O-20 Phase I/IB study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer

Abstract

Regorafenib is a multi-tyrosine kinase inhibitor that blocks many pathways including CSF1R which is a receptor involved in macrophage proliferation. Inhibition of the CSF1R may reduce the recruitment of immune-suppressive tumor-associated macrophages (TAMs) to the tumor bed. In addition, recent preclinical data demonstrated regorafenib blocked IFNɣ-induced PD-L1 and IDO1 expression while maintaining MCH-I expression. Therefore, regorafenib can potentially augment the antitumor immunity of checkpoint inhibitors such as nivolumab. This is a phase I/IB trial using the combination of nivolumab and regorafenib in refractory MMR proficient metastatic colorectal cancer. A 3+3 dose-escalation design was used. Patients received nivolumab 240mg IV q2wk and regorafenib according to dose escalation of 80mg, 120 mg or 160mg 21 days on 7 days off. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose for the expanded cohort. Additional pts were enrolled in the expanded cohort to further establish the safety and determine the preliminary efficacy. At the data cutoff of March 2, 2020, 28 patients were enrolled during phase I (n = 12) and the expanded cohort (n = 16). Baseline demographics are as follows: median age 54.5 years old (31-79), median lines of prior therapy of 2.5 (2-3), location of primary tumor: colon (17) vs rectal (11); metastatic sites: liver (19), lung (17), and both (11); and 8 patients had wild type RAS, 20 patients had RAS mutations (KRAS: 19, NRAS:1). During the dose-escalation, 1 DLT (Grade 3 rash) was observed in 80 mg of regorafenib and 2 DLTs (two grade 3 rash) were observed at 120mg. The MTD of regorafenib was 80 mg. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had a partial response and 9 (53%) had stable disease with a disease control rate of 59%. Five pts are still waiting to be restaged. Median PFS was 5.7mo (95% CI 0-11.9) and OS was not reached with median follow-up of 4.6 months. Dose modifications (reductions or interruptions) for drug-related TEAEs occurred in 4 pts. The most common Gr 3 or 4 treatment-emergent adverse events (TEAEs) were rash (N=3), hypertension (N=1) and decreased lymphocytes (N=1). The combination of regorafenib of 80 mg and nivolumab 240mg IV q2wk has modest anti tumor activity in MSS colon cancer. The plan is to enroll a total of 40 pts in the expanded cohort.