BERLIN — Combining the off-the-shelf anticancer vaccine IO102-IO103 with pembrolizumab does not offer any progression-free survival (PFS) benefit in patients with untreated advanced melanoma vs pembrolizumab alone, revealed the IOB-013 trial, presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2025 on October 20.

IO102-IO103 plus pembrolizumab “showed an improved median progression-free survival of 19.4 months versus 11.0 months with pembrolizumab alone,” said study presenter Jessica C. Hassel, MD, Department of Dermatology, Heidelberg University, and National Centre for Tumor Diseases, Heidelberg, Germany.

“However, the statistical significance threshold was narrowly missed,” she added, despite “a profound effect” with the combination seen in the subgroup of patients with PD-L1-negative tumors.

Hassel concluded that the results “support the potential benefit of this immune-modulatory cancer vaccine in combination with pembrolizumab in patients with untreated advanced melanoma.”

Discussant Ines Pires da Silva, MD, PhD, Melanoma Institute Australia, the University of Sydney, Sydney, Australia, who was not involved in the study, said she wanted to “highlight this novel and mechanistically rational combination,” especially in terms of its improvement in PFS for selected subgroups and its favorable and manageable safety profile.

However, she continued that “there are some ‘buts,’” the most important one being that the overall PFS difference between IO102-IO103 plus pembrolizumab and pembrolizumab alone did not reach statistical significance.

da Silva also pointed to the relatively short follow-up of the trial and said that there are question markers over whether it was the right study population or the right control group and whether PD-L1 was the best biomarker, which underlines that “we still lack some biomarkers.”

She added that, although the trial did not reach statistical significance, “my question is: Is this clinically significant?” Comparing the current results with prior immunotherapy trials, she said that “clearly this combination with a vaccine is very safe but does not seem to add much” in terms of efficacy.

da Silva continued that unanswered questions around this approach include whether the vaccine is actually generating an antitumor immune response, whether baseline predictive biomarkers can be identified, and whether there are better immunomodulatory targets.

Hassel explained that IO102-IO103 is an immune-modulatory, off-the-shelf dual peptide anticancer vaccine that is administered subcutaneously and targets indoleamine-pyrrole 2,3-dioxygenase and PD-L1-positive tumor and immunosuppressive cells in the tumor microenvironment.

“This leads to a more immune-friendly tumor microenvironment, facilitating tumor killing by surrounding effector T cells,” she said.

Recently, a phase 1 or 2 trial was conducted in 30 patients with anti-PD-1 treatment-naive metastatic melanoma, in which the combination of IO102-IO103 with the immune checkpoint inhibitor nivolumab was found to have encouraging clinical activity, without greatly increasing systemic toxicity.

Methods and Results

For the phase 3 IOB-013 trial, patients with untreated unresectable stage III and metastatic stage IV melanoma and a good performance status were recruited. They were allowed to have had neoadjuvant or adjuvant therapy if the last dose was more than 6 months prior to study treatment. They could also have stable central nervous system disease.

The patients were randomly assigned to pembrolizumab every 3 weeks for up to 2 years, with or without the IO102-IO103 vaccine. They were stratified by disease stage and by BRAF V600 mutation status.

Hassel reported that 407 patients enrolled at approximately 100 sites globally. The median age was 71 years for those given the IO102-IO103 plus pembrolizumab group vs 69 years in the pembrolizumab-alone group. The majority (63.5% and 62.3%, respectively) were PD-L1-positive, while 58.6% and 59.3%, respectively, were BRAF V600 wild type. In addition, 65.5% and 64.2%, respectively, had lactate dehydrogenase (LDH) levels up to the upper limit of normal.

The results showed that, after a median follow-up of 23 months, combining IO102-IO103 and pembrolizumab did not significantly improve PFS, and so the trial did not meet its primary endpoint. The median PFS with IO102-IO103 plus pembrolizumab was 19.4 months vs 11.0 months with pembrolizumab, at a nonsignificant hazard ratio (HR) of 0.77 (P = .0558 vs a significance threshold of 0.045).

Trial Showed Interesting Results for Some Subgroups

The trial yields some interesting results for certain patient subgroups, said da Silva.

A subgroup analysis indicated that patients who were BRAF V600-mutated (HR, 0.60), PD-L1-negative (HR, 0.54), or who had LDH levels above the upper limit of normal (HR, 0.60) had a significant improvement in PFS with the combination vs pembrolizumab alone.

Indeed, for patients with PD-L1-negative tumors, the median PFS was 16.6 months in the IO102-IO103 plus pembrolizumab group vs just 3.0 months in the pembrolizumab-alone group. Among those with PD-L1-positive tumors, the median PFS was 22.1 months vs 16.6 months.

Further analysis revealed that the objective response rate was 44.8% for IO102-IO103 plus pembrolizumab vs 41.2% with pembrolizumab alone.

“The duration of response seemed to be longer in the vaccination arm,” Hassel noted, at HR for duration of confirmed objective response of 0.44.

Numerically, there were far more adverse events of any grade with IO102-IO103 plus pembrolizumab vs pembrolizumab, although the rates of treatment-related, immune-mediated, and serious grade 3-4 events were comparable.

The most common adverse events of any grade with the combination therapy were pruritus (21.0% vs 20.2% for pembrolizumab alone), fatigue (20.0% vs 18.7%), injection site swelling (15.5%; not applicable for pembrolizumab), and diarrhea (14.5% vs 13.1%).

The study was funded by IO Biotech ApS and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

Hassel declared having relationships with BMS, Novartis, Sanofi, MSD, Sun Pharma, Pierre Fabre, Immunocore, Delcath, Philogen, Onkowissen, Genentech, 4SC, BioNTech, Iovance, Regeneron, Replimune, Immatics, Pfizer, Genmab, Seagen, and IO Biotech.

da Silva declared having relationships with Roche, BMS, MSD, Novartis, Pierre Fabre, and Regeneron.