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Indication: 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
CADTH recommends that Opdualag be reimbursed 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 if certain conditions are met.
Opdualag should only be covered to treat patients aged 12 years or older who have a histologically confirmed diagnosis of unresectable stage III or stage IV (metastatic) melanoma and have not received prior systemic therapy for advanced melanoma. Patients should be in relatively good health (i.e., have a good performance status, as determined by a specialist).
Patients who had prior adjuvant or neoadjuvant anti–programmed death-1 (PD-1) or anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) therapy if the therapy was completed at least 6 months before the date of recurrence are eligible for reimbursement. Opdualag should not be reimbursed in patients with active brain metastases, uveal melanoma, and active autoimmune disease. Opdualag should only be reimbursed if the price of Opdualag is reduced. The feasibility of adoption of Opdualag must also be addressed.
Melanoma is a cancer that occurs in skin cells that produce melanin. Melanoma that cannot be removed by surgery (unresectable) or that has spread to other parts of the body (metastatic disease) is associated with a low survival rate.
Current treatments may be associated with a number of side effects that may lead to treatment interruptions, delays, or discontinuation. There is an unmet medical need for an additional novel immune checkpoint inhibitor combination therapy in metastatic melanoma which can be used regardless of BRAF mutation status. The novel therapy should offer increased efficacy in relation to anti–PD-1 monotherapy and should have a favourable safety profile that does not result in additive toxicities as seen with conventional dual immunotherapy combinations.
Based on the CADTH base case, the budget impact from the introduction of Opdualag is expected to be $4,734,946 in year 1, $12,890,614 in year 2, and $16,679,027 in year 3. The 3-year net budget impact was estimated to be $34,304,588.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that nivolumab-relatlimab be reimbursed 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 only if the conditions listed in Table 1 are met.
Evidence from 1 phase II/III, double-blinded, randomized, active controlled and ongoing trial (RELATIVITY-047) demonstrated that treatment with nivolumab-relatlimab fixed-dose combination (FDC), when compared with nivolumab monotherapy, resulted in added clinical benefit in patients with previously untreated, histologically confirmed, unresectable stage III or stage IV (metastatic) melanoma. Nivolumab-relatlimab was associated with a statistically significant and clinically important increase in progression-free survival (PFS) benefit when compared with nivolumab monotherapy (primary analysis: median follow-up = 13.2 months; hazard ratio [HR] = 0.75; 95% confidence interval [CI], 0.62 to 0.92; P = 0.0055). Nivolumab-relatlimab may result in a clinically important increase in overall survival (OS) when compared with nivolumab monotherapy (HR = 0.80; 95% CI, 0.64 to 1.01; P = 0.0593). However, there remains uncertainty in the OS results due to the inadequate length of follow-up for this outcome and the 95% CI included no difference between nivolumab-relatlimab and nivolumab monotherapy. Based on descriptive final analyses, a total of 10.3% (95% CI, 3.4% to 17.3%) more patients in the nivolumab-relatlimab group achieved an objective response compared with the nivolumab group after a median follow-up of 19.3 months. After a median follow-up of 19.3 months, health-related quality of life (HRQoL) (Functional Assessment of Cancer Therapy-Melanoma [FACT-M], 3-Level EQ-5D [EQ-5D-3L] utility index scores, and EQ-5D visual analogue scale [VAS]) in the nivolumab-relatlimab group and nivolumab group remained generally stable (no clinical meaningful improvement or deterioration) during the treatment period. There were little to no differences between nivolumab-relatlimab and nivolumab monotherapy in FACT-M, EQ-5D-3L utility index scores, and EQ-5D-VAS.
Despite the available treatment options, there remains an unmet therapeutic need for effective treatment options for patients with unresectable or metastatic melanoma. Patient groups indicated that there is an ongoing need for better options with fewer adverse events (AEs) and longer responses as well as the need to have available treatment options when 1 therapy does not work or stops working. Nivolumab-relatlimab compared to nivolumab monotherapy was effective with respect to PFS. Although there were numerically more patients who experienced AEs (e.g., grade 3 or 4 AEs) in the nivolumab-relatlimab group than in the nivolumab monotherapy group, the AEs were generally manageable.
At the sponsor-submitted price for nivolumab-relatlimab and publicly listed prices for immunotherapies considered in the submitted indirect treatment comparison (nivolumab-ipilimumab combination, pembrolizumab, ipilimumab, and nivolumab monotherapy) nivolumab-relatlimab was more costly than nivolumab-ipilimumab combination, pembrolizumab, ipilimumab, and nivolumab monotherapy. Because there was insufficient evidence to conclude that nivolumab-relatlimab is as effective or better than nivolumab-ipilimumab combination to justify a cost premium, the total drug cost of nivolumab-relatlimab should not exceed the total drug cost of nivolumab-ipilimumab combination.
Reimbursement Conditions and Reasons.
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, hard lump on the skin, unexplained pain, feeling very tired or unwell, and unexplained weight loss. The mean age at diagnosis of advanced metastatic melanoma is approximately 59 years in Canada. The diagnosis of melanoma is based on skin examination, physical examination, skin and/or lymph node biopsy, and diagnostic imaging (i.e., CT). 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 Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, elevated lactate dehydrogenase, nodal involvement and metastases, increased tumour thickness, ulceration, and mitoses at least 1 per mm2 in thin T1 melanomas. Approximately 70% of metastatic melanomas have mutually exclusive mutations in B-Raf proto-oncogene (BRAF), neuroblastoma RAS viral oncogene homologue (NRAS) gene , c-KIT, and GNAQ or GNA11, which activate the mitogen-activated protein kinase pathway leading to promotion of cell proliferation, prevention of apoptosis, and angiogenesis.
Approximately 38% to 51% of patients with stage III or IV melanoma have a mutation in the BRAF gene. An Australian study of patients with advanced melanoma reported a similar rate, with 48% of tumours being BRAF V600 mutation positive. In Canada, melanoma accounted for 3.8% of new cancer cases and 1.5% of cancer deaths in 2021. An estimated 9,000 people were diagnosed with melanoma in 2022 in Canada, with an age-standardized incidence rate of 23.5 per 100,000 in 2018 (excluding Quebec) based on data from Statistics Canada. Incidence is slightly higher in men than in women (25.9 per 100,000 versus 21.2 per 100,000). An estimated 1,200 persons died from melanoma in 2022 in Canada, with an age-standardized mortality rate of 2.7 per 100,000. In Canada, stage IV distant metastatic disease is associated with a 5-year survival rate of 18%. 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 with BRAF and MEK inhibitors.
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. According to the clinical experts CADTH consulted for this review, immunotherapy is the first line of choice for melanoma regardless of BRAF status. The ICI immunotherapies routinely used for the first-line treatment of metastatic melanoma in Canada include nivolumab-ipilimumab combination therapy, nivolumab (anti–programmed death [PD]-1) monotherapy, ipilimumab (anti–cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) monotherapy, and pembrolizumab (anti–PD-1) monotherapy. However, the use of nivolumab-ipilimumab has been increasing. According to the clinical experts CADTH consulted for this review, nivolumab-ipilimumab is the first line of choice among the ICIs. After the first line, the treatment decisions are largely determined by BRAF mutation status. Patients with no BRAF mutation are treated with immunotherapies, and patients with BRAF mutations are eligible for treatment with targeted therapies. Targeted-therapy regimens that have been approved by Health Canada and are recommended for reimbursement by pERC include encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor), vemurafenib (BRAF inhibitor) plus cobimetinib (MEK inhibitor), and dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor). The clinical experts CADTH consulted for this review indicated that targeted therapy use as monotherapy is negligible and not reflective of clinical practice in Canada. It was reported that patients with advanced melanoma rarely receive targeted therapy as a single drug (< 5%). According to the clinical experts CADTH consulted for this review, there is an unmet medical need for an additional novel ICI combination therapy in metastatic melanoma that can be used regardless of BRAF mutation status. The novel therapy should offer increased efficacy in relation to anti–PD-1 monotherapy and should have a favourable safety profile that does not result in additive toxicities as seen with conventional dual immunotherapy combinations — a combination treatment regimen involving an ICI combined with a drug with a different mechanism of action.
Nivolumab is a humanized IgG4 monoclonal antibody ICI that binds to the PD-1 receptor and blocks its interaction with programmed death-ligand 1 (PD-L1) and ligand 2 (PD-L2), releasing PD-1 pathway–mediated inhibition of the immune response, including the antitumour immune response. Relatlimab is a novel, first-in-class ICI that targets the lymphocyte-activation gene 3 (LAG-3) receptor. 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. LAG-3 and PD-1 are 2 distinct inhibitory immune checkpoint pathways, often co-expressed on tumour-infiltrating lymphocytes. They act synergistically on effector T cells, leading to the development of T-cell exhaustion and impaired cytotoxic function. The recommended dose of nivolumab-relatlimab for adult patients is 480 mg nivolumab and 160 mg relatlimab every 4 weeks.
The recommended nivolumab-relatlimab dosage for pediatric patients who are at least 12 years old and weigh at least 40 kg is the same as for adults. A recommended dose has not been established for pediatric patients who are 12 years or older and weigh less than 40 kg. Nivolumab-relatlimab is supplied as 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).
The Health Canada–approved indication of interest for this review is nivolumab-relatlimab FDC 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. 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.
To make its recommendation, the committee considered the following information:
CADTH received 2 patient group submissions from Melanoma Canada and 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; 35 patient respondents indicated they had no caregiver. Of the total responses for patients, 81 were female and 38 were male. There were 26 patients that had stage 0 melanoma, 17 had stage I, 10 had stage II, 18 had stage III, and 29 had stage IV; 19 patients did not know their stage. Two patients in this survey were treated with nivolumab-relatlimab FDC.
Information was obtained by SYSF through online surveys, virtual patient roundtables and one-on-one conversations, which included 60 patients with melanoma of 12 patients on the drug under review (nivolumab-relatlimab) and was gathered 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 (the US, Australia, 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 for patients and their families. Caregivers reported that the biggest impact on them of dealing with the diagnosis is the mental stress, the negative financial impact to the family with the loss of income from a working partner, and the additional responsibilities that they have to perform for the home and family and caring for their loved one. Some respondents explained the impact of melanoma using the following terms: scared, disbelief, unsettled, anxious, teary, disrupted life, and totally life changing.
In terms of current therapy options, based on 119 of the respondents from Melanoma Canada’s survey, 55% of respondents had been treated with some form of drug therapy. There were 9 patients who were treated with multiple therapies. A total of 92% of patients treated with available drug therapies indicated that they felt the side effects were worth it for the anticipated results. Moreover, approximately 20% of patients experienced issues in accessing treatment. SYSF’s survey results also mentioned the same issues because patients in remote areas of Canada have problems getting to treatment if needed, the travel costs and time off from work put extra stress on patients and caregivers, there are huge expenses and increased stress to themselves and their family, and there is also concern about being treated far from home and their support system. There was very little access to the drug under review (Ontario and Quebec only). There were a number of patients in Canada who could not get access to the drug under review, which might have been their only option.
Regarding the improved outcomes, both patient groups identified that there is a vast opportunity for improvement with a wider variety of more effective treatment options with minimal side effects and a longer response being made available.
There were 2 respondents from Melanoma Canada’s survey and 12 respondents from SYSF’s survey who indicated that they had experience with the drug under review with the primary method of access to the drug under review through a clinical trial. There were 12 respondents who explained that the benefits outweighed the experience of side effects, primarily rash and fatigue, which were somewhat manageable.
Melanoma Canada believes 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 very 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 is another improvement and option for a cancer that continues to be on the rise and is complex to treat.
The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of adult and pediatric patients (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 OS rates, to slow down progression, improve symptoms, improve quality and quantity of life, and to minimize toxicity, especially 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 nivolumab-ipilimumab if the patient is able to tolerate the drugs relating to potential toxicities. Failure to respond to nivolumab-ipilimumab leads to potentially switching to BRAF inhibitor plus MEK inhibitor in patients who are BRAF positive. Pembrolizumab may be attempted as monotherapy or nivolumab as monotherapy if a patient experiences too many AEs due to nivolumab-ipilimumab combination treatment. The clinical experts indicated that immunotherapy is not 100% effective. The response rates of combination nivolumab-ipilimumab is approximately 56%. Patients may initially get a response and then progress eventually. After progression, new treatments are needed. Moreover, sometimes treatments are effective, but the AEs are not tolerable and treatment has to be aborted despite efficacy so less toxic treatments that are more tolerable and less dangerous are needed. This is an unmet need. According to the clinical experts, there is no real beneficial second-line therapy better than nivolumab-ipilimumab right now. New therapy is needed to increase response rates with fewer AEs. Furthermore, current standard practice, according to the clinical experts, would be to discuss dual drugs versus single-drug immunotherapy if there are no contraindications with the patient. 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. If the patient elected dual-drug therapy, they may de-escalate to a single drug for toxicity management. If the patient progresses on dual therapy and has a BRAF mutation, BRAF or MEK inhibitors would be offered. According to the clinical expert, dual immunotherapy has been recognized as a potentially curable 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 nivolumab-ipilimumab and fewer toxicities, they consider the new treatment (nivolumab-relatlimab FDC) under review as a first-line treatment for patients. The clinical experts highlighted that fewer AEs may mean more patient compliance thus better outcomes overall. Less toxicity may mean fewer hospital admissions which is better for patients overall and more economically sound and would offset the extra cost of the drug. Nivolumab-relatlimab FDC could also be an alternative to nivolumab-ipilimumab, which is currently first line in Ontario. The other clinical expert indicated that if this regimen is approved, then the options would be discussed with patients, nivolumab-ipilimumab versus nivolumab-relatlimab FDC, regarding OS, PFS, and toxicities. 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 line or second line of ICIs; nivolumab-relatlimab FDC would not be reserved for those patients who are intolerant, but rather would benefit from an effective regimen with less toxicities; nivolumab-relatlimab FDC is expected to cause a shift in treatment paradigms; those receiving candidates for single-drug immunotherapy would be offered nivolumab-relatlimab FDC; and those candidates considered for ipilimumab plus nivolumab may be offered or choose nivolumab-relatlimab FDC. The clinical expert stated that this nivolumab-relatlimab FDC regimen may replace nivolumab-ipilimumab for less robust patients.
The clinical experts indicated that all patients with metastases can be offered this treatment because it was beneficial regardless of BRAF status, PDL-1 and LAG-3 percentage, or stage. It is similar to other immunotherapy combinations and thus could be offered to all patients. In addition, the experts also stated that it will be important to follow OS data as it matures, to know the efficacy in brain metastases, and to know if the combination decreases or delays the occurrence of brain metastases.
Regarding response assessment, the clinical experts indicated that it is needed to assess response for improved patient symptoms and the modified immunotherapy RECIST criteria because there can be pseudoprogression in the beginning of treatment. Usually, it can take up to 2 to 3 months to evaluate a true response. At the beginning, response is 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 the clinical outcomes assessments are aligned with the clinical trial outcomes; physicians and patients review toxicities, symptom control, and objective evidence of disease response in an ongoing fashion during active treatment.
Regarding discontinuation, the clinical experts indicated the nivolumab-relatlimab FDC should be discontinued when obvious disease progression on imaging occurs with no improvement in symptoms. According to the clinical experts, when harmful grade 3 to 4 AEs occur, patients should at least pause the treatment and start to treat the AE then determine if the treatment can be restarted at a lower dose.
The clinical expert noted that treatments for metastatic melanoma should be provided by specialist medical oncologists and pharmacists in a Canadian cancer centre or, if at a community centre, then supervised or somehow connected to a cancer centre and experts for advice. According to the clinical expert, a centre administering or managing patients on nivolumab-ipilimumab are well equipped to manage this regimen.
CADTH received 1 clinician group submission from the OH-CCO Skin Cancer Drug Advisory Committee. Of note, at the time of OH-CCO’s input, the proposed Health Canada indication was not line specific (i.e., indicated for the treatment of adult and pediatric patients [12 years and older and weighing at least 40 kg] with unresectable or metastatic melanoma); however, after the clinician group input was received, the indication was approved to first line (i.e., 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). In the first-line metastatic or unresectable setting, the current treatments can include single-drug nivolumab or pembrolizumab, nivolumab-ipilimumab combination, and BRAF-targeted agents (for patients with BRAF mutations). The BRAF-targeted therapy options are dabrafenib-trametinib, cobimetinib-vemurafenib, and binimetinib-encorafenib. If patients received pembrolizumab or nivolumab in first line, the subsequent line options are ipilimumab alone or BRAF-targeted therapy (for patients with BRAF mutation). If nivolumab-ipilimumab followed by nivolumab maintenance is used in first line, only patients with a BRAF mutation have a second-line option to use BRAF-targeted therapy. Patients who received first-line BRAF-targeted therapy may be eligible for pembrolizumab, nivolumab, or nivolumab-ipilimumab 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 Drug Advisory Committees, the drug under review has a higher response rate than single-drug nivolumab in patients with unresectable or metastatic melanoma as per the RELATIVITY 047 trial. Although there is no head-to-head comparison trial, this combination also has less toxicity than nivolumab-ipilimumab (the treatment-related AEs are reported in the CHECKMATE 067 trial), which might fill some of the unmet needs of the standard treatment.
OH-CCO’s Drug Advisory Committees reported that :
Patients who are not able to tolerate nivolumab-ipilimumab or who would be treated with single-drug PD-1 inhibitor would be suitable for receiving drug under review in the first-line metastatic or unresectable setting.
OH-CCO’s Drug Advisory Committees believed that a clinically meaningful response would be improved survival, reduction in the frequency 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.
OH-CCO’s Drug Advisory Committees mentioned that the most likely reason to discontinue treatment would be confirmed disease progression and/or unmanageable toxicities.
OH-CCO’s Drug Advisory Committees noted that the drug under review should be administered in an outpatient cancer clinic, prescribed by a medical oncologist.
The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 2.
Summary of Drug Plan Input and pERC Response.
One pivotal, phase II/III, double-blinded, randomized controlled and ongoing trial (the RELATIVITY-047, N = 714) is included in the systematic review. The objective of RELATIVITY-047 was to evaluate 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 12 years of age 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 years). The majority (n = 655; 91.7%) of patients had metastatic stage IV cancer at study entry. The medium duration from diagnosis to the study treatment was 1.26 years. A total of 62 (8.7%) patients received previous adjuvant or neoadjuvant treatment. A total of 275 (38.5%) patients were BRAF positive. A total of 16 (2.2%) patients from Canada and 63 (8.8%) patients from the US were included. The primary outcome was PFS. The 2 secondary outcomes were OS and ORR. Tertiary or exploratory outcomes included duration of response (DOR), time to response (TTR), and HRQoL measurements (i.e., FACT-M, EQ-5D-3L). The sample size for the study was based on a primary end point of PFS using blinded independent central review for both phase II and phase III studies. Results presented in this submission reflect the phase III component of RELATIVITY-047. The final analysis for PFS was conducted after a median follow-up of 13.2 months. The final analysis for OS and ORR was conducted after a median follow-up of 19.3 months. Results for median DOR and TTR are based on the updated descriptive analysis conducted after a median follow-up of 25.3 months. HRQoL measurements (i.e., FACT-M, EQ-5D-3L) were conducted 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 after a median follow-up of 25.3 months.
Based on the final analysis after a median follow-up of 13.2 months, the median PFS was 10.12 months (95% CI, 6.37 to 15.74 months) in the nivolumab-relatlimab FDC group, which was statistically significantly and clinically meaningfully longer compared to 4.63 months in the nivolumab monotherapy group (nivolumab-relatlimab FDC versus nivolumab: HR = 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 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 OS final analysis 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, median OS was not reached in the nivolumab-relatlimab group compared to 33.18 months in the nivolumab group in updated descriptive analysis. Therefore, the comparative OS of nivolumab-relatlimab FDC compared with nivolumab monotherapy was uncertain.
Based on 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 those in the nivolumab group after a median follow-up of 19.3 months. 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 and progressive disease, no formal statistically analysis or any descriptive analysis was done to report the between-group difference or 95% CI of between-group difference. No HR (95% CI) was provided. Therefore, the comparative complete response and progressive disease of nivolumab-relatlimab FDC compared with nivolumab monotherapy remains inconclusive.
After a median follow-up of 25.3 months, no statistical and clinical meaningful between-group difference was observed for DOR. TTR appeared the same after a median follow-up of 25.3 months. However, no between-group difference and no HR was reported for TTR. The comparative DOC and TTR of nivolumab-relatlimab FDC compared with nivolumab monotherapy remain uncertain.
After a median follow-up of 19.3 months, HRQoL (FACT-M, EQ-5D-3L utility index scores and EQ-5D-VAS) 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-5D-VAS.
No adolescents (aged ≥ 12 to 18 years) were enrolled in the pivotal study. However, in the Health Canada product monograph, the indication of nivolumab-relatlimab FDC includes for the use for pediatric patients 12 years of age or older and weighing at least 40 kg. In the product monograph, it was indicated that use of nivolumab-relatlimab FDC in pediatric patients is supported by predicted drug exposures at the recommended nivolumab-relatlimab FDC dose that are expected to result in similar safety and efficacy to that of adults. The safety and efficacy of nivolumab-relatlimab FDC have not been established in pediatric patients younger than 12 years or in patients 12 years or older and weighing less than 40 kg.
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 versus 95.8% in the nivolumab monotherapy group). However, the most common any-grade AEs (occurred in > 20% patients in either of the 2 groups) appeared to occur in more patients in the nivolumab-relatlimab FDC group than the nivolumab monotherapy group, such as fatigue (nivolumab-relatlimab FDC versus nivolumab: 30.7% versus 20.9%) and diarrhea (27.9% versus 19.5%). The frequency of serious AEs (SAEs) appeared similar in both groups, and individual SAE events were relatively rare. With the exception of malignant neoplasm progression (nivolumab-relatlimab FDC versus nivolumab: 3.9% versus 5.6%), there were no other SAEs that occurred in more than 2% of patients in either group. The frequency of withdrawal due to AEs also appeared numerically higher in the nivolumab-relatlimab FDC group than in the nivolumab monotherapy group (nivolumab-relatlimab FDC versus nivolumab: 23.1% versus 15.9%). Discontinuation treatment due to specific AEs occurred in less than 2% patients in either of the groups, with the exception of malignant neoplasm progression (nivolumab-relatlimab FDC versus nivolumab: 1.7% versus 2.8%). The frequency of death due to AEs (i.e., study drug toxicity) was rare in both groups (nivolumab-relatlimab FDC versus nivolumab: 1.1% versus 0.6%). Adrenal insufficiency was considered as particular special immune-mediated adverse event, which occurred numerically higher in the nivolumab-relatlimab FDC group than in the nivolumab group (5.6% versus 1.1%). The other particular notable harm, myocarditis, rarely occurred (1.7% versus 0.6%). Grade 3 or 4 all-causality AEs were numerically more frequent with nivolumab-relatlimab FDC versus nivolumab (nivolumab-relatlimab FDC versus nivolumab: 44.8% versus 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.
Appropriate methods of randomization, blinding, and allocation concealment were reported. Objective outcomes and validated health-related outcomes were assessed. However, a minimal important between-group difference, which is the threshold used for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) for all outcomes, are not available. Therefore, clinical expert opinion informed the thresholds to determine whether the between-group difference observed for each outcome was clinically meaningful or not.
Metastatic stage M1c was relatively 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 impact the comparative study results between the nivolumab-relatlimab FDC and nivolumab monotherapy groups.
In terms of the OS assessment, OS was designed and assessed as a secondary outcome, the study was not powered to assess OS between-group differences 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). Therefore, the comparative efficacy on OS of nivolumab-relatlimab FDC compared with nivolumab remains uncertain.
The statistical significance of ORR (per blinded independent central review) 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 complete response 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 between-group differences or HRs were reported. Therefore, results on ORR, complete response, and progressive disease should be interpreted with caution.
DOR and TTR were assessed as tertiary or exploratory outcomes but were not controlled for the hierarchical testing procedure to control type I error. Analyses of DOR and TTR were not statistically powered, and they were reported using descriptive statistics only. No between-group differences were reported for DOR or TTR, although 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 or exploratory outcomes but were not controlled for the hierarchical testing procedure to control type I error. For those patients that 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 the recall bias on the patient-reported HRQoL outcomes is unknown. HRQoL analyses were not statistically powered and were reported using descriptive statistics. Overall, the findings of HRQoL should be viewed as supportive evidence only.
All subgroup analyses were not part of the randomization scheme; therefore, imbalances in characteristics may bias the results observed between the subgroups. In addition, the subgroup analyses may not be powered to detect between-group differences in each subgroup. Therefore, the findings of the subgroup analyses should be viewed as supportive evidence only.
In addition, 1 of the limitations of the RELATIVITY-047 trial is lack of comparison to current standard-of-care therapy, except nivolumab monotherapy, the comparative efficacy and safety of nivolumab-relatlimab FDC compared with nivolumab-ipilimumab, encorafenib-binimetinib, dabrafenib-trametinib, vemurafenib-cobimetinib, ipilimumab, pembrolizumab, dabrafenib, and trametinib is unknown.
It is uncertain whether the finding can be generalized to patients with CNS metastases or patients with ECOG performance status greater than 1 because patients with these were not included in the study. Only 17 (2.4%) patients with brain metastasis were included (1.7% and 3.1% in the nivolumab-relatlimab FDC group and nivolumab monotherapy group, respectively). Patients with active CNS metastases were excluded. The clinical experts CADTH consulted for this review indicated that although higher ECOG performance status (> 1) usually indicates more severe disease and more likely with unfavourable prognosis, that the nivolumab-relatlimab FDC combination treatments could be extended to patients with ECOG 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, although age 12 years or older was an inclusion criterion, no children (≥ 12 years to < 18 years) were enrolled in the pivotal study. Therefore, the comparative efficacy and safety profile of nivolumab-relatlimab FDC versus nivolumab monotherapy is unknown whether the findings from the RELATIVITY-047 trial can be generalized to adolescent patients (≥ 12 years to < 18 years) remains unknown. However, in the Health Canada product monograph, it is indicated 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 dose that are expected to result in similar safety and efficacy 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 CADTH consulted for this review 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 — especially if body habitus is similar to an adult or close to that of an adult. The clinical expert noted that currently immuno-oncology (IO) agent is given in the pediatric population, and it is well tolerated.
For pivotal studies and randomized controlled trials 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, and a final certainty rating was determined as outlined by the GRADE Working Group. Following the GRADE approach, evidence from randomized controlled trials 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.
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, and HRQoL (i.e., FACT-M, EQ-5D-3L utility index, and EQ-5D-VAS) 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 to the null. For this review, the target of the certainty of evidence assessment was based on the presence or absence of a clinically important effect, as informed by minimum important differences (MIDs) and thresholds suggested by the clinical experts (for all outcomes). Results of GRADE Assessments are presented in Table 3.
Summary of Findings for Nivolumab-Relatlimab Versus Nivolumab Monotherapy in Adult and Pediatric Patients With Unresectable or Metastatic Melanoma Without Prior Systemic Therapy.
This information is not available.
Overall, 2 ITC reports were submitted. One ITC, a Bayesian network meta-analysis, assessed the safety and efficacy of nivolumab-relatlimab relative to other IO agents for adult patients in the first-line management of patients with advanced melanoma. The second ITC, a patient-level propensity-weighted comparison, assessed nivolumab-relatlimab relative to nivolumab-ipilimumab among patients with advanced melanoma treated in first line.
The first ITC, a Bayesian network meta-analysis assessed nivolumab-relatlimab relative to nivolumab monotherapy, ipilimumab monotherapy, nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg), nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), pembrolizumab-cobimetinib plus atezolizumab.
The first ITC indicated that nivolumab-relatlimab is associated with improvements to OS relative to ipilimumab monotherapy at 48 months (HR = 0.48; 95% credible interval [CrI], 0.34, 0.69). For PFS at 48 months, nivolumab-relatlimab is associated with improvements relative to ipilimumab (HR = 0.32; 95% CrI, 0.22 to 0.48), pembrolizumab (HR = 0.59; 95% CrI, 0.35 to 0.97), and ||||||||||| | |||||||||||| |||| ||||| ||| |||| ||||| ||||||.
For the second ITC, the results indicated that there was no difference between nivolumab-relatlimab relative to ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) with respect to PFS and OS.
No data were available in either ITC with respect to ORR, time to progression, or any patient-reported outcome.
In the first ITC, nivolumab-relatlimab was associated with higher proportions of patients having grade 3 to 4 treatment-related AEs when compared to nivolumab (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) + ipilimumab (3 mg/kg) (OR = 0.43; 95% CrI, 0.25 to 0.73). For discontinuations due to AEs, |||||||||| | ||||||||| ||| |||||||||| |||| |||||| ||||||||||| || |||||||| |||||||||||| ||||| |||||| |||||||| || ||||||||| |||| ||||| ||| |||| ||||| |||||| ||| ||||| ||||||||||| || |||||||| |||||||||||| ||||| |||||| |||||||| || ||||||||| |||||||| | |||||||||| |||||||| |||| ||||| ||| |||| ||||| |||||| ||| |||||||||||||||| ||| || ||||||||||||||||| ||||||| ||||||| |||||||||| | ||||||||| ||| |||||||||| |||| |||||| ||||||||||| || |||||||| |||||||||||| ||||| |||||| |||||||| || ||||||||| |||| ||||| ||| |||| ||||| ||||| ||| |||||||||| |||| ||||| ||| |||| ||||| |||||| ||| ||||| ||||||||||| || |||||||| |||||||||||| ||||| |||||| |||||||| || ||||||||| |||||||| | |||||||||| |||||||| |||| ||||| ||| |||| ||||| ||||||.
No comparative data were presented from the second ITC with respect to safety outcomes, as no formal statistical comparison of the differences in safety events were conducted.
Sponsor-submitted evidence from the first ITC was provided with comparisons to non-IO interventions of interest, such as BRAF and MEK inhibitors, but owing 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 with respect to comparative efficacy and safety within this population. Several trials reporting on OS for the IO network of evidence still had ongoing observation for survival data at the time of analysis, so there may be additional uncertainty with these comparisons.
Cost and Cost-Effectiveness.
CADTH identified the following limitations in the sponsor’s base case: uncertainty in estimates of market size resulting from assuming 92.67% of patients will be diagnosed at stage I to III (resectable), ||| of patients will recur to stage III (unresectable) or stage IV following an initial diagnosis of stage I to III (resectable), and ||| of patients will be diagnosed at stage III (unresectable).
CADTH performed a reanalysis, which explored how changes in each assumption affected the estimated budget impact. Clinical experts consulted by CADTH assumed 85% of patients will be diagnosed at stage I to III (resectable), 5% of patients will recur to stage III (unresectable) or stage (IV) following an initial diagnosis of stage I to III (resectable), and 10% of patients will be diagnosed at stage III (unresectable).
Based on the CADTH base case, the budget impact from the introduction of nivolumab-relatlimab is expected to be $4,734,946 in year 1, $12,890,614 in year 2, and $16,679,027 in year 3. The 3-year net budget impact was estimated to be $34,304,588.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Phillip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung, Dr. Michael Crump, Dr. Jennifer Fishman, Mr. Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Christian Kollmannsberger, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: December 5, 2023
Regrets: 3 expert committee members did not attend.
Conflicts of interest: None
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Indication: 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
Sponsor: Bristol Myers Squibb Canada
Final recommendation: Reimburse with conditions
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