Regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer: an open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603)
Immune-suppressive cells such as regulatory T cells (Tregs) or tumor-associated macrophages (TAMs) may contribute to resistance to anti-PD-1/PD-L1 inhibitors (A-PD1). Regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, reduced TAMs in tumor models. The combination of regorafenib plus A-PD1 exhibited superior tumor growth suppression compared to either treatment alone in murine models.
In this study, we enrolled patients (pts) with previously treated, advanced gastric cancer (GC) or colorectal cancer (CRC). The pts received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase to further establish the safety and determine the preliminary efficacy. Regorafenib at 80 to 160 mg was administered once-daily in a schedule of 21 days on/7 days off, with intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose.
Fifty pts were enrolled (25 CRC; 25 GC) until October 2018. The median prior treatment line was 3 (range 2-8). During dose-escalation, 3 DLTs were observed with regorafenib 160 mg, including grade (G) 3 maculopapular rash, proteinuria and colonic perforation, while there was no DLT with 80 or 120 mg. In the dose expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg owing to frequent G3 skin toxicities. Grade ≥ 3 treatment-related adverse events occurred in 17 pts; the common events (>5%) being rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%). Objective tumor response was observed in 19 pts (38%) including 11 MSS GC, 7 MSS CRC and 1 MSI-H CRC for response rates of 44% in GC and 29% in MSS CRC. Three of the 7 A-PD1 pretreated GC pts achieved a partial response. The pre- and post-treatment tumor samples showed a reduction of FoxP3hiCD45RA-Tregs fraction at the tumor response.
The combination of regorafenib 80mg plus nivolumab had a manageable safety profile and encouraging anti-tumor activity in MSS GC and CRC pts, which warrants further investigations in a larger cohort. Updated biomarker analysis will be presented.
