Vemurafenib Adds to PFS in BRAF-mutant mCRC

Scott Kopetz, MD, PhD

Adding vemurafenib to the routinely employed combination of irinotecan and cetuximab prolonged progression-free survival (PFS) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), according to the results from a randomized clinical trial.¹

In the 106-patient trial, median PFS improved from 2.0 months in the arm randomized to cetuximab and irinotecan to 4.4 months in patients assigned to the combination plus vemurafenib, reported Scott Kopetz, MD, PhD, at the 2017 Gastrointestinal Cancers Symposium.

The data support the concept that vemurafenib “sensitizes BRAF-mutant colorectal tumors to cetuximab and irinotecan, and is consistent with the multiple preclinical and early phase 1 studies,” said Kopetz, Associate Professor of Gastroenterology Medical Oncology at the University of Texas MD Anderson Center. “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.”

BRAF V600E mutations are present in 5 to 10% of patients with mCRC. The biology is aggressive in this subset of patients, he noted. BRAF V600E mutations are associated with distinct clinicopathologic features such as proximal colon location, gene hypermethylation, and tumor microsatellite instability. Overall survival in BRAF-mutant mCRC is short and response to standard chemotherapy is limited.

The BRAF V600E mutation results in constitutive activation of MAP kinase signaling. In preclinical models, inhibiting BRAF V600E has been shown to transiently reduce MAP kinase signaling but with resultant feedback activation of EGFR, which can reactivate MAP kinase activity, explained Kopetz. As a result, single-agent vemurafenib has limited activity.² Dual inhibition of EGFR and BRAF can shut down this signaling.

In preclinical models of BRAF V600E mCRC, a dual BRAF and EGFR blockade has generated an anti-tumor response. Adding irinotecan to vemurafenib and cetuximab led to a sustained anti-tumor response and prolonged survival compared with the vemurafenib/cetuximab doublet in a patient-derived xenograft model of BRAF V600E mCRC, which suggests additional clinical benefit by adding vemurafenib to standard irinotecan and cetuximab. Early results from a phase I clinical trial suggest that the triplet is safe and tolerable with efficacy in patients with refractory BRAF V600E mCRC.³

The 106 patients enrolled in the study Kopetz described in his presentation had histologically or cytologically documented BRAF V600E-mutated and extended RAS wild-type mCRC. Patients had to have ECOG performance status of 0/1 to be eligible. They were randomized to irinotecan, 180 mg/m² IV every 14 days, and cetuximab, 500 mg/m² IV every 14 days, with or without vemurafenib, 960 mg orally twice daily. Patients were allowed 1 or 2 prior regimens of systemic chemotherapy for metastatic or locally advanced unresectable mCRC. Prior irinotecan was allowed but prior anti-EGFR therapy or RAF or MEK inhibitors were not permitted nor was receipt of any chemotherapy within 14 days of registration. Thirty-nine percent of patients were treated with irinotecan prior to enrollment.

Crossover from the control arm to the triplet arm was allowed with documented progression. The primary endpoint was PFS.

Of the 106 patients, 7 were deemed ineligible due to inadequate hematologic function, not having a BRAF V600E mutation, or received chemotherapy within 14 days prior to randomization, leaving 99 available for analysis. The median age of patients was 62 years and >90% were white. More than half of the patients in each arm had 1 prior regimen for the treatment of mCRC, and about one third in each arm had 2 prior regimens.

PFS was improved with the addition of vemurafenib (HR, 0.42, P = .0002) with the aforementioned median PFS of 4.4 months in the triplet arm compared with 2.0 months with the doublet.

Four percent of patients in the cetuximab plus irinotecan arm and 16% in the triplet arm had a partial response. Seventeen percent and 48%, respectively, had stable disease, for a disease control rate of 22% in patients randomized to cetuximab and irinotecan, and 67% in patients randomized to vemurafenib, cetuximab, and irinotecan (P = .001). “Importantly, the durations of response were higher with the addition of vemurafenib, and the 2 responders in the control arm had very short durations of response,” Kopetz said.

The rates of grade 3/4 adverse events (AEs) that were higher in the experimental arm included neutropenia (28% vs 7%), 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,” Kopetz said. Eighteen percent discontinued treatment due to AEs in the triplet arm compared with 8% in the doublet arm.

Future analyses will include overall survival. Crossover occurred in 48% of patients assigned to cetuximab and irinotecan; the outcomes of these patients remain immature. Subgroup analysis will be conducted to examine the role of irinotecan pre-treatment and to evaluate the outcomes of patients according to microsatellite instability, “recognizing that 25% of the BRAF population in metastatic disease has microsatellite instability,” Kopetz said.

References

1. Kopetz S, McDonough S, Morris V, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Abstract 520.
2. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227-35.
3. Hong DS, Morris VK, El Osta B, et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation, Cancer Discov. 2016;6:1352-1365.