Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603)

Abstract

PURPOSE This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose. RESULTS Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability–high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair–proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively. CONCLUSION The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy

“…The counterparts in the TCGA cohort are shown in (online supplemental figure 6SF-H). As recently the combination of regorafenib plus nivolumab has shown a manageable safety profile and encouraging antitumor activity in colon cancer, 37 we further investigated the association of the MSRS and VEGF activities in MSS, MSI-L, and MSI-H tumors. The results indicated a strikingly higher association of the MSRS and VEGF in MSI-H tumors (0.53) than in MSI-L tumors (0.34) and MSS tumors (0.14) ( figure 7D).…”

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

“…No responses were detected in a cohort of pMMR mCRC treated with compassionate administration of nivolumab or pembrolizumab in combination with regorafenib in a single United States (U.S.) center. Among five patients (31%) who experienced stable disease as best response, four had no liver metastases [28]. In line with REGONIVO, this finding could suggest that patients with liver metastases are characterized by a lower antitumor immune response and may be less likely to benefit from checkpoint inhibition [121].…”

PD-L1 expression in liver metastasis: its clinical significance and discordance with primary tumor in colorectal cancer

“…[4] In CRC, EPOC1603 clinical trial of regorafenib plus nivolumab therapy showed promising effect with an ORR of 36% in treatmentrefractory CRC, but relatively unsatisfactory outcomes in the subgroup of patients with liver metastases. [18] Meanwhile, phase IIIb CONSIGN study showed that regorafenib signi cantly improved survival in treatment-refractory CRC, but liver metastases was a signi cant adverse factor in the progression-free survival (PFS) of regorafenib for metastatic CRC. [19] The poor outcome of patients with liver metastases suggested a possibly distinct microenvironment in liver metastases.…”

“…[17] Unfortunately, in patients with liver metastases, the e cacy of regorafenib monotherapy or its combination with immunotherapy was undesirable. [18,19] Previous studies have found the heterogeneity of lymphocyte type, lymphocyte number, KRAS status between primary tumors and liver metastases of colorectal cancer, which suggested that there may be different in the microenvironment between primary tumors and liver metastases. [20,21] The current study aim to explore the status of the PD-L1 expression difference between in primary tumors and in liver metastases of CRC to nd those in uence factors to evaluate the PD-L1 expression status accurately.…”