Background: The combination of multi-kinase VEGF inhibitor regorafenib and anti-EGFR monoclonal antibody cetuximab overcame intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). (Clin Cancer Res; 21(13); 2975-83)

Methods: We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of the oral multi-kinase inhibitor regorafenib and the anti-EGFR monoclonal antibody cetuximab in patients (pts) with advanced cancer including metastatic colorectal cancer. Tumor responses were assessed using RECIST v1.1.

Results: Twenty seven pts were enrolled between May 2014 and August 2015. 22 (81%) pts were evaluable for toxicity and response. 5 heavily pre-treated pts were not evaluable for DLTs because they discontinued the trial before the end of the DLT window, mainly because of disease progression. 21 pts were treated at dose level 1 (cetuximab IV 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) and 6 pts at dose level 2. MTD was exceeded at dose level 2 (cetuximab IV 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily), with 2 DLTs observed, including G3 thrombocytopenia (n = 1) and G3 thrombocytopenia with intraperitoneal bleeding (n = 1). The most common adverse events observed in all patients across both dose levels tested included G1-2 rash, G1-2 hypomagnesaemia, G1 myalgia, G1 fatigue, G1 nausea/vomiting. In addition other AE's included G2 hand-foot syndrome (n = 5), and G2 hypertension (N = 2). One patient with KRAS wt CRC achieved a partial response (PR) (46% decrease) lasting 15 months who was previously resistant to cetuximab. Another KRAS wt CRC patient with a hyper-mutated genotype [Lynch syndrome (MSI High), both BRCA1 and 2 mutations, FGFR3 mutation] achieved stable disease (SD) for > 10 months. 10 patients (37%) achieved SD>4 months or PR that included renal cell carcinoma (n = 1), EGFR mutant glioblastoma multiforme (n = 1), squamous cell cancer (n = 1) and carcinoma of unknown primary (n = 1).

Conclusions: The combination of cetuximab and regorafenib was well tolerated at doses of cetuximab IV 200 mg/m2 followed by 150 mg/m2 weekly, with regorafenib 80 mg daily. Anticancer activity was observed in patients with wild type colorectal cancer.

Citation Format: Vivek Subbiah, David S. Hong, Behrang Amini, Sarina Piha-Paul, Joanna Grace Fernandez, Siquing Fu, Apostolia M. Tsimberidou, Aung Naing, Filip Janku, Daniel D. Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S. Falchook. Phase I dose escalation study of the oral multi-kinase VEGF inhibitor regorafenib and the anti-EGFR monoclonal antibody cetuximab in patients with advanced solid tumors including colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C50.