CTA: What, if any, safety issues were encountered in COMBI-d or in long-term follow up? Were any surprising?

Dr Flaherty: There weren’t new findings with regard to safety after having 3 years of follow-up time compared with the 1 year follow-up at the time of the initial analysis.

This is not particularly surprising, as we had previously seen that the vast majority of new adverse events occur within the first 6 months of therapy. After that, the dust largely settles and patients who continue on therapy beyond 1 year are unlikely to develop new side effects thereafter.

CTA: What, in your opinion, is the most important takeaway from COMBI-d now that 3-year follow-up data have been analyzed?

Dr Flaherty: The most important takeaway is that there is a sizeable subpopulation of patients who maintain disease control at the 3-year mark, and that the likelihood of losing disease control actually falls substantially once patients make it beyond 2 years. In other words, those who do well up to 2 years are very likely to continue doing well at to 3 years, and thereafter.

CTA: How might these long-term data change clinical practice for this patient group?

Dr Flaherty: I would say that the primary clinical practice impact of these data is to reassure patients who are receiving BRAF/MEK combination therapy and maintaining benefit that treatment should be continued indefinitely until there is evidence of disease progression.

And, the more evidence of long-term benefit observed for this regimen, the more patients need to consider targeted therapy as a viable first-line treatment option, even though immunotherapy is also available.

CTA: The patients with unfavorable baseline lactate dehydrogenase (LDH) levels had shorter OS rates. Are there any treatment approaches that might improve the efficacy of dabrafenib plus trametinib in these patients?

Dr Flaherty: This is the subset for whom the impact of all of our available therapies is quite limited. BRAF/MEK inhibitor therapy can offer meaningful short-to-intermediate term benefit, but very little likelihood of long-term benefit beyond 2 years. It is for this population, in particular, that we are most hopeful for the BRAF/MEK/PD-(L)1 regimens to have significant efficacy.

CTA: In your opinion, what other data are needed to improve outcomes for patients with advanced melanoma who carry BRAF V600E/K mutations?

Dr Flaherty: We definitely need to track long-term follow-up data for targeted therapy and immunotherapy for the BRAF-mutant population.

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We also need to further dissect those data based on readily available disease features (eg LDH, burden of metastatic disease) and more deeply explore molecular features that distinguish those patients who obtain long-term benefit vs those who do not.

We need to direct our clinical trial efforts to those who are predicted not to derive long-term benefit from either of these treatment approaches.

References

  1. Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.
  2. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877-88.
  3. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametninb 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. 2017 May 5. doi: 10.1093/annonc/mdx176 [Epub ahead of print]
  4. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised trial. Lancet. 2015;386:444-51.