lunresertib (RP-6306) / Repare Therap - LARVOL DELTA

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

IND.241: A Canadian cancer trials group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer (AACR 2025) - "Substudy B is evaluating lunresertib (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression / amplification. Substudy C is evaluating niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2 (germline)... IND.241 employs a biomarker-driven platform trial designed to evaluate CDK4/6i resistant ER+/HER2- MBC, using non-invasive ctDNA tumor genotyping to select patients for biomarker-driven substudies with the goal of defining the ctDNA landscape across 1L to 3L treatments."

Biopsy • Liquid biopsy • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • CCNE1 • ER • FBXW7 • HER-2 • PALB2 • PKMYT1 • PPP2R1A

Targeting CCNE1 amplification in gastric cancer (AACR 2025) - "Lunresertib (RP-6306) is a selective, first-in-class, oral PKMYT1 inhibitor that leads to unscheduled mitotic entry and catastrophic DNA damage selectively in CCNE1-amplified cells... Lunresertib demonstrated synthetic lethality in CCNE1-amplified gastric cancer across multiple in vitro and in vivo experiments. Lunresertib had synergistic effects with anti-PD1 in vivo against CCNE1-amplified gastric cancer, potentially due to induced DNA damage and inflammatory cytokine induction."

IO biomarker • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • CD4 • CDK1 • CXCL10 • PKMYT1 • STING

VRN16: A novel PKMYT1 kinase selective inhibitor with wide therapeutic window (AACR 2025) - "In contrast, lunresertib inhibits BRAF kinase, confirmed to cause paradoxical activation of phospho-MEK and phospho-ERK signaling in the cells, similar to the effects observed with vemurafenib, a BRAF inhibitor...Although CDK2 inhibitors are also undergoing clinical trials with CCNE1+ as a major biomarker, VRN16 demonstrated superior efficacy in combination with gemcitabine in the OVCAR3 CDX, compared to the combination of BLU-222, a CDK2 inhibitor, with paclitaxel or carboplatin.In a 2-week repeated-dose oral toxicity study, VRN16 achieved a wide preclinical safety margin, more than 8-fold, compared to lunresertib with a limited safety margin. This wide therapeutic window highlights VRN16 as a novel therapeutic option for patients with CCNE1+ solid tumors or DNA damage sensitive tumors."

Late-breaking abstract • Breast Cancer • Carcinosarcoma • Gastric Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • Uterine Cancer • CCNE1 • CDK1 • PKMYT1 • TP53

The WEE1 inhibitor Debio 0123 is synergistic with the PKMYT1 inhibitor lunresertib in preclinical models of ovarian and breast cancer (AACR 2025) - "Lunresertib (RP6306) is a selective and potent PKMYT1 inhibitor currently in phase 1 clinical studies as a monotherapy or in combination. These results demonstrate, in preclinical models of ovarian and breast cancer, the WEE1 inhibitor, Debio 0123, is synergistic with the PKMYT1 inhibitor, lunresertib, and consistently leads to deep and sustained regressions in vivo."

Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • PKMYT1

INK4A/B as predictive biomarkers for enhanced efficacy of dual WEE1 and PKMYT1 inhibition in CDK4/6 inhibitor-resistant breast cancer (AACR 2025) - "This study aimed to identify predictive biomarkers of response to WEE1/PKMYT1 dual inhibition while maintaining manageable toxicity. Evaluating WEE1 inhibitors (adavosertib or azenosertib) in combination with the PKMYT1 inhibitor (lunresertib) across CDK4/6i-R and TNBC models, including patient-derived xenografts (PDXs) and organoids, demonstrated significant tumor suppression, with the novel dual WEE1/PKMYT1 inhibitor SGR-3515 showing comparable efficacy... Dual inhibition of WEE1 and PKMYT1 presents a compelling therapeutic strategy for CDK4/6i-R breast cancer and TNBC. Elevated baseline levels of INK4A and INK4B are strongly associated with enhanced treatment responses, highlighting their potential as predictive biomarkers for selecting patients likely to benefit from WEE1/PKMYT1 dual inhibition therapy."

Biomarker • Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDKN2A • CDKN2B • ER • HER-2 • PKMYT1

Efficacy and safety of the combination PKMYT1-inhibitor lunresertib and ATR-inhibitor camonsertib in patients with ovarian and endometrial cancers: Phase I MYTHIC study (NCT04855656) (AACR 2025) - P1 | "Lunre + cam is a tolerable and effective oral combination therapy of two novel targeted agents in molecularly-selected OC and EC with poor prognostic features and no approved targeted therapies. Enrollment closed in Dec 2024, the presentation will provide updated data for potential late-stage clinical development."

Clinical • P1 data • Carcinosarcoma • Endometrial Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • CCNE1 • CDK1 • FBXW7 • PKMYT1 • PPP2R1A

Repare Therapeutics Announces Six Abstracts Accepted for Presentation at AACR Annual Meeting 2025 (Businesswire) - "Repare Therapeutics Inc...announced the acceptance of two abstracts for mini-oral presentation and the acceptance of four abstracts for poster presentation at the American Association for Cancer Research (AACR) Annual Meeting, taking place April 25-30, 2025, in Chicago, Illinois."

P1 data • Preclinical • Endometrial Cancer • Gastric Cancer • Neuroblastoma • Ovarian Cancer

Debiopharm to Reveal Insights From Their ADC, DDR Inhibitor, and Antibody Conjugation Technology Research at the 2025 AACR Conference in Chicago (Businesswire) - "Comprehensive preclinical results will be presented for Debio 1562M, a next-generation Antibody-Drug Conjugate (ADC) targeting the cell surface glycoprotein CD37 soon to undergo first-in-human evaluation. Two preclinical data releases will be included in the poster display sessions for Debio 0123, a selective WEE1 kinase inhibitor disrupting the DNA-damage response (DDR) of cancer cells. The first data release shows how Debio 0123 can be used in combination with the PKMYT1 inhibitor lunresertib as a promising therapeutic strategy in ovarian and breast cancer....The company also announces joint poster presentation with new partner on the use of its AbYlink technology in preclinical setting."

Preclinical • Acute Myelogenous Leukemia • Breast Cancer • Myelodysplastic Syndrome • Ovarian Cancer

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR. (PubMed, Nat Commun) - "Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is an effective therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs."

Journal • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • CDK1 • PKMYT1

Targeting ATR and PKMYT1 to overcome carboplatin resistance in triple-negative breast cancer patient-derived models (ESMO-TAT 2025) - "Our results highlight the susceptibility of TNBC to targeted cell cycle modulators when used with DNA damage agents like carboplatin and this vulnerability could enhance treatment efficacy in TNBC."

Clinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK1 • FOXM1 • PKMYT1

RP-6306 in Patients With Advanced Cancer (clinicaltrials.gov) - P2 | N=78 | Recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Triple Negative Breast Cancer • CCNE1 • HER-2 • KRAS • TP53 • UGT1A1

Repare Therapeutics Announces Portfolio Re-Prioritization, Partnering Initiatives and Cost Reductions (Businesswire) - "Repare Therapeutics...announced a re-alignment of resources and a re-prioritization of its clinical portfolio to focus on the continued advancement of its Phase 1 clinical programs, RP-1664 (PLK4 inhibitor) and RP-3467 (Polθ ATPase inhibitor). Repare also announced its intention to seek partnering opportunities across its portfolio, including for lunresertib and camonsertib ('Lunre+Camo') prior to any start of pivotal development. The consequent savings of late-stage clinical funding combined with planned cost and headcount reductions are expected to extend Repare’s cash runway into mid-2027."

Commercial • Solid Tumor

Recent Pipeline Progress & Upcoming Milestones of Prioritized Clinical Programs (Businesswire) - "(i) RP-3467: Potential best-in-class Polθ ATPase inhibitor...Upcoming Expected Milestones: Q3 2025: Topline safety, tolerability and early efficacy data from the POLAR trial in monotherapy and in combination with olaparib.... (ii) Lunresertib and Camonsertib...Upcoming Expected Milestone: Q2 2025: Enrollment completion of MYTHIC trial evaluating lunresertib in combination with Debio 0123 (WEE1 inhibitor)."

Enrollment status • P1 data • Solid Tumor

PKMYT1 Kinase Is an Actionable Synthetically Lethal Target for Del17p Myeloma (ASH 2024) - "We next evaluated RP-6306 (lunresertib) a selective inhibitor of PKMYT1 catalytic activity for its potential preferential activity against del17p MM cells...We also assessed whether DNA-damaging agents (melphalan, bendamustine) rendered cells sensitive to PKMYT1 inhibition or synergized with it...In conclusion, PKMYT1 is an actionable target for MM cells harboring del17p. PKMYT1 inhibition with lunresertib specifically induced DNA damage, mitotic catastrophe, and subsequent cell death in MM cell lines with del17p or TP53 impairment, representing a potential tailored therapeutic option for this high-risk group of MM patients."

Synthetic lethality • Tumor mutational burden • Hematological Malignancies • Multiple Myeloma • Oncology • CDK1 • CHEK2 • PKMYT1 • RPA2 • SDC1 • TMB

Repare Therapeutics Announces Positive Results of the Lunresertib and Camonsertib Combination from the MYTHIC Phase 1 Gynecologic Expansion Clinical Trial (Businesswire) - P1 | N=364 | MYTHIC (NCT04855656) | Sponsor: Repare Therapeutics | "Key efficacy outcomes in evaluable patients with endometrial cancer (N=27): ORR was 25.9% (confirmed ORR in 5 out of 7 patients); Clinical benefit was observed in 48.1% of patients, with responses frequently occurring after 12 weeks or more; At the 24-week landmark analysis, nearly half of patients experienced durable clinical benefit (24-week PFS [PFS24w] = 43% [95% CI, 21-63%])....Key efficacy outcomes in evaluable patients with PROC (N=24): ORR was 37.5% (confirmed ORR in 4 out of 9 patients); Clinical benefit was observed in 79% of patients; PFS at the 24-week landmark analysis was PFS24w = 45% [95% CI, 22-66%]....Repare...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."

New trial • P1 data • Endometrial Cancer • Ovarian Cancer

Repare Therapeutics to Host Webcast to Report Data from the Lunresertib and Camonsertib Combination Phase 1 MYTHIC Clinical Trial (Businesswire) - "Repare Therapeutics...announced it will host a conference call and live webcast to present the latest data from its ongoing Phase 1 MYTHIC clinical trial evaluating lunresertib in combination with camonsertib at the recommended Phase 2 dose in an expansion cohort in patients with platinum-resistant ovarian and endometrial cancers harboring CCNE1 amplification or FBXW7 or PPP2R1A mutations, on Thursday, December 12, 2024 at 4:30 p.m. Eastern Time."

P1 data • Endometrial Cancer • Ovarian Cancer

IND.241: A Canadian Cancer Trials Group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer (EORTC-NCI-AACR 2024) - P2 | "Substudy B evaluates RP-6306 (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression/amplification...Substudy C evaluates niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2. IND.241 employs a biomarker-driven platform study design approach to the evaluation of CDKi resistant ER+/HER2- MBC, using non-invasive ctDNA tumor genotyping to select patients for biomarker-driven substudies and define the ctDNA landscape across 1st, 2nd and 3L treatments."

Biopsy • Liquid biopsy • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • CCNE1 • ER • HER-2 • PALB2 • PKMYT1

Rational design of a superior single agent active, potential best-in-class WEE1/PKMYT1 inhibitor using Acrivon Predictive Precision Proteomics (AP3) (EORTC-NCI-AACR 2024) - "WEE1 inhibitors azenosertib and Debio0123, or the PKMYT1 inhibitor lunresertib, had a best response of stable disease at maximum achievable dose... ACR-2316 is a potent, selective dual inhibitor of WEE1 and PKMYT1, uniquely designed using Acrivon's AP3 platform for superior single agent activity through potent activation of CDK1, CDK2, and PLK1, and is on track for IND submission in Q3 2024 and first-in-human dosing in Q4 2024."

Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CDK1 • CDK2 • PKMYT1 • PLK1

Repare Therapeutics Provides Business and Clinical Update and Reports Third Quarter 2024 Financial Results (Businesswire) - "'We look forward to reporting data from our MYTHIC dose expansion clinical trial evaluating lunresertib in combination with camonsertib at the recommended Phase 2 dose at a company event in December, with the plan to begin a registrational trial in 2025'...Repare expects to report initial data from Module 4 of the MYTHIC trial in 2025...Repare expects to report initial data from the TRESR clinical trial in 2025."

P1 data • P1/2 data • Oncology • Solid Tumor

IND.243: a multiple expansion cohort, signal seeking and dose confirmation phase 2 trial of the PKMYT1 inhibitor lunresertib (EORTC-NCI-AACR 2024) - "Background Lunresertib (LUN, RP-6306) is a potent and selective oral inhibitor of PKMYT1, a negative regulator of the cyclin-dependent kinase CDK1 with a synthetic lethal relationship with CCNE1 amplification or FBXW7 loss-of-function (LOF) mutations...LUN has dose dependent in vitro activity in multiple models and is synergistic with gemcitabine (GEM).In phase I trials, the most common adverse events were skin and hematologic toxicities.Material and MethodsEligible patients (pts) are enrolled to one of 7 cohorts (serous endometrial cancer (SEC); platinum refractory high grade serous ovarian cancer (PR-HGSOC), uterine and ovarian carcinosarcoma, triple negative breast cancer (TNBC), pancreatic adenocarcinoma (PDAC), non-small cell carcinoma of lung (NSCLC) selected for p53 status (abnormal IHC or mutation) and after initial enrolment, prescreened for CCNE1-amp, FBXW7 / PPP2R1A mutations...A total of 59 cycles have been delivered. Rash related to LUN appears early and..."

P2 data • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • High Grade Serous Ovarian Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Adenocarcinoma • Pancreatic Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Triple Negative Breast Cancer • CCNE1 • CDK1 • FBXW7 • PKMYT1 • PPP2R1A • TP53

Individualised schedule optimisation improves rates and severity of anaemia in patients (pts) treated with lunresertib (lunre), a PKMYT1 inhibitor, and camonsertib (cam), an ATR inhibitor, in the phase I MYTHIC study (NCT0485565) (EORTC-NCI-AACR 2024) - "For the lunre + cam combination, individualised weekly schedule selection and modification— rather than a daily dose reduction—proved to be an effective strategy for reducing severe anaemia and need for transfusions, while appearing to maintain efficacy."

Clinical • P1 data • Oncology • CDK1 • PKMYT1

Repare Therapeutics Announces Updated Positive Safety and Tolerability Results from the Phase 1 MYTHIC Clinical Trial (Businesswire) - P1/1b | N=364 | MYTHIC (NCT04855656) | Sponsor: Repare Therapeutics | "Repare Therapeutics Inc...presented updated data highlighting the benefits of its individualized schedule for the management of anemia in the Phase 1 MYTHIC clinical trial treating patients with the combination of lunresertib, a first-in-class PKMYT1 inhibitor, and camonsertib....'We look forward to sharing efficacy data from the gynecological cancer expansion cohort of the MYTHIC clinical trial in December 2024'....Overall clinical benefit was maintained after schedule change with generally maintained radiographic regressions and molecular responses: Despite the change in schedule, deepening of target lesion regression was noted in some patients; After 9 weeks on therapy, there was no observed impact on Progression Free Survival (PFS) in patients who started on or switched to the schedule of 2 weeks on / 1 week off of treatment."

P1 data • Gynecologic Cancers • Oncology • Solid Tumor

Repare Therapeutics Announces New Data Underscoring Need for Additional Treatment Solutions for Patients with Metastatic Gynecologic Cancers (Businesswire) - "The presence of Lunre BM (alterations in CCNE1, PPP2R1A, or FBXW7) in ovarian cancer patients (n=1,029) is linked to a substantially lower survival rate compared to those without these biomarkers, underscoring their prognostic significance: Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 26 months (95% CI, 18-38), compared to 36 months (95% CI, 30-43) for patients without these biomarkers (Lunre BM-; HR = 1.46 [95% CI, 1.14-1.87], p=0.003), a 28% decrease in mOS. Endometrial cancer patients (n=895) with biomarkers CCNE1, PPP2R1A, and FBXW7 demonstrate poorer survival outcomes, which are influenced by their association with high-risk histologies and genetic alterations: Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 30 months (95% CI, 24-38), compared to 41 months (95% CI, 31-60) for patients without these biomarkers..."

Biomarker • Retrospective data • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Repare Therapeutics Announces Strategic Reprioritization to Focus on Broad Clinical Portfolio (Businesswire) - "Repare Therapeutics Inc...today announced the strategic reprioritization of its research and development activities to focus its efforts on the advancement of its portfolio of clinical-stage oncology programs. With multiple upcoming clinical milestones and potential near-term registration-enabling studies, the Company is streamlining its operations to focus on the advancement of its lunresertib, camonsertib, RP-1664 and RP-3467 programs while materially reducing the scale of its preclinical research and discovery activities...'We remain on track to report data from our MYTHIC dose expansion trial evaluating lunresertib in combination with camonsertib in patients with ovarian and endometrial cancers in the fourth quarter of 2024, with the potential to begin a registrational trial in 2025.'"

New trial • P1 data • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor