Regorafenib/Nivolumab Combo Elicits Responses in CRC and Gastric Cancer

Shota Fukuoka, MD, PhD

The combination of regorafenib (Stivarga) and nivolumab (Opdivo) elicited an overall response rate (ORR) of 40% and a disease control rate (DCR) of 88% in previously treated patients with gastric cancer or colorectal cancer (CRC), according to phase Ib results of the REGONIVO trial, which were presented at the 2019 ASCO Annual Meeting.

In the study, two cohorts of 50 total patients with previously treated advanced or metastatic gastric cancer or CRC were enrolled and received the combination of regorafenib and nivolumab. Ninety-eight percent of patients had microsatellite stable (MSS) disease, 59% had PD-L1—negative tumors, and 14% had received prior treatment with a PD-1/PD-L1 inhibitor(s).

The purpose of the first cohort was to find the least toxic dosage for treatment (the dose-finding cohort), while the second cohort helped researchers develop an understanding of the combination’s safety and efficacy (the dose-expansion cohort). Patients in the dose-escalation cohort were given 80 mg, 120 mg, or 160 mg of regorafenib once daily for 21 days with 7-day gaps in between plus 3 mg of nivolumab every 2 weeks.

The primary endpoint was dose-limiting toxicities (DLTs) to determine the recommended dosage; key secondary endpoints included ORR, progression-free survival (PFS), overall survival (OS), and DCR.

Results also showed that DLTs were observed with the 160-mg dose of regorafenibm and several cases of skin toxicity occurred at 120 mg and 160 mg. Investigators set the recommended dose of regorafenib at 120 mg when given in combination with nivolumab.

Additional data showed that the ORR was 36% in patients treated with the recommended dose of 120 mg of regorafenib. Specifically, the ORR was 44% in patients with gastric cancer and 36% in patients with CRC. The median PFS across all patients was 6.3 months, and was 6.3 months and 5.8 months in patients with CRC and gastric cancers, respectively.

Following these findings, the combination of regorafenib and nivolumab will be compared with regorafenib alone in a phase III trial of patients with MSS CRC.

In an interview with OncLive, Shota Fukuoka, MD, PhD, of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, shared insight on the study results and the future plans to expand the research with a larger cohort.

OncLive: Can you provide an overview of your study?

Fukuoka: Our clinical trial was composed of 2 cohorts. First, the dose-escalation cohort and second, the dose-expansion cohort. The dose-escalation cohort was [focused on defining the] DLT, maximum-tolerated dose (MTD), and the recommended dose. After the determination of the recommended dose, [we used] a set dose for the dose-expansion cohort, for [both patients with] gastric and colorectal cancers.

What were the finding of this study and how are they significant?

I'd like to focus on the efficacy of the combination. The overall response rate was 40% in all patients. In gastric cancer [it was] 44%, in colorectal cancer [it was] 36%, and in [patients with] MSS colorectal cancer, 33%. I think those are amazing results.

Hyper-progression of disease is very rare. An interesting thing seen is that our study showed hyper-progression of disease in relation to the tumor-associated macrophages and regulatory T cells. Regorafenib reduces [the amount of] immune suppressive cells, so that is why in our cohort, hyper-progression was not observed.

What was the rationale to explore this combination?

[We do know that] anti—PD-1/PD-L1 therapy is effective but there is a limitation with efficacy. [The response with] monotherapy was, I think, over 50% in gastric cancer. [But treatment of patients with] MSS colorectal cancer was not effective with anti–PD-1/PD-L1 therapy alone but [this may be because of immune suppressive cells such as tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, and so on].

In a preclinical study, regorafenib reduced [the amount of] tumor-associated macrophages. We confirmed the combination regorafenib and PD-L1 monotherapy in [in vivo] models. [We observed] a very significant synergistic effect.

Can you discuss the safety data?

Actually, [with] regorafenib 120 mg and 160 mg, the toxicity was not that manageable. For example, [some patients experienced] grade 3 rash, grade 3 [proteinuria] and [other conditions]. So, finally the dose was decreased to 80 mg regorafenib [and] that toxicity was manageable.

What are the next steps for this research?

We are discussing both cancer types, colorectal and gastric, in a large cohort randomized study. I hope this trial will proceed to the next step.

Fukuoka S, Hara H, Takahashi N, et al. 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). J Clin Oncol. 2019;37(suppl; abstr 2522).