The investigational therapeutic cancer vaccine Cylembio (imsapepimut and etimupepimut) combined with pembrolizumab demonstrated clinical improvement in progression-free survival compared to pembrolizumab monotherapy in patients with advanced melanoma, according to results from the pivotal phase 3 IOB-013/KN-D18 trial.
The combination achieved a median progression-free survival of 19.4 months versus 11.0 months with pembrolizumab alone, representing a hazard ratio of 0.77 (95% CI, 0.58-1.00; p=0.056). While the prespecified statistical significance threshold of p≤0.045 was narrowly missed, the results showed consistent clinical benefit across multiple patient subgroups.
Pronounced Benefits in PD-L1-Negative Patients
The most striking results were observed in patients with PD-L1-negative tumors, where the combination demonstrated a hazard ratio of 0.54 (95% CI, 0.35-0.85; nominal p=0.006). In this subgroup, patients receiving Cylembio plus pembrolizumab (n=67) achieved a median PFS of 16.6 months compared to 3.0 months for those receiving pembrolizumab monotherapy (n=63).
"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," said Omid Hamid, MD, Director of Clinical Research and Immunotherapy at The Angeles Clinic and Research Institute. "The significant benefit seen across patients with poor prognostic factors, including PD-L1 negative patients, cannot be overlooked."
Study Design and Patient Population
The randomized, open-label phase 3 trial enrolled 407 patients across more than 100 centers in the United States, Europe, Australia, Turkey, Israel, and South Africa, with enrollment completed in December 2023. Patients were randomized to receive either Cylembio in combination with pembrolizumab (n=203) or pembrolizumab alone (n=204).
The primary endpoint was progression-free survival as assessed by a blinded independent review committee per RECIST v1.1. Secondary endpoints included overall response rate, overall survival, durable objective response rate, complete response rate, duration of response, time to complete response, disease control rate, and safety assessments.
Additional Efficacy Findings
In a post hoc analysis of patients without prior anti-PD-1 treatment (n=371), the combination yielded even greater benefit with a hazard ratio of 0.74 (95% CI, 0.56-0.98; nominal p=0.037), achieving a median PFS of 24.8 months versus 11.0 months for pembrolizumab alone.
Although overall survival data remain immature, a trend toward improvement was observed with the combination (HR, 0.79; 95% CI, 0.57-1.10). The company expects OS data to mature over the next six to nine months.
Safety Profile
The combination was well-tolerated with no new safety signals identified. Injection site reactions were the most frequently reported adverse events in the combination arm, occurring in 56% of patients. These reactions were transient and resolved during treatment.
"These data show the potential of a therapeutic cancer vaccine in patients with metastatic melanoma," said Jessica Hassel, MD, Professor at the Department of Dermatology and National Center for Tumor Diseases at the University Hospital Heidelberg, Germany, and lead enrolling investigator. "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."
Regulatory Next Steps
Based on these findings, IO Biotech plans to meet with the US FDA this fall to review the totality of data and discuss potential next steps for submission of a Biologics License Application for the treatment of advanced melanoma. The company also intends to present more detailed efficacy and safety results at an upcoming medical meeting.
"In this study, we observed a highly encouraging improvement in PFS and consistent trend in OS in patients treated with [imsapepimut and etimupepimut]," said Mai-Britt Zocca, PhD, president and chief executive officer of IO Biotech. "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."
Mechanism of Action
Cylembio is an investigational, immunomodulatory, off-the-shelf therapeutic cancer vaccine designed to activate T-cell expansion against IDO1-positive and/or PD-L1-positive cells in the tumor microenvironment. The vaccine is based on IO Biotech's T-win platform, which targets both tumor cells and immune-suppressive cells in the tumor microenvironment.
