for 7 months of follow-up, which was the time of the third on-study scan. The prespecified final analysis of ORR was carried out at the same time of the OS final analysis at the October 28, 2021, DBL (median follow-up of 19.3 months). However, because OS was not statistically significant, ORR could not be formally tested, and results are reported descriptively. The number and percentage of patients in each category of BOR according to BICR (CR, PR, stable disease, progressive disease, or unable to determine) were presented by treatment group. Estimates of response rate, with an exact 2-sided 95% CI based on the Clopper and Pearson method were presented by group, and a 2-sided 95% CI was calculated for the OR and the difference in response rates between the nivolumab-relatlimab FDC and nivolumab monotherapy treatment groups.

Subgroup analyses of ORR reported unweighted differences in ORR between groups based on the same variables as in the PFS analysis.

Duration of Response and Time to Response

Analyses of DoR and TTR were not statistically powered and were reported using descriptive statistics. The DoR for each treatment group was estimated using the Kaplan-Meier product-limit method for patients achieving a PR or CR. Median DoR and 2-sided 95% CIs were calculated based on a log-log transformation method. Patients censored in the Kaplan-Meier analysis of DoR were categorized as: ongoing follow-up (current [last scan within adequate window versus cut-off date], not current); off-study (lost to follow-up, withdraw consent, never treated); and received subsequent anticancer therapy. The TTR was summarized in all responders who achieved a confirmed PR or CR using descriptive statistics. No censoring was applied. DoR and TTR results presented in this submission are based on the most recent DBL, conducted on October 27, 2022, reflecting a longer duration of treatment and follow-up (25.3 months).

Health-Related Quality of Life (Patient-Reported Outcomes)

HRQoL was evaluated before dosing in each 4-week treatment cycle using the EQ-5D-3L and FACT-M. Analyses were conducted in all randomized patients with a baseline assessment and at least 1 postbaseline assessment. Analyses were not statistically powered and were reported using descriptive statistics. For the EQ-5D-3L utility index scores, EQ VAS, and FACT-M total, the mean score and mean change from baseline at each assessment time point was summarized by treatment group using descriptive statistics (N, mean, standard deviation, 95% CI, median, 25th and 75th percentiles, minimum, and maximum). The change from baseline in each HRQoL score was analyzed at time points with 10 or more patients using a longitudinal mixed model for repeated measures, with randomization strata, treatment, visit, interaction of treatment, and visit as fixed effects, and baseline HRQoL score as a covariate.

Multiple-Testing Procedure

A statistical hierarchical procedure was used to control for type I error of end points in the phase III part of the RELATIVITY-047 trial. The primary analysis was for PFS, and if this was significantly superior for the comparison of nivolumab-relatlimab FDC versus nivolumab monotherapy, then the secondary end points of OS followed by ORR could be tested. Other end points were not formally tested. A hierarchical testing procedure was employed for the phase III study to control for type I errors across end points (Figure 2). The overall alpha for the phase III study was 0.05 (2-sided). If the results of the PFS and OS analyses were statistically significant, then the ORR between treatment groups was to be tested when it had matured, which was after all randomized patients had the potential for 7 months of follow-up. Other end points were not formally tested.

Figure 2: Phase III Hierarchical Procedure With Group Sequential Testing in All Randomized Patients (Original Plan)

BMS = Bristol Myers Squibb; FA = final analysis; IA = interim analysis; IA2 = interim analysis 2; ORR = overall response rate; OS = overall survival; PFS = progression-free survival.

Notes: The second OS interim analysis (OS IA2) was removed, and the final OS analysis (OS FA) was directly performed.

Sources: BMS (2022), Statistical Analysis Plan and sponsor's summary of clinical evidence.⁴²

Data Imputation Methods

The conventions used for imputing partial dates are presented in Table 12.

Table 12: Conventions Used for Imputing Partial Dates in Efficacy and Safety Analyses

AE = adverse event; BMS = Bristol Myers Squibb; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; PFS = progression-free survival.

^aProrating by subscale when data are missing is acceptable providing more than 50% of the items are answered. The Functional Assessment of Cancer Therapy scale is considered an acceptable indicator of patient quality of life if overall item response rate is greater than 80%.

Note: Appendix 2 of the BMS (2022) Statistical Analysis plan provides imputation algorithms for missing and partial radiotherapy and surgery dates.

Source: BMS (2022), Statistical Analysis Plan.⁴²

Table 13: Statistical Analysis of Efficacy Outcomes

AE = adverse event; AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; BMS = Bristol Myers Squibb; BOR = best overall response; CFB = change from baseline; CI = confidence interval; CR = complete response; DoR = duration of response; EQ VAS = visual analogue scale; FA = final analysis; FACT-M, = Functional Assessment of Cancer Therapy–Melanoma; HR = hazard ratio; HRQoL = health-related quality of life; IMAE = immune-mediated adverse event; IRT = interactive response technology; LAG-3 = lymphocyte activation gene 3; MedDRA v5.0 = Medical Dictionary for Regulatory Activities version 5.0; MID = minimal important difference; MS = melanoma scale; NA = not applicable; NCI-CTCAE v25.0 = National Cancer Institute Common Terminology Criteria for Adverse Events version 25.0; OESI = other event of special interest; ORR = overall response rate; OS = overall survival; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival; PR = partial response; PT = preferred term; RAVE = Medidata Rave RTSM Agile Randomization and Trial Supply Management;⁷⁰ SAE = serious adverse event; SOC = system organ class; TTR = time to response; UTD = unable to determine; vs. = versus.

^aPD-L1 was removed from the models as a stratification factor because there were fewer than 10 subjects in at least 1 of the 16 strata.

^bPrespecified in the statistical analysis plan based on Pickard et al. (2007).^42,65

^cPrespecified in the statistical analysis plan based on the midpoint of the range reported for MS in the literature.^42,67,68

Sources: BMS (2021), Primary Clinical Study Report;⁴¹ BMS (2021), Addendum 01 – Primary Clinical Study Report;⁶¹ Addendum 02 – Primary Clinical Study Report;⁶² BMS (2022), Statistical Analysis Plan; and sponsor's summary of clinical evidence.⁴²

Safety

Safety was assessed in all treated patients and reported by treatment group using descriptive statistics. Safety results presented in this submission are based on the most recent DBL, conducted on October 27, 2022, reflecting a longer duration of treatment and follow-up (25.3 months). Safety assessments included the frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study treatment, select AEs, IMAEs, OESIs, and clinical laboratory abnormalities. Analyses were conducted using the 30-day and/or 100-day safety window from the day of the last dose received and were categorized by system organ class and preferred term using the Medical Dictionary for Regulatory Activities (version 25.0). The severity of AEs was graded using the worst grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). The frequency, management, and time to resolution of IMAEs and select AEs were analyzed. Laboratory parameters, which included hematology, chemistry, electrolytes, liver function, thyroid function, and renal function, were summarized using the worst grade per the Common Terminology Criteria for Adverse Events and conducted using the 30-day safety window.

The analysis population for each laboratory test was limited to patients who underwent that laboratory test. AEs were considered to be drug-related where the relationship to the study drug was missing.

Analysis Populations

The main analysis population sets in RELATIVITY-047 are presented in Table 14. The analysis of the primary end point was performed on the randomized analysis set, i.e., the ITT analysis set. Safety analyses were performed on the treated population, which included all patients who received at least 1 dose of the double-blind study drug. Of note, the randomized (ITT) analysis set is the same as the treated analysis set, as all randomized patients received at least 1 dose of the study drug.

Table 14: Analysis Populations of RELATIVITY-047

BMS = Bristol Myers Squibb; IRT = interactive response technology; ITT = intention-to-treat; ORR = overall response rate; OS = overall survival; PFS = progression-free survival.

Sources: BMS (2022), Statistical Analysis Plan and sponsor's summary of clinical evidence.⁴²

Results

Patient Disposition

The disposition of patients in the RELATIVITY-047 trial is summarized in Table 15. Of the 1,281 patients enrolled (i.e., screened), a total of 714 patients (55.7%) were randomized to receive nivolumab-relatlimab FDC (N = 355) and monotherapy (N = 359). Although the reasons for discontinuation were not always similar between treatment groups, the overall proportion of patients discontinuing treatment was similar between the 2 treatment groups at all 3 DBLs for the final PFS analysis (median follow-up of 13.2 months), final OS and ORR analysis (median follow-up of 19.3 months), and at the updated descriptive analysis (median follow-up of 25.3 months). Disease progression was the most common reason for treatment discontinuation in both groups at all 3 DBL time points. A greater proportion of patients treated with nivolumab-relatlimab FDC discontinued treatment due to toxicity compared with those treated with nivolumab, although treatment discontinuation rates were largely similar between the 2 groups for each DBL.

Baseline Characteristics

Baseline characteristics of the all-randomized population of the RELATIVITY-047 trial are presented in Table 16. Overall, the enrolled patient population was generally representative of an untreated and unresectable or metastatic melanoma population, with a median age of 63 years and slightly more males than females (58.3% versus 41.7%, respectively). At baseline, the majority of patients had metastatic stage IV disease (AJCC, 8th edition) and 59% had disease with PD-L1 tumour cell expression levels of less than 1%. Although patients aged 12 years and older were eligible for enrolment, no adolescents (aged ≥ 12 to < 18 years) were enrolled.⁴¹ Baseline demographic and disease characteristics were well balanced between the nivolumab-relatlimab FDC and nivolumab monotherapy groups, including for key stratification factors of LAG-3 expression (< 1% versus ≥ 1%), PD-L1 expression (< 1% versus ≥ 1%), BRAF mutation status, and disease metastasis (M) stage based on the AJCC (8th edition).⁴¹ However, a higher proportion of patients in the nivolumab-relatlimab FDC group had M1c stage disease (42.5% versus 35.4%).⁴¹ A total of 60 patients had received adjuvant or neoadjuvant treatment before enrolment. Patients were not enrolled into the RELATIVITY-047 trial if they had received prior systemic anticancer therapy for unresectable or metastatic melanoma but could be enrolled if they had received prior adjuvant or neoadjuvant melanoma therapies, and all related AEs had either returned to baseline or stabilized.^41,63

Table 15: Summary of Patient Disposition From Studies Included in the Systematic Review

AE = adverse event; BMS = Bristol Myers Squibb; DBL = database lock; ITT = intention-to-treat; Nivo = nivolumab; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; Rela = relatlimab.

Sources: BMS (2021), Primary Clinical Study Report;⁴¹ BMS (2022), Addendum 01 – Primary Clinical Study Report;⁶¹ BMS (2023), Addendum 02 – Primary Clinical Study Report; and sponsor's summary of clinical evidence.⁶²

Table 16: Summary of Baseline Characteristics From Studies Included in the Systematic Review (ITT Population)

AJCC = American Joint Committee on Cancer; BMS = Bristol Myers Squibb; ECOG PS = European Cooperative Oncology Group Performance Status; ITT = intention-to-treat; LAG-3 = lymphocyte activation gene 3; PD-L1 = programmed cell death ligand 1.

Sources: BMS (2021), Primary Clinical Study Report and sponsor's summary of clinical evidence.⁴¹

The baseline characteristics outlined in Table 16 are limited to those that are most relevant to this review or were likely to affect the outcomes or interpretation of the study results.

Exposure to Study Treatments

At the 3 DBLs for the final PFS analysis, final OS and ORR analysis, and updated descriptive analysis, the majority of patients in both treatment groups (ranging from 83.6% to 87.9%) had received 90% or more of the intended dose intensity.^41,61,62 No meaningful difference was observed in the number of doses received between treatment groups at each of the 3 DBL time points (Table 17).^41,61,62 At the time of the DBL for the updated descriptive analysis (October 27, 2022,), the median duration of treatment was approximately 2 months longer with nivolumab-relatlimab FDC than with nivolumab monotherapy (8.31 versus 6.47 months).⁶²

Concomitant Medications and Co-Interventions

After a median follow-up of 25.3 months at the longer follow-up analysis, the majority of patients (97.9%) had received concomitant medication(s) during the treatment period.⁶² Concomitant medications used in 10% or greater of the total population are summarized in Table 18.

Patients were able to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids where there was minimal systemic absorption. Adrenal replacement steroid doses of greater than 10 mg of prednisone daily equivalent and a brief (< 3 week) course of corticosteroids to prevent or treat nonautoimmune conditions were also permitted.⁶³ In addition, palliative radiotherapy and palliative surgery were allowed if patients met certain criteria and following discussion with the BMS medical monitor or designee.⁶³ Immune-modulating concomitant medications recommended to treat certain AEs included corticosteroids, immune-modulating drugs, immunosuppressive drugs, and glucocorticoids.⁶² These were more frequently administered to manage AEs in patients receiving nivolumab-relatlimab FDC compared with nivolumab monotherapy (58.9% versus 44.0%).⁶² Surgical resection of solitary lesions was permitted only following consultation with the BMS medical monitor or designee and after the week 20 efficacy assessments.⁶³ immunosuppressive drugs (except those used to treat a drug-related AE) and immunosuppressive doses of systemic corticosteroids were prohibited during the study⁶³ (Table 18).

Subsequent Treatment

Approximately 46% of all randomized patients received subsequent anticancer therapy.⁶¹ The use of subsequent therapies was higher in the nivolumab group, including the use of PD-L1 or CTLA-4 inhibitors (15% and 18%, respectively), and targeted BRAF and MEK inhibitors (14% and 16%, respectively).⁶¹ The primary definition of PFS accounted for subsequent therapy by censoring at the last available tumour assessment on or before the date of subsequent therapy. Table 19 summarizes the subsequent anticancer therapies received by patients after a median follow-up of 25.3 months (on October 27, 2022, DBL).

Table 17: Summary of Patient Exposure From Study Included in the Systematic Review (All Treated Patients, ITT Population)

BMS = Bristol Myers Squibb; DBL = database lock; ITT = intention-to-treat; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; SD = standard deviation

Sources: BMS (2021), Primary Clinical Study Report;⁴¹ BMS (2022), Addendum 01 – Primary Clinical Study Report;⁶¹ BMS (2023), Addendum 02 – Primary Clinical Study Report; and sponsor's summary of clinical evidence.⁶²

Table 18: Concomitant Medication Use in 10% or More of the Total Population (All Treated Patients — Updated Descriptive Analysis)

BMS = Bristol Myers Squibb.

Notes: October 27, 2022, DBL median follow-up of 25.3 months.

Sources: BMS (2023), Addendum 02 – Primary Clinical Study Report Supplementary Table S.6.30 and sponsor's summary of clinical evidence.⁶²

Table 19: Subsequent Cancer Treatment (All Randomized Patients — Updated Descriptive Analysis)

BMS = Bristol Myers Squibb; BMS 986218 = fixed-dose combination of nivolumab and relatlimab; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; PD-1 = programmed cell death protein 1.

Note: October 27, 2022, DBL median follow-up of 25.3 months.

^aPatients may have received more than 1 type of subsequent therapy. Subsequent therapy was defined as therapy started on or after first dosing date (randomization date if the patient was never treated).

^bOn-treatment radiotherapy and surgery were allowed if protocol-defined criteria were met.

^cOther anticancer therapies included chemotherapies, cancer vaccines, imatinib, and investigational drugs.

Source: BMS (2023), Addendum 02 – Primary Clinical Study Report Supplementary Table.⁶²

Efficacy

Only those efficacy outcomes presented in the sponsor’s evidence summary and included in CADTH GRADE Summary of Findings table and some supportive outcomes are reported here.

Progression-Free Survival According to Blinded Independent Review Committee (Primary End Point)

The primary final analysis of PFS was conducted after a median follow-up of 13.2 months (March 9, 2021, DBL). At the final analysis, a total of 391 events (180 in the nivolumab-relatlimab FDC group [50.7%] and 211 in the nivolumab group [58.8%]) had occurred. The median PFS was 10.12 months in the nivolumab-relatlimab FDC group versus 4.63 months in the nivolumab monotherapy group in all randomized patients. The HR for nivolumab-relatlimab FDC versus nivolumab) was 0.75 (95% CI, 0.62 to 0.92; P = 0.0055) (Table 20 and Figure 3). The PFS rates at 6 months were 57.2% (95% CI, 51.5% to 62.5%) in the nivolumab-relatlimab FDC group and 44.1% (95% CI, 38.5% to 49.5%) in the nivolumab monotherapy group. The PFS rates at 12 months were 47.7% (95% CI, 41.8% to 53.2%) in the nivolumab-relatlimab FDC group and 36.0% (95% CI, 30.5% to 41.6%) in the nivolumab group. The PFS rates over the fixed-landmark time points up to 48 months are presented in Table 20 and Figure 3. No between-group differences for PFS rates at the fixed time points were provided by the sponsor.

Table 20: Final Analysis of PFS According to BICR (Primary Definition) in RELATIVITY-047 (All Randomized Patients)

BMS = Bristol Myers Squibb; CI = confidence interval; DBL = database lock; HR = hazard ratio; PFS = progression-free survival.

Note: March 9, 2021, DBL median follow-up of 13.2 months.

^aNo provision of P values for updated results on efficacy (PFS, OS, and ORR) for October 2022 DBL.⁷¹

^bBased on Kaplan-Meier estimates

Sources: BMS (2021), Primary Clinical Study Report109;⁴¹ with additional data provided by the sponsor on September 11, 2023, and sponsor’s summary of clinical evidence.⁷¹

As shown in Figure 3, separation of the Kaplan-Meier curves occurred at approximately 3 months and remained separated over the course of follow-up.⁴¹ Similar PFS results were observed in the updated descriptive analysis conducted at the October 27, 2022, DBL after a longer median follow-up of 25.3 months. The median PFS with nivolumab-relatlimab FDC was 10.18 months versus 4.63 months with nivolumab monotherapy, representing a prolongation of PFS of 5.6 months (HR 0.81; 95% CI, 0.67 to 0.97) after a longer median follow-up of 25.3 months.⁶²

Nivolumab-relatlimab FDC also resulted in a significant improvement in median PFS compared with nivolumab monotherapy based on the secondary definition of PFS (without censoring for subsequent therapy).⁴¹ At the final analysis (March 9, 2021, DBL), PFS results using the secondary definition were similar to those reported for the primary definition (HR = 0.76; 95% CI, 0.63 to 0.93; P = 0.0055).⁴¹

Progression-Free Subgroup Analysis

The PFS benefit of nivolumab-relatlimab FDC versus nivolumab monotherapy across key subgroups in exploratory prespecified subgroup analyses was largely consistent with that observed in the overall population (except at the ≥ 10% threshold) at the final PFS analysis (March 9, 2021, DBL median of 13.2 months follow-up) (Figure 4).⁴¹ In addition, PFS outcomes across subgroups remained consistent with those observed in the primary analysis after a longer median follow-up of 25.3 months at the October 27, 2022, DBL⁶² (data not presented in the sponsor’s evidence summary).

Progression-Free Sensitivity Analyses

Sensitivity analyses showed that the primary analysis of PFS according to BICR (median follow-up of 13.2 month) was also robust under the assumption that PFS according to BICR irrespective of subsequent therapy was similar to the primary analysis,⁴¹ indicating results were robust to the adjustment for subsequent therapy. The proportional hazards assumption was tested by the addition of a time-dependent covariate, defined by treatment-by-time interaction, to the stratified Cox regression model. A 2-sided Wald chi-square P value of less than 0.1 may indicate a potential nonconstant treatment effect. The P value in this analysis was 0.1497, indicating no evidence of a nonconstant hazard. There was no crossover of treatment effect between strata for PFS according to BICR (using the Gail and Simon test). Results were consistent with those of the primary analysis after adjusting for baseline covariates on multivariate analysis (LDH, age, sex, ECOG PS, and brain metastases). Missing data (2 consecutive missing disease assessment imaging sessions) did not affect the results; results from an unstratified analysis of PFS were consistent with the primary analysis. At the time of the final PFS analysis, the number of relevant protocol deviations was low (< 3% of the randomized patient population) and balanced between groups, with the most common deviations related to the timing of screening imaging and prohibited prior systemic therapy. As there were no on-treatment relevant protocol deviations, protocol deviations did not affect the interpretation of results, and COVID-19 did not affect the overall quality or outcome of study results.

Figure 3: Kaplan-Meier Analysis of PFS According to BICR (Primary Definition) — All Randomized Patients

BMS = Bristol Myers Squibb; AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival.

Notes: The statistical model to estimate HR and P values was a stratified Cox proportional hazard model and stratified log-rank test. Stratified by LAG-3 (≥ 1% versus < 1%), BRAF mutation status (mutation-positive versus wild-type), AJCC M stage (M0/M1any[0] versus M1any[1]). PD-L1 was removed from stratification because it led to subgroups with fewer than 10 patients. Symbols represent censored observations. The March 9, 2021, DBL median follow-up was 13.2 months.

Sources: BMS 2021, Primary Clinical Study Report and sponsor’s summary of clinical evidence.⁴¹

Figure 4: Forest Plot of Treatment Effect on PFS According to BICR (Primary Definition) in Predefined Subgroups (All Randomized Patients)

BMS = Bristol Myers Squibb; AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; CI = confidence interval; DBL = database lock; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HR = hazard ratio; IRT = interactive response technology; LAG-3 = lymphocyte activation gene 3; LDH = lactate dehydrogenase; M = metastasis stage; mPFS = median progression-free survival; N.A. = not available; N.R. = not reported; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival; Q = quarter; ULN = upper limit of normal.

Notes: HR and median (displayed as N.R.) are not computed for subset category with less than 10 patients per treatment group. PD-L1 data were from LabCorp LA, LAG-3 and BRAF mutation status data were from IRT, and AJCC M-stage data were from Medidata Rave RTSM Agile Randomization and Trial Supply Management and laboratory values. N.A: not available (i.e., not reached), median or limit of CI not estimable. March 9, 2021, DBL median follow-up of 13.2 months.

Sources: BMS (2021), Primary Clinical Study Report and sponsor’s summary of clinical evidence.⁴¹

Overall Survival

The primary final analysis of OS was conducted after a median follow-up of 19.3 months (October 28, 2021, DBL). In the final analysis of OS, a total of 297 events (137 in the nivolumab-relatlimab FDC group [38.6%] and 160 in the nivolumab group [44.6%]) had occurred. The median OS was not reached (95% CI, 34.20 to not reached) in the nivolumab-relatlimab FDC group versus 34.10 months (95% CI, 25.23 to not reached) in the nivolumab monotherapy group in all randomized patients. The HR for nivolumab-relatlimab FDC versus nivolumab was 0.80 (95% CI, 0.64 to 1.01; P = 0.0593) (Table 21 and Figure 5). The OS rates at 6 months were 86.7% (95% CI, 82.75% to 89.8) in the nivolumab-relatlimab FDC group and 84.6% (95% CI, 84.4% to 88.0%) in the nivolumab monotherapy group. The OS rates at 12 months were 77.0% (95% CI, 72.2% to 81.1%) in the nivolumab-relatlimab FDC group and 71.6% (95% CI, 66.6% to 76.0%) in the nivolumab group. The OS rates at 24 months were 63.7% (95% CI, 58.1% to 68.7%) in the nivolumab-relatlimab FDC group and 58.3% (95% CI, 52.7% to 63.4%) in the nivolumab group. The OS rates at 36 months were 55.8% (95% CI, 49.8% to 61.4%) in the nivolumab-relatlimab FDC group and 48.8% (95% CI, 42.7% to 54.7%) in the nivolumab group. The OS rates at 48 months were 51.5% (95% CI, 45.9% to 56.9%) in the nivolumab-relatlimab FDC group and 42.5% (95% CI, 36.4% to 48.5%) in the nivolumab group. The OS rates over the fixed-landmark time points up to 48 months are presented in Table 21 and Figure 5. No provision was made by the sponsor for between-group differences for OS rates at landmark time points.⁷¹

Table 21: Final Analysis of Overall Survival in RELATIVITY-047 (All Randomized Patients)

BMS = Bristol Myers Squibb; CI = confidence interval; DBL = database lock; HR = hazard ratio; NR = not reached, median or limit of CI not estimable; OS = overall survival.

Notes: The statistical model to estimate HR and P values was stratified Cox proportional hazard model and stratified log-rank test. The O’Brien-Fleming boundary for statistical significance of the OS final analysis was P < 0.04302 (2-sided) analyzed at 69% power; target HR, 0.75. October 28, 2021, DBL median follow-up of 19.3 months.

^aNo provision of P values for updated results on efficacy (progression-free survival, OS and overall response rate for October 2022 DBL.⁷¹

^bBased on Kaplan-Meier estimates.

Sources: BMS (2022), Addendum 01 – Primary Clinical Study Report;⁶¹ additional data provided by the sponsor on September 11, 2023 and sponsor’s summary of clinical evidence.⁷¹

At the time of the final OS analysis, 61.4% of patients in the nivolumab-relatlimab FDC group and 55.4% in the nivolumab monotherapy group were censored for OS. The proportion of those censored for being off-study was equally low. The biphasic censoring pattern for the OS Kaplan-Meier analysis (Figure 5) is reflective of the adaptive design of the study with 2 enrolment periods (phases II and III) in addition to a slowdown in enrolment due to the COVID-19 pandemic.

In addition, OS continued to favour nivolumab-relatlimab FDC in the updated descriptive analysis conducted at the October 27, 2022, DBL (median follow-up of 25.3 months).⁶² After a longer median follow-up of 25.3 months, OS results were consistent with that of the final analysis; median OS was not reached with nivolumab-relatlimab FDC versus 33.18 months with nivolumab monotherapy (HR = 0.82; 95% CI, 0.67 to 1.02)⁶² (Table 21).

Overall Survival Subgroup Analysis

The trend toward an OS benefit with nivolumab-relatlimab FDC versus nivolumab monotherapy demonstrated in the overall population was consistent across key subgroups in prespecified subgroup analyses at the final analysis of OS (October 28, 2021, DBL; median follow-up of 19.3 months). As observed with the PFS subgroup analyses, there was an OS benefit with nivolumab-relatlimab FDC across the majority of subgroups, which was seen regardless of PD-L1 expression (except at the ≥ 5% and ≥ 10% thresholds), LAG-3 expression, LDH level, AJCC metastatic stage, and BRAF mutation status (HR < 1; Figure 6).⁶¹ In addition, OS outcomes across subgroups remained consistent with those observed in the primary analysis after a longer median follow-up of 25.3 months at the October 27, 2022, DBL.⁶² An OS benefit was seen with nivolumab-relatlimab FDC versus nivolumab monotherapy across the majority of key demographic and clinical subgroups in exploratory unstratified analyses, including PD-L1 less than 1%, LAG-3 less than 1%, elevated LDH, BRAF mutation-positive, and high burden of metastases (M1c) subgroups⁶² (data not provided in the sponsor’s evidence summary).

Figure 5: Kaplan-Meier Analysis of Overall Survival (All Randomized Patients)

BMS = Bristol Myers Squibb; AJCC = American Joint Committee on Cancer; CI = confidence interval; DBL = database lock; HR = hazard ratio; LAG-3 = lymphocyte activation gene 3; NA = not available (not reached), median or limit of CI not estimable; PD-L1 = programmed cell death ligand 1.

Notes: The statistical model to estimate HR and P values was stratified by a Cox proportional hazards model and stratified log-rank test. Stratified by LAG-3 (≥ 1% versus < 1%), BRAF mutation status (mutation-positive versus wild-type), AJCC M stage (M0/M1any[0] versus M1any[1]). PD-L1 was removed from stratification because it led to subgroups with fewer than 10 patients. Symbols represent censored observations. The O’Brien-Fleming boundary for statistical significance of the OS final analysis was P < 0.04302 (2-sided) analyzed at 69% power; target HR = 0.75. October 28, 2021, DBL median follow-up of 19.3 months.

Sources: BMS (2022), Addendum 01 – Primary Clinical Study Report and sponsor’s summary of clinical evidence.⁶¹

Overall Survival Sensitivity Analysis

As the number of OS events due to COVID-19 or suspected COVID-19 infection was low in each group (3 patients in the nivolumab-relatlimab FDC group and 4 in the nivolumab monotherapy group), the prespecified sensitivity analysis that was planned if 10% of OS events were due to COVID-19 was not performed.⁶¹

Overall Response Rate

As the OS final analysis did not reach statistical significance, the significance of ORR (according to BICR) could not be formally tested due to its position in the statistical hierarchy (Figure 2).^42,61 Based on descriptive analyses, after a median follow-up of 19.3 months (October 28, 2021, DBL). The OR was 1.58 (95% CI, 1.16 to 2.15; descriptive P value = 0.004). A greater proportion of patients in the nivolumab-relatlimab FDC than in the nivolumab monotherapy group achieved a CR and PR and BOR (i.e., CR plus PR) (Table 22).⁶¹ The improvement in ORR with nivolumab-relatlimab FDC was observed as early as the first 12-week scan (30.1% versus 21.7%).⁶¹

Across prespecified patient subgroups, ORR favoured nivolumab-relatlimab FDC over nivolumab in subgroup analyses (ORR difference > 0%), regardless of PD-L1 and LAG-3 expression, LDH level, AJCC metastatic stage except M0, and BRAF mutation status.⁶¹ As the ORR could not be formally tested for significance, a summary forest plot of ORR across all subgroups is not presented. Consistent findings with a between-groups difference of 9.8% (43.7% versus 33.7%) were observed in the updated descriptive analysis after a median follow-up of 25.3 months (Table 22). The RELATIVITY-047 trial was not powered to formally assess outcomes by subgroups. Subgroup analyses were exploratory, not statistically powered, and limited by small sample sizes.

Table 22: ORR According to BICR in RELATIVITY-047 (All Randomized Patients)

BMS = Bristol Myers Squibb; AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; BOR = best overall response; CI = confidence interval; CR = complete response; DBL = database lock; OR = odds ratio; ORR = overall response rate; PR = partial response; vs. = versus.

Note: October 28, 2021, DBL median follow-up of 19.3 months.

^aCR + PR, CI based on the Clopper and Pearson method.

^bStrata-adjusted difference in ORR (nivolumab-relatlimab over nivolumab) was based on the Cochran-Mantel-Haenszel method of weighting.

^cStratified by LAG-3 (≥ 1% vs. < 1%), BRAF mutation status (mutation-positive vs. wild-type) AJCC M stage (M0/M1any[0] vs. M1any[1]).

^dNo provision of P value for the between-group difference of objective response rates and no effect measures for comparison of progressive disease rates in October 2021, DBL.

^eStrata-adjusted OR (nivolumab-relatlimab over nivolumab) conducted using the Mantel-Haenszel method.

^fTwo-sided P value from stratified Cochran-Mantel-Haenszel test (descriptive P value).

Sources: BMS (2022), Addendum 01 – Primary Clinical Study Report⁶¹ with additional data provided by the sponsor on September 11, 2023.⁷¹

Complete Response

A total of 16.3% of patients in the nivolumab-relatlimab FDC group and 14.2% of patients in the nivolumab monotherapy group experienced a CR. No formal statistically analysis or any descriptive analysis was carried out to report the between-group difference and 95% CI. No HR (95% CI) was provided (Table 22).

Progressive Disease

A total of 29.6% (95% CI, 24.9% to 34.6%) of patients in the nivolumab-relatlimab FDC group and 41.5% (95% CI, 36.4% to 46.8%) of patients in the nivolumab monotherapy group experienced a CR. No formal statistically analysis or any descriptive analysis was carried out to report the between-group difference and 95% CI. No HR (95% CI) was provided (Table 22).

Figure 6: Forest Plot of Treatment Effect on Overall Survival in Predefined Subgroups (All Randomized Patients)

BMS = Bristol Myers Squibb; AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; CI = confidence interval; DBL = database lock; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HR = hazard ratio; IRT = interactive response technology; LAG-3 = lymphocyte activation gene 3; LDH = lactate dehydrogenase; mOS = median overall survival; N.A. = not available, median or limit of CI not estimable; N.R. = not reported; OS = overall survival; PD-L1 = programmed cell death ligand 1; ULN = upper limit of normal.

Notes: HR and median (displayed as N.R.) are not computed for subset category with fewer than 10 patients per treatment group. October 28, 2021, DBL median follow-up of 19.3 months.

Sources: BMS (2022), Addendum 01 – Primary Clinical Study Report and sponsor's summary of clinical evidence.⁶¹

Duration of Responses and Time to Response

The DoR and TTR were assessed as exploratory end points. Results for median DoR and TTR are based on the updated descriptive analysis conducted at the October 27, 2022, DBL (median follow-up of 25.3 months).⁶² For all confirmed responders, median DoR was not reached in either treatment group. Over the duration of follow-up (median of 25.3 months), the proportion of responders at fixed-landmark time points was comparable between the nivolumab-relatlimab FDC and nivolumab groups (Table 23).⁶² The HR (nivolumab-relatlimab FDC versus nivolumab) was 1.07 (95% CI, 0.71 to 1.63). The median TTR (according to BICR) was the same in both groups (2.79 months each). No provision of effect measures for comparison of treatments with respect to TTR, and no difference of DoR rates at specific time points were provided by the sponsor.

Table 23: TTR and DoR According to BICR in RELATIVITY-047 (All Randomized Patients)

BMS = Bristol Myers Squibb; BICR = blinded independent central review; CI = confidence interval; DBL = database lock; DoR = duration of response; NA = not available (i.e., not reached; median or limit of CI not estimable); TTR = time to response.

Note: October 27, 2022, DBL median follow-up of 25.3 months.

^aNo provision of effect measures for comparison of treatments with respect to TTR, and no difference of DoR rates at specific fixed-landmark time points.⁷¹

^a“+” symbol indicates a censored value.

^bMedian computed using the Kaplan-Meier method.

^cBased on Kaplan-Meier estimates of the duration of response.

Sources: BMS (2023), Addendum 02 – Primary Clinical Study Report,⁶² with additional data provided by the sponsor on September 11, 2023.⁷¹

Health-Related Quality of Life

All HRQoL results, including FACT-M and EQ-5D-3L data from the RELATIVITY-047 trial were analyzed as exploratory end points and based on the October 28, 2021, DBL after a median follow-up of 19.3 months (Figure 8, Figure 9, and Table 24). HRQoL analyses were not updated at the subsequent DBL conducted on October 27, 2022 (median of 25.3 months follow-up). The findings of FACT-M, EQ-5D-3L utility index score and EQ VAS after a median follow-up of 19.3 months and their fixed-landmark time points (12 months and 24 months) are presented in Figure 8, Figure 9, and Table 24.

Functional Assessment of Cancer Therapy–Melanoma

In all randomized patients, HRQoL scores at baseline were similar to those of the US general population for the FACT-M (total and subscales) measures.⁴¹ Scores were also similar between treatment groups across patient-reported outcome measures.⁴¹ After a median follow-up of 19.3 months (October 28, 2021, DBL), the FACT-M total score in the nivolumab-relatlimab FDC group remained generally stable during the treatment period⁶¹ (Figure 8 and Table 24). HRQoL also remained stable in the nivolumab-relatlimab FDC group at time points beyond 128 weeks.⁶¹

Table 24: Summary of FACT-M, EQ-5D-3L, and EQ VAS Results From RELATIVITY-047

CI = confidence interval; EQ VAS = EQ visual analogue scale; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; LSM = least squares mean.

Sources: Clinical Study Report⁴¹ and additional data provided by the sponsor on September 11, 2023.⁷¹

Figure 7: Kaplan-Meier Analysis of DoR According to BICR (Randomized Patients, All Responders)

BICR = blinded independent review committee; BMS-72213 = fixed-dose combination of relatlimab and nivolumab; CI = confidence interval; N.A. = not available.

Figure 8: Change From Baseline in FACT-M Total Scores (All Randomized Patients)

BMS = Bristol Myers Squibb; DBL = database lock; FACT-M = Functional Assessment of Cancer Therapy–Melanoma; FU1 = follow-up 1; FU2 = follow-up 2; HRQoL = health-related quality of life; MID = minimal important difference.

Notes: Error bars represent standard error for the mean. The horizontal reference line indicates MID. Only time points where data were available for 10 or more patients in each treatment group are plotted. All randomized patients must have had an assessment at baseline and at least 1 postbaseline. Higher scores indicate better HRQoL. October 28, 2021, DBL median follow-up of 19.3 months.

Source: BMS (2022), Addendum 01 – Primary Clinical Study Report Supplementary Figure S.10.5.3.⁶¹

EQ-5D-3L Utility Index Scores and VAS

In all randomized patients, HRQoL scores at baseline were similar to those of the US general population for the EQ-5D-3L (utility index and EQ VAS).⁴¹ Scores were also similar between treatment groups across patient-report outcome measures.⁴¹ EQ-5D-3L utility index scores were maintained from baseline in the nivolumab-relatlimab FDC group, as well as in the nivolumab group. EQ VAS scores were likewise maintained from baseline with nivolumab-relatlimab FDC and improved at later visits, after week 124 (Figure 9 and Table 24).

Even after completing treatment, health utility index and EQ VAS scores were maintained in the nivolumab-relatlimab FDC group during follow-up and survival visits.⁶¹ A similar trend was observed in the nivolumab monotherapy group.

Figure 9: EQ-5D-3L Utility Index Score and EQ VAS (All Randomized Patients)

BMS = Bristol Myers Squibb; EQ VAS = EQ visual analogue scale; HRQoL = health-related quality of life; MID = minimal important difference.

Notes: Error bars represent standard error for the mean. The horizontal reference line indicates the MID. Only time points for which data are available for 10 or more patients in each treatment group are plotted. All randomized patients must have had an assessment at baseline and at least 1 postbaseline. Higher scores indicate better HRQoL for both measures. DBL: October 28, 2021 (median follow-up of 19.3 months).

Source: BMS (2022), Addendum 01 – Primary Clinical Study Report Supplementary Figures S.10.5.1 and S.10.5.2.⁶¹

Harms

Only harms identified in the sponsor’s evidence summary review protocol are reported here. Table 25 provides detailed harms data.

Table 25: Summary of Safety (All Treated Patients)

AE = adverse event; AESI = adverse event of special interest; BMS-986213 = fixed-dose combination of nivolumab and relatlimab; BMS = Bristol Myers Squibb; DBL = database lock; IMAE = immune-mediated adverse event; OESI = other event of special interest; SAE = serious adverse event.

Note: Safety data are based on the October 27, 2022, DBL after a median follow-up of 23.5 months, using the Medical Dictionary for Regulatory Activities version 25.0 and National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

^aThere were 3 additional deaths with a primary reason of “other” (i.e., deaths not due to study drug toxicity, disease progression, or unknown reasons) since the October 28, 2021, DBL (Addendum 01 Clinical Study Report 2): 2 in the BMS-986213 arm (verbatim terms: septic shock and lung infection, sepsis) and 1 in the nivolumab monotherapy group (verbatim terms: severe ketoacidosis and diabetes mellitus 2).

Sources: BMS (2023), Addendum 02 – Primary Clinical Study Report⁶² and BMS (2023), Addendum 02 – Primary Clinical Study Report supplementary tables.⁶²

Adverse Events

After a median follow-up of 25.3 months, 99.2% of patients in the nivolumab-relatlimab FDC group and 95.8% in the nivolumab monotherapy group experienced at least 1 AE (Table 25). The most common AEs (≥ 20% in either of the groups) were fatigue (30.7% in the nivolumab-relatlimab FDC and 20.9% in the nivolumab group), diarrhea (27.9% and 19.5%, respectively), pruritus (27.6% and 18.1%, respectively), arthralgia (26.2% and 17.5%), nausea (20.6% and 15.3%), and headache (20.0% and 12.3%).

The overall rate of grade 3 and 4 AEs was higher in the nivolumab-relatlimab FDC than the nivolumab monotherapy group (44.8% versus 36.8%, respectively)⁶² (Table 26).

Table 26: Summary of All-Cause AEs by GRADE in RELATIVITY-047 (20% or Greater — All Treated Patients)

AE = adverse event; BMS = Bristol Myers Squibb.

Notes: Safety data presented in the table are based on the Clinical Study Report 02 Addendum to the Primary Clinical Study Report at the October 27, 2022, DBL (follow-up of 25.3 months). The 10% or greater AE threshold used in the table is from that used in the product monograph (≥ 1% threshold), which also presents AE data for a slightly longer follow-up period compare with the Clinical Study Report. AE data at ≥ 1% or greater threshold is not reported in the Clinical Study Report; the higher 10% or greater threshold is presented based on data reported in the Clinical Study Report and for conciseness. Further details on the incidence of treatment-emergent AEs at a threshold of 5% or greater are provided in Table S.6.1.31.1 in the list of supplementary tables of the Clinical Study Report Addendum 02 of the Primary Clinical Study Report (October 27, 2022, DBL).⁶²

Source: BMS (2023), Addendum 02 – Primary Clinical Study Report.⁶²

Serious Adverse Events

After a longer median follow-up of 25.3 months, 38.9% of patients in the nivolumab-relatlimab FDC group and 33.1% in the nivolumab monotherapy group experienced at least 1 SAE (Table 25). The most common SAEs (≥ 1.1% in either of the groups) were malignant neoplasm progression (3.9% in the nivolumab-relatlimab FDC and 5.6% in the nivolumab group), diarrhea (1.4% and 0.6%, respectively), anemia (1.4% and 0.3%), and adrenal insufficiency (1.4% and 0%) (Table 25). The overall rate of grade 3 and 4 SAEs was higher in the nivolumab-relatlimab FDC group compared with the nivolumab monotherapy group (29.9% versus 21.7%)⁶² (Table 27).

Table 27: Summary of SAEs in RELATIVITY-047 (in More Than 1.1% of Patients — All Treated Patients)

BMS = Bristol Myers Squibb; SAE = serious adverse event.

Note: October 27, 2022, median follow-up of 25.3 months.

Source: BMS (2023), Addendum 02 – Primary Clinical Study Report Supplementary Table S.6.3.1.2.1.⁶²

Mortality

As of the October 27, 2022, DBL, after a median follow-up of 25.3 months, 45.6% of patients (N = 162) had died in the nivolumab-relatlimab FDC group and 51.5% (N = 185) had died in the nivolumab monotherapy group. Disease progression was the most common cause of death in both treatment groups⁶² (Table 28).

Deaths due to AEs occurred in 4 patients in the nivolumab-relatlimab group (1.1%) and 2 patients in the nivolumab monotherapy group (0.6%) (Table 28).

Table 28: Summary of Deaths in RELATIVITY-047 (All Treated Patients)

BMS = Bristol Myers Squibb; DBL = database lock.

Note: October 27, 2022, median follow-up of 25.3 months.

Source: BMS (2023), Addendum 02 – Primary Clinical Study Report.⁶²

Withdrawals due to Adverse Events

After a median follow-up of 25.3 months, AEs of any grade leading to study drug discontinuation occurred in 23.1% of patients in the nivolumab-relatlimab FDC group and in 15.9% of the nivolumab monotherapy group. Grade 3 or 4 AEs leading to discontinuation occurred in 13.0% of patients in the nivolumab-relatlimab FDC group and 8.4% in the nivolumab monotherapy group (Table 29). Except for malignant neoplasm progression, grade 3 or 4 AEs resulting in treatment discontinuation occurred in less than 1% of patients in both groups.⁶²

The most frequently reported (> 1% patients) AEs leading to treatment discontinuation in the nivolumab-relatlimab FDC group were malignant neoplasm progression (1.7%), pneumonitis (1.4%), myocarditis (1.4%), colitis (1.1%), and diarrhea (1.1%).⁶² In the nivolumab monotherapy group, the most common AE leading to discontinuation was malignant neoplasm progression (2.8%) (Table 29).⁶²

Dose reductions were not permitted with either study treatment. In both treatment groups, the majority (> 93%) of treated patients received all doses of the study drug without an infusion interruption. Overall, treatment interruption occurred in a minority of patients (approximately 6% in both groups)⁶² (Table 29).

Table 29: Adverse Events Leading to Treatment Discontinuation or Interruption in RELATIVITY-047 (All Treated Patients)

BMS = Bristol Myers Squibb.

Note: Database lock was on October 27, 2022; median follow-up of 25.3 months.

^aPercentages are calculated based on the total number of doses interrupted by group.

Sources: BMS (2023), Addendum 02 – Primary Clinical Study Report⁶² and BMS (2023), Addendum 02 – Primary Clinical Study Report supplementary table.⁶²

Notable Harms (Adverse Events of Special Interest)

The most common (> 5% in either of the treatment group) IMAEs reported in the nivolumab-relatlimab FDC group were hypothyroidism (18.3%), rash (12.7%), diarrhea and/or colitis (8.2%), hyperthyroidism (6.8%), hepatitis (6.2%), and adrenal insufficiency (5.6%). In the nivolumab monotherapy group, the previously noted most commonly reported IMAEs were hypothyroidism (14.2%), rash (8.6%), diarrhea and/or colitis (3.9%), hyperthyroidism (7.2%), hepatitis (3.3%) and adrenal insufficiency (1.1%).⁶² The majority of events in both groups were grade 1 or 2 in severity (Table 30).⁶² The sponsor indicated that no statistical comparisons between treatment groups were planned for any safety end point. Analyses are descriptive only and show the number of patients with events for both treatment groups. Due to different follow-up times for individual patients, the difference or OR based on incidences is not an appropriate effect measure to compare treatment groups for safety. For the notable harm (i.e., myocarditis), the number of patients with an event was low (< 10 patients per treatment group and in total), and even a descriptive analysis does not allow for any meaningful conclusions to be drawn.

Across OESIs, in the RELATIVITY-047 trial within 100 days of last dose, elevated troponin was the most commonly reported event in both treatment groups (12.7% in the nivolumab-relatlimab FDC group and 10.0% in the nivolumab group).⁶² The majority of events were grade 1 or 2 in severity and fewer than 1% of OESIs were grade 3 or 4 (Table 31).⁶² Among the notable harms, myocarditis and adrenal insufficiency are considered notable harms of particular interest. Myocarditis occurred infrequently and was reported in 1.7% of patients in the nivolumab-relatlimab FDC group and 0.6% in the nivolumab monotherapy group.⁶¹ Grade 3 or 4 myocarditis events occurred in 0.6% of patients in the nivolumab-relatlimab FDC group and no patients in the nivolumab monotherapy group (Table 31).⁶² Adrenal insufficiency occurred in 5.6% of patients the nivolumab-relatlimab FDC group and in 1.1% of the nivolumab monotherapy group (Table 30).

Critical Appraisal

Internal Validity

The included pivotal study (RELATIVITY-047) was a relatively well-designed, prospective, multicentre, double-blind, randomized, parallel, and active-controlled trial. The study used an appropriate randomization and allocation method (i.e., IRT). The primary analysis of PFS, OS, and ORR were based on an ITT analysis. No important protocol deviations were reported. Overall, most of the demographic and baseline characteristics were well balanced between groups (Table 25). The key effect or prognostic factors, such as an ECOG PS of 0 or 1, previous adjuvant and neoadjuvant therapy, and tumour cell surface biomarker expression (PD-L1 and LAG-3 inhibitors and BRAF mutation status) were well balanced between groups. The potential methodological limitations of the study are discussed in the following section.

Metastatic stage M1c accounted for a relatively high proportion of melanomas in the nivolumab-relatlimab FDC group (N = 151 [42.5%]) compared with the nivolumab monotherapy group (N = 127 [35.4%]); however, the clinical experts consulted for this review stated that minor between-group imbalances of metastatic stage M1c would have been unlikely to affect the comparative study results of the 2 groups.

Table 30: Summary of IMAEs in RELATIVITY-047 Within 100 Days of Last Dose (All Treated Patients)

AE = adverse event; BMS = Bristol Myers Squibb; CS = corticosteroid; IMAE = immune-mediated adverse event; IMM = immune-modulating medication.

Notes: IMAEs include AEs of any grade occurring in 1% or more of patients considered by investigators to be potentially immune-mediated that met the following criteria: occurred within 100 days of the last dose, regardless of causality, treated with immune-modulating medication with no clear alternate etiology, or had an immune-mediated component. October 27, 2022, median follow-up of 25.3 months.

^aBased on patients who experienced an IMAE.

Source: BMS (2023), Addendum 02 – Primary Clinical Study Report.⁶²

Table 31: Summary of OESIs (Greater Than 1%) in RELATIVITY-047 Within 100 Days of Last Dose (All Treated Patients With or Without Immune-Modulating Medication)

BMS = Bristol Myers Squibb; OESI = other event of special interest.

Note: October 27, 2022, median follow-up of 25.3 months.

Source: BMS (2023), Addendum 02 – Primary Clinical Study Report.⁴¹

Based on the study design, during the treatment phase, patients were prohibited from receiving additional concurrent anticancer therapies. Immune-modulating concomitant medications were recommended to treat certain AEs; these included corticosteroids, immune-modulating drugs, immunosuppressive drugs, and glucocorticoids. It was noted that they were more frequently administered to manage AEs in patients receiving nivolumab-relatlimab FDC compared with those receiving nivolumab monotherapy (58.9% versus 44.0%). In addition, palliative radiotherapy and palliative surgery were allowed if patients met certain criteria and following discussion with the BMS medical monitor or designee, but no detail information for palliative radiotherapy and palliative surgery use in each group was provided. The clinical experts CADTH consulted for this review indicated that the potential impact of minor imbalanced immune-modulating concomitant medications, palliative radiotherapy, and palliative surgery on the comparative efficacy between the treatment groups (nivolumab-relatlimab FDC versus nivolumab) would be negligible.

Subsequent systemic anticancer treatment (e.g., PD1 and/or PD-L1 inhibitors) may contribute to patients’ OS benefit in both groups. The impact of the subsequent systemic anticancer treatment on the comparative OS may introduce potential bias. However, the proportions of patients using the subsequent treatment in both groups were relatively comparable. It is therefore unlikely to have a substantial impact on the comparative OS findings observed in this study.

In terms of the OS assessment, OS was designed and assessed as a secondary outcome, and the study was not powered to assess OS between-group difference at the prespecified final analysis (after a median follow-up of 19. 3 months) and updated analysis (after a follow-up of 25.3 months). The efficacy on OS of nivolumab-relatlimab FDC compared with nivolumab therefore remains uncertain.

The statistical significance of ORR (according to BICR) could not be formally tested due to its position in the statistical hierarchy because the OS final analysis did not reach statistical significance. As a result, ORR, as well as CR and progressive disease (which were part of the overall response analysis), are based on only descriptive analyses after a median follow-up of 19.3 months. Only descriptive analyses without a between-group difference or HR were reported. Results for ORR, CR and progressive disease should be interpreted with caution.

The DoR and TTR were assessed as tertiary or exploratory outcomes but without a hierarchical testing procedure to control for type I error. Analyses of DoR and TTR were not statistically powered and were reported using descriptive statistics only. No between-group difference was reported for DoR or TTR, although an HR was reported for DoR; overall, the findings of DoR and TTR should be viewed as supportive evidence only.

Similarly, FACT-M and EQ-5D-3L were assessed as tertiary and/or exploratory outcomes but without hierarchical testing procedures to control for type I error. For these patient-reported HRQoL outcomes (FACT-M and EQ-5D-3L), a differential recall bias may have occurred, although the magnitude and direction of the impact of any recall bias on the patient-reported HRQoL outcomes is unknown. The HRQoL analyses were not statistically powered and were reported using descriptive statistics.⁴² Overall, the HRQoL findings should be viewed as supportive evidence only.

As the subgroup analysis were not part of the randomization scheme, imbalances in characteristics may bias the results observed between the subgroups. In addition, the subgroup analysis may be not powered to detect the between-group difference in each subgroup. The findings of the subgroup analysis should therefore be viewed as supportive evidence only.

Finally, 1 of the limitations of the RELATIVITY-047 trial is a lack of a comparison to current standard of care (i.e., dual-combination therapy and all available monotherapy except nivolumab). The efficacy and safety of nivolumab-relatlimab FDC compared with encorafenib-binimetinib, dabrafenib-trametinib, vemurafenib-cobimetinib, ipilimumab-nivolumab, ipilimumab, pembrolizumab, dabrafenib, and trametinib is unknown.

External Validity

Only 16 patients (2.2%) from Canada and 63 (8.8%) from the US were included in the trial. According to the clinical experts CADTH consulted for this review, the RELATIVITY-047 study population (i.e., adult patients with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma) is considered reflective of patients in Canada. There is no concern regarding the generalizing findings from the pivotal study to Canadian clinical settings. The following considerations are of importance regarding the external validity of the RELATIVITY-047 study.

It is uncertain whether the finding can be generalized to patients with CNS metastases or patients with ECOG PS higher than 1 as no such patients were included in the study. Only 17 patients with brain metastasis (2.4%) were included (1.7% and 3.1% in the nivolumab-relatlimab FDC and nivolumab monotherapy groups, respectively). Patients with active CNS metastases were excluded. The clinical experts CADTH consulted for this review indicated that excluding patients with active CNS metastases and an ECOG PS higher than 1 in clinical trial is a common and reasonable practice for observing favourable benefits, risk ratios, and safety profiles. While a higher ECOG PS (> 1) usually indicates more severe disease and likely a more unfavourable prognosis, the nivolumab-relatlimab FDC combination treatments could be extended to patients with an ECOG PS higher than 1. In terms of patients with CNS metastasis, the clinical experts CADTH consulted for this review indicated that additional studies are needed to understand the comparative efficacy of relatlimab-nivolumab versus nivolumab monotherapy in patients with CNS metastasis.

Patients with active, known, or suspected autoimmune disease were excluded. The clinical experts CADTH consulted for this review indicated that patients with autoimmune disorders should be considered for nivolumab-relatlimab FDC treatment at the discretion of the treating physician.

Finally, although the Health Canada indication for nivolumab-relatlimab FDC is for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma, no children aged 12 years or older but younger than 18 years were enrolled in the pivotal study, Therefore, the comparative efficacy and safety profile of nivolumab-relatlimab FDC versus nivolumab monotherapy in children is not available. Whether the findings from the pivotal study (RELATIVITY-047) can be generalized to adolescent patients (≥ 12 to < 18 years old) remains unknown. However, the Health Canada product monograph indicates that the use of nivolumab-relatlimab FDC in pediatric patients 12 years of age or older and weighing at least 40 kg is supported by predicted drug exposures at the recommended nivolumab-relatlimab FDC dose that are expected to result in safety and efficacy similar to that of adults. One clinical expert CADTH consulted for this review indicated that pediatric patients with unresectable or metastatic melanoma should be enrolled in clinical trials if available to assess the efficacy and safety profile of the nivolumab-relatlimab FDC treatment. The other clinical expert indicated that, because of the potential unfeasibility of the trials on the pediatric patients, use of nivolumab-relatlimab FDC in adolescents should be considered on a case-by-case basis, particularly if the body habitus is similar to that of an adult. The clinical expert noted that currently IO is given to the pediatric population, and it is well tolerated.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations. A final certainty rating was determined based on definitions established by the GRADE Working Group (Balshem et al. [2011] and Santesso et al. [2020]):^43,44

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. For this review, PFS, OS, CR, progressive disease, DoR, TTR, and notable harms use the null as a threshold.

The target of the certainty of evidence assessment was based on the presence or absence of a clinically important effect, as informed by MIDs suggested by the sponsor and agreed upon by the clinical experts consulted by CADTH for this review (for ORR and FACT-M and EQ-5D3L change from baseline).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for nivolumab-relatlimab FDC versus nivolumab monotherapy in the treatment of adult patients with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma.

Long-Term Extension Studies

No long-term extension studies were available.

Indirect Evidence

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the CADTH review team.

Objectives for the Summary of Indirect Evidence

The objective of this section is to summarize and appraise the evidence from ITCs for the relative effects and safety of relatlimab plus nivolumab for the treatment of patients aged 12 years and over with unresectable or metastatic melanoma. While direct head-to-head evidence is available for the comparison of relatlimab plus nivolumab relative to nivolumab, there remains a lack of direct evidence for other relevant treatments of relevance to the Canadian population.

Description of Indirect Comparisons

Two ITCs were reviewed for this submission. ITC1 included a systematic literature review (SLR) and applied a Bayesian NMA to 2 major subpopulations: patients treated with immunotherapy only and a separate analysis for patients treated with either immunotherapy or BRAF and MEK inhibitors. ITC2 utilized patient-level data from the RELATIVITY-047 trial in conjunction with patient-level data from the CheckMate 067 trial to indirectly compare nivolumab-relatlimab FDC relative to nivolumab-ipilimumab by using an inverse probability of treatment-weighting approach to adjust for covariates between trials. As ITC2 did not include a literature review or study assessment process, a summary of the associated study inclusion criteria is only reported for ITC1, and its associated SLR is provided in Table 32.

Table 32: Study Selection Criteria and Methods for ITC1 Submitted by the Sponsor

ITC1 = indirect treatment comparison 1.

Source: Sponsor-submitted ITC1.⁷²

Indirect Treatment Comparison Design 1 — Bayesian Network Meta-Analysis

Objectives

The purpose of the first sponsor-submitted ITC and SLR was to assess the estimated comparative efficacy and safety of relatlimab and nivolumab relative to existing therapeutic regimens for the treatment of adult patients with previously untreated, unresectable, or metastatic melanoma.

Study Selection Methods

The SLR was conducted initially in 2017, followed by 7 updates, for a total of 8 searches, with the most recent search conducted in November 2022. The eligibility criteria for study inclusion are presented in Table 32. Using the Ovid platform, the following databases were reviewed for peer-reviewed publications: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Terms for RCTs were based on the study design filters recommended by the Scottish Intercollegiate Guidelines Network for MEDLINE and Embase. Non–peer-reviewed publications were considered as part of the study eligibility criteria, and the following scientific conferences were reviewed: annual meetings of the American Association for Cancer Research, American Society of Clinical Oncology, European Society of Medical Oncology, Society for Immunotherapy of Cancer, and Society of Melanoma Research. Publications were reviewed by 2 independent investigators with adjudication from a third investigator as required for disagreements on eligibility.

ITC1 Analysis Methods

Within this ITC, the sponsor provided a Bayesian NMA with varying outcome models conditional on the outcome being assessed. During dataset creation, the sponsor noted that several steps were taken to harmonize the associated data inputs. For time-to-event HR data (for OS and PFS), the sponsor utilized the HR with the shortest follow-up time in primary publications as the preferred parameter of interest. Where no HR was reported, Kaplan-Meier curves were presented, and the sponsor derived an HR using the Guyot algorithm on digitized and manually extracted curves using DigitizeIt. Imputation of standard errors used the average standard deviation among trials reporting dispersion of the outcome of interest. The mean standard deviation was then converted to a standard error using study-specific sample sizes. Both fixed- and random-effects models were considered.

For time-to-event outcomes (for OS and PFS) utilizing time-varying HRs, the sponsor used multidimensional treatment effects, which model hazard functions of interventions within a trial against known parametric survival functions or fractional polynomials, where differences in parameters are indirectly compared across studies. The sponsor assessed Weibull, Gompertz, and second-order fractional polynomials covering P1 = 0 or 1 and P2 = −1, 0.5, 0, 0.5, or 1. Goodness of fit for model selection was based on the deviance information criterion (DIC) utilizing the following steps:

1. Run full and less-complex fractional polynomial models for all combinations of P1 and P2.

2. Rank models according to DIC.

3. Review curve fits and extrapolation for top 4 best-fitting models according to DIC.

4. Compare full models with less-complex models based on best choice of P1 and P2; opt for the less-complex model if similar goodness of fit (most parsimonious model).

Noninformative priors were used for mean hazards and treatment effects. Specifically, they were reported as multivariate normals, with mean vectors centred at 0 and covariance matrices with diagonals of 10,000 and off-diagonal elements of 0.

For time-to-event outcomes (OS and PFS) utilizing reported constant HRs, the sponsor assessed the proportional hazard assumption with a Grambsch and Therneau test. Analyses conducted on constant HRs were performed using a regression model with a contrast-based normal likelihood for the log HR (and corresponding standard error) of each trial (or comparison) in the network. Normal noninformative priors were used, with a mean of 0 and a variance of 10,000.

For binary outcomes (used for safety outcomes), the sponsor reported on the proportion of patients experiencing the event of interest using a regression model with a binomial likelihood and logit link. Normal noninformative prior distributions for the parameters were used with a mean of 0 and a variance of 10,000. Relative treatment effects were expressed as ORs.

Consistency was evaluated between direct and indirect comparisons by edge-splitting.

Risk of bias was assessed using the Cochrane Collaboration’s risk-of-bias tool with 2 independent researchers reviewing and a third adjudicating in cases of divergent opinions.

Table 33: ITC1 Analysis Methods