Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma

• Published in: Clinical cancer research 2018-07, Vol.24 (14), p.3263-3272
• Main Authors: Hong, David S, Moore, Kathleen, Patel, Manish, Grant, Stefan C, Burris, 3rd, Howard A, William, Jr, William N, Jones, Suzanne, Meric-Bernstam, Funda, Infante, Jeffrey, Golden, Lisa, Zhang, Wei, Martinez, Ricardo, Wijayawardana, Sameera, Beckmann, Richard, Lin, Aimee Bence, Eng, Cathy, Bendell, Johanna
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Anus; Biomarkers; Cancer; Carcinoma, Squamous Cell - diagnosis; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Checkpoint Kinase 1 - antagonists & inhibitors; Checkpoint Kinase 1 - genetics; Combined Modality Therapy; Confidence intervals; Deoxyribonucleic acid; DNA; DNA damage; Enzyme inhibitors; Female; Gene Expression Profiling; Head; Humans; Inhibitors; Kaplan-Meier Estimate; Lung cancer; Male; Middle Aged; Neck; Neoplasm Metastasis; Neoplasm Staging; Neutropenia; Patients; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - therapeutic use; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Pyrazoles - therapeutic use; Retreatment; Safety; Squamous cell carcinoma; Treatment Outcome; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-3347

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. Patients were given prexasertib 105 mg/m 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. 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% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 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. Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m was confirmed as the recommended phase II dose. .