On May 31, 2024 Immunocore Holdings plc (Nasdaq: IMCR) ("Immunocore" or the "Company"), a commercial-stage biotechnology company pioneering and delivering transformative immunomodulating medicines to radically improve outcomes for patients with cancer, infectious diseases and autoimmune diseases, reported Phase 1 data with the first off-the-shelf ImmTAC targeting PRAME, brenetafusp (IMC-F106C), in patients with late-line, post-checkpoint cutaneous melanoma (Press release, Immunocore, MAY 31, 2024, View Source [SID1234643903]). Brenetafusp was shown to be well tolerated, in monotherapy and in combination with anti-PD1, and demonstrated durable clinical benefit.
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"Brenetafusp continues to demonstrate promising monotherapy clinical activity in late-line cutaneous melanoma patients who were previously treated with checkpoint therapies," said Dr. Omid Hamid, Chief, Translational Research and Immunotherapy, Co-Director, Melanoma Therapeutics at Cedars-Sinai Cancer at the Angeles Clinic and Research Institute. "The disease control and PFS benefit for these brenetafusp-treated melanoma patients compares favorably to data with other immunotherapies."
"The best measure of brenetafusp monotherapy activity is disease control, which is observed in 56% of checkpoint pre-treated melanoma patients," said David Berman, Head of Research and Development. "We expect brenetafusp PFS to be even higher in first-line based on our analysis of blood T cell fitness. These data points, in conjunction with the significant molecular response and the expected additive benefit of combining with an active anti-PD1, provide confidence for PFS as an endpoint in our ongoing Phase 3 first-line trial."
Phase 1 data in post-checkpoint cutaneous melanoma
As of 18 March 2024, 47 patients have received brenetafusp (IMC-F106C) monotherapy at clinically active target dose levels. All monotherapy treated patients had received prior immune checkpoint inhibitors (100% anti-PD1, 81% anti-CTLA4). PRAME expression was high amongst evaluable patients (median H score of 215). Only 11% of patients had PRAME negative tumors, as measured by immunohistochemistry.
Brenetafusp was well-tolerated, with treatment-related adverse events (TRAEs) that were manageable and consistent with the mechanism of action. The most frequent TRAE reported was Grade 1 or 2 cytokine release syndrome (CRS) and rash; these events occurred predominantly following the initial three doses. There were no Grade 3 or higher CRS TRAEs.
Of the 47 monotherapy patients, 36 had a RECIST evaluable tumor assessment. The disease control rate (DCR), consisting of partial response (PR) and stable disease (SD), was 56% including 4 PR (ORR 11%) and 16 SD (44%). Durable tumor reduction, confirmed by at least one subsequent scan, was observed in 28% of patients and is an attribute of the ImmTAC platform1. Clinical benefit was enriched in the 31 evaluable PRAME positive patients. The DCR in this group was 58% and included all 10 patients (32%) with confirmed tumor reduction.
Both median progression free survival (mPFS) and 6-month overall survival (OS) rates were greater in PRAME positive than in PRAME negative monotherapy patients: 4.2 vs 2.1 months and 95% vs 40%, respectively.
42% of ctDNA-evaluable, PRAME positive monotherapy patients had a molecular response (10/24) and there was a trend for longer PFS and OS in molecular responders. No ctDNA-evaluable PRAME negative patients had ctDNA reduction.
In addition to the monotherapy patients treated with brenetafusp, there were 9 cutaneous melanoma patients who received brenetafusp in combination with an anti-PD1 (pembrolizumab), all of whom had received prior checkpoint inhibitors (100% prior anti-PD1, 89% prior CTLA4). Overall, patients were more heavily pre-treated in the combination cohort compared to monotherapy (median prior lines: 4 vs 2; PD-1 refractory: 67% vs 30%). Brenetafusp in combination with pembrolizumab was well tolerated, with TRAEs that were manageable and consistent with the mechanism of action of both agents. There was one dose-limiting toxicity (transaminitis) reported in one patient with prior history of checkpoint inhibitor induced autoimmune hepatitis.
Of the 7 patients evaluable for efficacy in combination, 4 achieved disease control including 1 ongoing PR (confirmed after the data cut off for the presentation), and 3 of the 4 ctDNA evaluable patients having molecular response.
In 41 gene-expression evaluable monotherapy patients, a gene signature was identified from baseline peripheral blood that was a measure of systemic T cell fitness. Patients with gene signature expression levels greater than or equal to the median had higher clinical benefit including a median PFS of 6 months and DCR of 69%, compared to those with less than the median gene expression levels (2 months and 42%, respectively). Patients with only 1-2 prior lines of therapy had higher T cell fitness gene signature, on average, than those with 3 or more prior lines of therapy.
The advanced cutaneous melanoma data from the ongoing Phase 1/2 trial of brenetafusp will be presented today at 2:45 PM CT / 3:45 PM ET, in the Melanoma/Skin Cancers oral abstract session at the 2024 American Society of Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The presentation will be accessible in the ‘Events & Presentations’ section of the Investor Relations section of the Company’s website.
PRISM-MEL-301 – First PRAME Phase 3 clinical trial with brenetafusp in first-line advanced cutaneous melanoma
The Company is enrolling patients in a registrational Phase 3 clinical trial with brenetafusp in first-line advanced cutaneous melanoma (CM) with a primary endpoint of progression-free survival (PFS) (NCT06112314). The trial will randomize HLA-A*02:01-positive, first-line advanced CM patients to brenetafusp + nivolumab versus a control arm of either nivolumab or nivolumab + relatlimab, depending on the country where the patient is enrolled.
Under the terms of a clinical trial collaboration and supply agreement, Immunocore will sponsor and fund this registrational Phase 3 clinical trial, and Bristol Myers Squibb will provide nivolumab.
Audio Webcast
Immunocore will host a conference call today, May 31, 2024 at 7:15 PM ET / 6:15 PM CT, to discuss the Phase 1 PRAME expansion data and Phase 3 registrational trial in cutaneous melanoma. The call will also be available via webcast by visiting the Events & Presentations section on Immunocore’s website. A replay of this webcast will be available for 30 days.
Conference Call Details:
U.S. (toll-free): 877-405-1239
International (toll): +1 201-389-0851