First-in-human trial of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab in advanced cancer patients

Abstract

Background: The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC).

Methods: Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder.

Results: Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI).

Conclusion: Regorafenib 80 mg daily plus cetuximab 200 mg/m2 loading dose, followed by 150 mg/m2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high.

Trial registration: clinicaltrials.gov NCT02095054FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).

Keywords: Clinical Trials; Oncology.

Conflict of interest statement

Conflict of interest: V. Subbiah received research funding from Novartis, Bayer, GSK, Nanocarrier, Vegenics, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Amgen, and Abbvie. D.S. Hong received research funding from Novartis, Genentech, Eisai, Astra-Zenica, Pfizer, and MiRNA. F. Janku received research funding from Novartis. S. Piha-Paul received research funding from Merck, Puma, Samumed, Curis, Cerulean, Incyte, AbbVie, FivePrime, GlaxoSmithKline, Helix, Biomarin, Bayer, and XuanZhu. A. Johnson, S. Ali, J.X. Sun, D. Fabrizio, and A. Schrock are employees of Foundation Medicine and own stock in the company. F. Meric-Bernstam received research funding from Novartis and Genentech. G. Falchook is an employee of the Sarah Cannon Research Institute at HealthONE.

Figures

Figure 1. Dose escalation schema showing the number of dose levels, doses, number of patients enrolled, and dose-limiting toxicities (DLTs).

Figure 2. Representative examples of imaging studies of patients with response in the phase 1 trial.

Top 2 rows: A 54-year-old woman with metastatic colorectal cancer and partial response. (A–D) A left lower lobe nodule decreases in size over the course of the first 3 followup scans, obtained approximately every 6 weeks. (E–H) A right hepatic lobe lesion decreases in size and enhancement over the same time period. Bottom 2 rows: A 35-year-old woman with metastatic carcinoma of unknown primary and stable disease. (I–L) Maximum intensity projections from 18F-FDG PET/CTs obtained approximately every 6 weeks show a left breast mass, left axillary adenopathy, and a right lower lobe metastasis. (M–P) Axial fused images at the level of the left breast mass show stable maximum standard uptake value (SUVmax) when accounting for scan-to-scan variation. The postobstructive consolidation in the right lower lobe related to a right perihilar lesion can also be seen.