19 / 32
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
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
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%.
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.
PracticeUpdate Editorial Team
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
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.
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.
ASCO GI 2017
19
VOL. 2 • NO. 2 • 2017