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. (November 2021)

• Record Type: Journal Article
• Authors: Clarke, Jeffrey M.; Patel, Jyoti D.; Robert, Francisco; Kio, Ebenezer A.; Thara, Eddie; Ross Camidge, D.; Dunbar, Martin; Nuthalapati, Silpa; Dinh, Minh H.; Bach, Bruce A.
• Is Part Of: Lung cancer. Volume 161(2021)
• Page Start: 180
• Page End: 188
• Publication Date: 2021-11
• Subjects: AUC0-x area under the plasma concentration-time curve from time 0 to x hour post dose concentration -- AUCt area under the plasma concentration-time curve from time 0 to the last measurable concentration -- AUC∞ area under the plasma concentration-time curve from time 0 to time infinity -- AE adverse event -- AUC target area under the concentration time curve -- BID twice daily -- C cycle -- CI confidence interval -- Cmax maximum observed plasma concentration -- C/PAC carboplatin + paclitaxel -- C/PEM carboplatin + pemetrexed -- CT chemotherapy -- CTCAE Common Terminology Criteria for Adverse Events -- CV coefficient of variation -- D day -- DDI drug-drug interaction -- DLT dose-limiting toxicities -- ECOG Eastern Cooperative Oncology Group -- h hour -- HPLC LC-MS/MS high-performance liquid chromatography with tandem mass spectrometric determination -- LLOQ lower limit of quantitation -- NCI National Cancer Institute -- NSCLC non-small cell lung cancer -- ORR objective response rate -- PARP poly (ADP-ribose)-polymerases -- PARylation poly (ADP-ribosyl)ation -- PD-1 programmed death receptor-1 -- PD-L1 programmed death receptor-ligand 1 -- PD-L2 programmed death receptor-ligand 2 -- PK pharmacokinetic -- PS performance score -- RECIST Response Evaluation Criteria in Solid Tumors -- RP2D recommended phase 2 dose -- TEAE treatment-emergent adverse event -- Tmax time to maximum observed plasma concentration observed plasma -- TNM tumor, node, metastasis; Veliparib -- Nivolumab -- Combination chemotherapy -- Immunotherapy -- NSCLC -- Phase 1; 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.2021.09.004
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Veliparib, a PARP inhibitor, enhances cytotoxicity induced by chemotherapy (CT). Nivolumab, a PD-1 inhibitor, plus CT demonstrated efficacy for NSCLC treatment. This is a phase 1 trial of veliparib + nivolumab + CT in unresectable stage III NSCLC. This quadruple therapy was tolerated, and no drug-drug interaction was observed. This combination suggests promising antitumor activity. Abstract: 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.