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

MYTHIC: Study of Lunresertib Alone or in Combination With RP-3500 or Debio 0123 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=464 | Recruiting | Sponsor: Debiopharm International SA | Trial completion date: Dec 2026 ➔ Jun 2028 | Trial primary completion date: Jun 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • Ovarian Cancer • Prostate Cancer • Solid Tumor • CCNE1 • FBXW7 • MUC16 • PPP2R1A

Phase I study of the PKMYT1 inhibitor lunresertib (lunre) in combination with FOLFIRI in advanced gastrointestinal (GI) cancers (MINOTAUR study) (ESMO-GI 2024) - P1 | "In the first evaluation of this novel combination, standard FOLFIRI and daily lunre 60 mg BID (RP2D) was well tolerated, with a safety profile consistent with FOLFIRI alone, and promising efficacy in a heavily pretreated CCNE1 amp and FBXW7 mut population, including prior iri exposure. Prolonged DOT in mCRC offers a valid therapeutic strategy and warrants confirmation in a randomized study."

Combination therapy • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Solid Tumor • CCNE1 • FBXW7 • PKMYT1

PKMYT1 inhibition induces DNA damage and synergizes with immune checkpoint blockade in CCNE1 -amplified gastroesophageal adenocarcinoma. (PubMed, bioRxiv) - "We evaluated lunresertib (RP-6306), a selective first-in-class PKMYT1 inhibitor, in CCNE1 -amplified and wild-type GEA cell lines to define its effects on cell viability, DNA damage, and gene expression changes...In a syngeneic murine model of CCNE1 -amplified gastric cancer, we further identified that PKMYT1 inhibition induced T cell infiltration and tumor microenvironment remodeling, and synergized with anti-PD-1 therapy to drive tumor regression. Together, these results support further development of PKMYT1 inhibition in combination with PD-1 blockade for CCNE1 -amplified GEA."

Checkpoint inhibition • IO biomarker • Journal • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • CCNE1 • PKMYT1 • TP53

GyneRep: Phase 1 Study of RP-6306 With Carboplatin and Paclitaxel in TP53 Ovarian and Uterine Cancer (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: University Health Network, Toronto | N=24 ➔ 6 | Trial completion date: Dec 2026 ➔ Jan 2026 | Trial primary completion date: Dec 2026 ➔ Oct 2025

Enrollment change • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer • TP53

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

ACR-2316 is a novel, differentiated, clinical-stage WEE1/PKMYT1 inhibitor designed by Acrivon's Generative Phosphoproteomics AP3 Platform for optimal pro-apoptotic pathway effects in tumor cells resulting in superior preclinical activity (AACR-NCI-EORTC 2025) - "In cellular TE assays, ACR-2316 displayed more potent WEE1 TE than all benchmark WEE1 inhibitors (azenosertib, adavosertib, Debio0123), while simultaneously targeting MYT1... WEE1 inhibitor-induced MYT1 activation constitutes a resistance mechanism that may limit the clinical efficacy of WEE1 inhibition. ACR-2316 is a potent, selective WEE1/MYT1 inhibitor that displays superior preclinical efficacy via its differentiated profile optimized by AP3 pathway-based structure-activity relationships in the intact cell. Acrivon's ongoing Phase 1 ACR-2316 monotherapy trial in solid tumors has already demonstrated clinical activity during dose escalation prior to reaching Recommended Phase 2 Dose."

Preclinical • Tumor cell • Oncology • Solid Tumor • BRAF • CDK1 • CDK2 • PKMYT1 • PLK1

Global pharmacodynamic effects uncovered with AP3 phosphoproteomic profiling of novel WEE1/PKMYT1 inhibitor ACR-2316 reveals the critical importance of PLK1 for ACR-2316's superior preclinical activity and differentiated mechanism of action (AACR-NCI-EORTC 2025) - "The clinical WEE1 inhibitors azenosertib and Debio0123, and the PKMYT1 inhibitor lunresertib were administered in parallel at maximum tolerated/formulable doses... ACR-2316 is a potential first- and best-in-class dual inhibitor of WEE1 and PKMYT1, rationally designed using Acrivon's proprietary AP3 platform to deliver superior single-agent efficacy. Potent activation of PLK1, together with CDK1/2, is essential for the superior activity of ACR-2316. ACR-2316 has shown clinical activity in its ongoing Phase 1b monotherapy trial in solid tumors during dose escalation."

PK/PD data • Preclinical • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • CDK1 • PKMYT1 • PLK1 • RRM2 • WEE1

Unraveling resistance mechanisms to the novel nucleoside analog RX-3117 in lung cancer: insights into DNA repair, cell cycle dysregulation and targeting PKMYT1 for improved therapy. (PubMed, J Exp Clin Cancer Res) - "By integrating CRISPR-Cas9 with functional assays and transcriptomics, our study established a framework for decoding resistance mechanisms and highlights potential therapeutic strategies to enhance RX-3117 efficacy in NSCLC. We demonstrated for the first time that aberrant DNA repair and cell cycle dysregulation led resistance, identifying PKMYT1 as a promising target."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PKMYT1 • UCK2

RP-6306 in Patients With Advanced Cancer (clinicaltrials.gov) - P2 | N=28 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Recruiting ➔ Active, not recruiting | N=78 ➔ 28

Enrollment change • Enrollment closed • P53mut • 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 Enters Exclusive Worldwide Licensing Agreement with Debiopharm for Lunresertib (Businesswire) - "Repare Therapeutics...announced it has entered into an exclusive worldwide licensing agreement with Debiopharm International S.A. ('Debiopharm')...for lunresertib, a first-in-class precision oncology PKMYT1 inhibitor....Under the terms of the agreement, Repare will receive a $10 million upfront payment, and is eligible to receive up to $257 million in potential clinical, regulatory, commercial and sales milestones, including up to $5 million in potential near-term payments, and single-digit royalties on global net sales."

Licensing / partnership • Solid Tumor

IN MULTIPLE MYELOMA, DEL17P CONFERS VULNERABILITY TO THE INHIBITION OF PKMYT1 KINASE. (EHA 2025) - "These data suggest PKMYT1 as an actionable target for MM cells with del17p impairment, representing a potential tailored therapeutic option for this high-risk group of MM patients."

Hematological Malignancies • Multiple Myeloma • Oncology • CDK1 • PKMYT1 • SDC1 • TP53

MINOTAUR: Study of RP-6306 With FOLFIRI in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=38 | Terminated | Sponsor: Repare Therapeutics | Trial completion date: Nov 2026 ➔ Feb 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2026 ➔ Feb 2025; Sponsor decided to terminate the study

Trial completion date • Trial primary completion date • Trial termination • Esophageal Cancer • Solid Tumor

MAGNETIC: Study of RP-6306 With Gemcitabine in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=67 | Terminated | Sponsor: Repare Therapeutics | N=104 ➔ 67 | Trial completion date: Apr 2025 ➔ Aug 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Aug 2024; Sponsor decided to terminate the study

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Solid Tumor

IND.241: A Canadian Cancer Trials Group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast. (ASCO 2025) - P2 | "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)...Substudy D, which has recently been added, is evaluating lunresertib + camonsertib (ATR inhibitor) in patients +/- CCNE1 overexpression/amplification, FBXW7 or PPP2R1A alterations. Additional substudies are in development for inclusion in this platform trial."

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

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

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

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

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

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

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