IO Biotech's experimental melanoma vaccine Cylembio fell short of its primary endpoint in a Phase 3 trial, but the Danish biotech company remains optimistic about potential regulatory approval based on promising subgroup analyses and the narrow margin by which the study missed statistical significance.
The Phase 3 IOB-013/KN-D18 trial, which enrolled more than 400 patients with newly diagnosed melanoma that couldn't be surgically removed or had metastasized, compared the combination of Cylembio plus Merck's immunotherapy Keytruda to Keytruda alone. While the combination showed clinical benefit, it failed to meet the prespecified statistical threshold for progression-free survival (PFS).
Trial Results Show Clinical Promise Despite Statistical Miss
Patients receiving the Cylembio-Keytruda combination achieved a median PFS of 19.4 months compared to 11.0 months for those on Keytruda monotherapy. The hazard ratio of 0.77 represented a 23% relative risk reduction in disease progression or death, but the p-value of 0.056 exceeded the prespecified significance level of p ≤ 0.045.
"It was a very narrow miss, just by a hair," said Mai-Britt Zocca, IO Biotech's CEO, during a Monday conference call with analysts.
The vaccine consists of engineered peptides designed to provoke an immune response against PD-L1 and IDO1 proteins expressed on tumor cells. Unlike personalized cancer vaccines being developed by companies like Moderna and BioNTech, Cylembio is designed as an "off-the-shelf" vaccine that would be simpler to manufacture.
Subgroup Analyses Reveal Stronger Benefits
Several prespecified subgroup analyses showed more pronounced benefits. Among patients who had not received prior neoadjuvant or adjuvant therapy (n=371), the combination therapy achieved a median PFS of 24.8 months versus 11.0 months with Keytruda alone, with a hazard ratio of 0.74 and nominal p-value of 0.037.
The most striking results emerged in patients with PD-L1-negative tumors, where the combination led to a median PFS of 16.6 months compared to just 3.0 months with Keytruda monotherapy. This represented a hazard ratio of 0.54 with a nominal p-value of 0.006.
Additionally, people who tested negative for a protein linked to immunotherapy responses showed a 46% relative risk reduction. This analysis was part of IO Biotech's pre-specified statistical plan, which may be viewed more favorably by regulators.
Regulatory Path Forward Despite Market Skepticism
IO Biotech executives indicated they will meet with the FDA in the third quarter to discuss the trial findings and hope to seek approval by the end of the year. The company believes the narrow statistical miss and positive subgroup data could support regulatory consideration.
However, investors remain skeptical of the approval prospects. IO Biotech's stock price fell more than 20% during Monday morning trading, adding to losses for a company that has lost most of its value since going public in 2021.
Competitive Landscape and Future Outlook
The vaccine approach enters a competitive immunotherapy arena that includes novel bispecific antibodies. Ivonescimab, a PD-1/VEGF bispecific from Akeso Biopharma and Summit Therapeutics, has demonstrated objective response rates of 45-55% and median PFS of up to 9 months in early-phase NSCLC studies. BioNTech and Bristol Myers Squibb's BNT327 is also advancing through Phase 3 trials in several solid tumors.
IO Biotech has stated it will engage in discussions with health authorities once overall survival data become available. The company's ability to establish a foothold in the melanoma treatment landscape will depend on longer-term outcomes, biomarker-driven patient positioning, and differentiation from increasingly sophisticated immunotherapeutic strategies currently in development.
