1. Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.
- Author
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Abel ML, Takahashi N, Peer C, Redon CE, Nichols S, Vilimas R, Lee MJ, Lee S, Shelat M, Kattappuram R, Sciuto L, Pinkiert D, Graham C, Butcher D, Karim B, Sharma AK, Malin J, Kumar R, Schultz CW, Goyal S, Del Rivero J, Krishnamurthy M, Upadhyay D, Schroeder B, Sissung T, Tyagi M, Kim J, Pommier Y, Aladjem M, Raffeld M, Figg WD, Trepel J, Xi L, Desai P, and Thomas A
- Subjects
- Male, Humans, Camptothecin adverse effects, Camptothecin administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Immunoconjugates adverse effects, Immunoconjugates administration & dosage
- Abstract
Purpose: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations., Patients and Methods: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels., Results: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer., Conclusions: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557., (©2023 American Association for Cancer Research.)
- Published
- 2023
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