A dose-finding study followed by a phase II randomized placebo-controlled trial of chemoradiotherapy (CRT) with or without veliparib in stage III non-small cell lung cancer (NSCLC)

Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were randomized to receive concurrent CRT with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) with V at 120 mg or placebo (P) twice daily during CRT followed by 2 cycles (every 21 days) of consolidation carboplatin (AUC 6), paclitaxel (200 mg/m2) with V at 80 mg or P (per randomized arm) orally on days 1-7 of each cycle. Progression-free survival (PFS) was the primary endpoint. The accrual goal was 132 patients. Results: The dose-finding study results were previously presented (ASCO 2016;A8537). V 120 mg twice daily was the recommended phase II dose. A total of 31 eligible and evaluable patients were enrolled in the phase II randomized trial: 17 on V and 13 on P (1 patient in the V arm withdrew prior to starting any treatment, thus was not evaluable). The study was closed to accrual early due to the positive results from the PACIFIC trial that changed standard practice. Median follow-up among alive patients was 16 months. During CRT, the following grade (G) 3-4 adverse events (AE) were seen with V vs P: any G3 AE (6 vs 6), any G4 AE (2 vs 3), G3 pneumonitis (0 vs 1), G3 esophagitis (1 vs 1), G3 oral mucositis (1 vs 0), G3 anorexia (1 vs 1), G3 hyponatremia (0 vs 3), G3 anemia (1 vs 0), G3 neutropenia (3 vs 1), G3 thrombocytopenia (1 vs 0), G4 hypoglycemia (0 vs 1). Also, 2 patients per arm had G4 lymphopenia. During consolidation (11 evaluable patients with V; 10 with P), G3 anemia (1 vs 0), G3 anorexia (1 vs 0), G3 weight loss (0 vs 1), G3 dehydration (1 vs 0), G3 dysphagia (2 vs 0), G3 fatigue (1 vs 0), G3 hypomagnesemia (0 vs 1), G3 nausea (1 vs 0), G4 hyperglycemia (0 vs 1), G3-4 neutropenia (3 vs 0), G3 thrombocytopenia (1 vs 0), G3-4 lymphopenia (2 vs 1); a G5 pneumonitis occurred in the P arm. Response rates were 56% (95% CI, 31-78%) and 69% (95% CI, 38-91%) on the V and P arms, respectively. PFS at 1 year was 47% (95% CI, 23%-68%) with V and 46% (95% CI, 19%-70%) with P. Overall survival (OS) at 1 year was 89% (95% CI, 61%-97%) with V and 54% (95% CI, 25%-76%) with P. Adding the 6 patients treated at 120 mg in the phase I part, 1-year with V was 91% (95% CI, 69%-98%).Conclusions: V in combination with CRT was tolerable with expected toxicities that relate to the backbone regimen. In the small number of randomized patients there was a suggestion of promising survival with V that may provide rationale for future trials of PARP inhibitors with CRT