Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer
David Kozono, Thomas E. Stinchcombe, Joseph K. Salama, Jeffrey A. Bogart, W. Jeffrey Petty, Michael J. Guarino, Lyudmila Bazhenova, James M. Larner, Jared Weiss, Thomas A. DiPetrillo, Steven J. Feigenberg, Xin Chen, Zhaowen Sun, Silpa Nuthalapati, Lindsey Rosenwinkel, Eric F. Johnson, Bruce Allen Bach, Yan Luo, Everett E. Vokes
Abstract
Objectives Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods Patients received veliparib orally twice daily (BID) in escalating doses (60–240 mg, Day –3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m 2 ), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120–240 mg BID, Days –2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m 2 , Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. Results Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7–32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0–not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0–not reached). Conclusions When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.