FDA Advises Against BLA for Novel Vaccine Combo/Pembrolizumab in Melanoma

The FDA has advised that a biologics license application not be submitted for adjuvanted imsapepimut and etimupepimut (Cylembio) as treatment for first-line advanced melanoma based on data from the phase 3 IOB-013 trial (NCT05155254), according to a press release from the developer, IO Biotech.¹

The advisement came after the trial failed to meet statistical significance in its improvement of progression-free survival (PFS) with imsapepimut and etimupepimut combined with pembrolizumab (Keytruda) in the patient population.

The developer plans to continue discussions with the FDA regarding the design of a potentially new registrational study for the cancer vaccine candidate as a first-line treatment for advanced melanoma.

Updated results from the trial were shared in a press release in August 2025.²

The experimental combination achieved a median PFS of 19.4 months compared with 11.0 months with pembrolizumab monotherapy (HR, 0.77; 95% CI, 0.58-1.00; P = .056); the trial’s statistical significance threshold was P ≤.045.

Across virtually all subgroups, the experimental combination improved PFS. Notably, in patients with PD-L1–negative tumors, the median PFS was 16.6 months with the experimental regimen vs 3.0 months with pembrolizumab monotherapy (HR, 0.54; 95% CI, 0.35-0.85; P = .006). In a post hoc analysis of patients who did not receive prior anti–PD-1 therapy, the median PFS was 24.8 months vs 11.0 months, respectively (HR, 0.74; 95% CI, 0.56-0.98; P = .037).

At the time of reporting, a trend toward improvement for overall survival (OS) was observed, although data were not mature (HR, 0.79; 95% CI, 0.57-1.10).

“We had a productive meeting with [the] FDA; while this is not the outcome we had hoped for, we respect [the] FDA’s feedback and remain confident in the therapeutic potential of [adjuvanted imsapepimut and etimupepimut],” stated Mai-Britt Zocca, PhD, president and chief executive officer of IO Biotech, in the press release.¹ “We look forward to continuing the dialogue with [the] FDA to align on the design for a potential new registrational study. Additionally, we plan to discuss the data from our IOB-013 study with European regulators and determine a path to submission in the EU.”

The trial enrolled a total of 407 patients with unresectable or metastatic melanoma across 100 centers in the US, Europe, Australia, Turkey, Israel, and South Africa, who were randomly assigned to receive either adjuvanted imsapepimut and etimupepimut plus pembrolizumab (n = 203) or pembrolizumab monotherapy (n = 204).

Patients received adjuvanted imsapepimut and etimupepimut subcutaneously at 85 µg every 3 weeks for up to 35 cycles, with an additional dose given during the induction period on day 8 of cycles 1 and 2.³ In both groups, pembrolizumab was administered intravenously at 200 mg every 3 weeks for up to 35 cycles.

Eligible patients had histologically or cytologically confirmed stage III or IV melanoma per AJCC 8th edition guidelines not amenable to local therapy, had at least 1 measurable lesion per RECIST v1.1 criteria, had provision of archival or newly acquired biopsy tissue, and were treatment naïve with no previous systemic anticancer therapy for unresectable or metastatic melanoma.

Those with known or suspected central nervous system metastases, those who received prior radiotherapy within 2 weeks of trial treatment, and those with BRAFV600-positive disease experiencing rapid progression were among the excluded patient groups.

The trial’s 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 incidence of adverse events (AEs) and serious AEs.

Regarding safety, the combination was well tolerated, and no new safety signals were observed. The most commonly reported AEs with the combination were injection site reactions (56%), although most were transient and resolved on treatment.

References

1. IO Biotech provides update following pre-BLA meeting with FDA. News release. IO Biotech. September 29, 2025. Accessed September 30, 2025. https://tinyurl.com/4jrysyxw
2. 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 September 30, 2025. https://tinyurl.com/yzkcvvc2
3. IO102-IO103 in combination with pembrolizumab versus pembrolizumab alone in advanced melanoma (IOB-013 /​ KN-D18). ClinicalTrials.gov. Updated August 28, 2025. Accessed September 30, 2025. https://tinyurl.com/umnaztt8