CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 02, 2023
Expiration: August 01, 2024
CheckMate 238: Adjuvant Nivolumab vs Ipilimumab in Stage III-IV High-Risk Melanoma
CheckMate 238 is a randomized phase III study comparing adjuvant nivolumab with high dose ipilimumab (10 mg/kg) in patients with resected high-risk stage IIIB through IV melanoma (N = 906).1,2
The primary endpoint for the study is recurrence free survival (RFS) in the intention-to-treat population. Secondary endpoints include OS and safety. Distant metastasis-free survival (DMFS) is an exploratory endpoint.
CheckMate 238: 5-Year RFS and OS
The 5 year update from this study demonstrated sustained long term improvement in median RFS with nivolumab at 61.0 months vs 24.1 months (HR: 0.72; 95% CI: 0.60-0.86). There was also a benefit in DMFS compared with high dose ipilimumab.2 The OS data remain immature.
KEYNOTE-054: Adjuvant Pembrolizumab vs Placebo for Stage III Melanoma
KEYNOTE 054 is a randomized phase III study comparing adjuvant pembrolizumab with placebo in patients with resected stage III melanoma (N = 1019).3,4 Patients received treatment for 18 doses or until recurrence, unacceptable toxicity, or withdrawal. Patients with recurrence were eligible for crossover or repeat treatment with pembrolizumab.
The coprimary endpoints are RFS in the intention-to-treat population and RFS in the PD-L1–positive subgroup. The secondary endpoints are DMFS, OS, safety, and quality of life.
KEYNOTE-054: 5-Year RFS and DMFS
The 5 year update demonstrated that adjuvant therapy with pembrolizumab maintained improvements in RFS and DMFS compared with placebo.4 The 5-year RFS rates were 55% with pembrolizumab and 38% with placebo (HR: 0.61; 95% CI: 0.51-0.72), and the 5-year DMFS rates were 61% and 44%, respectively (HR: 0.62; 95% CI: 0.52-0.75).
Clinically, the results from this study reinforce the standard of care (SoC) for patients with resected high risk melanoma, which is to consider the administration of adjuvant anti–PD 1 monotherapy in patients with resectable stage III melanoma.
KEYNOTE-716: Adjuvant Pembrolizumab vs Placebo in High-risk, Resected, Stage II Melanoma
KEYNOTE 716 is a randomized double-blind phase III trial comparing adjuvant pembrolizumab with placebo in patients aged ≥12 years with resected stage IIB/C melanoma (N = 976).5 At recurrence, patients were rechallenged/crossed over to receive pembrolizumab Q3W until progression or recurrence for up to 2 years.
The primary endpoint of the trial is investigator-assessed RFS, and the key secondary endpoints are DMFS, OS, and safety.
KEYNOTE-716: RFS in ITT Population
With a median follow-up of 39.4 months, investigators reported that adjuvant pembrolizumab continued to improve DMFS and RFS compared with placebo.6 The 36-month RFS rate was 76.2% with pembrolizumab and 63.4% with placebo, and the median RFS was not reached in either arm. Although OS analyses remain immature, results from this study reinforce the SoC to consider adjuvant therapy with anti–PD-1 in this patient population.
CheckMate 76K: Adjuvant Nivolumab vs Placebo in Resected Stage IIB/IIC Melanoma
CheckMate 76K is a randomized phase III study evaluating adjuvant nivolumab vs placebo in patients aged ≥12 years with newly diagnosed, resected stage IIB/C melanoma (N = 790).7 There was an optional on-protocol open-label treatment with nivolumab after the first recurrence (≥6 months after nivolumab treatment or any time after placebo).
The primary endpoint of CheckMate 76K is investigator-assessed RFS and secondary endpoints are OS, PFS2, DMFS, and safety.
Phase III CheckMate 76K of Adjuvant Nivolumab vs Placebo in Stage IIB/C Melanoma: RFS
CheckMate 76K demonstrated an RFS benefit with nivolumab (HR: 0.42; 95% CI: 0.30-0.59).7 Although nivolumab is not currently approved by the FDA for this indication, these data underline the current SoC in this patient population, which is the consideration of anti–PD 1 monotherapy.
COMBI-AD: Adjuvant Dabrafenib/Trametinib vs Placebo in BRAFV600E/K-Mutant Melanoma
COMBI AD is a randomized double-blind phase III study evaluating adjuvant dabrafenib/trametinib vs placebo in adult patients with BRAFV600E/K-mutant resected stage III melanoma (N = 870).8 Patients with stage IIIA disease had completely resected disease with lymph node metastasis >1 mm and patients with stage IIIB/C disease had cutaneous melanoma. All patients were disease free ≤12 weeks before randomization.
The primary endpoint is RFS, and secondary endpoints include OS, DMFS, and safety.
Phase III COMBI-AD Adjuvant Dabrafenib/Trametinib vs Placebo: 5-Year RFS
The 5 year analysis demonstrated increased RFS and DMFS compared with placebo.8 The median RFS has not been reached with the combination and was 16.6 months with placebo. Clinically, these results show that adjuvant dabrafenib/trametinib is a viable therapy for patients with resected BRAFV600E/K-mutant stage III melanoma. These agents have a different toxicity profile than immune based agents and may avoid some of the longer term toxicities sometimes associated with immune checkpoint inhibitors.
Interactive Decision Tool Patient Case 1
This case focuses on a patient with stage IIIA wild-type BRAF melanoma who is post resection, and who has 1 positive lymph node ≥1 mm.
Based on the clinical trial results just described, in a patient with BRAF wild type melanoma with 1 lymph node ≥1 mm, we generally have a detailed conversation about the risk of disease recurrence and the potential benefits and risks of pursuing adjuvant therapy vs close observation alone. Four out of 5 expert faculty recommended anti–PD 1 monotherapy, with the other expert recommending observation, which was commented on as a reasonable option by 2 of the other experts.
Expert Insight on Adjuvant Therapy
The consideration of adjuvant therapy is SoC for patients with stage IIB/C or stage III melanoma following surgical resection.
In considering the risks and benefits of pursuing adjuvant therapy, it is important to discuss with the patient the potential toxicities associated with adjuvant therapy regimens as well as the likelihood of surgical cure of disease after resection vs risk of recurrence. Additionally, routes of medication administration and patient preferences should be discussed.
KEYNOTE-942: Adjuvant Therapy With a Personalized Neoantigen Vaccine + Pembrolizumab vs Pembrolizumab
KEYNOTE 942 is a randomized open-label phase II study evaluating a personalized neoantigen mRNA vaccine in combination with pembrolizumab compared with pembrolizumab monotherapy in patients with completely resected stage IIIB through IV cutaneous melanoma (N = 157).9 Patients were disease free at study entry and had tissue available for next-generation sequencing. Patients were randomized 2:1 to receive the personalized neoantigen mRNA vaccine mRNA-4157 (V940) every 3 weeks for a maximum of 9 doses with pembrolizumab at the standard dose vs pembrolizumab alone. Pembrolizumab was given for a maximum of 18 cycles within 1 year. Follow-up was for 3 years after the first dose of pembrolizumab.
The primary endpoint is RFS, and secondary endpoints are DMFS, safety, and tolerability.
mRNA-4157-P201/KEYNOTE-942: RFS
Results presented at the American Association for Cancer Research (AACR) 2023 annual meeting revealed a 44% reduction in the risk of recurrence or death with 2 years of follow-up (HR: 0.56; 95% CI: 0.309-1.017; P = .0266).9,10 The 18-month RFS rate was 78.6% with the combination and 62.2% with pembrolizumab monotherapy.
This is a small study, and the biostatistical outcomes supporting those conclusions are borderline, so additional evaluation is required. The mRNA-4157 therapy plus pembrolizumab is currently undergoing testing in a phase III clinical trial (NCT05933577).
SWOG S1801: Adjuvant Pembrolizumab ± Neoadjuvant Pembrolizumab in Resectable Stage III-IV Melanoma
SWOG S1801 is a randomized, open-label phase II study comparing neoadjuvant pembrolizumab before surgical resection followed by adjuvant pembrolizumab vs surgical resection and adjuvant pembrolizumab in patients with resectable stage IIIB or IV melanoma (N = 313).11 Patients with brain metastases and uveal melanoma were excluded.
The primary endpoint was event free survival (EFS), which was defined as the time from randomization to the first of the following: progression or toxicity preventing surgery, no adjuvant therapy within 84 days of surgery, postsurgery melanoma recurrence, or death. Secondary endpoints are OS and safety.
SWOG S1801: Radiographic Response Before Surgery
Radiographic progression is shown in the slide.11 On local review, 21% of patients with a submitted pathology report achieved a pathologic complete response (pCR).
SWOG S1801: Survival
The results published in 2023 illustrated an improvement in EFS in the neoadjuvant arm over the adjuvant-only arm (2-year EFS: 72% vs 49%, HR: 0.58; 95% CI: 0.39-0.87; P <.004).11 At the time of data cutoff, a limited number of deaths had been reported, which precluded the definitive comparison of the groups with respect to OS.
Results from this study support the use of neoadjuvant therapy in this patient population after consultation with the multidisciplinary team. Current guidelines recommend neoadjuvant therapy in the context of a clinical trial.12
OpACIN-neo: Different Doses of Neoadjuvant Ipilimumab/Nivolumab
The randomized open-label phase II OpACIN neo study examined different doses of neoadjuvant ipilimumab plus nivolumab or ipilimumab followed by nivolumab in patients with resectable stage IIIB/C melanoma (N = 86).13 All patients had measurable disease and received no previous immunotherapy or radiation therapy.
The primary endpoints include the rate of grade 3/4 immune-related adverse events (irAEs) within 12 weeks, response rates seen on imaging, and pathologic response rates at the time of surgery.
OpACIN-neo: RFS and OS
The OpACIN neo ipilimumab/nivolumab regimens demonstrated ongoing disease control at 3 years, with no significant differences between the arms.13 The authors report that pathologic response rate at the time of surgery remains the strongest predictor for disease recurrence. These results also suggest that neoadjuvant therapy continues to be a promising approach in this patient population, especially in consultation with the multidisciplinary team.
Neoadjuvant Relatlimab + Nivolumab for Resectable Stage IIIB/C/D or IV Melanoma
A small phase II study investigated the safety and efficacy of neoadjuvant relatlimab plus nivolumab in patients with resectable stage IIIB/C/D or oligometastatic (<3 sites) stage IV melanoma (N = 30).14,15 The patients received 2 doses of therapy followed by surgical resection and 10 doses of adjuvant relatlimab and nivolumab therapy.
The primary endpoint is pCR rate and secondary endpoints are objective response rate (ORR), RFS, EFS, OS, safety, and mechanisms of response.
Neoadjuvant Relatlimab + Nivolumab: Efficacy
In total, pCR and near pCR were seen in 19 patients.14,15 Achieving a pathologic response was associated with improved RFS compared with patients who did not have a pathologic response.
Expert Insight on Neoadjuvant Therapy in Melanoma
Taken together, the SWOG S1801, OpACIN-neo, and nivolumab/relatlimab studies underline that neoadjuvant therapy should be considered in patients with high risk resectable melanoma. Indeed, in June 2023, the Pharmaceutical Benefits Advisory Committee in Australia recommended expanding coverage to include neoadjuvant pembrolizumab therapy for patients with resectable stage IIIB through IIID melanoma. Although not yet approved by the FDA, this announcement may be an indicator of what is to come from other regulatory agencies around the world.
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