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Indication: Adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection
CADTH recommends that Keytruda should be reimbursed by public drug plans for the treatment of stage IIB/IIC melanoma following complete resection only if certain conditions are met.
Keytruda should only be covered to treat patients who have stage IIB or stage IIC melanoma who have not received prior treatment beyond surgery.
Keytruda should only be reimbursed if prescribed in an outpatient oncology clinic and supervised by a specialist who has experience in delivery of immunotherapy, and if the cost of Keytruda is reduced.
Stage IIB or IIC melanoma is a kind of skin cancer that occurs in skin cells that produce melanin. The Canadian Cancer Society has estimated that in 2022, 9,000 Canadians will be diagnosed with melanoma skin cancer and 1,200 people will die from it.
Surgery for stage IIB or IIC melanoma is intended to cure patients. However, in some cases, patients have a poor prognosis and are at risk for their skin cancer returning. Therefore, there is a need for treatment options that can help prevent melanoma from coming back.
Treatment with Keytruda is expected to cost approximately $11,733 per patient per 28-day cycle.
The CADTH pCODR Expert Review Committee (pERC) recommends that pembrolizumab be reimbursed for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection only if the conditions listed in Table 1 are met.
One phase III, randomized, multi-centre, placebo-controlled study (KEYNOTE-716) demonstrated that adjuvant treatment with pembrolizumab resulted in added clinical benefit for patients with resected stage IIB or IIC cutaneous melanoma. The KEYNOTE-716 study demonstrated that administration of pembrolizumab every 3 weeks for up to 1 year of treatment (or 17 cycles) was associated with statistically significant and clinically meaningful improvements in recurrence-free survival (RFS) compared to placebo. This was based on the primary analysis of RFS at interim analysis 1 (IA1) (hazard ratio [HR] = 0.65; 95% CI, 0.46 to 0.92; P = 0.00658), which was consistent with the results of the final analysis of RFS at IA2 (HR = 0.61; 95% CI, 0.45 to 0.82; nominal P = |||||||), at 18 months of follow-up. Distant metastasis-free survival (DMFS) was a key secondary end point in the KEYNOTE-716 study and was also in favour of pembrolizumab at 18 months (HR = 0.64; 95% CI, 0.47 to 0.88; P = 0.00292). Although exploratory, treatment with pembrolizumab was not associated with a detriment in health-related quality of life (HRQoL). Pembrolizumab was associated with a manageable toxicity profile.
pERC acknowledged the need for a treatment for patients with stage IIB or IIC cutaneous melanoma, as this population generally has a poor prognosis and high risk of disease recurrence. Patients identified a need for access to effective treatments that reduce the risk of disease recurrence and improve quality of life, particularly by reducing the severity of side effects associated with treatment. Given the totality of the evidence, pERC concluded that pembrolizumab met some of the needs identified by patients in terms of reducing the risk of disease recurrence and providing a manageable toxicity profile.
The cost-effectiveness of pembrolizumab is highly uncertain due to the absence of overall survival data in a format CADTH can assess and extrapolate, and the lack of face validity of the sponsor’s extrapolated overall survival curves. CADTH could not derive a base-case analysis due to serious uncertainty, and therefore, an exploratory analysis was conducted which considered the cost-effectiveness of pembrolizumab relative to observation. Based on the sponsor’s submitted price for pembrolizumab and publicly listed prices for all other drug costs, the estimated incremental cost-effectiveness ratio (ICER) was $110,594 per quality-adjusted life-year (QALY) gained, compared with observation. At that ICER, a price reduction would be required for pembrolizumab to achieve an ICER of $50,000 per QALY gained. The committee indicated that greater price reductions may be required due to the uncertainty around the exploratory reanalysis.
Reimbursement Conditions and Reasons.
Melanoma is a cancer that begins in the melanocyte cells of the skin, also referred to as cutaneous melanoma. Cutaneous melanomas can develop anywhere on the skin, including the eyes, mouth, genitals, and anal area; however, they are most likely to start on the chest, back, and legs. In contrast, non-cutaneous melanoma develops from skin cells other than melanocytes, such as basal cells. The first signs of melanoma skin cancer are typically a change in the mole colour, size, or shape. Other common signs and symptoms include a mole that is asymmetric, has an uneven or irregular border, is not the same colour throughout, is large in diameter (more than 6 mm), or is evolving. The cancerous growth has the potential to grow into and destroy nearby tissue or metastasize to other parts of the body. The Canadian Cancer Society has estimated that in 2022, 9,000 Canadians will be diagnosed with melanoma skin cancer and 1,200 people will die from it. The Canadian Cancer Society also reported that melanoma accounts for about 3.8% and 3.3% of new cancer cases in men and in women, respectively. Further, melanoma accounts for 1.9% and 1.2% of all cancer deaths in men and in women, respectively. Risk factors for melanoma skin cancer include: UV radiation; many moles; atypical moles; congenital melanocytic nevi; familial atypical multiple mole melanoma syndrome; other hereditary conditions (xeroderma pigmentosum, Werner syndrome, retinoblastoma); light-coloured skin, eyes, and hair; personal or family history of skin cancer; CDKN2A gene mutation; and a weakened immune system.
A diagnosis of melanoma usually begins with a family physician, based on reported signs or symptoms and a skin exam. Patients may then be referred to a specialist, such as a dermatologist or surgeon, as needed. The presence of cancerous cells, and extent and characteristics of disease, may be identified by performing a skin biopsy or lymph node biopsy, or through histology, imaging (CT scan, MRI, chest X-ray, PET scan), or blood tests. Patients with stage IIB and IIC melanoma are defined by having high-risk node-negative disease. The primary tumour is thick and/or ulcerated (greater than 4 mm thick with or without ulceration, or greater than 2 to 4 mm thick with ulceration), but there is no lymph node involvement.
According to the clinical experts consulted by CADTH, following a diagnostic biopsy, all patients should undergo wide-local excision (WLE) of the primary site, which is a curative-intent surgical procedure. Following definitive WLE, the standard of care is to follow patients for surveillance. As per the 2020 Canadian Melanoma Conference recommendations, surveillance should be conducted by an appropriate specialist, including biannual visits and PET/CT with brain MRI among the systemic imaging modalities available. The Canadian Melanoma Conference recommendation statement also indicated that high-risk surveillance should follow a 5-year schedule, beginning with an intensive 2-year period, followed by a less-intensive 3-year period, as the median time to relapse for stage IIB to III melanoma is less than 2 years after treatment.
Pembrolizumab is an immune checkpoint inhibitor (ICI) that binds to programmed cell death receptor-1 (PD-1), resulting in the reactivation of tumour-specific cytotoxic T lymphocytes in the tumour microenvironment. Pembrolizumab is indicated for the adjuvant treatment of adult and pediatric patients (aged 12 years and older) with stage IIB or IIC melanoma following complete resection. The sponsor has requested that pembrolizumab be reimbursed as per the indication. The Notice of Compliance (NOC) was received on July 5, 2022. In December 2021, the FDA approved pembrolizumab for the adjuvant treatment of adult and pediatric patients (aged 12 years and older) with stage IIB, IIC, or III melanoma following complete resection. Pembrolizumab was previously reviewed by CADTH for the adjuvant treatment of patients with stage IIIA to stage IIID cutaneous melanoma and received a recommendation for reimbursement with conditions.
Pembrolizumab has been approved by Health Canada for adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection. Pembrolizumab is an immunoglobulin G4 (IgG4) monoclonal antibody against programmed cell death protein 1 (PD-1). Pembrolizumab is administered as an IV infusion over 30 minutes. For adults, the recommended dosage for adjuvant treatment of melanoma is either 200 mg every 3 weeks or 400 mg every 6 weeks, for up to 1 year or until disease recurrence or unacceptable toxicity. For pediatric patients, recommended dosage for adjuvant treatment of melanoma is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, until disease progression or unacceptable toxicity, or for a maximum of 12 months.
To make their recommendation, the committee considered the following information:
Two patient groups, SYSF and Melanoma Canada, submitted patient input for this review. Both groups included patients from across Canada with melanoma, regardless of cancer stage. SYSF gathered data through online surveys, virtual roundtables, and one-on-one discussions with 25 melanoma patients (68% female), 18 of which received the treatment under review. Melanoma Canada received input from 172 melanoma patients (67% female) and 15 caretakers through an online survey. Twenty patients from the Melanoma Canada submission indicated that they had been on treatment with adjuvant pembrolizumab for stage IIB or IIC melanoma following complete resection.
According to the SYSF input, respondents who were diagnosed with stage II melanoma reported having limited access to available treatment options, which increased their initial fear and anxiety. The Melanoma Canada survey respondents indicated that the main day-to-day impacts of their diagnosis included scarring and disfigurement, fear or anxiety, and disrupted sleep, as well as pain, fatigue, and depression. Respondents also indicated mobility and lymphedema issues caused by surgery including lymph node dissection. The input suggested that there is an unmet need for treatment options to prevent recurrence of disease, as there are currently no treatment options available beyond surgery for stage IIB or IIC disease in Canada.
In both submissions, most patients who had experience with the treatment under review reported experiencing at least 1 side effect. In the SYSF submission, the main side effects reported by the survey respondents included fatigue, cognitive impairment, nausea, skin rash, gastrointestinal problems, and weight loss or gain. Most patients found these side effects to be manageable. In the Melanoma Canada submission, the main reported side effects included fatigue or weakness, skin rash, thyroid or pituitary gland issues, and muscle or joint pain. Most of the respondents indicated that they were willing to accept the side effect profile of pembrolizumab if it would potentially mean that they would not have to deal with a recurrence. A common concern among patients was the length of time and cost of travel to get to a clinical trial site for treatment. According to the submissions received, patients expressed a need for future treatments that would be curative; be accessed close to home and delivered in a timely fashion; allow them to work and continue normal day-to-day activities without significant long-term side effects; and be available to them if their disease was to progress or recur.
The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of stage IIB or IIC melanoma who were consulted by CADTH on this review.
The clinical experts described the prognosis of stage IIB or IIC patients as similar to that observed in Stage III (lymph node positive) malignant melanoma. The clinical experts stated that the standard of care for patients with resected Stage III melanoma involves systemic treatment as adjuvant treatment after surgery. In contrast, the experts noted that there are no currently available systemic therapies other than high-dose interferon, which is rarely used, for adjuvant treatment to surgery for patients with resected stage IIB or IIC melanoma. Given the similarities between the prognoses of patients with stage IIB or IIC and III melanoma diagnoses, the experts indicated that patients and clinicians would likely want access to systemic treatment for similar adjuvant treatment of these patients.
The clinical experts indicated that pembrolizumab would be the first available systemic therapy for adjuvant use in resected stage IIB or IIC melanoma, although clinical trials investigating the efficacy and safety of nivolumab and encorafenib plus binimetinib are ongoing. According to the clinical experts, one would expect that pembrolizumab would be used as monotherapy, with a small minority of patients within this category qualifying for consideration of radiation therapy as adjuvant treatment to surgery. The clinical experts felt that approval of pembrolizumab for adjuvant treatment to surgery for patients with resected stage II melanoma would shift the current treatment paradigm. The clinical experts indicated that for reference, in their experience, the incidence of stage II melanoma diagnoses is roughly twice that of stage III, suggesting a significant increase in the number of melanoma patients eligible for treatment with adjuvant immunotherapy. However, that number may overestimate the impact of introducing pembrolizumab to the stage II patient population, as presumably a proportion of patients would recur with nodal disease (at which point they may be candidates for treatment with adjuvant systemic therapy).
The clinical experts explained that currently, there are no biomarkers in regular clinical use that would guide treatment decision-making in melanoma. The clinical experts felt that patients with stage IIB and IIC melanoma will likely be considered equally for treatment with pembrolizumab as adjuvant treatment to surgery, in alignment with the criteria used in the KEYNOTE-716 study. According to the experts, patient-specific factors, including performance status, the presence or absence of relevant comorbidities, patient age, and patient wishes will guide decisions about treatment with pembrolizumab for patients with resected stage IIB or IIC melanoma. They also noted that patients with active autoimmune medical comorbidities (i.e., inflammatory bowel disease, rheumatoid arthritis), would not be exempt from treatment, but may be less likely to pursue treatment with adjuvant immunotherapy.
The clinical experts acknowledged that although an improvement in OS is the primary outcome of interest, an improvement in RFS is still of clinical value. They further described response to treatment, defined by the absence of disease, as a clinically meaningful outcome that is consistent with outcomes used for other adjuvant indications. According to the clinical experts, most clinicians will re-stage patients to ensure against disease relapse during adjuvant therapy. They further noted that practices are likely to vary between jurisdictions, and it is unlikely that most patients and clinicians will adhere to a schedule as robust as that used in the KEYNOTE-716 trial.
With regard to discontinuation of treatment, the experts indicated that patients should be monitored for treatment-related toxicities during pembrolizumab therapy, and treatment may be discontinued if moderate or severe toxicities occur. The clinical experts referenced the recommendations from the European Society for Medical Oncology9 and the American Society for Clinical Oncology10 as generally accepted algorithms that exist for managing immune-related toxicities. The experts felt that whether or not adjuvant therapy should be automatically discontinued in the setting of disease recurrence is debatable and should be decided on a case-by-case basis. The clinical experts recommended that treatment with pembrolizumab as an adjuvant treatment to surgery be overseen by a qualified medical oncologist, with support from community cancer centres and allied health care providers.
Clinician group input was received from the Ontario Health (Cancer Care Ontario) Skin Cancer Drug Advisory Committee, with 5 clinicians contributing to the submission. The clinician group noted that there is currently no treatment for this high-risk patient population, and currently sentinel node-negative patients are ineligible for adjuvant treatment, indicating an unmet need. The treatment goal for this patient population would be RFS, as it is an important end point for patients while being a possible surrogate for OS. The input stated that pembrolizumab would be provided as an adjuvant treatment after appropriate surgical management. The input suggests that treatment should be provided in an outpatient setting; physical exams and CT scans should be used to determine if a patient is responding to treatment; and treatment should be discontinued upon disease recurrence and toxicity.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for pembrolizumab:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
The pivotal trial for pembrolizumab (KEYNOTE-716) was the only study included in the CADTH systematic review. The KEYNOTE-716 study (N = 976) was a randomized, placebo-controlled, parallel-group, crossover/rechallenge, multi-centre study of adjuvant pembrolizumab in patients 12 years of age and older with resected stage IIB or IIC cutaneous melanoma. The study consisted of 2 parts: adjuvant treatment in part 1 and crossover/rechallenge after first recurrence in part 2. In part 1, pembrolizumab or placebo was administered every 3 weeks for 17 cycles. The results from part 2 were not available at the time of this review. At the time of this review, data up to interim analysis (IA) 3 was available. The data cut-off (DCO) for interim analyses were: IA1, December 4, 2020; IA2, June 21, 2021; and IA3, January 4, 2022.
The primary objective of the KEYNOTE-716 study was to compare RFS between the treatment groups, pembrolizumab and placebo. Patients included in the trial must have been enrolled within 12 weeks of final surgical resection with complete surgical wound healing and have no evidence of metastatic disease on imaging. The mean age of included patients was 59.3 years (standard deviation [SD] = 12.9) and 2 pediatric patients were included (1 randomized to each treatment group). Almost all included patients did not exhibit functional impairment (Eastern Cooperative Oncology Group [ECOG] performance status of 0 or Karnofsky Performance Scale [KPS] status of 100), and the remaining patients (7% in each treatment group) exhibited some functional impairment (ECOG performance status of 1). Most patients had stage IIB melanoma at baseline (64%) and 35% had stage IIC melanoma. In addition to RFS, data were available for the following outcomes as of IA3: DMFS, and HRQoL measured using the EORTC QLQ-C30 and the EQ-5D-5L visual analogue scale (VAS).
OS was identified as the most important outcome for patients with melanoma. At the time of this review, the available evidence did not include an assessment of OS due to data immaturity and was limited to RFS, an interim analysis of DMFS, and an exploratory analysis of HRQoL. The final OS analysis for the study is not expected to occur until approximately 180 months (15 years) of follow-up. Key efficacy results from the KEYNOTE-716 study are described below.
The final analysis of RFS was based on the June 21, 2021 DCO (IA2). Recurrence was defined as recurrence of melanoma at any site (local, in-transit, or regional lymph nodes, or distant recurrence) or death due to any cause. The median duration of follow-up for all participants (intention-to-treat population) was 20.5 months (range, 4.6 months to 32.7 months) as of the DCO, with a similar median duration of follow-up across treatment groups. The estimated HR suggested a reduction in risk of recurrence at 18 months follow-up, based on an HR of 0.61 (95% CI, 0.45 to 0.82; nominal P = |||||||). At that time point, 72 patients (14.8%) randomized to pembrolizumab and 115 patients (23.5%) randomized to placebo had experienced recurrence of disease. The HR for RFS at IA2 was consistent with the results of the primary analysis of RFS at IA1 (HR = 0.65; 95% CI, 0.46 to 0.92; P = 0.00658) and subsequent analysis at IA3 (HR = 0.64; 95% CI, 0.50 to 0.84). In the pembrolizumab treatment group, 7.8% of events were local/regional/locoregional recurrence, 6.4% were distant recurrence, and 0.62% were deaths. In the placebo treatment group, 10.2% were local/regional/locoregional recurrence, 12.3% were distant recurrence, and 1.0% were deaths. The 2 sensitivity analyses of RFS accounted for new primary melanomas included in the RFS analysis and different censoring rules; both were consistent with the primary analysis.
The first interim analysis of DMFS was available for this review. Neither patient nor clinician groups highlighted DMFS as an outcome of particular interest compared to RFS and OS. As of IA3, the median duration of follow-up for all patients was 26.9 months (range, 4.6 months to 39.2 months). At IA3, 13% and 19% of patients randomized to pembrolizumab and placebo, respectively, experienced DMFS. The reduction in risk of DMFS at 18 months was in favour of pembrolizumab (HR = 0.64; 95% CI, 0.47 to 0.88; P = 0.00292); however, this was based on a small number of events and immature data.
The analysis of HRQoL outcomes was exploratory, but suggested little to no change in HRQoL in the placebo treatment group, and a small numerical reduction in HRQoL in the pembrolizumab treatment group. The results were reported as a change from baseline to week 48 and week 72. At week 72, the LS mean of the change from baseline in the EORTC QLQ-C30 Global Health Status/QoL scale was |||| (95% CI, |||| to ||||) for patients randomized to pembrolizumab and |||| (95% CI, |||| to |||) for patients randomized to placebo. The LS mean change from baseline to week 72 for the EQ-5D-5L VAS was |||| (95% CI, |||| to ||||) for patients randomized to pembrolizumab and ||| (95% CI, |||| to |||) for patients randomized to placebo.
Safety results reported herein were based on the January 4, 2022 DCO. A total of | deaths were reported, | of which were patients randomized to placebo. The frequency of adverse events (AEs) and serious adverse events (SAEs) reported by patients was similar between treatment groups; 95.7% and 91.6% of patients in the pembrolizumab and placebo treatment groups, respectively, reported at least 1 AE. Diarrhea (|||||| ||| for pembrolizumab versus placebo, respectively), pruritus (|||||| |||), arthralgia (|||||| |||), rash (|||||| ||), headache (|||||| |||), hypothyroidism (|||||| ||), alanine aminotransferase increase (|||||| ||), and hyperthyroidism (|||||| ||) were reported more frequently by patients in the pembrolizumab treatment group than placebo. Serious AEs were reported by ||||| of patients in the pembrolizumab treatment group and ||||| of patients in the placebo treatment group. The most frequently reported SAEs were basal cell carcinoma (|||||| ||||| in the pembrolizumab and placebo treatment groups, respectively), squamous cell carcinoma of the skin (||||||| ||||), malignant melanoma in situ (|||||| |||||), and malignant melanoma (||||||| ||||). Neither of the pediatric patients in the study reported a SAE. Numerically, more patients discontinued from treatment due to AEs in the pembrolizumab treatment group (||| of patients) compared with placebo (| | of patients); however, discontinuation from treatment did not appear to be the result of any specific AEs. The clinical experts consulted by CADTH stated that patients with stage IIB or IIC melanoma following complete resection are overall considered healthy patients. They posed that as a result, some patients may not be willing to tolerate the AEs associated with pembrolizumab (for which they were involved in a trial, therefore with unknown benefit) while they felt healthy otherwise.
Notable AEs (i.e., the AEs of special interest for this review), including immune-mediated reactions (colitis and pneumonitis), severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis), infusion-related reactions, and endocrine-related reactions were observed in less than | | of patients in any treatment group, with the exception of hyperthyroidism and hypothyroidism, as previously described.
The KEYNOTE-716 study was a well-designed, randomized, placebo-controlled, parallel-group, multi-centre study. Part 1 of the study, which is the focus of this review, was double-blind. At the time of this review, data from IA3 (January 4, 2022 DCO) was the most recent analysis available. At IA3, the final analysis of RFS and the interim analysis of DMFS were the only analyses of the primary and key secondary end points that were available. Overall survival was identified as the most important outcome for the review of pembrolizumab for stage IIB or IIC melanoma; however, the final OS analysis for the study is not expected to occur until approximately 180 months (15 years) after the first patient was randomized. There was evidence based on interferon-based therapies to support RFS as a surrogate outcome for an HR of at least 0.77; however, another study concluded that more evidence is needed to confirm the strength of association between RFS and OS for immunotherapies such as pembrolizumab. Based on the evidence that is currently available, RFS may be an appropriate surrogate outcome for OS, but this is associated with notable uncertainty given the limited data available in terms of the therapies that are the current standard of care, the small number of events available for analysis, and the relatively short duration of follow-up at this time. Patient-reported HRQoL outcomes (EORTC QLQ-C30 and EQ-5D-5L VAS) were exploratory, subject to potential bias due to missing data, and not controlled for multiplicity. As such, limited conclusions can be drawn about HRQoL. Subgroup analyses were not pre-specified and not powered to show efficacy, and therefore should be considered exploratory.
Although the sponsor is requesting reimbursement of pembrolizumab for patients at least 12 years of age, only 2 pediatric patients (aged 12 to 17 years) were included in the study; therefore, the appropriateness of generalizing the results to pediatric populations is unknown. At the time of this review, the evidence was limited to Part 1 of the study, which only included patients who were not previously treated for melanoma beyond complete surgical resection. Additionally, some of the exclusion criteria in the trial — such as patients who had received prior therapy with anti-PD1, anti-programmed death-ligand 1 (anti-PD-L1), or anti-programmed death-ligand 2 (anti-PD-L2) agents; patients with a known additional malignancy or who had required active antineoplastic therapy or surgery in the past 5 years; and patients with immunodeficiencies — are likely to miss a subset of patients that would be seen in clinical practice (an estimated 5% to 10% of patients). The clinical experts indicated that these criteria would not preclude patients from treatment with pembrolizumab in practice, but the safety and efficacy of treatment in these patients is associated with uncertainty. Concomitant medication use described in the trial was considered appropriate and consistent with clinical practice. The evidence is limited to a placebo-controlled trial; however, given that the current standard of care is surveillance, this was considered to be a reasonable comparator. At the time of this review, the final analysis was only available for the primary end point, RFS. The clinical experts indicated that approximately one-third of patients who do experience recurrence of disease will recur in the first 12 months following resection. Despite having enough events to perform the final analysis of RFS, the small number of events available for analysis may have rendered the effect estimates and corresponding confidence intervals fragile. The duration of follow-up as of IA2 and IA3 is likely too short, causing uncertainty around the generalizability of the estimate for recurrence to what would be expected in clinical practice. In contrast, the clinical experts felt that the duration of follow-up was sufficient to observe AEs of interest.
A focused literature search for indirect treatment comparisons (ITCs) dealing with melanoma was run in MEDLINE All (1946–) on May 20, 2022. No search limits were applied. No ITCs were identified for this review.
A sponsor-submitted ITC was used to support the economic model. This ITC compared interventions of interest on the outcomes of progression-free survival (PFS) and OS in patients with unresectable stage III or IV melanoma receiving first-line treatment for advanced disease. In the BRAF all-comers/wild type population, the network meta-analysis (NMA) showed that pembrolizumab may be favourable for PFS relative to ipilimumab monotherapy, dacarbazine, ipilimumab plus dacarbazine, and binimetinib, but nivolumab plus ipilimumab was favoured relative to pembrolizumab for PFS analysis. For the OS analysis in the BRAF all-comers/wild type population, the NMA showed that pembrolizumab may be favourable relative to ipilimumab and to dacarbazine. In the population with BRAF mutation positive melanoma, pembrolizumab may be favourable for PFS relative to ipilimumab monotherapy, dacarbazine, ipilimumab plus dacarbazine, and binimetinib, but may be less favoured than nivolumab plus ipilimumab, encorafenib plus binimetinib, vemurafenib plus cobimetinib, atezolizumab plus vemurafenib and cobimetinib, dabrafenib plus trametinib, and pembrolizumab plus dabrafenib and trametinib. For the OS analysis in the population with BRAF mutation positive melanoma, pembrolizumab may be favourable to monotherapy with ipilimumab, dacarbazine, or vemurafenib.
Limitations to this NMA include variation in patient characteristics (BRAF status, PD-L1, M1c metastases, baseline characteristics such as lactate dehydrogenase [LDH] above normal and ECOG status) and trial characteristics (e.g., open label and phase II versus phase III trial), which indicate that the underlying assumption of transitivity is likely to have been violated. Potential heterogeneity was not further investigated, for example with subgroup analyses or meta-regression. Consistency between direct and indirect evidence could not be verified due to the lack of closed loops. All of the contributing evidence was indirect, which reduces the certainty of all effects. Additionally, there was limited data available for the NMAs that were conducted for OS and PFS; therefore, fixed effects models were used for these end points, which is likely to have resulted in estimates that are more precise than in reality. These limitations preclude making conclusions about the comparative effectiveness of pembrolizumab in the setting of advanced melanoma.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations: the referral rate to oncologists may be underestimated, market shares of subsequent treatments for patients who developed locoregional or distant recurrence do not reflect Canadian clinical practice, the assumption regarding patient enrolment in clinical trials as a comparator is inappropriate, and the relative dose intensity (RDI) and budget impact of patients diagnosed in years 1 to 3 were not fully captured.
CADTH’s base-case revisions included: revising the proportion of patients who were assumed to be in clinical trials to 0%, increasing the referral rate to oncologists, changing subsequent treatment market shares, and setting RDI to 100%. CADTH also explored uncertainty in the price reduction, use of a weight-based pembrolizumab dose, and the incident case distribution throughout the year.
Based on CADTH’s base case, the expected budget impact for funding pembrolizumab for the adjuvant treatment of adult and pediatric patients (aged 12 years and older) with stage IIB or IIC melanoma following complete resection is expected to be $8,708,492 in Year 1, $36,209,278 in Year 2, and $41,052,409 in Year 3, with a 3-year budget impact of $85,970,178.
Results of CADTH’s scenario analyses demonstrate that the estimated budget impact is sensitive to the change in weight-based dosing and the timing of when individuals were diagnosed in the model.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung, Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: September 14, 2022
Regrets: 1 expert committee member did not attend.
Conflicts of interest: None
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Indication: Adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection
Sponsor: Merck Canada Inc.
Final recommendation: Reimburse with conditions
Note: This document was initially published on November 22, 2022, and subsequently revised on January 31, 2023, to correct an error in the results for the budget impact analysis.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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