Melanoma Phase 3 Trial Narrowly Misses But Paves Path Forward

In a pivotal phase 3 study (NCT05155254), the investigational therapeutic cancer vaccine Cylembio (imsapepimut and etimupepimut) demonstrated a clinically meaningful improvement in progression-free survival (PFS) for patients with first-line advanced melanoma when combined with pembrolizumab (Keytruda).¹ While the trial did not meet its primary end point for statistical significance by a narrow margin, the totality of the data suggests a potential path forward for this novel combination therapy.

“In this study, we observed a highly encouraging improvement in progression free survival and consistent trend in overall survival in patients treated with Cylembio,” said Mai-Britt Zocca, PhD, president and chief executive officer of IO Biotech, in a press release. “The magnitude and durability of clinical effect observed consistently across subgroups supports our confidence in Cylembio and its potential as a treatment for advanced melanoma patients.”

The trial, designated IOB-013/KN-D18, randomized 407 patients with unresectable or metastatic melanoma to receive either Cylembio with pembrolizumab or pembrolizumab alone.^1,2 According to the topline results announced by IO Biotech, the median PFS in the combination arm was 19.4 months, an increase compared with 11.0 months in the control arm. This represents a 23% reduction in the relative risk of disease progression or death, though the P-value of 0.056 fell just outside the predefined threshold for statistical significance (P ≤.045).¹

The clinical benefit of imsapepimut and etimupepimut was particularly pronounced in key subgroups. A post hoc analysis of patients with PD-L1–negative tumors, a population often associated with a poorer prognosis and reduced response to immunotherapy, revealed a hazard ratio of 0.54 (95% CI, 0.35–0.85). This profound effect in a high-risk group highlights the potential of the therapeutic vaccine to address an unmet need within the advanced melanoma treatment landscape. The combination therapy also showed a consistent trend toward improved PFS across nearly all patient subgroups, including those without prior anti–PD-1 therapy, where the hazard ratio was 0.74 (range, 0.56–0.98), with a median PFS of 24.8 months.

Overall survival (OS) data for the trial remain immature, but a favorable trend was observed in the combination arm. The company expects the OS data to mature over the next 6 to 9 months, which could provide further evidence of the long-term clinical benefit of the imsapepimut and etimupepimut regimen. The combination was also well tolerated, with no new safety signals identified. Injection site reactions were the most common adverse events, occurring in 56% of patients in the combination arm, and were generally transient and resolved with treatment.

The mechanism of action of Cylembio, based on IO Biotech's T-win® platform, is designed to generate a T-cell response against both tumor cells and the immunosuppressive cells in the tumor microenvironment. This dual-action approach aims to enhance the efficacy of checkpoint inhibitors like pembrolizumab, which has become a standard of care in advanced melanoma. By targeting 2 distinct immunoregulatory pathways—IDO1 and PD-L1—the vaccine seeks to prime the immune system for a more robust antitumor response. The study’s results, while not statistically significant by the initial metric, support the biological premise of this approach and its potential to augment the effects of existing immunotherapies.

“We look forward to engaging with the FDA to determine a potential path to approval based on these data,” said Zocca in the press release. The company intends to discuss the totality of the data and explore a potential path to submission for a biologics license application for the treatment of advanced melanoma. Detailed results from the study are expected to be presented at an upcoming medical meeting.

REFERENCES:

1. IO Biotech Announces Clinical Improvement in Progression Free Survival Demonstrated in Pivotal Phase 3 Trial of Cylembio® plus KEYTRUDA® (Pembrolizumab) for the Treatment of First-line Advanced Melanoma, but Statistical Significance Narrowly Missed. News release. IO Biotech. August 11, 2025. Accessed August 12, 2025. https://tinyurl.com/mry8u77f

2. IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-013 /​ KN-D18). ClinicalTrials.gov. Updated January 9, 2024. Accessed August 12, 2025. https://clinicaltrials.gov/study/NCT05155254