First-Line Dabrafenib Plus Trametinib Extends Survival For BRAF V600-Mutated Metastatic Melanoma

Patients beginning treatment for metastatic melanoma benefit more from combination therapy with dabrafenib and trametinib than dabrafenib given alone

medwireNews: Dabrafenib plus trametinib may lead to better survival in patients with treatment-naive metastatic melanoma with a BRAF V600E/K mutation compared with dabrafenib monotherapy, suggest follow-up COMBI-d findings.

The phase III trial results “support long-term use of dabrafenib plus trametinib as a standard first-line targeted treatment” in this population, the investigators report in the Annals of Oncology.

They write: “Importantly, these findings do not support the idea that most patients treated by mitogen-activated protein kinase inhibitors rapidly develop deterioration due to secondary resistance.”

Three-year progression-free survival (PFS) was 22% in the 211 patients who were randomly assigned to receive the B-Raf inhibitor dabrafenib 150 mg twice daily alongside the MEK1/2 inhibitor trametinib 2 mg/day , and this was significantly higher than the 12% rate for the 212 patients given dabrafenib plus placebo, giving a hazard ratio (HR) of 0.71.

The corresponding rates for 3-year overall survival (OS) were 44% versus 32% with a HR of 0.75, report Georgina Long, from the University of Sydney in New South Wales, Australia, and co-workers.

They explain that 12% of the patients in the dabrafenib only arm crossed over to the combination treatment, including six patients who had experienced disease progression, but these individuals continued to be followed up under the monotherapy arm.

At 3 years, 31 of the dabrafenib plus trametinib group were free from progression and 76 were alive, with 90% and 58% of these patients remaining on treatment, respectively.

Further analysis indicated that long-term PFS and OS were consistently better with the combination treatment than dabrafenib monotherapy regardless of baseline prognostic markers.

In particular, the subgroup of patients who had a lactose dehydrogenase level on or below the upper limit of normal and fewer than three organ sites affected by metastases derived the greatest benefit from combination therapy, with 3-year PFS rates of 38% versus 16% (HR=0.53) and OS rates of 62% vs 45% (HR=0.63).

RECIST-confirmed response to treatment occurred in 68% of patients given combination therapy and 55% of patients given monotherapy, with complete responses reported for 18% and 15% of the groups, respectively. Median duration was 12.0 months with dabrafenib plus trametinib and 10.6 months for dabrafenib alone.

Almost all (97%) patients in the study experienced side effects and grade 3–4 adverse events occurred in 48% of the combination group and 50% of those given monotherapy. Serious events occurred in 45% and 38%, respectively.

Dabrafenib plus trametinib was associated with a higher incidence of any pyrexia, chills, diarrhoea, vomiting, and peripheral oedema, whereas dabrafenib monotherapy was associated with higher rates of hyperkeratosis, alopecia, skin papilloma, palmoplantar hyperkeratosis, squamous cell carcinoma/keratoacanthoma and basal cell carcinoma.

The frequency of key adverse events did not change over follow-up. “Thus, although patients who remain on and benefit from treatment can become an increasingly biased population due to the disappearance of those with very poor tolerance and/or development of secondary resistance, long-term treatment with [dabrafenib plus trametinib] appears to be well tolerated in the subgroup of patients who benefit”, the authors comment.

Georgina Long et al write that a “more comprehensive model including clinical factors […], along with molecular and/or immune-markers associated with efficacy is needed to further guide treatment decisions (eg, BRAFi/MEKi and checkpoint inhibitor immunotherapy sequencing strategies) in this melanoma population.”

“Continued follow-up planned for up to 5 years for COMBI-d will provide further understanding of the extent of benefit achievable with [dabrafenib plus trametinib] in this setting”, they hope.

Reference

Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol; Advance online publication 5 May 2017. DOI: https://doi.org/10.1093/annonc/mdx176

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