Small Study Evaluates Treatment Sequencing in Patients With Metastatic Colorectal Cancer

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THE OPTIMAL treatment sequence for two approved agents in metastatic colorectal cancer may be regorafenib (Stivarga) before cetuximab (Erbitux), according to results from the small randomized Japanese REVERCE trial presented at the 2018 Gastrointestinal Cancers Symposium.1

Giving regorafenib before cetuximab resulted in a median overall survival of 17.4 months, compared with 11.6 months when cetuximab preceded regorafenib, translating into a 39% reduction in risk (P = .0293), reported Kohei Shitara, MD, of the National Cancer Center Hospital East in Kashiwa, Japan, and colleagues. The benefit for regorafenib first was consistent across subgroups, including almost a 9-month difference in those with left-sided tumors.

Kohei Shitara, MD

Kohei Shitara, MD

“Safety and quality of life were comparable between the two arms but were generally lower during regorafenib treatment,” Dr. Shitara said. “A biomarker analysis is still ongoing.”

Both regorafenib and cetuximab—inhibitors of the epidermal growth factor receptor (EGFR)—are approved for metastatic colorectal cancer. The optimal sequencing of these drugs, which are used in patients with RAS/BRAF wild-type tumors, has not been determined.


THE 29-CENTER phase II trial enrolled 101 patients who had previously received combination therapy with a fluoropyrimidine, oxaliplatin, and irinotecan. They were randomized to receive treatment with either regorafenib followed by cetuximab or the same drugs in the reverse sequence. Treatment with the initial drug continued until disease progression, at which time patients switched to the alternative drug. Investigators had the option to give cetuximab with or without irinotecan.

Overall survival was the primary endpoint, with key secondary endpoints including first progression-free survival, second progression-free interval, safety, and quality of life. Serial biomarker analyses, including oncogenic alterations in circulating tumor DNA and various serum proteins, were exploratory.

“The benefit for regorafenib first was consistent across subgroups, including almost a 9-month difference in those with left-sided tumors.”
— Kohei Shitara, MD

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Regorafenib First Was Favored

IN ADDITION to the 5.8-month difference in survival for patients who initiated treatment with regorafenib, the study found that finishing treatment with cetuximab resulted in a more prolonged second progression-free interval (ie, after progressing and being treated a first time); the first progression-free survival did not differ significantly according to the drug sequence.

Median first progression-free interval was 2.4 months for patients who received regorafenib first and 4.2 months for those who began treatment with cetuximab, which did not achieve statistical significance (hazard ratio [HR] = 0.97; P = .91). In contrast, median second progression-free interval was significantly longer with the regorafenib-first sequence (5.2 vs 1.8 months, HR = 0.29; P < .0001).

A total of 81 patients had left-sided primary tumors. In that subgroup, patients who started treatment with regorafenib had a median overall survival of 20.5 months compared with 11.9 months for those receiving cetuximab first, a 49% reduction in mortality risk that was significant (P = .011).

DISCLOSURE: Dr. Shitara disclosed relevant relationships with AbbVie, Novartis, Ono Pharmaceutical, Yakult, Astellas, Bristol-Myers Squibb, Lilly, Pfizer, Takeda, Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Merck Sharp and Dohme, and Taiho Pharmaceutical.


1. Shitara K, Yamanaka T, Denda T, et al: REVERCE: Randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan. 2018 Gastrointestinal Cancers Symposium. Abstract 557. Presented January 20, 2018.

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