Rationale for Immunotherapy in Melanoma Regardless of BRAF Status

Marc S. Ernstoff, MD, discusses why physicians would treat metastatic melanoma with immunotherapy prior to small molecule inhibitors in most cases.

Marc S. Ernstoff, MD, chief for the ImmunoOncology branch of the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis at the National Cancer Institute, discusses why physicians would treat metastatic melanoma with immunotherapy prior to small molecule inhibitors in most cases.

The immune checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) have shown durable, long-term disease control for melanoma. Nivolumab combined with ipilimumab (Yervoy) or nivolumab/relatlimab (Opdualag) extend survival, though with added toxicity.

In patients with BRAF V600 mutations, a BRAF/MEK inhibitor combination is also effective in targeting the MAP kinase pathway. The DREAMseq trial (NCT02224781) investigated the sequence of nivolumab/ipilimumab and dabrafenib (Tafinlar)/trametinib (Mekinist). Patients with BRAF V600 mutations who received nivolumab/ipilimumab first had superior overall survival to those who received the BRAF/MEK targeted therapy combination first.

Because of these results, giving immunotherapy first for these patients is common. Ernstoff says that physicians will decide between using a single-agent immune checkpoint inhibitor or a combination based on the patient’s ability to tolerate the additional toxicity.


0:08 | The immunotherapies, particularly the foundational anti–PD-1s—typically that's nivolumab and pembrolizumab—have provided a long tail on the [survival] curve. The addition of ipilimumab, [an] anti–CTLA-4, or the anti–LAG-3 molecule, has provided potentially enhanced survival benefit. At the current time—that works both in BRAF-mutated as well as BRAF wild-type cancers. There was a study that was designed by Dr Atkins that looked at the sequence of giving BRAF inhibitors or what are called dual MEK inhibitors first, before immunotherapy, or immunotherapy before these dual MAP kinase inhibitors. In that study, it appears that there is a benefit for starting with immunotherapy first.

1:20 | In 2022, I think most of us would recommend for either BRAF mutated or BRAF wild-type to start with immunotherapy first, and many of us would start with a combination of anti–PD-1 and anti–CTLA-4 if the patient is willing to tolerate the toxicity of that combination. The toxicity is significantly higher than the combination versus an anti–PD-1 agent alone. That’s a discussion that goes on with the patient's risks and benefits before one determines which approach to use.

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