On December 12, 2024 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported positive data from its MYTHIC Phase 1 gynecologic expansion clinical trial evaluating the combination of lunresertib and camonsertib (Lunre+Camo) at the recommended Phase 2 dose (RP2D) in patients with endometrial cancer and platinum-resistant ovarian cancer (PROC) harboring lunre-sensitizing biomarkers (Press release, Repare Therapeutics, DEC 12, 2024, View Source [SID1234649081]).

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Lunresertib is a first-in-class precision oncology small molecule PKMYT1 inhibitor which targets cell cycle regulation in Lunre BM+ tumors (CCNE1 amplifications or FBXW7 or PPP2R1A deleterious alterations). Camonsertib is a potential best-in-class oral small molecule inhibitor of ATR, a critical component of the DNA damage response pathway.

"We are encouraged by the strong response and the clear benefit we observed in patients with endometrial and platinum-resistant ovarian cancers in the MYTHIC clinical trial," said Lloyd M. Segal, President and Chief Executive Officer of Repare. "These patients need new treatment options and our results support the potential for Lunre+Camo to make a real, positive difference if approved, particularly as a chemotherapy alternative. We have positive feedback from regulatory agencies in both the US and Europe and we look forward to getting started on a registrational Phase 3 trial of Lunre+Camo in endometrial cancer in the second half of 2025."

The MYTHIC clinical trial (NCT04855656) is a first-in-human, global, open-label Phase 1 dose-escalation clinical trial to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of Lunre+Camo in patients with advanced solid tumors. As of the data cut-off date of November 14, 2024, 51 evaluable patients were enrolled in the gynecologic cancer expansion cohort of the MYTHIC trial.

Across all tumor types treated at the optimized RP2D (n=67), Lunre+Camo therapy demonstrated a favorable and differentiated tolerability profile when compared to current and emerging therapies. The most common adverse event was anemia (26.9%, Grade 3).

Key Cohort Clinical Findings

Endometrial Cancer Patients:

The 27 evaluable patients with endometrial cancer had a median age of 67 years. All patients exhibited high-risk profiles:

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100% of patients have undergone prior platinum therapy

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77.8% of patients received immune checkpoint inhibitors

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59% of patients received the combination as a fourth line of therapy or beyond

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18.5% of patients had carcinosarcoma

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85% of tumors had p53 mutations

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No tumors with microsatellite instability (MSI)-high status were enrolled indicating proficient mismatch repair (pMMR) status
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Within the Lunre BM+ subset: 56% of tumors had PPP2R1A mutations; 22% carried FBXW7 mutations; 15% had CCNE1 amplification; and 7% of tumors had multiple mutations

Key efficacy outcomes in evaluable patients with endometrial cancer (N=27):

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ORR was 25.9% (confirmed ORR in 5 out of 7 patients)

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Clinical benefit was observed in 48.1% of patients, with responses frequently occurring after 12 weeks or more

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At the 24-week landmark analysis, nearly half of patients experienced durable clinical benefit (24-week PFS [PFS24w] = 43% [95% CI, 21-63%])

Platinum-Resistant Ovarian Cancer Patients:

The 24 evaluable patients with PROC had a median age of 63 years. All patients exhibited high-risk profiles:

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100% of patients were platinum-resistant or platinum ineligible

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45.8% of patients had received prior PARP inhibitors

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70.8% of patients had received prior bevacizumab

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54% of patients received the combination as a fourth line of therapy or beyond

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100% of tumors had p53 mutations

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Within the Lunre BM+ subset: 87.5% of tumors had CCNE1 amplification; 4.2% had FBXW7 mutations; 4.2% had PPP2R1A mutations; and 4.2% of tumors had multiple mutations

Key efficacy outcomes in evaluable patients with PROC (N=24):

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ORR was 37.5% (confirmed ORR in 4 out of 9 patients)

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Clinical benefit was observed in 79% of patients

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PFS at the 24-week landmark analysis was (PFS24w = 45% [95% CI, 22-66%]).

"Those patients with recurrent gynecologic cancers have limited treatment options as tumors often become resistant to standard of care therapy," said Brian Slomovitz, MD, MS, FACOG, Director, Gynecologic Oncology, Co-chair of the Cancer Research Center, Mount Sinai Medical Center. "They urgently need new treatment options. Repare’s differentiated, biomarker-driven approach addresses this population and may offer a solution. These data support the potential of Lunre+Camo as a new treatment option to fill this unmet need for patients with endometrial and platinum-resistant ovarian cancers."

Repare has consulted with both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, who have provided guidance into the Company’s registrational development plans for Lunre+Camo in gynecologic tumors, including assessment of the contribution of components, dose and schedule and preliminary alignment on the proposed registrational development approach. Repare plans to provide the final Phase 3 trial protocols for regulatory clearance imminently and intends to start the first Phase 3 Lunre+Camo trial in endometrial cancer in the second half of 2025. Additionally, the Company expects to initiate a small contribution of components trial in up to 40 patients with endometrial cancer in the first quarter of 2025.

"The results of the MYTHIC clinical trial increase our confidence in the potential to bring Lunre+Camo to patients living with this aggressive subset of recurrent endometrial cancer," said Maria Koehler, MD, PhD, Chief Medical Officer of Repare. "We are deeply grateful to the patients and investigators who participated in this trial, and we look forward to building on these promising data through the registrational clinical trials using Lunre+Camo as a potential new standard of care for those patients, if approved."

Conference Call and Webcast:

Repare will host a conference call and webcast today, December 12, at 4:30 p.m. ET to discuss the results. Repare’s executive management team will be joined by Brian Slomovitz, MD, MS, FACOG, Director, Gynecologic Oncology, Co-chair of the Cancer Research Center, Mount Sinai Medical Center.

To access the call, please dial (646) 357-8785 (U.S. and Canada) or (800) 836-8184 (international) at least 10 minutes prior to the start time and ask to be joined to the Repare Therapeutics call. A live webcast and presentation materials will be available in the Investor section of the Company’s website at View Source A webcast replay will also be archived for at least 30 days.