Combination therapy with BRAF and MEK inhibitors conferred significant PFS benefit compared with BRAF inhibitor monotherapy among patients with metastatic melanoma with rare BRAF mutations or translocations, according to results of an international, retrospective study published in Journal of Clinical Oncology.

“Patients with rare BRAF mutations may respond to targeted therapy, however, efficacy seems to be lower compared with patients V600E-mutated melanoma,” Christian Menzer, MD, researcher at Heidelberg University Hospital in Heidelberg, Germany, and colleagues wrote. “Combination BRAF/MEK inhibitor therapy seems to the best regimen for both V600 and non-V600 mutations. Yet, interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.”

BRAF and MEK inhibitors have become a standard of care for patients with advanced melanoma with BRAF V600E or V600K mutations. However, efficacy of these targeted therapies among patients with less common V600 or non-V600 BRAF mutations has not been studied extensively.

Menzer and colleagues evaluated data on 103 patients (median age, 62 years; 74% men) with metastatic melanoma with activating non-V600E/K BRAF mutations treated with a BRAF inhibitor (37%), MEK inhibitor (5%) or combined BRAF/MEK inhibitor (58%) between November 2009 and April 2018.

Overall, 56% of tumors harbored a non-V600E/K mutation, 37% had non-V600 mutations, and 7% had both V600E and a rare BRAF mutation. The most common mutations included V600R (43%), L597P/Q/R/S (15%) and K601E (11%). Most patients (96%) had stage IV disease and 42% of patients had elevated lactate dehydrogenase at treatment initiation.

Researchers excluded seven patients with a V600E/K and a rare mutation from the analysis due to suspicion that the E/K mutation had more of an influence on patient outcome. Assessed patients (n = 96) included those with BRAF V600 mutations (n = 58; 56%) and BRAF non-V600 mutations (n = 38; 37%). Most melanomas had cutaneous origin (non-V600, 89%; V600, 81%).

Among those with V600 mutations, results showed overall response rates of 27% (n = 6 of 22) with BRAF inhibitor monotherapy vs. 56% (n = 20 of 36) with combination BRAF/MEK inhibitor therapy, median PFS of 3.7 months vs. 8 months (P = .002), and median OS of 7.3 months vs. 17.3 months (P .05).

Among those with non-V600 mutations, researchers observed a higher ORR with MEK inhibitor monotherapy (40%; n = 2 of 5) compared with combination therapy (28%; n = 5 of 18) and BRAF inhibitor monotherapy (0%; n = 0 of 15). Median PFS was 1.8 months with BRAF inhibitor monotherapy, 3.7 months with MEK inhibitor monotherapy and 3.3 months with combination therapy, whereas median OS was 7.6 months vs. 5.9 months vs. 11.3 months.

Multivariable analysis showed patients with V600 mutations achieved superior outcomes with combination therapy compared with BRAF inhibitors alone in terms of PFS (HR = 0.42; 95% CI, 0.22-0.8) and OS (HR = 0.21; 95% CI, 0.1-0.45) .

In addition, those with non-V600 mutations treated with combination therapy had superior OS compared with those treated with BRAF inhibitor monotherapy (HR = 0.21; 95% CI, 0.06-0.72) or MEK inhibitor monotherapy (HR = 0.25; 95% CI, 0.05-1.12). These patients also demonstrated superior PFS compared with those treated with BRAF (HR = 0.28; 95%CI, 0.09-0.82) and MEK (HR = 0.26; 95% CI, 0.07-0.98) inhibitors alone.

The study’s primary limitations included the retrospective collection of data, the heterogeneity of patients and the small sample sizes for some of the reported mutations.

“As the [BRAF/MEK inhibitor] drug combination results in less toxicity than either [a BRAF inhibitor or MEK inhibitor] alone, its use in patients with advanced melanoma with rare V600 BRAF mutations should be considered,” Menzer and colleagues wrote.

BRAF/MEK inhibitors have been highly successful among patients who harbor BRAF V600E mutations — present in between 30% to 50% of patients with melanoma. There are three FDA-approved combinations available for patients in this setting — dabrafenib (Tafinlar, Novartis) plus trametinib (Mekinist, Novartis), vemurafenib (Zelboraf; Genentech, Daiichi Sankyo) plus cobimetinib (GDC-0973/XL518, Exelixis), and encorafenib (LGX818, Array BioPharma) plus binimetinib (MEK162, Array BioPharma).

Although much is known about the responsiveness of these agents among patients who harbor the typical BRAF V600E mutation and, to a lesser extent, the V600K mutation, there is a paucity of data regarding the rarer variants of BRAF mutations that occur in between 3% and 14% of patients with melanoma. This interesting analysis by Menzer and colleagues showed that, for these patients, combination therapy was more effective than BRAF monotherapy, with an ORR of 56% vs. 27% and PFS of 8 months vs. 3.7 months. Not surprisingly, all endpoints assessed showed superiority of the combination over monotherapy. This is the first large analysis to provide this data for patients with these rare mutations, and it is an important addition to the literature.

Despite the limitations of the study as pointed out by the authors, this analysis assists clinicians with decisions regarding choice of therapy for patients who harbor a BRAF mutation — regardless of type. Prior to this, most data were anecdotal and based on case reports. As the authors point out, there is little rationale to use BRAF monotherapy for any patient harboring a BRAF mutation due to the superior results with combination therapy in multiple trials and in this analysis, as well. Menzer and colleagues also analyzed a small subset of patients with non-V600 mutations, and although the sample size was small, researchers observed responses, but these results should be interpreted with caution.

Another option available to all patients with advanced melanoma, regardless of BRAF mutation status, is immunotherapy. We have no data to understand the differential responsiveness to immunotherapy in the various types of BRAF mutations, but this is unlikely to be a factor. The debate of whether to use targeted therapy vs. immunotherapy for patients will continue, but this paper allows us to be more comfortable choosing targeted therapy for patients with rare BRAF V600 mutations.

Source Healio

Menzer C, et al. J Clin Oncol. 2019;doi:10.1200/JCO.19.00489.

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