Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.
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Abel Melissa L, Takahashi Nobuyuki, Peer Cody, Redon Christophe E, Nichols Samantha, Vilimas Rasa, Lee Min-Jung, Lee Sunmin, Shelat Meenakshi, Kattappuram Robbie, Sciuto Linda, Pinkiert Danielle, Graham Chante, Butcher Donna, Karim Baktiar, Sharma Ajit Kumar, Malin Justin, Kumar Rajesh, Schultz Christopher W, Goyal Shubhank, Del Rivero Jaydira, Krishnamurthy Manan, Upadhyay Deep, Schroeder Brett, Sissung Tristan, Tyagi Manoj, Kim Jung, Pommier Yves, Aladjem Mirit, Raffeld Mark, Figg William Douglas, Trepel Jane, Xi Liqiang, Desai Parth, Thomas Anish
Аннотация
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.