A phase 1 study of berzosertib (M6620, VX-970) in combination with cisplatin and radiation in patients with locally advanced head and neck squamous cell carcinoma (ETCTN 9950).

Abstract

Ataxia telangiectasia Rad3-related (ATR) protein kinase regulates DNA damage response and is essential for tumor cell survival. Preclinically, ATR inhibition can sensitize tumor cells to radiation and chemotherapy. The authors conducted a phase 1 trial of berzosertib, a selective ATR inhibitor, in combination with definitive radiation and cisplatin in locally advanced head and neck squamous cell cancers (LA-HNSCC). LA-HNSCC patients received daily radiation (2 Gy per fraction to 70 Gy) and weekly intravenous (iv) cisplatin 40 mg/m². Berzosertib was administered (iv) once weekly, starting with a pharmacokinetic lead-in dose. Three berzosertib dose levels (DL) were tested: 120 mg/m² (DL1), 160 mg/m² (DL2), and 200 mg/m² (DL3). Forty-one of 43 enrolled patients were evaluable for safety and preliminary efficacy assessments. Four patients experienced dose-limiting toxicities (DLTs) in dose-escalation: grade 4 thrombocytopenia (1), grade 4 respiratory failure (1), grade 3 renal injury and hypoxia (1), and inability to receive 90% of the planned radiation dose (1). DL3 was the recommended phase 2 dose, and 15 patients were enrolled at this DL as an expansion cohort. Objective response rates (ORR) in patient cohorts treated with any amount of berzosertib; treated with at least 50% of planned treatment; and in the expansion cohort were 78.8% (26 of 33), 78.8% (26 of 33), and 63.6% (7 of 11), respectively, after excluding eight inevaluable patients without post-treatment imaging assessment. Berzosertib (200 mg/m² iv weekly) was safe when combined with chemoradiation but did not improve complete response rate in LA-HNSCC.