Advanced Melanoma Features Predict Dabrafenib–Trametinib Prognosis

Combined BRAF inhibitor and MEK inhibitor treatment outcome in metastatic BRAF-mutated melanoma is associated with clinical and prognostic disease markers

medwireNews: Research has identified key patient and clinical characteristics that can predict the outcome of patients  with metastatic BRAF-mutated melanoma treated with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib.

The findings published in The Lancet Oncology are derived from a pooled analysis of data from the previously reported BRF113220, COMBI-d and COMBI-v trials of patients with BRAFV600E or BRAFV600K mutations treated with dabrafenib 150 mg twice daily plus trametinib 2 mg/day.

In all, 396 of the 617 patients followed-up for a median of 20.0 months experienced disease progression or death and 290 patients died, giving a median progression-free survival (PFS) of 11.1 months and a median overall survival (OS) of 25.6 months. One-year PFS and OS was achieved by 48% and 74% of patients, respectively, falling to 30% and 53% at 2 years. 

Regression tree analysis showed that the 237 patients who had a normal lactate dehydrogenase (LDH) concentration and no more than two organs containing metastases had the longest PFS and OS, with 1-year rates of 68% and 90%, respectively, and 2-year rates of 46% and 75%.

By contrast, the shortest PFS and OS rates were identified in patients who had an LDH concentration at least twice the upper limit of normal, with 1-year rates of 8% and 40%, respectively, and 2-year rates of just 2% and 7%, respectively.

Among 379 patients with disease progression who had not died, the 205 with progression of lesions present at baseline or who had new non-central nervous system metastases had the longest survival after progression, at a median of 10.0 months. This compared with a median survival after progression of 4.0 months in the 171 patients who had new CNS lesions or who had both progression of baseline and new lesions.

A complete RECIST response during treatment was achieved by 16% of patients and 51% had a partial response; patients with a complete response had 2-year PFS and OS rates of 68% and 88%, respectively.

However, the researchers note that overall response was achieved by many patients from subgroups with an unfavourable prognosis, such as 68% of patients with normal LDH but at least three organ sites with metastases and 50% of patients with an LDH concentration at least twice the upper limit of normal.

“[O]ur study provides a framework for the assessment of therapeutic development programmes in advanced melanoma to understand the heterogeneity of patients and to identify those with an unmet need for improved treatments”, write Georgina Long, from the Melanoma Institute Australia in Sydney, New South Wales, and co-authors.

“Furthermore, we show that a subgroup of patients have long-term disease control with the combination of dabrafenib plus trametinib, and for patients who received this combination rapid resistance is not inevitable.”

They believe that the findings may also be useful for research investigating treatment resistance and identification of targetable features in patient subgroups with a poor outcome.

“Such studies are crucial for the design of future treatments and trials to further improve outcomes in patients with melanoma”, the team concludes.

Reference

Long GV, Grob J-J, Nathan P, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol; Advance online publication 15 November 2016. http://dx.doi.org/10.1016/S1470-2045(16)30578-2

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