lunresertib (Debio2513) / XenoTherapeutics, Debiopharm - LARVOL DELTA

E2F3 amplification primes bladder cancer cells for premature mitosis. (PubMed, Cancer Gene Ther) - "These findings identify PKMYT1-dependent CDK1 inhibition as a critical safeguard against premature mitosis in E2F3-amplified bladder cancer. Thus, we uncover an opportunity for precision medicine strategies aimed at G2/M checkpoint inhibition to promote catastrophic mitosis in bladder cancer patients with E2F3 amplification and excessive cyclin B1 expression."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNB1 • CDK1 • CDKN2A • E2F3 • PKMYT1 • RB1

First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations (AACR 2026) - P1 | "We report the first disclosure of clinical data of the first-in-field synthetic lethal combination of WEE1 and PKMYT1 inhibitors in a molecularly defined pt population. The safety profile of zedo and lunre was expected and manageable. Promising antitumor activity was observed in pts with CCNE1 amp or FBXW7 mut solid tumors, especially pts with OC."

Clinical • Metastases • P1 data • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • FBXW7 • MUC16 • PKMYT1 • 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

Design, Synthesis, Biological Activity Evaluation, and Molecular Docking of 2-Aminopyrimidine-Based PKMYT1 Inhibitors. (PubMed, Biomedicines) - "Molecular dynamics simulations indicated a favorable binding mode between compound MS13 and PKMYT1 (docking score: -9.322 kcal/mol). MS13 is a promising highly potent tool compound that provides a clear direction for the future optimization of PKMYT1 inhibitors."

Journal • Oncology • CCNE1 • CDK1 • PKMYT1

Design, synthesis, and biological evaluation of pyrrolo[2,3-c]pyridin-7-one derivatives as PKMYT1 inhibitors targeting CCNE1-amplified cancers. (PubMed, Eur J Med Chem) - "Notably, combination therapy with gemcitabine achieved near-complete inhibition of tumor progression in OVCAR3 xenograft models, with no overt systemic toxicity. Collectively, these results validate compound 6-A as an attractive lead scaffold for further development and underscore the value of the proposed scaffold optimization approach in facilitating targeted treatment of CCNE1-amplified cancers."

Journal • Oncology • CCNE1 • CDK1 • PKMYT1

PKMYT1 in Cancer: Beyond Cell Cycle Checkpoints to Context-Dependent Therapeutic Vulnerability. (PubMed, Genes Chromosomes Cancer) - "This review critically evaluates PKMYT1's mechanistic underpinnings, clinical landscape, and biomarker strategies. We advocate for precision targeting based on genetic signatures (CCNE1, TP53, ER) to optimize therapeutic efficacy and overcome resistance in replication stress-high malignancies."

Journal • Review • Oncology • CCNE1 • PKMYT1 • STING • TP53

PRECLINICAL EVALUATION OF PKMYT1 INHIBITION AS A NOVEL THERAPEUTIC OPPORTUNITY IN SMALL CELL LUNG CANCER (EACR 2026) - "Introduction: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour characterised by a 7% 5-year survival rate, reflecting early metastasis and rapid resistance to first-line standard-of-care (SoC) platinum/etoposide chemotherapy. We showed, in multiple SCLC patient-faithful CDX models, that PKMYT1 inhibition induces DNA damage and apoptosis ex vivo and contributes to tumour growth control in vivo, and identified multiple candidate predictive biomarkers of PKMYT1 inhibition sensitivity."

IO biomarker • Preclinical • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • CCNE1 • CDK1 • CDK2 • FOXM1 • PKMYT1 • RB1 • 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 | Trial completion date: Jan 2026 ➔ Sep 2026

Trial completion date • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer • TP53

Debio 0123-106: A phase 1 trial to study how safe and tolerable Lunresertib is, alone or in Combination with RP-3500 or Debio 0123, whennadministered in patients with certain types of cancer (clinicaltrialsregister.eu) - P1 | N=63 | Recruiting | Sponsor: Debiopharm International S.A. | N=38 ➔ 63

Enrollment change • Oncology • Solid Tumor • CCNE1 • FBXW7 • MUC16 • POLE • TP53

PKMYT1 is a Targetable Vulnerability in del(17p) High-Risk Multiple Myeloma. (PubMed, Blood) - "RP-6306 also reduced tumor burden and extended survival in vivo in both xenograft and TP53-deficient syngeneic models. Collectively, our findings nominate PKMYT1 as an actionable target and support PKMYT1 inhibition as a biomarker-driven therapeutic strategy for patients with del(17p)/TP53-deficient MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • PKMYT1 • TP53

Brain metastasis from KRAS wild-type pancreatic cancer and organoid correlates: a case report. (PubMed, J Gastrointest Oncol) - "Successful generation of a BrM-derived organoid line enabled high-throughput drug screening, which recapitulated the patient's clinical resistance to standard therapies [gemcitabine/nab-paclitaxel, 5-fluorouracil (5-FU)], and showed sensitivity to afatinib, everolimus and RMC-6236...Physicians should also be aware that KRAS wild-type pancreatic cancer with atypical amplifications is likely to exhibit unique metastatic tropisms. Finally, we suggest that patient-derived organoids pharmacotyping can mirror clinical drug responses and help evaluate therapeutic avenues for patient treatment."

Journal • Back Pain • Musculoskeletal Pain • Oncology • Pain • Pancreatic Cancer • Pancreatitis • Solid Tumor • KRAS • PKMYT1

Recent advances in the discovery of PKMYT1-targeting drugs: a patent review (2021-2025). (PubMed, Expert Opin Ther Pat) - "The rapid advancement of PKMYT1 inhibitors and degraders underscores their potential as a synthetic‑lethal therapeutic strategy for cancers with CCNE1 amplification or FBXW7 alterations. Clinical proof‑of‑concept for this approach has been established by RP‑6306 trial outcomes, while insights from this comprehensive review are expected to inform strategies addressing the current limitations in this field."

Journal • Review • Oncology • Targeted Protein Degradation • CCNE1 • CDK1 • FBXW7 • PKMYT1

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

ACR-2316: A potentially first-in-class, potent, selective WEE1/PKMYT1 inhibitor rationally designed for superior single agent activity through synergistic disruption of cell cycle checkpoints (AACR 2024) - "ACR-2316 is more selective than adavosertib, azenosertib, and lunresertib based on >200 kinases profiled by AP3 and 468 kinases assessed by KINOMEscan...In conclusion, ACR-2316 is a potent, selective dual WEE1/PKMYT1 inhibitor with superior single-agent activity compared to clinical WEE1 or PKMYT1 inhibitors. ACR-2316 is progressing through IND-enabling studies in preparation for clinical monotherapy development."

Oncology • Ovarian Cancer • Solid Tumor • CDK1 • CDK2 • CHEK1 • PKMYT1 • PLK1

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

Debiopharm to Unveil New Pre-Clinical and Clinical Research Advances in DDR Inhibition, Dual Payload ADCs, and AI-Driven Biomarkers at AACR 2026 (PharmiWeb) - "Preliminary clinical results of the MYTHIC study will be presented, revealing for the first time data of the combination of WEE1 and PKMYT1 inhibition (zedoresertib and lunresertib) for the treatment of solid tumors with specific genetic alterations...A major highlight of this year’s conference participation is the first clinical data disclosure from the MYTHIC Study (NCT04855656), a Phase I trial evaluating the combination of Debiopharm’s WEE1 inhibitor, zedoresertib (Debio 0123), with the PKMYT1 inhibitor lunresertib (Debio 2513) in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations."

P1 data • Preclinical • Gynecologic Cancers • Solid Tumor

AACR: Zedoresertib and lunresertib combination shows promising antitumor activity (Newswise) - "The overall disease control rate for 54 evaluable patients across all dosing levels was 68.5%. In 51 patients with target lesions, 26 showed tumor shrinkage and 10 patients achieved a radiological response. Among patients with advanced ovarian cancers harboring CCNE1 amplification, FBXW7 or PPP2R1A mutations, 80% showed consistent tumor shrinkage, with durable responses observed. At least 10 patients (37%) remained on treatment for more than 16 weeks, and five patients (18.5%) remained on treatment for longer than 32 weeks. The molecular response rate (MRR) was 47% for all patients across all dose levels. In patients with advanced ovarian cancer, the MRR was 67%."

P1 data • Ovarian Cancer

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

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

Debiopharm...announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the combination of its PKMYT1 inhibitor, lunresertib (Debio2513), and its WEE1 inhibitor, zedoresertib (Debio 0123). (Businesswire) - "The designation is for the treatment of adult patients with CCNE1 amplified, or a deleterious mutation in either FBXW7 or PPP2R1A, platinum-resistant/refractory ovarian cancer."

Fast track • Platinum resistant • Ovarian Cancer • Refractory Ovarian Cancer

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

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

P53mut • Trial completion • 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 • FBXW7 • HER-2 • KRAS • PPP2R1A • TP53 • UGT1A1

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