Repare Therapeutics Reports Positive Initial Data from Phase 1 MINOTAUR Trial of Lunresertib with FOLFIRI at ESMO GI

Repare Therapeutics Inc., a precision oncology company, has released promising early data from their ongoing Phase 1 MINOTAUR clinical trial. This trial evaluates lunresertib (RP-6306) combined with FOLFIRI in patients with advanced solid tumors. The findings were presented by Dr. Elisa Fontana from the Sarah Cannon Research Institute UK at the European Society of Medical Oncology (ESMO) Gastrointestinal (GI) Cancers Congress 2024 in Munich, Germany.

Dr. Fontana highlighted the significance of the trial results, noting the potential efficacy and tolerability of the lunresertib and FOLFIRI combination in tumors that constitute 20% of all gastrointestinal cancers. This combination treatment shows promise for patients with CCNE1 amplification and deleterious FBXW7 mutations, who typically face poor prognoses and limited treatment options. Notably, some patients, particularly those with colorectal cancer (CRC), have experienced prolonged benefits from this therapy.

Lunresertib is a pioneering small molecule PKMYT1 inhibitor targeting CCNE1 amplification, FBXW7, and PPP2R1A alterations in solid tumors. It is currently being tested in combination with other therapies across several Phase 1 and Phase 2 trials, along with multiple investigator-sponsored studies.

The Phase 1 MINOTAUR trial (NCT05147350) is a multi-center, open-label, dose-escalation study aimed at evaluating the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of lunresertib combined with FOLFIRI in advanced solid tumors. The primary objectives were safety, tolerability, and determining the recommended Phase 2 dose (RP2D) and schedule. Secondary objectives included pharmacokinetics, preliminary evidence of anti-tumor activity, pharmacodynamics, and circulating tumor DNA (ctDNA) monitoring. As of May 2, 2024, 38 patients had been enrolled in the trial.

Key findings from the trial include:
1. The preliminary RP2D was established at 60mg BID lunresertib continuous plus standard FOLFIRI.
2. The combination showed promising efficacy in patients with tumors harboring CCNE1 amplification and FBXW7 mutation alterations.
3. The overall response rate (OR) across tumor types was 18.2%, including four confirmed and two unconfirmed partial responses, regardless of prior irinotecan exposure.
4. The prolonged clinical benefit rate (CBR) across tumor types, primarily digestive system tumors, was 51.5%, with 46.7% of recurrent CRC patients showing benefits.
5. Patients with CRC exhibited a prolonged duration of therapy, with 40% of irinotecan-naïve patients and 20% of irinotecan-experienced patients on treatment for over nine months.
6. The ctDNA molecular response rate was 61% among evaluable patients.
7. Lunresertib combination therapy was well tolerated, with no safety-related treatment discontinuations at the preliminary RP2D.
8. The most common Grade 3/4 treatment-related adverse events (TRAEs) were neutropenia and leukopenia, consistent with FOLFIRI alone, and reversible with FOLFIRI interruption. Low-grade, reversible rash rates were also in line with lunresertib monotherapy.

Dr. Maria Koehler, Executive Vice President and Chief Medical Officer of Repare, emphasized the encouraging tolerability and early antitumor efficacy data. She noted that the combination of lunresertib and FOLFIRI in this heavily pretreated patient population merits further development in a randomized Phase 2 study. This combination could offer a new therapeutic option for tumors with CCNE1 amplification and FBXW7 mutation alterations in gastrointestinal cancers, which are typically associated with poor outcomes and have no approved treatment options.

Repare Therapeutics is dedicated to discovering and developing targeted cancer therapies focusing on genomic instability and DNA damage repair. Their pipeline includes several promising candidates, such as lunresertib and camonsertib, and they continue to explore additional preclinical programs.