In the JournalsPerspective

Dabrafenib-trametinib combination confers durable survival benefit in BRAF-mutated metastatic melanoma

About one-third of patients with unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation who received first-line dabrafenib plus trametinib in two clinical trials achieved 5-year OS, according to results of a data analysis published in The New England Journal of Medicine.

“Historically, metastatic melanoma has been associated with a poor prognosis,” Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave Roussy in France, and colleagues wrote. “The introduction of BRAF- and MEK-targeted therapies and immune checkpoint inhibitors has substantially improved outcomes in these patients. Each of these therapies — including drugs that target programmed cell death 1 (PD-1) with or without inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) — has resulted in a durable survival benefit in a subgroup of patients.”

However, many patients develop resistance, either acquired or primary, which results in death due to the underlying disease, researchers noted.

For their analysis, Robert and colleagues pooled extended-survival data on 563 participants in the COMBI-d (n = 211) or COMBI-V (n = 352) randomized phase 3 trials.

The double-blind COMBI-d trial evaluated the BRAF inhibitor dabrafenib (Taflinar, Novartis) plus the MEK inhibitor trametinib (Mekinist, Novartis) vs. dabrafenib plus placebo. The open-label COMBI-v trial compared dabrafenib plus trametinib with the BRAF inhibitor vemurafenib (Zelboraf, Genentech). Both trials stratified participants according to BRAF genotype and baseline lactate dehydrogenase concentration.

The current study assessed patients with BRAF V600E- or V600K-mutant metastatic melanoma who had been randomly assigned 150 mg dabrafenib twice daily plus 2 mg trametinib once daily.

PFS served as the primary endpoint of the COMBI-d trial and OS served as the primary endpoint of the COMBI-v trial. Median follow-up was 22 months (range, 0-76).

Results showed PFS rates of 21% (95% CI, 17-24) at 4 years and 19% (95% CI, 15-22) at 5 years, and OS rates of 37% (95% CI, 33-42) at 4 years and 34% (95% CI, 30-38) at 5 years.

Multivariate analysis showed significant associations between PFS and OS and several baseline variables, including performance status, age, sex, number of metastatic organ sites and lactate dehydrogenase level.

More than two-thirds of patients (68%) demonstrated an objective response to dabrafenib plus trametinib. Among the 109 patients (19%) who achieved a complete response, researchers observed a 5-year OS rate of 71% (95% CI, 62-79) and 5-year PFS of 49% (95% CI, 39-58). All but one of the 59 patients who were progression-free at 5 years had a confirmed objective response (98%; 95% CI, 91-100).

Nearly all patients (98%; n = 548) experienced adverse events, none of which was unexpected. Ninety-nine patients (18%) permanently discontinued the study regimen due to adverse events. These included pyrexia (4%), reduced ejection fraction (4%) and increased alanine aminotransferase levels (1%).

“We found that first-line treatment with dabrafenib plus trametinib led to 5-year survival in approximately one-third of patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation,” the researchers wrote. “Having a complete response to the combined treatment appears to be a strong and early predictor of prolonged benefit. However, no biomarkers are currently available to determine which patients who discontinue therapy are likely to have disease progression.” – by Jennifer Byrne

Disclosures: Robert reports personal fees from Amgen, Bristol-Myers Squibb, Merck, Pierre Fabre and Sanofi outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.

About one-third of patients with unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation who received first-line dabrafenib plus trametinib in two clinical trials achieved 5-year OS, according to results of a data analysis published in The New England Journal of Medicine.

“Historically, metastatic melanoma has been associated with a poor prognosis,” Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave Roussy in France, and colleagues wrote. “The introduction of BRAF- and MEK-targeted therapies and immune checkpoint inhibitors has substantially improved outcomes in these patients. Each of these therapies — including drugs that target programmed cell death 1 (PD-1) with or without inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) — has resulted in a durable survival benefit in a subgroup of patients.”

However, many patients develop resistance, either acquired or primary, which results in death due to the underlying disease, researchers noted.

For their analysis, Robert and colleagues pooled extended-survival data on 563 participants in the COMBI-d (n = 211) or COMBI-V (n = 352) randomized phase 3 trials.

The double-blind COMBI-d trial evaluated the BRAF inhibitor dabrafenib (Taflinar, Novartis) plus the MEK inhibitor trametinib (Mekinist, Novartis) vs. dabrafenib plus placebo. The open-label COMBI-v trial compared dabrafenib plus trametinib with the BRAF inhibitor vemurafenib (Zelboraf, Genentech). Both trials stratified participants according to BRAF genotype and baseline lactate dehydrogenase concentration.

The current study assessed patients with BRAF V600E- or V600K-mutant metastatic melanoma who had been randomly assigned 150 mg dabrafenib twice daily plus 2 mg trametinib once daily.

PFS served as the primary endpoint of the COMBI-d trial and OS served as the primary endpoint of the COMBI-v trial. Median follow-up was 22 months (range, 0-76).

Results showed PFS rates of 21% (95% CI, 17-24) at 4 years and 19% (95% CI, 15-22) at 5 years, and OS rates of 37% (95% CI, 33-42) at 4 years and 34% (95% CI, 30-38) at 5 years.

Multivariate analysis showed significant associations between PFS and OS and several baseline variables, including performance status, age, sex, number of metastatic organ sites and lactate dehydrogenase level.

More than two-thirds of patients (68%) demonstrated an objective response to dabrafenib plus trametinib. Among the 109 patients (19%) who achieved a complete response, researchers observed a 5-year OS rate of 71% (95% CI, 62-79) and 5-year PFS of 49% (95% CI, 39-58). All but one of the 59 patients who were progression-free at 5 years had a confirmed objective response (98%; 95% CI, 91-100).

PAGE BREAK

Nearly all patients (98%; n = 548) experienced adverse events, none of which was unexpected. Ninety-nine patients (18%) permanently discontinued the study regimen due to adverse events. These included pyrexia (4%), reduced ejection fraction (4%) and increased alanine aminotransferase levels (1%).

“We found that first-line treatment with dabrafenib plus trametinib led to 5-year survival in approximately one-third of patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation,” the researchers wrote. “Having a complete response to the combined treatment appears to be a strong and early predictor of prolonged benefit. However, no biomarkers are currently available to determine which patients who discontinue therapy are likely to have disease progression.” – by Jennifer Byrne

Disclosures: Robert reports personal fees from Amgen, Bristol-Myers Squibb, Merck, Pierre Fabre and Sanofi outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Gary K. Schwartz

    Gary K. Schwartz

    These drug combinations have been known to work for patients with BRAF-mutated melanoma for some time. This data set takes it one step further: We’re now looking at very favorable outcomes at 5 years, which is the longest data set we have.

    We’ve come a long way since the discovery of BRAF inhibitors. Just 15 years ago, single-agent therapies with dacarbazine were all we had, and median survival with dacarbazine was about 6 months, occasionally 1 year. Now, we have 37% of patients alive at 4 years and 34% at 5 years. These data are unheralded and represent the continuing paradigm shift we’re seeing with targeted therapies. I think we can now say as oncologists that we can cure patients with metastatic melanoma.

    One question that remains is, what is the optimal therapy for patients with metastatic melanoma? Although we have targeted therapies as part of our precision medicine approach for the patient with BRAF-mutated melanoma, we have immunotherapies as well, starting with checkpoint inhibitors that activate along the CTLA-4 pathway and now the PD-L1 pathway. These also have had a profound effect on the treatment of metastatic melanoma.

    Interestingly, many of the patients in this data set went on to treatment with inhibitors of either CTLA-4 or PD-L1. In fact, the results show immunotherapy was administered to 66% of patients. Half of them had anti-CTLA-4 therapy and 34% had anti-PD-L1 therapy. Anti-CTLA-4 therapy has been associated with increased toxicities and is being used less in favor of anti-PD-L1 therapy, for which the data are more favorable, either as a single agent or in combination with CTLA-4.

    There has been a dramatic shift in how we treat melanoma with immunotherapies, which may enhance OS. It’s a little bit complicated for oncologists now to decide whether to start with a targeted drug therapy for BRAF-mutant melanoma or with an immunotherapy — a PD-L1-based approach in the treatment of this disease for which the data look at least comparable, may be better.|

    This ongoing debate in the oncology community may be resolved soon. There are clinical trials evaluating targeted therapy followed by immunotherapy, immunotherapy followed by targeted therapy and, the granddaddy of them all, combining them upfront. I think more clinical data will be necessary to enable us to sort out this issue. One way or the other, patients can’t lose.

    • Gary K. Schwartz, MD
    • NewYork-Presbyterian/Columbia University Medical Center

    Disclosures: Schwartz reports no relevant financial disclosures.