peposertib (M3814) / EMD Serono - LARVOL DELTA

WNC0901 is a novel DNA-PK inhibitor and potent radiosensitizer of otherwise radioresistant solid tumors (AACR 2026) - "The in vivo efficacy of 50 mg/kg WNC0901 combined with 8 Gy was evaluated and compared to another DNA-PK inhibitor, 50 mg/kg peposertib, in A549 tumor heterotopic xenografts. In a second study, similarly robust sensitizing effects of WNC0901 was observed in HT29 xenografts (placebo - median 45 days; RT - median 75 days; RT + WNC0901 - median >110 days; p=.03 relative to RT). Together, these findings demonstrate the robust radiosensitizing effects of WNC0901 in radioresistant tumors and provide a rationale for continued development of this drug."

Lung Cancer • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

A phase 1 trial of M3814 (peposertib) in combination with lutetium 177 DOTATATE for metastatic well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (AACR 2026) - "Abstract is embargoed at this time."

Combination therapy • Metastases • P1 data • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

PRKDC regulates CDK2 expression and pancreatic neuroendocrine cancer sensitivity to chemotherapy (AACR 2026) - "These findings support a role for DNA-PK in mediating CDK2 upregulation in response to chemotherapy and highlight the clinical relevance of low PRKDC and CDK2 expression with improved survival in NET patients. Collectively, these findings identify a PRKDC-CDK2 survival axis as a driver of chemoresistance and demonstrate that sustained, low‑intensity DNA damage, when coupled with selective DNA‑PK inhibition, disrupts this adaptive program, substantially reduces metastatic burden, and delivers more durable responses in pNETs.AI use disclosure: Portions of this abstract were revised with the assistance of generative AI and were fully reviewed and verified by the authors."

Endocrine Cancer • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • CDK2 • PRKDC

Synthetic lethality opportunities for tumors with MMEJ deficiency (AACR 2026) - "In addition, the combination of Peposertib and the topoisomerase inhibitor etoposide synergistically eliminated EwS cells in vitro and in vivo. Third, the EWS-FLI1 fusion oncoprotein binds and inactivates EWSR1 and causes an exon 25 splicing defect, leading to exon skipping and loss of POLQ protein expression. Fourth, the MMEJ deficiency of EwS cells results in enhanced cellular sensitivity to inhibitors of other DNA Repair pathways, providing a strategy for synthetic lethality therapy."

Synthetic lethality • Breast Cancer • Ewing Sarcoma • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • EWSR1 • FLI1 • FUBP1 • HRD • LIG3 • POLQ

Phase I trial of M3814 (Peposertib) in combination with lutetium 177 DOTATATE for metastatic well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (ENETS 2026) - P1 | "The combination of oral peposertib with Lu-177 do - tatate is safe, a promising radiation sensitizer in NET patients, and should be investigated in larger randomized clinical trials."

Combination therapy • Metastases • P1 data • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Targeting the Non-Homologous End-Joining Pathway Sensitizes MDM2-Amplified Liposarcoma to Doxorubicin by Enhancing p53-Mediated Senescence. (PubMed, Cancer Res) - "Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or doxorubicin...Genetic perturbation of TDP2 or pharmacological inhibition of DNA-PKcs using peposertib synergized with prolonged administration of low-dose doxorubicin to induce cell cycle arrest and senescence, and subsequent senolytic treatment with Bcl2 inhibitor navitoclax triggered senescent cells to undergo apoptosis...These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-mediated cell cycle arrest and senescence. Furthermore, this study provides evidence of maintained baseline p53 activity in MDM2-amplified DDLPS."

Journal • Liposarcoma • Oncology • Sarcoma • Solid Tumor • CCNE1 • CDK2 • CKS1B • E2F3 • MDM2 • PRKDC • XRCC4

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris

New P1/2 trial • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=455 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 ➔ Feb 2031 | Trial primary completion date: Aug 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=397 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | N=285 ➔ 397 | Trial completion date: Dec 2020 ➔ Jan 2022 | Trial primary completion date: Dec 2020 ➔ Jan 2022

Enrollment change • Trial completion date • Trial primary completion date • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=460 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Jan 2022 ➔ Aug 2027 | Trial primary completion date: Jan 2022 ➔ Aug 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

DNA-PKcs Promotes Therapy Resistance and Metastatic Recurrence in Neuroblastoma. (PubMed, Cancer Lett) - "Our findings correlate elevated DNA-PKcs levels with poor patient prognosis and show that low-dose radiotherapy combined with peposertib effectively abrogates neuroblastoma self-renewal compared to chemotherapy-based regimens, thereby implicating DNA-PKcs as a key mediator of metastatic relapse and supporting radiotherapy plus DNA-PKcs inhibition as a compelling therapeutic strategy for relapsed or refractory high-risk neuroblastoma."

Journal • Neuroblastoma • Oncology • Solid Tumor

Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov) - P1/2 | N=103 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Enrollment closed • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Gallbladder Cancer • Oncology • Solid Tumor

Late toxicity after peposertib-enhanced chemoradiation in rectal cancer patients managed with organ preservation. (PubMed, Clin Transl Radiat Oncol) - "Combining peposertib with capecitabine-based chemoradiation was associated with disproportionately high risks of severe late rectal toxicities, particularly in patients entering WW. Thus, careful assessment of the toxicity and response profiles of novel neoadjuvant regimens is critically important in future clinical trials focused on organ preservation and the nonoperative management of rectal cancer."

Journal • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). (ASCO-GI 2023) - "In addition, the study will correlate clinical outcome with somatic tumor mutations and germline mutations. Clinical trial information: 04750954."

P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • SSTR

Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov) - P1/2 | N=103 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Jul 2027 | Trial primary completion date: Dec 2025 ➔ Jul 2027

Trial completion date • Trial primary completion date • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Gallbladder Cancer • Oncology • Solid Tumor

Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=48 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • PML • RARA

NRG-HN008: Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=42 ➔ 21 | Trial completion date: Dec 2025 ➔ Dec 2026

Enrollment change • Trial completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

Testing the Addition of An Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Pancreatic Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Jun 2026 | Trial primary completion date: Oct 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Endocrine Cancer • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor

Results of A phase I study of peposertib in combination with MEC in patients with relapsed or refractory Acute Myeloid Leukemia (ASH 2025) - P1 | "MEC, consisting of mitoxantrone, etoposide (ETOP), and cytarabine, is anestablished regimen for the treatment of R/R AML. Overall, combining peposertib with MEC was feasible and did not significantly affect ETOP PK. Despite thehigh risk and heavily pretreated study population, including 78% with prior venetoclax, activity was seenon multiple dose levels, including A2 and A4, which were both expanded and remain RP2D candidatesafter expansion. Additional PK and PD analyses, follow-up, and evaluation of duration of remission,event-free survival, and overall survival, will aid in selecting the final RP2D and informing future studies."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Mucositis • Septic Shock • CYP3A4

Comparative analysis of molecular targeted radiosensitizers in 2D and 3D cancer cell line models. (PubMed, Acta Oncol) - "Integrating multiple culture models enhances the detection of cell line - and drug-specific radiosensitization. Although 2D and 3D cultures produced largely similar results, and 2D assays provide a practical alternative when 3D methods are not feasible, the 3D cultures reveal additional ECM-dependent responses. These results emphasize the utility of physiologically relevant platforms for robust screening and prioritization of candidate radiosensitizers."

Clinical • Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor

Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov) - P1/2 | N=103 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Gallbladder Cancer • Oncology • Solid Tumor

Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes (SNO 2025) - P1 | "Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference."

Biomarker • Clinical • P1 data • Brain Cancer • Glioblastoma • Solid Tumor • H2AX • MGMT

Oncolytic Herpes Simplex Virus Synergizes with DNA-PKcs Inhibitors to Treat Glioblastoma (SNO 2025) - "To validate selectivity and restrict inhibition to GBM cells, we created GSCs with doxycycline-inducible DNA-PKcs shRNA, which significantly reduced sphere formation (Stemness). These findings underscore the vulnerability of human GSCs to DNA-PKcs inhibition in the absence of DNA-damaging agents and its robust synergy with oHSV. Given that both G47Δ and M3814 have been evaluated in clinical trials, this study supports their continued clinical translation and further investigation into combination therapies for GBM."

Brain Cancer • Glioblastoma • Herpes Simplex • Solid Tumor

Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes (SNO 2025) - P1 | "Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference."

Biomarker • Clinical • P1 data • Brain Cancer • Glioblastoma • Solid Tumor • H2AX • MGMT

Combined DNA-PK and PARP Inhibition as a Therapeutic Strategy in BRCA-Mutated Prostate Cancer: An in Vitro Pilot Study. (PubMed, Technol Cancer Res Treat) - "Scramble LNCaP, BRCA1 KO, and BRCA2 KO cells were treated with the PARPi talazoparib, the DNA-PK inhibitor nedisertib and their combination. Therapeutically targeting NHEJ presents a promising approach in treating BRCA-mutated PCa. Further in vivo investigations are required to assess the tolerability of this drug combination."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • BRCA • BRCA1 • BRCA2