Promising Phase 2 Results for BNT111 in Advanced Melanoma Treatment

New findings from the Phase 2 BNT111-01 trial reveal that combining BNT111 with cemiplimab-rwlc (Libtayo) shows significant potential in treating patients with PD-(L)1-relapsed/refractory melanoma. The trial demonstrated an objective response rate (ORR) of 18.1% (95% CI, 10.9%-27.4%; P = .0115), surpassing the null hypothesis of an ORR below 10%. These results were presented at the 2025 ESMO Congress.

The study’s best responses included a complete response (CR) rate of 11.7%, a partial response (PR) rate of 6.4%, and a stable disease (SD) rate of 37.2%. The disease control rate (DCR) was recorded at 55.3% (95% CI, 44.7%-65.6%). With a median follow-up of 15.7 months (range, 0.2-42.2), the median progression-free survival (PFS) was found to be 3.1 months (95% CI, 1.7-6.9), with a 24-month PFS rate of 24.9% (95% CI, 14.9%-36.1%). The median overall survival (OS) reached 20.7 months (95% CI, 14.4-28.3), with a 24-month OS rate of 47.8% (95% CI, 36.4%-58.4%).

Lead study author Paolo Ascierto, MD, a full professor of oncology at the University of Napoli Federico II and director at the Istituto Nazionale Tumori IRCCS Fondazione Pascale in Naples, Italy, highlighted the significance of these results. “The results indicated statistically significant improvement of BNT111 plus cemiplimab versus an assumed historical control ORR of 10% in heavily pretreated, PD-(L)1-relapsed/refractory advanced or metastatic cutaneous non-acral melanoma,” Ascierto stated.

The company had initially announced these positive topline results in July 2024, three years after BNT111 received fast track designation from the FDA for treating advanced melanoma. BNT111 is an investigational uridine RNA-based lipoplex cancer immunotherapy targeting nonmutated tumor-associated antigens, including NY-ESO-1, MAGE-A3, Tyrosinase, and TPTE.

Trial Design and Patient Demographics

The BNT111-01 trial was an open-label, randomized, multi-center interventional study aimed at evaluating the efficacy and safety of BNT111 combined with cemiplimab as a second-line treatment for patients with unresectable stage III or IV melanoma who had previously progressed on PD-(L)1 therapy. Participants had to demonstrate measurable disease, serum lactate dehydrogenase levels below the upper limit of normal, and had received up to five prior lines of therapy, including ipilimumab (Yervoy).

To be eligible, patients needed to enter the trial within six months of confirmed disease progression and had to have completed at least 12 weeks of treatment, which included a BRAF-based combination for those with BRAF-mutant disease. A total of 180 patients were enrolled and randomly assigned in a 2:1:1 ratio to receive either BNT111 plus cemiplimab (n = 94), BNT111 monotherapy (n = 46), or cemiplimab monotherapy (n = 44), all for a duration of up to 24 months.

Patients in the monotherapy arms could add the other agent upon confirmation of disease progression. The primary endpoint was the ORR assessed by blinded independent central review per RECIST 1.1 in the combination arm, which was compared against an assumed historical control ORR of 10%. Secondary endpoints included ORR in the monotherapy arms, duration of response, DCR, time to response, PFS, OS, safety, tolerability, and patient-reported outcomes.

Patient Outcomes and Safety Profile

Baseline characteristics revealed that the median age in the combination arm was 64.0 years (range, 18-84), with a majority being male (63.8%) and holding an ECOG performance status of 0 (78.7%). Most patients had stage IV disease at baseline (97.9%), with 44.7% diagnosed with M1c disease and between two to five prior therapies (56.4%). Notably, 56.4% were PD-(L)1 refractory, with 25.5% having liver metastases and 28.7% harboring BRAF V600 mutations.

The response rates for BNT111 as a monotherapy stood at an ORR of 17.4% (95% CI, 7.8%-31.4%), with best responses of CR at 13.0%, PR at 4.3%, and SD at 41.3%. The DCR in this arm was 58.7% (95% CI, 43.2%-73.0%). In comparison, cemiplimab monotherapy yielded an ORR of 13.6% (95% CI, 5.2%-27.4%), with best responses of CR at 4.5%, PR at 9.1%, and SD at 34.1%. The DCR for cemiplimab was 47.7% (95% CI, 32.5%-63.3%).

The median follow-up for the BNT111 arm was 11.8 months (range, 0.6-38.4), while for the cemiplimab arm, it was 16.9 months (range, 1.9-39.5). The median PFS for BNT111 monotherapy was 2.8 months (95% CI, 2.6-4.7), with a 24-month PFS rate of 20.9% (95% CI, 8.0%-37.9%). The median OS was recorded at 13.7 months (95% CI, 10.2-24.6), and the 24-month OS rate was 37.6% (95% CI, 22.7%-52.5%). In contrast, the cemiplimab monotherapy arm reported a median PFS of 3.2 months (95% CI, 1.5-5.0) and a median OS of 22.3 months (95% CI, 14.6-33.2).

The safety profile for the combination therapy indicated that treatment-emergent adverse events (TEAEs) associated with cytokine release included pyrexia (any grade, 76.1%; grade ≥3, 0%), hypertension (any grade, 12.0%; grade ≥3, 6.5%), and fatigue (any grade, 25.0%; grade ≥3, 3.3%). TEAEs were reported in 98.9% of cases, with 97.8% deemed related to BNT111 and 71.7% to cemiplimab.

Ascierto concluded that “BNT111, both as a monotherapy and in combination therapy, exhibited a manageable safety profile, which is primarily driven by the induction of cytokines through toll-like receptors by the single-stranded RNA immunotherapy.”

This trial presents a significant advance in melanoma treatment, illustrating the potential of BNT111 in combination with cemiplimab, particularly for patients previously resistant to PD-(L)1 therapy.