Imsapepimut and Etimupepimut Plus Pembrolizumab Shows Clinical Improvement in PFS for Advanced Melanoma

First-line treatment with adjuvanted imsapepimut and etimupepimut (Cylembio), an off-the-shelf therapeutic cancer vaccine, in combination with pembrolizumab (Keytruda) improved progression-free survival (PFS) vs pembrolizumab monotherapy in patients with advanced melanoma, according to data from the pivotal phase 3 IOB-013/KN-D18 trial (NCT05155254).

Although the prespecified statistical significance threshold (P ≤ .045) for the primary end point of PFS was narrowly missed, the combination achieved a HR of 0.77 (95% CI, 0.58–1.00; P = .056). The median PFS (PFS) with the vaccine plus pembrolizumab was 19.4 months vs 11.0 months with pembrolizumab alone.

Additionally, a pronounced benefit was seen in patients with PD-L1–negative tumors (HR, 0.54; 95% CI, 0.35-0.85; nominal P = .006); the median PFS of 16.6 months vs 3.0 months for patients in the combination (n = 67) vs monotherapy arms (n = 63), respectively. A trend toward improved overall survival (OS) with the combination vs monotherapy was also reported (HR, 0.79; 95% CI, 0.57–1.10), although OS data remain immature.

“In this study, we observed a highly encouraging improvement in PFS and consistent trend in OS in patients treated with [imsapepimut and etimupepimut],” Mai-Britt Zocca, PhD, president and chief executive officer of IO Biotech, stated in a news release. “The magnitude and durability of clinical effect observed consistently across subgroups supports our confidence in [imsapepimut and etimupepimut] and its potential as a treatment for advanced melanoma patients. We look forward to engaging with the FDA to determine a potential path to approval based on these data.”

IOB-013/KN-D18 Study Breakdown

IOB-013/KN-D18 was an open-label, randomized phase 3 pivotal study evaluating adjuvant imsapepimut and etimupepimut combination with pembrolizumab vs pembrolizumab monotherapy in patients with previously untreated, unresectable, or metastatic melanoma. Imsapepimut and etimupepimut is an investigational, immunomodulatory vaccine candidate designed to activate T-cell expansion against IDO1-positive and/or PD-L1–positive cells in the tumor microenvironment.

A total of 407 patients were enrolled onto the study across more than 100 centers in the United States, Europe, Australia, Turkey, Israel, and South Africa, with enrollment completed in December 2023.

The primary end point was PFS; secondary end points included overall response rate, OS, durable objective response rate, complete response rate, duration of response, time to complete response, disease control rate, and the incidence of adverse effects (AEs) and serious AEs to evaluate safety and tolerability. Biomarkers in blood and tumor tissue were assessed as exploratory end points.

Additional Efficacy and Safety Data

For patients who were not previously exposed to neoadjuvant or adjuvant anti–PD-1 therapy (n = 371), the combination yielded a greater PFS benefit vs pembrolizumab alone (HR, 0.74; 95% CI, 0.56–0.98; nominal P = .037), with a median PFS of 24.8 months vs 11.0 months, respectively. Notably, improvement in PFS was observed across nearly all subgroups, including those with poor prognostic factors.

The combination of imsapepimut and etimupepimut plus pembrolizumab was well tolerated, with no new safety signals identified. Injection site reactions were the most frequently reported AEs in the combination arm ( 56%). These effects were transient and resolved during treatment.

“These data show the potential of a therapeutic cancer vaccine in patients with metastatic melanoma,” Jessica Hassel, MD, a professor in the Department of Dermatology and National Center for Tumor Diseases at the University Hospital Heidelberg in Germany, and lead enrolling investigator for the phase 3 trial, added. “We were thrilled to play such an important part in this study and to have had the ability to offer our patients an investigational therapy that potentially offers improvements in PFS while not adding significant systemic toxicity.”

Next Steps for Investigating Imsapepimut and Etimupepimut

Based on these findings, IO Biotech plans to meet with the FDA in the fall of 2025 to review the totality of the data and discuss potential next steps for the submission of a biologics license application for the treatment of patients with advanced melanoma. The company also intends to present more detailed efficacy and safety results from the study at an upcoming medical meeting.

“The significant benefit seen across patients with poor prognostic factors, including PD-L1–negative patients, cannot be overlooked,” Omid Hamid, MD, director of clinical research and immunotherapy at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate in Los Angeles, California, concluded in the news release. “Given the notable safety profile and the strong clinical effect observed with [imsapepimut plus etimupepimut], as well as the unmet need in [patients with] advanced melanoma, [imsapepimut plus etimupepimut], if approved, has the potential to become a new standard of care for patients with advanced melanoma.”

Reference

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 11, 2025. https://iobiotech.com/press-releases/?workflow=6562e614-30a0-4300-9a37-ab75253933a2