Lunresertib/Camonsertib Gets Fast Tracked by FDA for CCNE1+ or FBXW7/PPP2R1A+ Ovarian Cancer

The FDA granted fast track drug designation to lunresertib (RP-6306) in combination with camonsertib (RP-3500) as a potential treatment option for adult patients with platinum-resistant ovarian cancer harboring CCNE1 amplifications, FBXW7 mutations, or PPP2R1A mutations.¹

The combination previously received fast track designation from the regulatory agency for the treatment of patients with CCNE1-amplified, FBXW7-mutated, or PPP2R1A-mutated endometrial cancer.

The ongoing phase 1 MYTHIC trial (NCT04855656) is evaluating the lunresertib alone or in combination with camonsertib or Debio 0123 in patients with advanced solid tumors.

The study includes dose-expansion cohorts investigating lunresertib plus camonsertib for the treatment of patients with ovarian or endometrial cancer harboring CCNE1 amplifications, FBXW7 mutations, or PPP2R1A mutations.¹

“The FDA’s decision to grant fast track designation supports our goal of quickly and efficiently developing the lunresertib-camonsertib combination for patients with genomically-defined platinum-resistant ovarian cancer,” Maria Koehler, MD, PhD, executive vice president and chief medical officer of Repare Therapeutics, stated in a news release. “[Patients with] ovarian cancer need therapies that provide long-term benefit beyond that observed with standard of care. Our precision medicine approach targets treatment to patients who could most benefit from a well-tolerated alternative to chemotherapy.”

Lunresertib is a first-in-class, oral, small molecule PKMYT1 inhibitor, and initial results from MYTHIC showed that the agent displayed safety, tolerability, and early efficacy when administered alone and in combination with camonsertib, which is an oral, potent and selective ATR inhibitor.³

The multicenter, open-label, dose-escalation and -expansion MYTHIC study is enrolling patients at least 12 years of age with locally advanced or metastatic resistant or refractory solid tumors. Notably, patients under 18 years of age are required to weigh at least 40 kg. Patients also need to have tumors that harbor CCNE1 amplifications per a tumor or plasma next-generation sequencing (NGS) test or fluorescence in situ hybridization; FBXW7 deleterious mutations per a tumor or plasma NGS test; or PPP2R1A deleterious mutations per a tumor or plasma NGS test.²

Other key inclusion criteria consist of a Lansky performance status of at least 50% for patients 16 years of age and younger or an ECOG performance status of 0 or 1 (or 2 for module 1) for patients over 16 years of age; measurable disease per RECIST 1.1 criteria; and acceptable hematologic and organ function.

Patients are being excluded if they receive chemotherapy or a small molecule antineoplastic agent within 21 days or less than 5 half-lives prior to first dose of study drug; undergo major surgery within 4 weeks prior to first study dose; have uncontrolled, symptomatic brain metastases; or have uncontrolled hypertension.

In the non-randomized study, patients are receiving lunresertib alone; lunresertib in combination with camonsertib; or lunresertib in combination with Debio 0123, which is an oral WEE1 inhibitor. Treatment is being continued until disease progression, unacceptable toxicity, or investigator/patient decision.

The primary end points of the study include safety and tolerability; defining the maximum tolerated dose and recommended phase 2 dose of lunresertib alone, lunresertib plus camonsertib, and lunresertib plus Debio 0123; and pharmacokinetics. Preliminary antitumor activity of the 3 regimens is serving as a secondary end point. Other secondary end points include plasma concentrations of lunresertib monotherapy; the relationship between pharmacodynamic biomarkers and pharmacokinetics of lunresertib at different dose levels and schedules; and plasma concentrations for lunresertib plus camonsertib.

In module 2, dose-expansion cohorts each include approximately 20 to 30 patients with ovarian or endometrial cancer. Data from these expansion cohorts are expected to be presented in the fourth quarter of 2024.¹

References

1. Repare Therapeutics announces fast track designation granted by the FDA for lunresertib in combination with camonsertib for the treatment of platinum-resistant ovarian cancer. News release. Repare Therapeutics. June 4, 2024. Accessed June 5, 2024. https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-fast-track-designation-granted-fda
2. Study of RP-6306 alone or in combination with RP-3500 or Debio 0123 in patients with advanced solid tumors (MYTHIC). ClinicalTrials.gov. Updated April 15, 2024. Accessed June 5, 2024. https://clinicaltrials.gov/study/NCT04855656
3. Lunresertib (RP-6306) PKMYT1 inhibitor. Repare Therapeutics. Accessed June 5, 2024. https://www.reparerx.com/rp-6306-pkmyti-inhibitor/