Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers

Abstract

Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs.

Background: The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs.

Patients and methods: Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance.

Results: Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment-related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed.

Conclusion: Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naive patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results.

Trial registration: ClinicalTrials.gov NCT01187615.

Keywords: Angiogenesis; Chemotherapy; Clinical Trial; NSCLC; Regorafenib.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Consort diagram - disposition of patients enrolled on study

Figure 2

Summary of pharmacokinetics of regorafinib, platinum, and pemetrexed. A–C: Geometric mean concentrations versus time profile of (A) regorafenib and its metabolites (B) M-2 and (C) M-5 following a 60mg dose of regorafenib administered without (Cycle 1, Day 21) or with (Cycle 2, Day 1) cisplatin and pemetrexed. D–E: Geometric mean concentration versus time profile of (D) total platinum and (E) pemetrexed without (Cycle 1, Day 1) or with (Cycle 2, Day 1) regorafenib.

Figure 3

Spider curve of radiographic response to therapy per RECIST v1.1. Patients with partial response are noted in green, stable disease in blue, and progressive disease in red.