Wafik S. El-Deiry, MD, PhD, FACP
WAFIK S. EL-DEIRY, MD, PhD, FACP, Deputy Cancer Center Director for Translational Research, and Co-Leader of the Molecular Therapeutics Program at Fox Chase Cancer Center, Philadelphia, shared his thoughts on these findings with The ASCO Post. In essence, Dr. El-Deiry suggested the comparison does not accurately reflect how cetuximab (Erbitux) is commonly used in the United States, but the findings could inform future studies of treatment sequencing.
The REVERCE study investigated the impact of the sequence of regorafenib (Stivarga) and cetuximab in patients with advanced colorectal cancer who had wild-type KRAS at exon 2 and were previously treated with a fluoropyrimidine, oxaliplatin, and irinotecan. The treating physicians had the option to include irinotecan when they used cetuximab. The results of this 2-arm randomized 101-patient phase II study revealed “a remarkable improvement” in overall survival (17.4 months) for the regorafenib-cetuximab sequence vs cetuximab-regorafenib (11.6 months). Similar results were found for left-sided tumors.
“Typically, cetuximab is used in combination with a fluoropyrimidine plus irinotecan and, in 2018, increasingly in the first line, as data show a benefit from FOLFIRI (fluorouracil [5-FU], leucovorin, irinotecan) plus cetuximab for wild-type KRAS left-sided colon tumors. Whether the sequence of regorafenib-cetuximab would show a superior overall survival advantage vs cetuximab plus FOLFIRI followed by regorafenib is unknown,” Dr. El-Deiry pointed out.
An ongoing study is evaluating regorafenib plus 5-FU (ClinicalTrials. gov identifier NCT03099486). Like cetuximab alone, regorafenib alone also may not be optimal in the earlier treatment setting, he indicated.
“The findings are important, as they point to the potential benefit from earlier use of regorafenib in advanced colorectal cancer that would need to be tested in clinical trials. Since cetuximab is most often used in combination with FOLFIRI, it is premature to recommend regorafenib be sequenced before cetuximab, as the cetuximab-alone arms probably were suboptimal in REVERCE,” he maintained.
THE RESULTS of REVERCE also require a better understanding of the biology and the determinants that possibly underlie the large survival difference with regorafenib first, he continued. The impact of each of the therapies in the regorafenib-cetuximab vs cetuximab-regorafenib sequence on drug resistance mechanisms and tumor heterogeneity needs to be investigated carefully, for example, by serial liquid biopsies, in future clinical trials as this could in part explain the clinical outcomes. The impact of prior antiangiogenic therapy is relevant (given the antiangiogenic targets of regorafenib), and this needs to be analyzed, given that bevacizumab is commonly used as front-line therapy in some parts of the world, including the United States, he said.
“In the future, there should be some consideration for a regorafenib/ cetuximab combination with or without fluoropyrimidine, properly designed to manage the potential toxicities,” he suggested. Such a study could take advantage of emerging data showing that 120 mg/d of regorafenib may be more beneficial than the classic 160 mg/d regimen. ■
DISCLOSURE: Dr. El-Deiry is the principal investigator of an investigator-initiated clinical trial open at Fox Chase Cancer Center offering regorafenib plus 5-FU beyond disease progression on single-agent regorafenib for patients with metastatic colorectal cancer. This trial is funded by Bayer.
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