Combining Checkpoint Blockade with a Dual-Targeted Peptide Vaccine in Melanoma

James W. Smithy, MD, MHS, of Memorial Sloan Kettering Cancer Center presents the findings of a single-arm phase 2 trial evaluating a novel therapeutic combination for patients with advanced melanoma. The study marks the first time an investigative peptide vaccine targeting both PD-L1 and IDO, IO102-IO103, has been combined with multi-checkpoint blockade. Although prior research combined this dual-targeted vaccine with anti–PD-1 monotherapy, this trial integrated it with the standard-of-care combination of nivolumab and relatlimab (Opdualag). Patients received both the standard-of-care checkpoint inhibitors and the peptide vaccine for up to 2 years of treatment.

The trial met its primary end point, demonstrating a positive objective response rate (ORR) of 60% and a confirmed ORR of 53% in the intent-to-treat population. To evaluate efficacy, investigators compared these outcomes against historical controls for nivolumab/relatlimab. The observed response rates were significantly higher than what would be expected with nivolumab/relatlimab alone, even when accounting for the proportion of PD-L1–positive patients enrolled in the trial. At the time of data analysis, the median duration of response had not yet been reached, and the median progression-free survival was 8.1 months.

In addition to encouraging efficacy, the study regimen demonstrated a highly favorable safety and tolerability profile. Severe toxicities were rare, with grade 3 or 4 adverse events occurring in only 14% of the study population. Although injection site reactions were a common side effect of the vaccination component, they were mild and generally restricted to grade 1 or 2 events.

Looking forward, Smithy notes that nivolumab/relatlimab was initially selected as the backbone due to its lower rate of immune-related adverse events compared to full-dose nivolumab (Opdivo) and ipilimumab (Yervoy). However, given the exceptional tolerability witnessed in this trial, a new area of investigation would be if the peptide vaccine can be safely incorporated into a nivolumab/ipilimumab regimen to further maximize antitumor activity.