KEYMAKER-U02 is a rolling-arm, adaptive-design study, which allows the rapid evaluation of multiple agents in combination with pembrolizumab. Neoadjuvant therapy with pembrolizumab plus anti-TIGIT agent vibostolimab, pembrolizumab plus oncolytic virus gebasaxturev or pembrolizumab monotherapy, followed by surgery and adjuvant pembrolizumab in each arm, had manageable safety in patients with stage IIIB–D melanoma. The efficacy observed in the combination arms was similar to that in the pembrolizumab monotherapy arm.
Longer follow-up will provide further insight into whether there is an incremental benefit in combining neoadjuvant pembrolizumab with other therapies according to Pof. Reinhard Dummer of the University Hospital Zurich in Zurich, Switzerland and colleagues, who published the findings on 7 January 2025 in the Nature Medicine.
The authors wrote in the background that neoadjuvant anti-PD1 therapy should be considered standard-of-care in patients with resectable melanoma. However, the approach to neoadjuvant therapy will probably evolve as new data become available, particularly data on the optimisation of agents and combinations and the selection of patients most likely to benefit.
TIGIT is an immunomodulatory receptor with a critical role in inhibiting adaptive and innate immunity, showing promise as a target for anticancer therapy. Mechanistically, it has been suggested that PD-(L)1 blockade alone may not be sufficient to fully restore CD226 signalling owing to the presence of TIGIT, with the combined inhibition of both PD1 and TIGIT required to promote an optimal antitumour CD8-positive T-cell response. Clinically, this dual-blockade approach was evaluated in the phase I KEYVIBE-001 study, which showed that the combination of vibostolimab, an anti-TIGIT antibody, and pembrolizumab, an anti-PD1 antibody, had a manageable safety profile and showed antitumour activity in patients with advanced solid tumours.
Gebasaxturev is a bioselected, genetically unmodified, oncolytic strain of the coxsackie virus. In preclinical studies, gebasaxturev was shown to have oncolytic activity in vitro and in melanoma xenograft mouse models. The use of oncolytic viruses has also been shown to increase intratumoural infiltration of CD8-positive T-cells, suggesting that their use may alter the tumour microenvironment in a way that could enhance the antitumour activity of PD1 inhibitors. This approach was evaluated in the phase Ib CAPRA study, the results of which showed that gebasaxturev had a manageable safety profile and encouraging antitumour activity when used in combination with pembrolizumab in patients with unresectable stage IIIB–IV melanoma.
Substudy 02C of the phase I/II KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab as monotherapy and in combination with investigational agents, followed by surgery and adjuvant pembrolizumab monotherapy, in patients with resectable stage IIIB–D melanoma. In the article published in the Nature Medicine, the study team reported the primary analysis of safety and antitumour activity in the pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy treatment arms, including a post hoc biomarker analysis.
Pathologic complete responses occurred in 10 of 26 patients (38%) who received pembrolizumab plus vibostolimab, 7 of 25 patients (28%) who received pembrolizumab plus gebasaxturev and 6 of 15 patients (40%) who received pembrolizumab monotherapy. Major pathologic responses occurred in 13 (50%), 10 (40%) and 7 patients (47%), respectively.
Some concordance was observed between the reduction in target lesion size and the degree of pathologic response for all treatment arms, although a number of patients with a pathologic complete response or near pathologic complete response had a reduction in the target lesion size of <30% or even an increase in the target lesion size.
The 18 month event-free survival rate was 81% in the pembrolizumab plus vibostolimab arm, 72% in the pembrolizumab plus gebasaxturev arm and 80% in the pembrolizumab monotherapy arm; the 18 month recurrence-free survival rates were 90%, 90% and 82%, respectively.
Safety was manageable. Treatment-related adverse events occurred in 24 of 26 patients (92%) who received pembrolizumab plus vibostolimab, 21 of 25 patients (84%) who received pembrolizumab plus gebasaxturev and 12 of 15 patients (80%) who received pembrolizumab monotherapy; grade 3 or 4 treatment-related adverse events occurred in 2 (8%), 7 (28%) and 1 patient (7%) in each arm. No deaths due to adverse events occurred.
Exploratory objective responses per RECIST v1.1 were observed in 13 (50%), 8 (32%) and 4 patients (27%) in each arm. In a post hoc analysis, scores for tumour mutational burden and an 18-gene T cell-inflamed gene expression profile were generally higher in patients with major pathologic response.
The authors commented that no other data are currently available from prospective studies assessing anti-TIGIT antibodies as neoadjuvant therapy in melanoma. Longer follow-up will provide further insight into the incremental benefit of combining neoadjuvant pembrolizumab with other therapies in stage IIIB–D melanoma.
Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc (MSD).
Reference
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. Nature Medicine; Published online 7 January 2025. DOI: https://doi.org/10.1038/s41591-024-03411-x