From the Journals

BRAF/MEK combo shows long-term efficacy in melanoma



In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

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