FDA Recommends Against Immediate BLA Filing for Melanoma Vaccine Candidate

IO Biotech has announced that the U.S. Food and Drug Administration (FDA) has advised the company not to submit a Biologics License Application (BLA) for imsapepimut and etimupepimut, adjuvanted (cylembio; IO Biotech) based on current phase 3 trial data. The decision follows a pre-BLA meeting with the agency, during which the FDA determined that results from the pivotal IOB-013/KN-D18 trial did not meet the necessary threshold for regulatory submission.^1-2

“In this study, patients treated with Cylembio in combination with pembrolizumab have achieved the longest median PFS ever observed in a phase 3 clinical study in advanced melanoma, and in the PD-L1 negative population, patients achieved a remarkable 16.6 months of median PFS, compared to 3.0 months in patients treated with pembrolizumab alone,” said Omid Hamid, MD, director, clinical research and immunotherapy at The Angeles Clinic and Research Institute, A Cedars Sinai Affiliate, in a press release. “The significant benefit seen across patients with poor prognostic factors, including PD-L1 negative patients, cannot be overlooked. 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.”

While drug demonstrated an improvement in progression-free survival (PFS) compared with pembrolizumab monotherapy, the trial narrowly missed statistical significance. IO Biotech has indicated its intent to continue discussions with the FDA regarding the design of a new registrational study that could support a future submission.

Key Clinical Findings

The IOB-013/KN-D18 trial was a pivotal phase 3 study evaluating the combination of imsapepimut and etimupepimut, adjuvanted, with pembrolizumab versus pembrolizumab alone in patients with advanced melanoma. Enrollment was completed in December 2023, and topline results were disclosed in the third quarter of 2025. While a favorable trend in PFS was observed, it fell short of the statistical significance required for regulatory approval.

In addition to the melanoma trial, IO Biotech is conducting 2 phase 2 basket studies of imsapepimut and etimupepimut, adjuvanted, in combination with pembrolizumab. These include:

• IOB-022/KN-D38: First-line treatment of patients with advanced solid tumors.
• IOB-032/PN-E40: Neo-adjuvant and adjuvant treatment in solid tumors.

Both studies have completed enrollment, and results will inform the broader applicability of the therapy beyond melanoma.

Mechanism of Action

This is an investigational, off-the-shelf therapeutic cancer vaccine designed to target the tumor microenvironment (TME). The vaccine consists of 2 peptides, imsapepimut and etimupepimut, adjuvanted to enhance immune response. By stimulating T cell activation and expansion against IDO1-positive and PD-L1–positive cells, Cylembio aims to eliminate both tumor cells and immunosuppressive cells within the TME. This dual mechanism has been explored in combination with pembrolizumab, an anti–PD-1 therapy, to potentially augment checkpoint blockade efficacy.

Regulatory and Strategic Outlook

IO Biotech plans to continue regulatory dialogue with both the FDA and European authorities. The company has stated it will seek guidance from EU regulators to evaluate whether submission of the existing data package may be feasible in Europe.

To extend its financial runway, IO Biotech is restructuring its operations, including a 50% workforce reduction. The restructuring is expected to result in a one-time charge of $1.0–$1.5 million in the third quarter of 2025. Following these measures, the company projects sufficient capital to support operations into the first quarter of 2026.

Clinical Implications

For clinicians involved in the care of patients with advanced melanoma, the update underscores both the promise and challenges of therapeutic cancer vaccines. While the concept of leveraging tumor-associated antigens such as IDO1 and PD-L1 to enhance immune recognition remains compelling, the FDA’s decision highlights the necessity of robust statistical significance in pivotal studies.

Checkpoint inhibitors have transformed the melanoma treatment landscape, yet resistance and limited durability of response remain unmet clinical needs. The drug’s mechanism, if validated in future trials, could offer an adjunctive strategy to improve patient outcomes. Until additional registrational data are available, it remains investigational and is not FDA-approved.

References

1. IO Biotech provides update following pre-BLA meeting with FDA. News release. IO Biotech. Published September 29, 2025. Accessed October 2, 2025. https://investors.iobiotech.com/news-events/news/news-details/2025/IO-Biotech-Provides-Update-Following-Pre-BLA-Meeting-with-FDA/default.aspx
2. 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. Published August 11, 2025. Accessed October 2, 2025. https://investors.iobiotech.com/news-events/news/news-details/2025/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/default.aspx