Three trials presented at the ASCO Annual Meeting 2023 showed continued success with immunotherapy in patients with melanoma.
In the phase 3 RELATIVITY-047 trial, nivolumab plus relatlimab showed a consistent benefit over nivolumab alone in patients with previously untreated metastatic or unresectable melanoma.1
In the phase 2 KEYNOTE-942 trial, adding a personalized mRNA vaccine to treatment with pembrolizumab improved outcomes for patients with high-risk, resected melanoma.2
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An update of the KEYNOTE-716 trial showed that pembrolizumab is still an effective adjuvant treatment for stage IIB or IIC melanoma after 3 years.3
On the other hand, a fourth study suggested that chemotherapy may be a better option than immunotherapy for patients with mucosal melanoma.4 In this retrospective study, temozolomide plus cisplatin produced better outcomes than toripalimab when used as adjuvant therapy in resected mucosal melanoma.
RELATIVITY-047: Sustained Benefit With Nivolumab Plus Relatlimab
In the phase 3 RELATIVITY-047 trial, treatment with the checkpoint inhibitor nivolumab and the LAG3 inhibitor relatlimab continued to show a clinical benefit over nivolumab alone in patients with previously untreated metastatic or unresectable melanoma after 2 years.1
The trial (ClinicalTrials.gov identifier: NCT03470922) included 714 patients who were randomly assigned to receive nivolumab at 480 mg plus relatlimab at 160 mg (n=355) or nivolumab at 480 mg every 4 weeks (n=359).
In a prior analysis, at a median follow-up of 13.2 months, nivolumab plus relatlimab showed a significant progression-free survival (PFS) benefit over nivolumab alone.5
In this updated analysis, at a median follow-up of 25.3 months, nivolumab plus relatlimab continued to show a PFS benefit over nivolumab alone.1 The median PFS was 10.2 months with the combination and 4.6 months with nivolumab alone (hazard ratio [HR], 0.81; 95% CI, 0.67-0.97). The 36-month PFS rate was 31% and 27%, respectively.
The median overall survival (OS) was not reached with nivolumab plus relatlimab and was 33.2 months with nivolumab alone (HR, 0.82; 95% CI, 0.67-1.02). The 36-month OS rate was 54% and 48%, respectively. The 48-month OS rate was 52% and 42%, respectively.
“Efficacy results continued to favor nivolumab plus relatlimab vs nivolumab across the majority of prespecified subgroups,” said study presenter Hussein A. Tawbi, MD, of The University of Texas MD Anderson Cancer Center in Houston. “Patients receiving nivolumab plus relatlimab had sustained benefit vs nivolumab beyond initial treatment and first progression.”
The median second PFS (PFS2) was 28.4 months in the combination arm and 20.1 months in the monotherapy arm (HR, 0.79; 95% CI, 0.65-0.96). The 48-month PFS2 rate was 42% and 35%, respectively.
Grade 3-4 treatment-related adverse events (AEs) occurred in 22% of patients in the combination arm and 12% of patients in the monotherapy arm. There were 6 treatment-related deaths, with 4 in the combination arm and 2 in the monotherapy arm.
The safety profile of nivolumab plus relatlimab was consistent with previous reports, with no new or unexpected safety signals, Dr Tawbi said.
“I see nivolumab plus relatlimab as an option in general in situations where single anti-PD-1 therapy is being considered, with more efficacy and less toxicity than nivolumab plus ipilimumab. Not all patients are able to tolerate toxicity from nivolumab plus ipilimumab,” said James Larkin, MD, PhD, of Royal Marsden Hospital NHS Foundation Trust in London, who was not involved in this study.
KEYNOTE-942: Personalized Cancer Vaccine Improves Outcomes
In the phase 2 KEYNOTE-942 trial, researchers found that adding a cancer vaccine to treatment with pembrolizumab improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk, resected melanoma.2
The personalized cancer vaccine, mRNA-4157, is designed to target an individual patient’s unique tumor mutations and encodes up to 34 neoantigens, explained study presenter Adnan Khattak, MBBS, PhD, of Hollywood Private Hospital and Edith Cowan University in Perth, Australia.
The KEYNOTE-942 trial (ClinicalTrials.gov identifier: NCT03897881) included 157 patients with resected, stage IIIB-IV cutaneous melanoma who had a high risk of recurrence.
The patients were randomly assigned to receive mRNA-4157 plus pembrolizumab (n=107) or pembrolizumab alone (n=50). Pembrolizumab was given at 200 mg every 3 weeks for up to 18 cycles, and mRNA-4157 was given at 1 mg every 3 weeks for a total of 9 doses. Baseline characteristics were well balanced between the arms.
The median follow-up was approximately 2 years (23 months in the combination arm and 24 months in the monotherapy arm). The study’s primary and secondary efficacy endpoints — RFS and DMFS, respectively — were met.
mRNA-4157 significantly improved RFS (hazard ratio [HR], 0.561; 95% CI, 0.309-1.017; P =.0266). The 12-month RFS rate was 83.4% in the combination arm and 77.1% in the monotherapy arm. The 18-month RFS rates were 78.6% and 62.2%, respectively.
DMFS was also improved in the mRNA-4157 arm (HR, 0.347; 95% CI, 0.145-0.828; P =.0063). The 18-month DMFS rate was 91.8% in the combination arm and 76.8% in the monotherapy arm.
“DMFS is an important endpoint that has been evaluated in several adjuvant melanoma trials in stage II/ III settings,” Dr Khattak said. “About one-third of patients experience distant disease relapse despite receiving effective adjuvant treatment.”
Treatment-related AEs were reported in 10% of patients in the mRNA-4157 arm and 82.0% of those in the pembrolizumab-alone arm. The rate of grade 3 or higher treatment-related AEs was 25% and 18.0%, respectively. The rate of immune-mediated AEs was 35.6% and 36.0%, respectively.
Vaccine-related AEs were typically grade 1-2 (80%-85%) or grade 3 (11.5%), Dr Khattak said. The most common were fatigue, injection site reaction or pain, pyrexia, headache, or chills. Most resolved within 48 hours. No new safety signal was seen in the combination arm.
“KEYNOTE-942 is the first randomized study to have demonstrated improvement in RFS and DMFS with an individualized neoantigen therapy approach,” Dr Khattak said in an interview.
He called the results “very promising” but said they need to be validated in a phase 3 study. A phase 3 trial for patients with stage IIB or higher resected melanoma is set to begin later this year, he added.
“This groundbreaking technology opens a new era in cancer vaccines,” said Olivier Michielin, MD, PhD, of Geneva University Hospital in Switzerland, who was not involved in this study.
“Though the data is early in this small phase 2 trial, the KEYNOTE-942 RFS and DMFS results are very encouraging. Upon confirmation, this could represent a double validation of RNA vaccines and neoantigen targeting.”
