BNT111/Cemiplimab Combo Significantly Improves ORR in Unresectable Melanoma

The safety profile of BNT111 plus cemiplimab was consistent with previous trials assessing BNT111 with anti–PD-L1 treatments.

Investigational mRNA cancer immunotherapy, BNT111, in combination with anti–PD-1 monoclonal antibody cemiplimab (Libtayo), has reached the primary end point of overall response rate (ORR) in a phase 2 clinical trial (NCT04526899) for patients with unresectable stage III or IV melanoma, according to a news release from the developer, BioNTech.¹

The combination therapy demonstrated a significant ORR improvement compared with historical control populations in this treatment setting and indication. Additionally, both randomized monotherapy arms showed meaningful activity. The ORR with cemiplimab alone was in line with historical control rates reported with anti–CTLA-4 and anti–PD-L1 treatments among this patient group. Treatment was well tolerated in the combination therapy arm, and the safety was consistent with previous trials assessing BNT111 with anti–PD-L1 treatments. Secondary end points were not mature as of primary analysis.

“These phase 2 results mark a significant step towards our vision of personalized cancer medicine.” Özlem Türeci, MD, chief medical officer and co-founder at BioNTech, said in a news release on the topline results announcement.¹ “These data are a proof of concept for us in 3 dimensions: First, for our decade-long improved mRNA cancer vaccine technology that uses uridine mRNA chemistry, a non-coding backbone that is engineered for optimal translational performance and our proprietary lipoplex formulation for delivery. Second, for our computational approaches for selecting suitable tumor antigens for our cancer indication-specific FixVac platform candidates. Third, for our strategy to combine synergistic modalities, in this case BNT111, with an established immune checkpoint treatment.”

The open-label, randomized, phase 2 trial randomly assigned 184 patients 2:1:1 to receive either BNT111 in combination with cemiplimab in arm 1, BNT111 monotherapy in arm 2, or cemiplimab monotherapy in arm 3. Furthermore, patients who experience disease progression in the monotherapy arms have the option to receive combination therapy for ongoing treatment following re-consent. Both therapies are administered intravenously.

The primary end point is ORR in the combination therapy arm for up to 24 months.² Secondary end points include ORR in each of the monotherapy arms, duration of response (DOR), disease control rate (DCR), time to response (TTR), and progression-free survival (PFS), all for a time frame of up to 24 months.

Inclusion criteria for the study include adult patients with histologically confirmed unresectable stage III or IV metastatic cutaneous melanoma who have confirmed disease progression after undergoing an approved anti–PD-1 or anti–PD-L1 regimen. Additional eligibility criteria include having undergone 1 to 5 lines of therapy, tolerability of anti–PD-1 or anti–PD-L1 therapy, known BRAF mutation status, and an ECOG performance status of 0 to 1.

Exclusion criteria for the study include patients with a history of uveal, acral, or mucosal melanoma; evidence within the past 5 years of significant autoimmune disease requiring treatment with systemic immunosuppressive treatments; and those with primary immunodeficiencies, including either cellular or combined T and B cell. Additionally, patients with uncontrolled chronic infection due to immunodeficiency diagnoses, hepatitis B or C infection, or another primary malignancy not in complete remission for at least 2 years before study enrollment were excluded.

Developers intend on presenting the data at an upcoming medical conference and submit the findings in a peer-reviewed journal for publication.

BNT111 received FDA fast track status in November 2021 for patients with anti–PD-1 refractory or relapsed unresectable stage III or IV melanoma.³ Furthermore, BNT111 monotherapy was granted orphan drug designation for treatment of stage IIB to IV melanoma in the same year.

References

1. BioNTech announces positive topline phase 2 results for mRNA immunotherapy candidate BNT111 in patients with advanced melanoma. News release. BioNTech. July 30, 2024. Accessed July 30, 2024. https://tinyurl.com/mr2xz8cs
2. Trial with BNT111 and cemiplimab in combination or as single agents in patients with anti-PD-1-refractory/​relapsed, unresectable stage III or IV melanoma. ClinicalTrials.gov. Updated March 6, 2024. Accessed July 30, 2024. https://clinicaltrials.gov/study/NCT04526899
3. BioNTech receives FDA fast track designation for its FixVac candidate BNT111 in advanced melanoma. News release. BioNTech. November 19, 2021. Accessed July 30, 2024. https://tinyurl.com/69493dr4