After Narrow Miss in Phase 3 Study, IO Biotech Ponders Next Steps for Immune-modulatory, Off-the-Shelf Cancer Vaccine

It’s been a bumpy month for IO Biotech, which will regroup after its lead candidate narrowly missed statistical significance for progression-free survival (PFS) in a phase 3 trial (NCT05155254) for patients with previously untreated advanced melanoma, with results presented Monday at the 50th Congress of the European Society for Medical Oncology (ESMO) in Berlin, Germany.¹ Topline results had been shared with FDA weeks prior, and Fierce Biotech reported that meeting prompted the company to lay off half its employees.²

IO Biotech is developing the immune-modulatory cancer vaccine Cylembio (imsapepimut and etimupepimut, adjuvanted) to combine with the PD-1 inhibitor pembrolizumab (Keytruda; Merck). The phase 3 data in melanoma came 5 years after promising phase 1/2 results for 30 patients were presented at ESMO,³ showing how the vaccine, then used with nivolumab (Opdivo; Bristol Myers Squibb), met its primary end point with an objective response rate of 80%, and median PFS (mPFS) “was not reached for responding patients.”⁴

In an interview earlier this year with The American Journal of Managed Care^® (AJMC), IO Biotech co-founder Mads Hald Andersen, DMSc, PhD, explained how these off-the-shelf vaccines battle cancer by disrupting the tumor microenvironment (TME): they kill tumors cells and set loose effector T cells to create an anti-tumor, proinflammatory TME.⁴

Both company officials and lead investigator Jessical Hassel, MD, professor at the Department of Dermatology and National Center for Tumor Diseases at the University Hospital Heidelberg, Germany, who presented the results, say there are plenty of reasons to move forward. Data for the 407 patients show that the vaccine with pembrolizumab achieved a “clinically relevant” mPFS of 19.4 months compared with 11.0 months for pembrolizumab alone⁵—and results revealed what Hassel called a “profound” effect on patients with PD-L1–negative tumors, vs those with PD-L1–positive tumors.

“The phase 3 results in advanced melanoma, together with final data from our phase 2 basket trial, continue to build on the encouraging clinical evidence seen with Cylembio in combination with anti-PD-1 therapy,” Mai-Britt Zocca, PhD, president and CEO of IO Biotech, said in a statement.⁵ “These data reinforce Cylembio’s potential to serve as a first-line treatment option across multiple tumor types, and we remain committed to advancing novel immune-modulatory vaccines that may help people living with cancer.”

Results showed the following:^1,5

• For the primary end point, mPFS was 19.4 months for the vaccine-pembrolizumab combination and 11.0 months for pembrolizumab alone, for HR 0.77; 95% CI, 0.58-1.00, P = .0558; which missed the prespecified threshold for statistical significance of P ≤ .045).
• In most subgroups, outcomes in PFS favored the vaccine-pembrolizumab combination; among patients with PD-L1–negative tumors, the PFS difference between the combination and pembrolizumab alone was 16.6 vs 3.0 months; HR 0.54; 95% CI, 0.35-0.85).
• Advantages were also seen among those with BRAF V600 mutated tumors, (HR 0.60; 95% CI, 0.40-0.90), and with elevated lactate dehydrogenase, of LDH (HR 0.60; 95% CI, 0.39-0.92).
• Safety results showed no increase in immune-mediated adverse events (34.0% vs 38.4%) or treatment-related adverse events (TRAEs) of grade 3 or higher (14.5% vs 15.6%) compared with pembrolizumab alone. Injection-site reactions were reported in 56% of patients in the vaccine arm and were mostly grade ½.
• IDO1- and PD-L1–specific T-cell responses were expanded in the vaccine arm versus the pembrolizumab arm, which IO Biotech officials said demonstrate the therapy’s proposed immune-modulatory mechanism.⁵

In her presentation during proffered paper session, Hassel noted that the duration of response appeared to be longer in the vaccine arm, with no added systemic toxicity. Even among patients who discontinued treatment, the percentage of TRAEs was “almost exactly the same,” she noted, at about 15%.

During an interview with AJMC after the presentation, Hassel outlined why she believes the PD-L1–negative tumors had stronger responses to the combination. Although the team is just now getting the translational data to support the result, it makes sense—the vaccine, she said, was offering the bulk of the benefit to these patients.

“I think that the explanation is that PD-L1–negative tumors and PD-L1–positive tumors are just very different tumors,” she said. “We know already is that PD-L1 expression is associated with T-cell infiltration….I think if there's PD-1 negative tumors, you have not so many T cells around.” There may be more immunosuppressive cells, “but there is an immune-unfriendly environment in PD-L1–negative tumors, and that's the reason the immune-modulating vaccine works so well.”

Despite the many positive takeaways from the study, Hassel said a new trial is probably in order. “The world is very black and white. Even though the P value is missed very narrowly, it’s missed,” she said, and that will likely be the viewpoint of regulators.

She noted there are many other trials involving the vaccine, in other cancers and other settings—IO Biotech also presented phase 2 results at ESMO in non–small cell lung cancer, and there are neoadjuvant trials, too.

As always, Hassel said, “You do a trial, and you have many more questions afterwards than before.”

References

1. IO102-IO103 cancer vaccine plus pembrolizumab for first line (1L) advanced melanoma: primary phase III results (IOB-O13/KN-D18). Presented at: European Society for Medical Oncology, Berlin, Germany; October 17-21, 2025; Abstract LBA53.
2. Waldron J. IO Biotech lays off 50 employees after FDA derails cancer vaccine approval plan. Fierce Biotech. September 29, 2025. Accessed October 20, 2025. https://www.fiercebiotech.com/biotech/io-lays-50-employees-after-fda-derails-cancer-vaccine-approval-plan
3. Kjeldsen JW, Lorentzen CL, Martinenaite E, et al. A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma. Nat Med. 2021;27:2212-222. https://doi.org/10.1038/s41591-021-01544-x
4. Caffrey M. From “super skeptical” beginnings, a new immune-modulatory vaccine awaits phase 3 results. AJMC. May 3, 2025. Accessed October 21, 2025. https://www.ajmc.com/view/from-super-skeptical-beginnings-a-new-immune-modulatory-vaccine-awaits-phase-3-results
5. IO Biotech presents phase 3 results for Cylembio plus Keytruda (pembrolizumab) in first-line advanced melanoma at ESMO 2025. News release. IO Biotech. October 20, 2025. Accessed October 22, 2025. https://iobiotech.com/press-releases/