COMMENTARY

'Optimistic' Longer-term Outcomes for Metastatic Melanoma

Jeffrey S. Weber, MD, PhD

Disclosures

March 21, 2019

This transcript has been edited for clarity.

Hello. I'm Dr Jeffrey Weber, a medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Health in New York City. Today I would like to briefly discuss with you two trials recently published in the Journal of Clinical Oncology relating to long-term outcomes associated with targeted therapy or immunotherapy for melanoma.

COMBI-AD is a randomized, large, phase 3, well-powered adjuvant trial which tested the targeted therapies dabrafenib and trametinib versus placebo in high-risk resected stage IIIA, IIIB, and IIIC melanoma (per American Joint Committee on Cancer 7th edition criteria). Initial results were published after about 3 years of follow-up in late 2017 at the European Society for Medical Oncology meeting.[1]

Recently, Hauschild and colleagues[2] described the 4-year follow-up (median, 44 months) of the COMBI-AD trial. Four-year relapse-free survival (RFS) was approximately 54% versus 38% for placebo (hazard ratio [HR], 0.49). There appeared to be a plateau on the survival and RFS curves. Distant metastasis-free survival, a surrogate for overall survival, had an HR of 0.53 which matched RFS. Using estimated cure rate, they determined that about 54% of patients treated with dabrafenib and trametinib were probably cured versus about 38% of those who received placebo. A forest plot for RFS for dabrafenib and trametinib versus placebo looking at virtually every prognostic factor (eg, gender, age, macrometastases, micrometastases, ulceration, tumor burden, substage) found that the HRs did not overlap 1, and they were all in favor of dabrafenib and trametinib. This study certainly suggests longer-term benefit with the targeted therapies dabrafenib and trametinib for adjuvant therapy of resected high-risk stage III melanoma.

Another article evaluating long-term outcome was published, but with a different scenario. Kluger and colleagues[3] treated 23 patients with metastatic melanoma, the majority (70%) of whom had received prior therapy. Patients had at least one brain metastasis ranging in size from 5 to 20 mm; they were without severe edema, not dependent on steroids, and asymptomatic from their central nervous system (CNS) disease. Patients were treated with single-agent pembrolizumab for up to 2 years. Six out of the 23 patients had an antitumor response in the CNS with virtually 100% concordance extracranially. Median progression-free survival was only 2 months but the median overall survival was 17 months. All six responders stayed in remission at 24 months when the study ended and treatment ceased. Eleven of the 23 patients were alive 24 months later, suggesting that brain metastases is not an imminent death sentence. The authors also looked at CD8 and PD-L1 staining, and, as in non-CNS disease, there was an association with CD8 and PD-L1 staining and outcome.

This is consistent with the data we have seen from the CheckMate 204 study that was relatively recently published in New England Journal of Medicine,[4] which suggests that patients with brain metastases can clearly have benefit from immunotherapy. And while the absolute benefit may not be quite as much, certainly it's clear that immunotherapy can generate benefit in the CNS. It also raises interesting issues of how and how well these immunotherapies, or the effector cells induced by these immunotherapies, penetrate the blood-brain barrier.

Again, these were two long-term studies with optimistic results. This is Dr Jeffrey Weber. Please do feel free to call in with comments, questions, and concerns. Thank you very much for your attention.

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