Purpose: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a Phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. Experimental Design: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed. Results: Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months (90% CI 1.9, 4.2) for SCC of the anus, 1.6 months (1.4, 2.8) for SCCHN, and 3.0 months (1.4, 3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response+partial response+stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response (overall response rate [ORR]=15%), and three patients with SCCHN had partial response (ORR=5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress. Conclusions: Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m2 was confirmed as the recommended Phase II dose.
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