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

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. 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%. 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. 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. 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.