PracticeUpdate: Haematology & Oncology

ASCO GI 2017 19

Simultaneous EGFR and BRAF inhibition proven effective in BRAF V600-mutated, metastatic colorectal cancer T he addition of vemurafenib to the combination of cetuximab and irinotecan has been shown to prolong progression-free survival and raise primary endpoint was progression-free survival, with a 90% power to detect a hazard ratio of 0.5, with a two-sided type 1 error of 5%.

the disease control rate in BRAF V600-mutated colorectal cancer. This improvement indicates that simultaneous epidermal growth factor receptor (EGFR) and BRAF inhibition is effective in BRAF V600-mutated metastatic colorectal cancer. Scott Kopetz, MD, PhD, of the University of Texas MDAnderson Cancer Center, Houston, explained that BRAF V600 mutations are associated with rare objective responses to single-agent treatment with the mutated BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer. Blockade of BRAF V600 by vemurafenib causes feedback upregulation of EGFR, whose signalling activities can be impeded by cetuximab. In murine models of BRAF V600 metastatic colorectal cancer, the combination of irinotecan, cetuximab, and vemurafenib leads to greater antitumour activity, as suggested in a phase 1B study. Dr Kopetz said, “We pursued this work because this population suffers from an aggressive variant of colorectal cancer and the unmet need is substantial. We were also motivated by the strong preclinical data and promising results in early studies.” Patients with BRAF V600-mutated and extended RAS wild-type metastatic colorectal cancer were randomised to irinotecan (180 mg/m 2 IV every 14 days) and cetuximab (500 mg/m 2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Patients had received one or two prior regimens, with no prior anti-EGFR agents, though prior irinotecan was allowed. Crossover from the control to the experimental arm was allowed after documented progression. The EDITOR’S NOTE By Axel Grothey MD T he presence of BRAF V600E mutations in metastatic colorectal cancer (mCRC) has long been known to be associated with an extremely poor prognosis with a median sur- vival of about 12 to 15 months in clinical trials. In contrast to melanoma carrying the very same mutation, single-agent BRAF inhibitors, or com- binations of BRAF and MEK inhibitors, have not shown relevant clinical activity in mCRC. The randomised phase II trial presented at ASCO GI now explored a triplet combination of the BRAF inhibitor vemurafenib added to the regulatory standard of care, cetuximab and irinotecan. The triplet combination met the primary endpoint

A total of 106 patients were enrolled (54 in the experimental arm) from 2014 to 2016. Eastern Cooperative Oncology Group performance status was ≤ 1, median patient age was 62 years, and 59% were female. Thirty-nine percent had received prior irinotecan therapy. Progression-free survival improved with the addition of vemurafenib (HR 0.42, 95% CI 0.26– 0.66, P < 0.001) with median progression-free survival of 4.4 months (95% CI 3.6–5.7) vs 2.0 (95% CI 1.8–2.1). The response rate was 16% vs 4% (P = 0.09), and the disease control rate 67% vs 22% (P < 0.001). Grade 3/4 adverse events higher in the experimental arm included neutropenia (28% vs 7%), anaemia (13% vs 0%), and nausea (15% vs 0%). No increase in skin toxicity or fatigue was observed, nor any new safety signal. Approximately 50% of patients in the control aim crossed over at the time of progression. Data on overall survival and efficacy remain immature. Dr Kopetz concluded that the addition of vemurafenib to the combination of cetuximab and irinotecan was shown to prolong progression-free survival and raise the disease control rate in BRAF V600-mutated colorectal cancer. This improvement indicates that simultaneous EGFR and BRAF inhibition is effective in BRAF V600-mutated colorectal cancer. “We hope this provides a new standard for treatment for this population,” he added.

The addition of vemurafenib to the combination of cetuximab and irinotecan was shown to prolong progression- free survival and raise the disease control rate in BRAF V600-mutated colorectal cancer.

PracticeUpdate Editorial Team

of the trial in the form of a clinically relevant improvement in progression-free survival with higher response and disease-control rates. It is of note that, in the triplet combination, cetux- imab likely serves to counteract feedback-loop activation of EGFR after BRAF blockade. It will remain to be seen if regulatory agencies or guideline committees will regard the results as practice-changing.

Dr Grothey is a consultant in the Division of Medical Oncology, Department of Oncology at Mayo Clinic.

VOL. 2 • NO. 2 • 2017