2554 - Genotypically-Selected Pan Cancer Trial of Camonsertib with Palliative Radiation in the Treatment of Metastatic Tumors Harboring an Ataxia-Telangiectasia Mutated (ATM) Mutation

N. Y. Lee¹, R. Michelle², M. Huang², R. Guo², V. Ferreira², M. Merrill², E. Sgroe², T. Unger², M. Koehler², J. Setton³, S. N. Powell¹, E. Rozen², and N. Riaz¹; ¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ²Memorial Sloan-Kettering Cancer Center, New York, NY, ³Memorial Sloan Kettering Cancer Center, New York, NY

Purpose/Objective(s): We have previously shown in pre-clinical models that camonsertib [potent/selective ataxia telangiectasia and rad3-related (ATR) inhibitor] combined with radiation markedly radiosensitizes ATM^-/- versus ATM^WT tumors, featuring radiation-induced synthetic cytotoxicity. We hypothesized that tumors with pathogenic ATM mutations versus those with variants of unknown significance (VUS) may respond markedly better to camonsertib with radiation, offering improved clinical benefit. Materials/Methods: This phase I trial enrolled patients with metastatic tumors harboring ATM mutations (somatic, germline, pathogenic, VUS) across all cancer types. Patients received camonsertib once daily starting at 80mg up to a maximum of 160mg given ~1 hour +/- 30 minutes prior to each radiation fraction [4Gy] for 5 days, followed by camonsertib for 5 additional days. The primary objective was to identify the tolerated dose of camonsertib with radiation using a 3+3 design. Toxicity was assessed using CTCAEv5. Tumor response [complete response (CR), partial response (PR), stable disease (SD), and progression (PD)] was assessed by computed tomography (RECIST) and/or positron emission tomography (PERSIST for bone lesions) at 2-, 6- months post-treatment.
Results: We enrolled 17 patients:11 tumors had pathogenic, 6 had VUS, 14 had somatic, 3 had germline ATM mutations. Primary tumor sites: gastrointestinal (n=5), pancreas (n=5), breast (n=2), lung (n=2), bladder (n=2), thyroid (n=1). The median number of discrete lesions radiated per patient was 3 (range: 1-6). Sites irradiated: lung (n=9), liver (n=7), bone (n=17), node (n=8), pancreas (n=3), and rectum (n=1). Initially, radiation was given on days 1-5 and camonsertib on days 1-10. One patient developed a dose limiting toxicity (DLT) of anemia at the starting dose of 80mg, and out of an abundance of caution, days 6-10 of camonsertib was dropped. Since this protocol change, 2 DLTs were noted: at 120 mg and 160 mg (both thrombocytopenia); otherwise, the treatment was well-tolerated. The tolerated dose was established at 160mg once daily. Response data was available for 15 patients at this submission time. At 2-months post-treatment, there were 1 CR, 5 PR, 3 SD observed in 9 patients with tumors with pathogenic mutations versus 1 PR, 5 SD in 6 patients in the VUS group. At 6-months post-treatment, there were 2 CR and 1PR in 3 patients with tumors that carried pathogenic mutation versus 1 PD and only 1 SD in 2 patients in the VUS group. Conclusion: The combination of camonsertib with radiation is well-tolerated. The Phase 2 study will progress with camonsertib given at 160mg daily with radiation. Encouraging response rates were observed for the pathogenic versus VUS ATM mutation group in this first genotypically-selected study where tumors were treated with camonsertib and radiation.