Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma
Mené sur 101 patients atteints d'un carcinome épidermoïde de stade avancé (26 cas de carcinome épidermoïde de l'anus, 57 cas de carcinome épidermoïde de la tête et du cou, 16 cas de carcinome épidermoïde du poumon non à petites cellules), cet essai de phase Ib évalue l'efficacité, du point de vue du taux de réponse et de la survie sans progression, la dose maximale tolérée et la toxicité du prexasertib, un inhibiteur des points de contrôle, après l'échec de plusieurs lignes thérapeutiques
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.
Clinical Cancer Research , résumé, 2017