Regorafenib/Nivolumab Combo to Be Explored in Phase III MSS CRC Trial


The combination of regorafenib and nivolumab will be compared with regorafenib alone in a phase III trial of patients with microsatellite stable colorectal cancer, following encouraging phase Ib findings of the REGONIVO study.

Scott Z. Fields, MD

Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer

Scott Z. Fields, MD

The combination of regorafenib (Stivarga) and nivolumab (Opdivo) will be compared with regorafenib alone in a phase III trial of patients with microsatellite stable (MSS) colorectal cancer (CRC), following encouraging phase Ib findings of the REGONIVO study.1

In the early-phase study of 50 evaluable patients, results of which were presented at the 2019 ASCO Annual Meeting, the combination led to an overall response rate (ORR) of 40% (95% CI, 26-55) in patients with CRC or gastric cancer, the majority of which were MSS tumors.2 The disease control rate (DCR) was 88% (95% CI, 76-95).

The trial will be a clinical collaboration agreement between Bayer, Bristol-Myers Squibb (BMS), and Ono Pharmaceuticals. Bayer manufactures regorafenib, while BMS develops nivolumab; Ono develops and commercializes the PD-1 inhibitor in Japan, South Korea, and Taiwan.

"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, stated in a press release.

Regorafenib is currently approved by the FDA as a second-line treatment for patients with advanced CRC who progressed on prior therapy. The FDA approved nivolumab in August 2017 for the treatment of adult and pediatric patients with microsatellite instability-high or mismatch repair deficient metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Approximately 95% of patients with advanced CRC have MSS tumors, for which immunotherapy has shown little activity in—demonstrating a high unmet medical need.

In the phase Ib REGONIVO (EPOC1603) trial, a dose-escalation cohort in a 3+3 design was evaluated to determine dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and recommended dose as the primary endpoint. In Level 1, regorafenib was given at 80 mg daily for 21 days on and 7 days off, while nivolumab was given at 3 mg/kg every 2 weeks. In Level 2, regorafenib was administered at 120 mg daily for 21 days on and 7 days off, and Level 3 dosed regorafenib at 160 mg daily for 21 days on and 7 days off. The nivolumab dosage continued at 3 mg/kg every 2 weeks in Levels 2 and 3. A dose-expansion cohort included 36 cases of CRC and gastric cancer.

Secondary endpoints included ORR, progression-free survival (PFS), overall survival (OS), and DCR.

Fifty patients with advanced or metastatic gastric cancer (n = 25) or CRC (n = 25) were evaluated. The median age was 60.5 years, and 80% of patients were male. The majority of patients had an ECOG performance status of 0 (98%), and 70% of patients had lymph node metastases. The median number of prior therapies was 3, which included angiogenesis inhibitors (96%) and PD-1/PD-L1 inhibition (14%). Twenty-four percent of patients had HER2-positive gastric cancer, 98% of patients had MSS tumors, and 41% of patients had PD-L1—positive disease.

The recommended dose and MTD of regorafenib was determined as 120 mg daily. However, in the dose-expansion cohort, the regorafenib dose was reduced to 80 mg due to frequent grade 3 skin toxicities that occurred in 20% of patients at the 120-mg dose.

The median duration of therapy was 6.1 months (range, 0.7-14.9), and study treatment is ongoing in 21 patients.

Broken down by regorafenib dose, the ORRs were 45%, 36%, and 33% at the 80-mg, 120-mg, and 160-mg doses, respectively. When stratified by tumor type, patients with CRC had an ORR of 36%, including 33% in those with MSS disease. The ORR was 44% in patients with gastric cancer, all of whom had MSS tumors.

At a median follow-up of 8.0 months, and a data cutoff date of April 23, 2019, the median PFS overall was 6.3 months (95% CI, 3.4-9.3). The median PFS for those with CRC and gastric cancer were 6.3 months and 5.8 months, respectively.

Regarding safety, all-grade adverse events (AEs) occurred in 100% of patients. Those occurring in ≥20% of patients overall were hand-foot syndrome (70%), hypertension (48%), fatigue (46%), rash (42%), fever (40%), proteinuria (30%), liver dysfunction (28%), oral mucositis (22%), and decreased appetite (22%). Grade ≥3 AEs included hand-foot syndrome (10%), hypertension (4%), rash (12%), proteinuria (12%), liver dysfunction (6%), diarrhea (2%), and decrease in platelet count (2%).

Further biomarker analyses are ongoing for the study.


  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. Bayer. Published July 18, 2019. Accessed July 18, 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 Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2019;37(suppl; abstr 2522). doi: 10.1200/JCO.2019.37.15_suppl.2522.
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