Regorafenib/Nivolumab Combo to Be Studied in Phase III Trial of Patients With MSS mCRC

A phase III trial is being initiated to evaluate the combination of regorafenib (Stivarga) and nivolumab (Opdivo) in comparison with regorafenib alone in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC).¹

Bayer, Bristol-Myers Squibb Company, and Ono Pharmaceutical Co. announced a clinical collaboration agreement for the investigation of the multikinase inhibitor and anti—PD-1 immune checkpoint inhibitor combination in the most common form of mCRC.

"We are looking forward to a strong collaboration to investigate nivolumab with regorafenib, with the goal of serving more patients who have cancer," said Fouad Namouni, MD, head of head of development, oncology, Bristol-Myers Squibb, in the press release announcing the collaboration.

Approximately 95% of patients with mCRC have MSS tumors, which single-agent immunotherapy treatments have shown limited activity against.

The trial comes after encouraging data with the combination in thephase Ib REGONIVO trialwere presented at the 2019 ASCO Annual Meeting.²

The Japanese dose-trial included 2 cohorts (a dose-finding cohort and a dose-expansion cohort) totaling 50 patients with previously treated advanced or metastatic gastric cancer or colorectal cancer. Ninety-eight percent of patients had microsatellite stable (MSS) disease, 59% had negative PD-L1 expression, and 14% had received prior treatment with an anti—PD-1/PD-L1 inhibitor.

The primary endpoint of the trial was dose-limiting toxicities found in search of the maximum-tolerated and recommended dosage of the combination, and secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) being secondary endpoints.

Patients in the dose-escalation cohort were given 80 mg, 120 mg, or 160 mg of regorafenib once per day for 21 days with 7-day gaps in the cycle plus 3 mg of nivolumab every 2 weeks. DLTs were observed with 160-mg doses of regorafenib. Several cases of skin toxicity occurred at 120 mg and 160 mg. The investigators set the recommended dose of regorafenib at 120 mg when given in combination with nivolumab.

Overall, the ORR was 40% (95% CI, 26%-55%) with a DCR of 88% (95% CI, 76%-96%). In patients treated with the recommended dose of 120 mg of regorafenib, the ORR was 36%. Specifically, the ORR was 44% in patients with gastric cancer and 36% in patients with colorectal cancer. All of the responders but 1 had MSS disease.

At a median follow-up of 8.0 months, the median PFS across all patients was 6.3 months (95% CI, 3.4-9.3), and was 6.3 months and 5.8 months in patients with colorectal and gastric cancers, respectively.

All-grade treatment-related adverse events (TRAEs) were seen in 100% of patients. The rate of grade ≥3 TRAEs seen overall was 40%. The most common grade ≥3 TRAEs were rash in 12%, proteinuria in 12%, palmar-plantar erythrodysesthesia in 10%, and liver dysfunction in 6%. 

In patients who received 80 mg regorafenib, the rate of grade ≥3 TRAEs was 27% compared with 44% in those who received 120 mg. 

"The data seen in REGONIVO warrant further exploration of the combination of regorafenib and nivolumab in patients with colorectal cancer. Regorafenib has proven its efficacy and positive safety profile as a third-line monotherapy and we are excited to enter into a clinical collaboration to evaluate this combination with the hope to deliver an additional therapeutic benefit to patients," Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer's Pharmaceuticals Division, said in the press release.

Regorafenib has been approved by the FDA for the treatment of previously treated patients with mCRC, and nivolumab has been approved for the treatment of previously treated patients with microsatellite instability-high or mismatch repair deficient mCRC.

References:

1. Bayer, Bristol-Myers Squibb and Ono Pharmaceutical enter into a clinical collaboration agreement to investigate Stivarga® (regorafenib) and Opdivo® (nivolumab) as combination therapy in patients with metastatic colorectal cancer [press release]. Whippany, Princeton, and Osaka: Bayer, Bristol-Myers Squibb Company, and Onco Pharmaceutical Co; July 18, 2019.https://bit.ly/2SnCeyX. Accessed July 19, 2019.
2. 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 252.