Culprit in Regorafenib Combo Failure in Metastatic Colorectal Cancer?

A 13% absolute increase in the radiographic response rate occurred in regorafenib-treated patients. Survival increases were not statistically significant.

Addition of the multikinase inhibitor regorafenib to the FOLFIRI regimen (leucovorin, fluorouracil [5-FU], and irinotecan) failed to significantly improve progression-free survival (PFS) in patients with metastatic colorectal cancer compared with FOLFIRI alone, according to results of a study published recently in Cancer.

According to the authors, led by Hanna K. Sanoff, MD, of Lineberger Comprehensive Cancer Center, the study demonstrated that adding regorafenib to FOLFIRI “resulted in a 27% relative reduction in progression or death in comparison with FOLFIRI alone as second-line therapy for metastatic colorectal cancer. Because the level of statistical significance for this phase II trial was set at .1, the trial met its primary endpoint for PFS; however, the corresponding absolute improvement in median survival was only 0.8 months, and this did not translate into a benefit in survival.”

Previous research had shown that single-agent regorafenib prolonged survival in patients with refractory colorectal cancer. The current study assessed the efficacy of combining regorafenib with FOLFIRI as a treatment for patients with metastatic disease.

Patients included in the study had progressed after undergoing treatment with first-line oxaliplatin and fluoropyrimidine. A total of 181 patients from 45 sites were randomly assigned in a 2:1 ratio to regorafenib or placebo. All patients underwent treatment with FOLFIRI on days 1 and 2 and days 15 and 16. Crossover was not permitted.

Although patients assigned to regorafenib had a numerically longer PFS time compared with placebo, the difference failed to meet statistical significance. Median PFS was 6.1 months for regorafenib plus FOLFIRI compared with 5.3 months for FOLFIRI alone (hazard ratio [HR], 0.73; P = .056). Similarly, overall survival (OS) was numerically but not statistically longer for regorafenib compared with FOLFIRI alone (13.8 months vs 11.7 months; P = .94).

“With the improvement in PFS, the 13% absolute increase in the radiographic response rate in regorafenib-treated patients lends further support for the increased clinical activity of the regorafenib-FOLFIRI combination over chemotherapy alone; however, it is tempered by the increase in moderate to severe toxicity,” Sanoff and colleagues noted.

Dose reductions were required in more than half (58%) of patients assigned regorafenib, which the researchers wrote could explain, in part, the lack of OS benefit seen with the combination treatment. More patients assigned to regorafenib had grade 3 or worse adverse events (79% vs 59%; P = .005). Among the increased events in the regorafenib arm were neutropenia, febrile neutropenia, diarrhea, hypophosphatemia, hypertension, and elevated lipase.

Based on these results, the researchers concluded that “with little clinical activity seen with the combination of regorafenib with FOLFOX [leucovorin, 5-FU, and oxaliplatin] in the first line, regimens combining regorafenib with FOLFOX or FOLFIRI are unlikely to provide clinically meaningful improvements for patients with metastatic colorectal cancer.”