Phase 2 Study of Talazoparib in Patients With Homologous Recombination Repair–Deficient Squamous Cell Lung Cancer: Lung-MAP Substudy S1400G

Approximately 50% of squamous non-small-cell lung cancer harbors somatic alterations. We tested the efficacy of talazoparib, a PARP inhibitor, in squamous non-small-cell lung cancer (SqNSCLC) harboring homologous recombination repair deficiency. Objective tumor response was recorded in a minority of patients with mutation in BRCA2, FANCM, FANCC, and CHEK1. This study provides guidance developing synthetic lethality as a therapeutic strategy in this subset of SqNSCLC. Purpose: This signal finding study (S1400G) was designed to evaluate the efficacy of talazoparib in advanced stage squamous cell lung cancer harboring homologous recombination repair deficiency. Patients and Methods: The full eligible population (FEP) had tumors with a deleterious mutation in any of the study-defined homologous recombination repair genes and without prior exposure to a PARP inhibitor. The primary analysis population (PAP) is a subset of FEP with alteration in ATM, ATR, BRCA1, BRCA2, or PALB2. Treatment consisted of talazoparib 1 mg daily continuously in 21-day cycles. A 2-stage design with exact 93% power and 1-sided 0.07 type I error required enrollment of 40 patients in the PAP in order to rule out an overall response rate (ORR) of 15% or less if the true ORR is >= 35%. Results: The study enrolled 47 patients in the FEP, of whom 24 were in the PAP. The median age for the FEP was 66.7 years; 83% were male and 85% white. ORR in the PAP was 4% (95% confidence interval [CI], 0, 21) with disease control rate of 54% (95% CI, 33, 74). Median progression-free survival and overall survival were 2.4 months (95% CI, 1.5-2.8) and 5.2 months (95% CI, 4.0-10), respectively. In the FEP, ORR was 11% (95% CI, 3.6, 23), the disease control rate was 51% (95% CI, 36, 66), and the median duration of response was 1.8 months (95% CI, 1.3, 4.2). Median progression-free and overall survival were 2.5 months and 5.7 months, respectively. Conclusions: S1400G failed to show sufficient level of efficacy for single agent talazoparib in a biomarker defined subset of squamous lung cancer with homologous recombination repair deficiency. (C) 2021 Elsevier Inc. All rights reserved.