A new phase 1/2 clinical trial has provided promising results for neoadjuvant immunotherapy combinations in patients with resectable stage IIIB-D melanoma. The study, published in the January 2025 issue of Nature Medicine, evaluated neoadjuvant pembrolizumab alone or in combination with other immunotherapies, followed by surgery and adjuvant pembrolizumab.
The KEYMAKER-U02 trial was a global, rolling-arm, adaptive-design study funded by Merck Sharp & Dohme LLC. It enrolled 66 patients across 26 centers between June 2020 and January 2022. Patients were randomized to receive one of three neoadjuvant regimens: pembrolizumab plus vibostolimab (an anti-TIGIT antibody), pembrolizumab plus gebasaxturev (an oncolytic virus), or pembrolizumab monotherapy.
To be eligible, patients had to be at least 18 years old with resectable stage IIIB-D melanoma, no in-transit metastases within 6 months, measurable disease, and an ECOG performance status of 0-1. Key exclusion criteria included ocular or mucosal melanoma, active autoimmune disease, and immunodeficiency.
The primary endpoints were safety and pathologic complete response rate. Secondary endpoints included near pathologic complete response rate, partial pathologic response rate, and recurrence-free survival.
In terms of efficacy, pathologic complete responses were observed in 38% of patients receiving pembrolizumab plus vibostolimab, 28% receiving pembrolizumab plus gebasaxturev, and 40% receiving pembrolizumab monotherapy. Major pathologic responses (complete or near complete) occurred in 50%, 40%, and 47% of patients in each arm, respectively.
The safety profile was manageable across all treatment arms. Treatment-related adverse events of any grade occurred in 92% of patients receiving pembrolizumab plus vibostolimab, 84% receiving pembrolizumab plus gebasaxturev, and 80% receiving pembrolizumab monotherapy. Grade 3-4 treatment-related adverse events were reported in 8%, 28%, and 7% of patients, respectively. No treatment-related deaths occurred.
At 18 months, event-free survival rates were 81% for pembrolizumab plus vibostolimab, 72% for pembrolizumab plus gebasaxturev, and 80% for pembrolizumab monotherapy. Recurrence-free survival rates at 18 months were 90%, 90%, and 82%, respectively.
The study also included exploratory biomarker analyses. Higher tumor mutational burden and T cell-inflamed gene expression profile scores were generally associated with improved response rates across treatment arms, though the predictive value varied.
While the results are encouraging, the study has several limitations. The sample size in each treatment arm was relatively small, limiting statistical power. The lack of a placebo arm prevents direct comparison to patients not receiving neoadjuvant therapy. Additionally, longer follow-up will be needed to assess the durability of responses and potential survival benefits.
The authors concluded that neoadjuvant pembrolizumab-based regimens demonstrated manageable safety and promising efficacy in resectable stage IIIB-D melanoma. They noted that the combination arms showed similar efficacy to pembrolizumab monotherapy in this initial analysis.
These findings have potentially significant clinical implications. Neoadjuvant immunotherapy is gaining consensus as a standard of care option for resectable melanoma, and this study provides further support for this approach. The high pathologic response rates and encouraging survival data suggest these regimens could improve outcomes for patients with high-risk melanoma.
However, several questions remain. Longer follow-up will be crucial to determine if the combination regimens provide incremental benefit over pembrolizumab monotherapy. Additionally, further research is needed to identify reliable biomarkers for patient selection and to optimize treatment sequencing and duration.
This study adds to a growing body of evidence supporting neoadjuvant immunotherapy in melanoma. As more data emerges from ongoing trials, treatment paradigms may continue to evolve. For now, these results provide clinicians with valuable information on the safety and efficacy of pembrolizumab-based neoadjuvant regimens, potentially expanding treatment options for patients with resectable stage III melanoma.
References
Dummer R, Robert C, Scolyer RA, et al. Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial. Nat Med. 2025;31(1):144-151. doi:10.1038/s41591-024-03411-x
