Concurrent EGFR and BRAF Inhibition Improves PFS in BRAF V600 Mutation–Positive Colorectal Cancer

Adding vemurafenib (Zelboraf) to cetuximab (Erbitux) and irinotecan (Camptosar) prolonged progression-free survival (PFS) and improved the disease control rate in patients with BRAF V600E mutation–positive colorectal cancer (CRC).

The median PFS was extended by more than 2 months in the arm receiving all 3 drugs compared with the arm receiving only cetuximab and irinotecan, in a randomized controlled clinical trial. This indicates that simultaneous EGFR and BRAF inhibition is effective in BRAF V600E mutation–positive CRC, suggested Scott Kopetz, MD, PhD, Associate Professor, Gastroenterology Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, who presented the study results at the 2017 Gastrointestinal Cancers Symposium.

These findings support that vem­urafenib “sensitizes BRAF-mutated colorectal tumors to cetuximab and irinotecan, and is consistent with the multiple preclinical and early phase 1 studies,” said Dr Kopetz. “Overall, novel therapies such as this are needed for this rare and aggressive subset of colorectal cancers, where our standard chemotherapy regimens are failing to provide substantial and meaningful clinical benefit.”

The BRAF V600E mutation is present in approximately 7% of patients with metastatic CRC, and this mutation is associated with aggressive biology, a short overall survival, and limited response to standard chemotherapy, Dr Kopetz noted.

BRAF inhibition with single-agent vemurafenib has limited activity in CRC. Although it can reduce MAP kinase signaling, feedback activation of EGFR can reactivate MAP kinase activity, he explained. Dual inhibition of EGFR and BRAF has synergy in shutting down MAP kinase signaling in this context.

Adding Vemurafenib Improves Outcomes

In the present trial, 106 patients with documented BRAF V600E mutation and extended RAS wild-type metastatic CRC were randomized to a 2-drug regimen of irinotecan 180 mg/m2 intravenously every 14 days, plus cetuximab 500 mg/m2 intravenously every 14 days, or to this regimen plus the addition of oral vemurafenib 960 mg twice daily.

Patients could have received up to 2 previous regimens of systemic chemotherapy, as long as it was at least 14 days before registration into the trial. A total of 39% of patients received irinotecan before enrollment. Patients who received previous anti-EGFR therapy or RAF or MEK inhibitors were excluded. Patients who crossed over from the control arm to the 3-drug arm were included if they had documented progression.

The PFS improved from 2 months in the 2-drug arm to 4.4 months with the addition of vemurafenib, corresponding to a hazard ratio of 0.42 (P = .0002).

In the 2-drug arm, 4% of patients had partial responses and 17% had stable disease, for a disease control rate of 22%. In the 3-drug arm with vemurafenib, 16% of patients had partial responses and 48% had stable disease, for a disease control rate of 67% (P = .001 in favor of the 3-drug arm).

“Importantly, the duration of responses was higher with the addition of vemurafenib, and the 2 responders in the control arm had very short durations of response,” said Dr Kopetz.

Grade 3 or 4 adverse events that were more common in the 3-drug arm versus the doublet arm included neutropenia (28% vs 7%, respectively), anemia (13% vs 0%), and nausea (15% vs 0%), “but these rates may be attributed to increased duration of exposure, and are similar to a prior second-line study of cetuximab and irinotecan,” Dr Kopetz suggested.

Future analyses will measure overall survival. Of the patients assigned to the 2-drug arm, 48% crossed over to the 3-drug arm that included vem­urafenib in addition to cetuximab and irinotecan; the outcomes data on these patients remain immature.

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