Cancer Vaccine Misses Mark in Phase 3 Advanced Melanoma Trial

IO Biotech's experimental cancer vaccine Cylembio failed to meet its primary goal in a phase 3 trial for advanced melanoma. The study evaluated Cylembio (imsapepimut and etimupepimut, adjuvanted) combined with Merck’s Keytruda (pembrolizumab) versus Keytruda alone in more than 400 patients with previously untreated advanced melanoma. While patients receiving the combination therapy showed improvement in progression-free survival, the results narrowly missed statistical significance.

Patients treated with the combination achieved a median progression-free survival of 19.4 months compared with 11 months for those receiving Keytruda alone, with a 23% reduction in the risk of disease progression or death.

Mai-Britt Zocca, Ph.D.

“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,” said Mai-Britt Zocca, Ph.D., president and chief executive officer of IO Biotech.

The open-label trial enrolled patients across more than 100 sites worldwide between 2022 and December 2023. An independent review committee assessed progression-free survival using standard cancer measurement criteria.

Despite missing the primary endpoint, several subgroups showed stronger responses. Patients with PD-L1 negative tumors — typically harder to treat with immunotherapy — saw particularly notable results. In this group of 130 patients, those receiving the combination had a median progression-free survival of 16.6 months versus 3 months for Keytruda alone, with a hazard ratio of 0.54.

Additionally, among the 371 patients who had not received prior anti-PD-1 treatment, the combination therapy showed a hazard ratio of 0.74 with median progression-free survival of 24.8 months versus 11 months.

A trend toward improved overall survival emerged, though data remains immature. The hazard ratio for overall survival was 0.79, and the company expects more mature data within six to nine months.

The combination therapy proved well tolerated with no new safety signals. Injection site reactions were the most common side effect, reported in 56% of patients receiving the combination. These reactions were temporary and resolved during treatment.

Cylembio works by stimulating T cells to target both tumor cells and immunosuppressive cells in the tumor microenvironment. The vaccine targets cells expressing IDO1 and PD-L1, proteins that help tumors evade the immune system.

"Given the notable safety profile and the strong clinical effect observed with Cylembio, as well as the unmet need in advanced melanoma patients, Cylembio, if approved, has the potential to become a new standard of care for patients with advanced melanoma," said Omid Hamid, M.D., director of clinical research and immunotherapy at The Angeles Clinic and Research Institute.

IO Biotech plans to meet with the FDA this fall to discuss the data and determine next steps for a potential biologics license application submission. The company will present detailed results at an upcoming medical meeting.

The trial represents one of several attempts to combine cancer vaccines with checkpoint inhibitors such as Keytruda to improve outcomes in melanoma, where approximately half of patients still experience disease progression within a year of starting treatment.

More than 100,000 new melanomas will be diagnosed in the United States this year, according to the American Cancer Society, and more than 8,400 people are expected to die from the condition. Melanoma is among the most aggressive forms of skin cancer, and while the introduction of immune checkpoint inhibitors over the past decade has significantly improved outcomes, many patients eventually stop responding.