Five-year study showed benefits of dabrafenib/trametinib therapy for metastatic melanoma

By Gene Emery

(Reuters Health) - 4/6/2019

Researchers combining the results of two large studies of volunteers with unresectable or metastatic melanoma have concluded that first-line therapy with dabrafenib combined with trametinib produces a 5-year benefit in about a third of patients with a BRAF V600E or V600K mutation.

The studies used were the COMBI-d and COMBI-v trials. All the patients had previously been untreated. Median follow-up was 22 months.

Progression-free survival was 21% at 4 years and 19% at 5 years.

Overall survival was 37% at 4 years and 34% at 5 years. The researchers had previously reported a 3-year rate of progression free survival of 23% and an overall survival rate of 44%.

In their analysis of the clinical characteristics of the patients who received a durable benefit of the treatment, the team, led by Dr. Caroline Robert of the Institut Gustave Roussy in France, found that progression-free survival rates were 26% lower for males than for females.

The rates were 8% lower for older patients, 28% if the number of organ sites with metastasis was 3 or more; 50% if lactate dehydrogenase levels were elevated, 32% if the 6-point Eastern Cooperative Oncology Group performance status was 1 or higher, and 35% if the BRAF genotype was V600E (unless the V600K was also present).

The sum of the diameters of the lesions or having a disease stage of III, IVM1a or IVM1b did not make a significant difference.

The trials were funded by GlaxoSmithKline and Novartis.

The results were reported at the American Society of Clinical Oncology's annual meeting in Chicago and online by the New England Journal of Medicine.

COMBI-d looked at patients who took dabrafenib, half of whom also received trametinib while the rest were given placebo. The COMBI-v trial compared dabravenib plus trametinib with vemurafenib. The two trials collectively randomized 563 volunteers.

After the tests, 53% of patients ended up receiving some other anticancer therapy., most commonly immunotherapy.

By the time of the new analysis, 62% of the 563 patients had died and the median overall survival was 25.9 months.

"Patients who had a complete response had particularly good outcomes, with 5-year rates of progression-free survival and overall survival of 49% and 71%, respectively, as compared with 19% and 34% in the overall population," the researchers said.

A lot of people think that only immune therapy holds the secret to long-term remission, Dr. Robert told Reuters Health in a telephone interview. "It's very important to realize that immunotherapy is not curing everybody; a lot of patients do not respond or they relapse. It's important to reset the minds of people to see that all weapons are useful."

In the case of the new analysis, "we have a very good rate of long-term benefits for people who have been in complete response," said Dr. Robert.

The 5-year progression-free survival rates were 49% among the 19% of the patients who had a complete response, 16% for the volunteers who had a partial response and only 1% among those who had stable disease.

Adverse events prompted 18% of the patients to leave the trials, with the biggest problems being pyrexia and decreased ejection fraction, which were seen in 4% of patients.

"Among patients with a normal lactate dehydrogenase level and fewer than three organ sites with metastasis at baseline, the estimated 5-year rate over overall survival was 55%," the Robert team reported.


N Engl J Med 2019

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