COMBI-v affirms combination MEK, BRAF blockade in melanoma
More complete blockade of
the MAP kinase pathway with both a BRAF and MEK inhibitor decreased the risk of
death by one-third among patients with advanced BRAF mutation–positive melanoma
in the phase III COMBI-v study.
After a median follow-up
of 10-11 months, the primary endpoint of overall survival was 17.2 months with
the BRAF inhibitor vemurafenib (Zelboraf) alone, but had not been reached with
the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK
inhibitor trametinib (Mekinist) (hazard ratio, 0.69; P = .005).
Dr. Caroline Robert
Patrice
Wendling/Frontline Medical News
“This combination has met all the endpoints
that were looked for, and I’d like to remind you that we compared this
combination to an already very active drug,” study author Dr. Caroline Robert,
head of dermatology at the Institut Gustave Roussy in Paris, said during a
presidential session at the European Society for Medical Oncology Congress.
Patients in the
combination arm had significantly better median progression-free survival than
those given vemurafenib monotherapy (11.4 vs. 7.3 months; HR, 0.56; P <
.001), as well as higher response rates (64% vs. 51%; P < .001), more
complete responses (13% vs. 8%), and a longer duration of response (13.8 vs.
7.5 months).
COMBI-v was stopped early
for efficacy at the interim analysis, which de facto became the final overall
survival analysis presented by Dr. Robert.
The study evenly
randomized 704 patients with stage IIIC or IV BRAF V600E or V600K
mutation–positive melanoma to first-line therapy with twice-daily dabrafenib
150 mg plus daily trametinib 2 mg or twice-daily vemurafenib 960 mg.
The study sponsor,
GlaxoSmithKline, gained accelerated approval in the United States in January
2014 for use of combination dabrafenib and trametinib in unresectable BRAF
V600E or V600K mutation–positive melanoma based on positive response data.
The strategy of up-front
BRAF and MEK inhibition in BRAF-mutant unresectable disease was supported by
data presented in the same session from the coBRIM study, where treatment with
vemurafenib and the investigational MEK inhibitor cobimetinib improved
progression-free survival, response rates, and overall survival, although the
overall survival data are immature. Listen to our interview with coBRIM study
author Dr. Grant McArthur.
Dr. Christian Blank, from
the Netherlands Cancer Institute in Amsterdam, who was invited to discuss both
studies, commented that the combinations used in COMBI-v and coBRIM had similar
toxicity to that of single-agent treatment, and that if mature data confirm the
presented observations, combined BRAF and MEK inhibition is the new standard
therapy for patients with BRAF V600 melanoma.
In COMBI-v, patients
receiving dabrafenib plus trametinib, as compared with vemurafenib alone, had
more pyrexia (53% vs. 21%), chills (31% vs. 8%), and decreases in ejection
fraction (8% vs. 0%), although the latter was easily reversible without
sequelae, Dr. Robert stressed. The addition of a MEK inhibitor, however,
reduced BRAF inhibitor–related adverse skin events such as cutaneous squamous
cell carcinoma and keratoacanthoma (1% vs. 18%), as well as photosensitivity
(4% vs. 36%).
GlaxoSmithKline funded the
study. Dr. Robert reported serving as a consultant to GlaxoSmithKline, Roche,
Bristol-Myers Squibb, Amgen, Novartis, and Merck. Dr. Blank disclosed an
advisory role with GSK, Roche, BMS, MSD, and Novartis, honoraria from GSK,
Roche, BMS, and MSD, and a research grant from Novartis.
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