Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).

Abstract

2522 Background: 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. Methods: In this study, we enrolled patients (pts) with previously treated, advanced GC or 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 of 80 to 160 mg was administered once daily for 21 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. Results: Fifty pts were enrolled (25 GC; 25 CRC) 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, mucositis and proteinuria, 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. Conclusions: The combination of regorafenib 80mg plus nivolumab had a manageable safety profiles 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. Clinical trial information: NCT03406871.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…However, the benefit of anti-angiogenic drugs is time-and dose-dependent, and identifying the normalization window of a tumor is challenging. Our model predictions are further validated by recent clinical trials showing that combination treatment with a low dose of an anti-angiogenic agent (regorafenib) with nivolumab is superior to high doses in advanced gastric or colorectal cancer (60). Our model suggests that administration of immunotherapy with anti-angiogenic treatment could protect blood vessels from excessive pruning (49).…”

Current status of immunotherapy in gastrointestinal malignancies

“…However, the consecutive phase III clinical trial (IMblaze 370) in 363 refractory patients did not show any difference in comparison to regorafenib alone [93]. Recent data directed the attention to the combination of regorafenib with nivolumab, showing an ORR of 33 % in 24 MSS MCRC patients [94].…”

Treatment Outcomes in Patients Receiving Regorafenib for Metastatic Colon Cancer

“…Grade 3 to 4 toxicities were observed in 20% in the monotherapy group, and 29% in the doublet group. 24 Based on these results, FDA indications have been granted for the use of nivolumab in patients with dMMR who have failed a fluoropyrimidine, oxaliplatin, and irinotecan; and for the use of nivolumab plus ipilimumab for patients with previously treated dMMR mCRC.…”