Adil Daud, MD: Sequencing Challenges in Melanoma

What are some of the challenges facing the sequencing of BRAF/MEK inhibitors, immunotherapy, and chemotherapy?

I think what some of the studies have shown, like for instance in the KEYNOTE-1 study that was looking at pembrolizumab treatment in melanoma, I think one of the things that was found is that in patients who are BRAF metastatic, the response rates for immunotherapy seem to be lower. It’s been hard to say for sure whether that’s because BRAF metastatic patients per se have lower response rates to immunotherapy, or whether it’s prior treatment with BRAF inhibitors that reduces the rate of response. But that’s something to keep in mind.

I think in patients who are BRAF metastatic, not only do they have this additional option of using targeted therapy but also to keep in mind that their response rates to immunotherapy might be lower. So that would be one factor to consider in terms of deciding targeted versus immunotherapy. I think theoretically or scientifically, I don’t think there’s a lot of reason to think that prior treatment with immunotherapy necessarily lowers the response rate to targeted therapy. We know that BRAF status does not change, and so given the fact that your tumor is not going to change from a BRAF mutant to a BRAF wild-type tumor, it seems like you would have just as good a chance of response to a BRAF metastatic tumor following immunotherapy as you would have prior to immunotherapy.

CASE: Metastatic Melanoma

Michelle is a 55-year old who was referred by her primary care physician to receive a biopsy for a suspicious mole during a routine visit. Results of the biopsy and other subsequent tests revealed that she had an M1b stage tumor (lung metastasis and a less than ULN LDH level). Her ECOG PS is 0.

• Initial BRAF testing using a laboratory-developed test was negative for BRAF V600E L

She was referred from the community setting to a tertiary center, at which point a second test was conducted using the bioMérieux HxID-BRAF kit. This assay was positive for the BRAF V600K mutation

• Following the finding ofBRAF-positivity, Michelle was prescribed the combination of dabrafenib (150 mg BID) and trametinib (1 mg daily)