Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer. (September 2021)

• Record Type: Journal Article
• Authors: Kozono, David E.; Stinchcombe, Thomas E.; Salama, Joseph K.; Bogart, Jeffrey; Petty, W. Jeffrey; Guarino, Michael J.; Bazhenova, Lyudmila; Larner, James M.; Weiss, Jared; DiPetrillo, Thomas A.; Feigenberg, Steven J.; Chen, Xin; Sun, Zhaowen; Nuthalapati, Silpa; Rosenwinkel, Lindsey; Johnson, Eric F.; Bach, Bruce A.; Luo, Yan; Vokes, Everett E.
• Is Part Of: Lung cancer. Volume 159(2021)
• Page Start: 56
• Page End: 65
• Publication Date: 2021-09
• Subjects: Veliparib -- Chemoradiotherapy -- Lung neoplasms -- Non-small cell -- Phase 1; AE adverse event -- AUC area under the curve -- BID twice daily -- CI confidence interval -- Cmax maximum observed concentration -- CP carboplatin/paclitaxel -- CR complete response -- CRT chemoradiotherapy -- DLT dose-limiting toxicities -- DOR duration of response -- ECOG Eastern Cooperative Oncology Group -- FEV1 forced expiratory volume in one second -- KM Kaplan-Meier -- mPFS median progression-free survival -- MTD maximum tolerated dose -- N node -- NSCLC non-small cell lung cancer -- ORR objective response rate -- OS overall survival -- PARP poly(ADP)-ribose polymerase -- PFS progression-free survival -- PK pharmacokinetics -- PR partial response -- RECIST Response Evaluation Criteria in Solid Tumors -- RP2D recommended phase 2 dose -- RT radiotherapy -- T tumor -- TEAE treatment-emergent adverse event -- Tmax time to Cmax -- V20 volume of lung to receive ≥20 Gy RT; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2021.06.028
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Veliparib, a PARP inhibitor, enhances cytotoxicity induced by chemoradiotherapy (CRT) This phase 1 trial investigated veliparib + CRT in unresectable stage III NSCLC. Veliparib + CRT was well-tolerated in these patients. MTD/RP2D was veliparib 240 mg BID + CRT, and 120 mg QD with consolidation CT. Veliparib + CRT showed antitumor activity with an mPFS of 19.6 months. 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.