MEK/BRAF Inhibition May Overcome Molecular Heterogeneity of BRAF-Mutant Melanoma

Deeper inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting both MEK and BRAF may help improve progression-free survival (PFS) outcomes in patients with advanced BRAF V600–mutated melanoma, according to a retrospective analysis.

“Therapeutic targeting of the constitutively active MAPK signaling pathway in patients with advanced melanomas harboring the BRAF V600 mutation has demonstrated meaningful clinical benefit,” wrote study authors led by Matthew J. Wongchenko, of Genentech in San Francisco. “However, tumor recurrence 6 to 7 months after initiation of treatment with BRAF inhibitor monotherapy is common.”

The investigators conducted a retrospective analysis of patients in the phase III coBRIM trial, to determine the effects of BRAF V600 allelic balance, coexisting mutations, loss of PTEN expression, and other factors on PFS. The trial compared the combination of the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib vs vemurafenib monotherapy; both of these medications are marketed by Genentech. Results of the analysis were published in JCO Precision Oncology.

Of 495 total patients, frequencies of BRAF V600 mutant alleles were available in 400. Variant allele frequency ranged from 5% to 90%, with a median of 33.9%, and it did not appear to have any correlation with PFS. The hazard ratios (HR) for those with frequency above and below the median were 0.97 and 1.11, respectively.

A total of 43 patients (11%) were found to have coexisting oncogenic mutations in RAS/RAF/RTK genes, but again, there was no difference in PFS between those who had the coexisting mutations and those who did not, with an HR of 0.95 (95% CI, 0.64–1.35).

A measure of baseline MAPK signaling found that in the group receiving the combination therapy that inhibited both MEK and BRAF, there was no difference in PFS based on that baseline signaling. In the vemurafenib monotherapy group, though, PFS was longer in those with lower baseline MAPK signaling levels. PTEN loss was associated with reduced PFS in the monotherapy group, but not in the combination group.

“The combination of MEK and BRAF inhibition…seems to override the poor prognostic effect of increased MAPK pathway activation,” the authors wrote. “This both supports and provides a rationale for the greater efficacy of combination therapy with BRAF and MEK inhibitors, which has become the standard of care, compared with BRAF inhibition alone.”