Questions Remain for First-line Treatment Selection and Sequencing in Advanced Melanoma

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Ongoing trials, including those that combine immunotherapy with BRAF inhibitors or a triple combination of an anti-PD-1 antibody with BRAF and MEK inhibitors, may provide more options to patients.
Ongoing trials, including those that combine immunotherapy with BRAF inhibitors or a triple combination of an anti-PD-1 antibody with BRAF and MEK inhibitors, may provide more options to patients.

The introduction of targeted therapy and immune checkpoint inhibitors over the last decade is greatly improving outcomes for patients with advanced melanoma.1 Questions remain, however, about treatment selection and sequencing, particularly for patients with BRAF-mutated disease.

BRAF Wild-type

For patients with BRAF wild-type disease, first-line therapy is frequently an immune checkpoint inhibitor.2

“For patients with less aggressive disease, single-agent anti-PD-1 therapy is appropriate, whereas patients with brain metastases and/or more aggressive disease should be considered for combined immune checkpoint therapy,” Ryan J. Sullivan, MD, of Harvard Medical School and Massachusetts General Hospital in Boston, told Cancer Therapy Advisor. This recommendation is consistent with a recently published algorithm based on clinical trial data, which suggests an immunotherapy combination for patients with prognosis measured in weeks or months, but single-agent nivolumab or pembrolizumab for patients with good prognostic features.2 The algorithm indicates, however, that single-agent anti-PD-1 therapy can be considered for patients with high PD-L1 tumor expression or heavy immune infiltrate.

The anti-PD-1 therapies approved for advanced melanoma, nivolumab and pembrolizumab, demonstrated response rates over 33% to 43% in the first-line setting.2 The 5-year overall survival (OS) among ipilimumab-naïve patients was 34% with nivolumab; the 2-year OS with pembrolizumab was 50%.1 Single-agent anti-PD-1 antibodies were superior to single-agent ipilimumab, an anti-CTLA-4 antibody.

Combining nivolumab and ipilimumab demonstrated higher response rates and prolonged OS compared with ipilimumab alone. The recommendation to use the combination for more aggressive disease stems from its faster activity than single-agent anti-PD-1 antibodies.2

BRAF-mutated

Selecting first-line therapy for BRAF-mutated disease is more challenging, and — because questions remain unanswered by strong clinical trial data — somewhat controversial.

“My colleagues and I typically select immunotherapy in the first line, though the data suggest that patients with less disease — normal lactate dehydrogenase, fewer than 3 disease sites, no brain metastases, excellent performance status — have excellent results with up-front BRAF/MEK combination therapy,” Dr Sullivan said.

Primarily retrospective data suggest that immunotherapy is as effective as targeted therapy for patients who harbor a BRAF mutation. The nivolumab plus ipilimumab combination, for example, resulted in similar 2-year OS outcomes among patients who harbored either mutated or wild-type BRAF.

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