PMID- 34607210 OWN - NLM STAT- MEDLINE DCOM- 20211022 LR - 20211022 IS - 1872-8332 (Electronic) IS - 0169-5002 (Linking) VI - 161 DP - 2021 Nov TI - Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study. PG - 180-188 LID - S0169-5002(21)00537-7 [pii] LID - 10.1016/j.lungcan.2021.09.004 [doi] AB - OBJECTIVES: Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. MATERIALS AND METHODS: Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m(2) (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m(2) (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. RESULTS: Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80-240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80-240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. CONCLUSION: Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug-drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity. CI - Copyright (c) 2021. Published by Elsevier B.V. FAU - Clarke, Jeffrey M AU - Clarke JM AD - Department of Medicine, Duke University School of Medicine, Box 31379 Med Ctr, Durham, NC 27710, USA. Electronic address: jeffrey.clarke@duke.edu. FAU - Patel, Jyoti D AU - Patel JD AD - Division of Hematology/Oncology, Northwestern University, 676 N. St Clair, Suite 850, Chicago, IL 60611, USA. Electronic address: jd-patel@northwestern.edu. FAU - Robert, Francisco AU - Robert F AD - University of Alabama at Birmingham, Comprehensive Cancer Center, 1802 6th Ave S, Birmingham, AL 35233, USA. Electronic address: pacorobertuab@cs.com. FAU - Kio, Ebenezer A AU - Kio EA AD - Goshen Center for Cancer Care, 200 High Park Ave, Goshen, IN 46526, USA. Electronic address: ebenkio@gmail.com. FAU - Thara, Eddie AU - Thara E AD - American Institute of Research, 15111 Whittier Blvd, Suite 216, Whittier, CA 90603, USA. Electronic address: ethara@airesearch.us. FAU - Ross Camidge, D AU - Ross Camidge D AD - University of Colorado-Denver, 1665 Aurora Ct, Aurora, CO 80045, USA. Electronic address: ross.camidge@ucdenver.edu. FAU - Dunbar, Martin AU - Dunbar M AD - Data and Statistical Sciences, AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: martin.dunbar@abbvie.com. FAU - Nuthalapati, Silpa AU - Nuthalapati S AD - Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: silpa.nuthalapati@Abbvie.com. FAU - Dinh, Minh H AU - Dinh MH AD - Oncology Development, AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: minh.dinh@Abbvie.com. FAU - Bach, Bruce A AU - Bach BA AD - Oncology Development, AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: bruce.bach@abbvie.com. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210917 PL - Ireland TA - Lung Cancer JT - Lung cancer (Amsterdam, Netherlands) JID - 8800805 RN - 0 (Benzimidazoles) RN - 01O4K0631N (veliparib) RN - 31YO63LBSN (Nivolumab) RN - 49DFR088MY (Platinum) SB - IM MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Benzimidazoles MH - *Carcinoma, Non-Small-Cell Lung/drug therapy MH - Humans MH - *Lung Neoplasms/drug therapy MH - Nivolumab/therapeutic use MH - Platinum/therapeutic use OTO - NOTNLM OT - Combination chemotherapy OT - Immunotherapy OT - NSCLC OT - Nivolumab OT - Phase 1 OT - Veliparib EDAT- 2021/10/05 06:00 MHDA- 2023/02/25 06:00 CRDT- 2021/10/04 20:25 PHST- 2021/04/14 00:00 [received] PHST- 2021/09/06 00:00 [revised] PHST- 2021/09/10 00:00 [accepted] PHST- 2021/10/05 06:00 [pubmed] PHST- 2023/02/25 06:00 [medline] PHST- 2021/10/04 20:25 [entrez] AID - S0169-5002(21)00537-7 [pii] AID - 10.1016/j.lungcan.2021.09.004 [doi] PST - ppublish SO - Lung Cancer. 2021 Nov;161:180-188. doi: 10.1016/j.lungcan.2021.09.004. Epub 2021 Sep 17.