COMMENTARY

The 'C' Word Whispered in Metastatic Melanoma

Jeffrey S. Weber, MD, PhD

Disclosures

July 08, 2016

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This is Dr Jeffrey Weber. I am a medical oncologist at the Perlmutter Cancer Center at the New York University Langone Medical Center. Today we will be talking about two abstracts presented at the recent American Society of Clinical Oncology (ASCO) meeting in Chicago that relate to long-term survival in patients with metastatic melanoma.

The first one was by Caroline Robert,[1] which reported the 2-year and 3-year survival for patients on the KEYNOTE-001 study, which studied the anti–programmed death receptor (PD)-1 antibody pembrolizumab at various doses and schedules. It encompassed a total of 655 patients of which about 150 were actually treatment naive. The interesting data from that presentation suggest that patients receiving pembrolizumab immunotherapy, whether second or first line, had a very good survival at 2 and 3 years in the treatment-naive patients as well as the pretreated patients. The 3-year survival was 41%, which is very impressive. Even more impressive was that the rate of complete responses was about 9%, or 61 patients.[2] If you look at those 61 patients, 59 (or 97%) remained in remission without evidence of relapse, with an average follow-up between 2 and 3 years—very impressive data indeed. If you look at the patients who were previously treated, median survival was about 25 months, but 32 months for those who were treatment naive, which is excellent.

Keith Flaherty[3] presented data on long-term follow-up in patients who received the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib in the COMBI-d study.[4] Patients were randomly allocated to receive either the combination of dabrafenib and trametinib or dabrafenib plus a placebo as a control. In that trial, the 3-year survival in patients, who were almost all treatment naive, was 44%. Again, this is excellent.

A number of very interesting factors fell out as being associated with an excellent survival. For example, to everyone's surprise, the mutational load was significantly associated—if you had a normal lactate dehydrogenase (LDH)—with a very long survival at 82%. The mutational load being elevated and being associated with a good outcome would suggest that there somehow is an immunologic effect of treatment with these two targeted drugs, which is very interesting. If you look at the tumor load as evidenced by number of sites of disease—say, fewer than three—or low LDH, or both, again the 3-year survival was excellent, in the range of 62%.

If you look at those patients who were wild-type for the CDKN2A gene, they had a 55% 3-year survival; whereas if you look back at those who had a mutation, survival was considerably less. Interestingly, those who had the V600K mutation in that trial had a significantly higher mutational load. The more elderly population had the potential, I suppose, for more UV damage and more mutation, which might set them up to have more so-called neoantigens and maybe a better immune response.

Either way, for the first time in metastatic melanoma, we now have more backup for the idea that maybe we can use the "C word" and maybe we can cure some of our patients, because it appears that beyond 3 years there may well be a plateau.

This is Dr Jeffrey Weber. Again, feel free to call in with questions. Thank you very much.

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