Lunresertib Plus Camonsertib Produces Durable Responses in Advanced Endometrial, Ovarian Cancer

Treatment with the combination of lunresertib (RP-6306) and camonsertib (RP-3500) led to durable responses in patients with heavily pretreated endometrial cancer and platinum-resistant ovarian cancer, according to data from the gynecologic expansion cohort of the phase 1 MYTHIC trial (NCT04855656).1

Findings showed that evaluable patients with endometrial cancer (n = 27) experienced an overall response rate (ORR) of 25.9% and a clinical benefit rate (CBR) of 48.1%. Five of the 7 responses were confirmed. The 24-week progression-free survival (PFS) rate was 43% (95% CI, 21%-63%).

In evaluable patients with platinum-resistant ovarian cancer (n = 24), lunresertib plus camonsertib generated an ORR of 37.5% and a CBR of 79%. Responses were confirmed in 4 of 9 responders. The 24-week PFS rate was 45% (95% CI, 22%-66%).

In all patients and tumor types treated with the recommended phase 2 dose of the combination (n = 67), lunresertib plus camonsertib demonstrated a favorable and differentiated safety profile. The most common adverse effect was grade 3 anemia (26.9%).

“Those patients with recurrent gynecologic cancers have limited treatment options as tumors often become resistant to standard-of-care therapy,” Brian Slomovitz, MD, MS, FACOG, director of Gynecologic Oncology and co-chair of the Cancer Research Center at Mount Sinai Medical Center in Miami Beach, Florida, stated in a news release. “They urgently need new treatment options. Repare [Therapeutics’] differentiated, biomarker-driven approach addresses this population and may offer a solution. These data support the potential of lunresertib plus camonsertib as a new treatment option to fill this unmet need for patients with endometrial and platinum-resistant ovarian cancers.”

Lunresertib is a first-in-class, small molecule PKMYT1 inhibitor designed to target cell cycle regulation in tumors harboring CCNE1 amplifications, deleterious FBXW7 alterations, or deleterious PPP2R1A alterations. Camonsertib is a potential best-in-class, oral, small molecule ATR inhibitor; ATR is a component of the DNA damage response pathway.

The first-in-human, global, open-label MYTHIC trial is evaluating the combination of lunresertib and camonsertib in patients with advanced solid tumors, including endometrial and ovarian cancer in a gynecologic cancer expansion cohort.

To enroll, patients are required to be at least 12 years of age with locally advanced or metastatic resistant or refractory solid tumors.2 Those younger than 18 years of age must weigh at least 40 kg. The study is including patients harboring CCNE1 amplifications, deleterious FBXW7 mutations, or deleterious PPP2R1A mutations. Measurable disease per RECIST 1.1 criteria is required; however, patients with prostate cancer with elevated prostate-specific antigen levels or those with ovarian cancer with elevated CA-125 levels are allowed to enroll in the absence of measurable disease. Other key inclusion criteria consist of a Lansky performance status of at least 50% for patients 16 years of age or younger; an ECOG performance status of 0 or 1 (or 2 for module 1) for those over 16 years of age; and adequate hematologic and organ function.

Key exclusion criteria consist of treatment with chemotherapy or a small molecule antineoplastic agent within 21 days or less than 5 half-lives of the first study dose; major surgery within 4 weeks of first study does; uncontrolled, symptomatic brain metastases; and uncontrolled hypertension.

Patients are receiving lunresertib alone, lunresertib in combination with camonsertib, or lunresertib in combination with the oral WEE1 inhibitor Debio 0123. Treatment in each cohort will continue until disease progression, unacceptable toxicity, or investigator/patient decision, and dose escalation will continue in each group until a maximum tolerated dose (MTD) is identified.

The study’s primary end points are the safety and tolerability of each regimen, identifying the MTD of each regimen, and pharmacokinetics. Preliminary antitumor activity is a secondary end point.

Patients with endometrial cancer enrolled to the study thus far and treated with lunresertib plus camonsertib had a median age of 67 years.1 Additionally, 18.5% of patients had carcinosarcoma, and 85% of patients had tumors harboring p53 mutations. No patients had microsatellite instability–high tumors. PPP2R1A mutations, FBXW7 mutations, and CCNE1 amplifications were detected in 56%, 22%, and 15% of patients, respectively. Seven percent of patients had tumors with more than 1 of these mutations. All patients had received prior platinum-based chemotherapy, and 77.8% of patients had received prior immune checkpoint inhibitors. The combination of lunresertib and camonsertib was given to 59% of patients in the fourth line or later.

In the ovarian cancer subgroup treated with lunresertib plus camonsertib, the median age was 63 years. All patients had platinum-resistant or -ineligible disease, 45.8% of patients had received a prior PARP inhibitor, and 70.8% of patients had received prior bevacizumab (Avastin). All patients harbored p53 mutations; the respective rates of CCNE1 amplifications, FBXW7 mutations, and PPP2R1A mutations were 87.5%, 4.2%, and 4.2%. More than 1 of these mutations were detected in 4.2% of patients. The combination of lunresertib and camonsertib was given to 54% of patients in the fourth line or later.

References

1. Repare Therapeutics announces positive results of the lunresertib and camonsertib combination from the MYTHIC phase 1 gynecologic expansion clinical trial. News release. Repare Therapeutics. December 12, 2024. Accessed December 19, 2024. https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-positive-results-lunresertib-and
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 December 19, 2024. https://clinicaltrials.gov/study/NCT04855656