On June 26, 2024 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported positive initial data from the ongoing Phase 1 MINOTAUR clinical trial evaluating lunresertib (RP-6306) in combination with FOLFIRI in patients with advanced solid tumors (Press release, Repare Therapeutics, JUN 26, 2024, View Source [SID1234644560]). The data are being presented in a mini oral presentation by Elisa Fontana, M.D., Ph.D., Medical Director, Sarah Cannon Research Institute UK at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Gastrointestinal (GI) Cancers Congress 2024, being held June 26-29 in Munich, Germany.

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"The initial results from the ongoing MINOTAUR trial demonstrate promising efficacy and tolerability data of lunresertib plus FOLFIRI in genomically defined tumors that represent 20% of all gastrointestinal cancers," said Dr. Elisa Fontana. "These early data suggest that lunresertib plus FOLFIRI combination therapy may effectively treat patients with CCNE1 amplification and deleterious FBXW7 mutations, who often suffer from poor prognosis and lack approved treatment options. We are excited by the prolonged benefit that some patients continue to experience on therapy, especially in colorectal cancer, and the favorable tolerability of this lunresertib combination therapy across tumor types, unlike other agents combined with irinotecan."

Lunresertib is a first-in-class precision oncology small molecule PKMYT1 inhibitor that targets CCNE1 amplification, FBXW7 and PPP2R1A alterations in solid tumors. Lunresertib is being evaluated in combination with other therapies across several Phase 1 and Phase 2 clinical trials, as well as in multiple investigator-sponsored trials.

Key Initial Findings from the Phase 1 MINOTAUR Clinical Trial:

MINOTAUR (NCT05147350) is a Phase 1, multi-center, open-label, dose-scalation study to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of lunresertib in combination with FOLFIRI in advanced solid tumors. Primary objectives of the study were safety and tolerability, and determination of the recommended Phase 2 dose (RP2D) and schedule. Secondary objectives were pharmacokinetics, preliminary evidence of anti-tumor activity, pharmacodynamics, and circulating tumor DNA (ctDNA) monitoring. As of May 2, 2024, the cutoff date for the data presented at the ESMO (Free ESMO Whitepaper) GI Congress, 38 patients were enrolled in the clinical trial.

Preliminary RP2D established as 60mg BID lunresertib continuous plus standard FOLFIRI
Promising efficacy in heavily pretreated population with tumors that harbor CCNE1 amplification and FBXW7 mutation alterations
Overall response (OR) across tumor types was 18.2% (n=33), including four confirmed and two unconfirmed partial responses (PR), regardless of prior irinotecan exposure
Prolonged clinical benefit rate (CBR) across tumor types, primarily digestive system tumors, was 51.5%, including 46.7% of patients with recurrent colorectal cancer (CRC)
Patients with CRC (n=15) had prolonged duration of therapy, with 40% (2/5) of irinotecan-naïve patients and 20% (2/10) of irinotecan-experienced patients on treatment for over nine months, compared to clinical benchmarks of 20% and 5-10%, respectively
ctDNA molecular response rate was 61% among evaluable patients (14/23)
Lunresertib combination therapy was well tolerated without excess toxicity above expected rates for lunresertib or standard FOLFIRI alone
No safety-related treatment discontinuations at preliminary RP2D
Neutropenia and leukopenia were the most common Grade 3/4 treatment-related adverse events (TRAE), consistent with that reported for FOLFIRI alone and reversible with FOLFIRI interruption
Rate of low-grade, reversible rash was consistent with lunresertib monotherapy experience
"The encouraging tolerability and early antitumor efficacy data and the potential duration of treatment advantage of the combination of lunresertib plus FOLFIRI in this heavily pretreated patient population warrant further development in a randomized Phase 2 study," said Maria Koehler, MD, PhD, Executive Vice President and Chief Medical Officer of Repare. "Lunresertib in combination with FOLFIRI has the potential to provide a new therapeutic option targeting tumors harboring CCNE1 amplification and FBXW7 mutation alterations in gastrointestinal tumors, which are known to be associated with poor prognosis and where there are currently no approved treatment options."