Does previous treatment with BRAF inhibitors affect response to immunotherapy in melanoma?

We have had conflicting reports over the years regarding BRAF status and immunotherapy - to include:  "Those folks do better."  "Those folks do worse."  "It makes no difference."  Likewise, there has been conflict regarding which therapy to do first - immunotherapy or targeted therapy with BRAF inhibitors - for those who are BRAF positive. Now there is this:

Correlation between previous treatment with BRAF inhibitors and clinical response to pembrolizumab in patients with advanced melanoma. Simeone, Grimaldi, Restino, et al. Oncoimmunology. 2017 Jan 19.

The optimal sequencing of targeted treatment and immunotherapy in the treatment of advanced melanoma is a key question and prospective studies to address this are ongoing. Previous observations suggest that treating first with targeted therapy may select for more aggressive disease, meaning that patients may not gain full benefit from subsequent immunotherapy. In a single-center retrospective analysis, we investigated whether response to pembrolizumab was affected by previous BRAF inhibitor therapy. A total of 42 patients with metastatic cutaneous or mucosal melanoma who had received previous treatment with ipilimumab were treated with pembrolizumab as part of the Italian expanded access program. Sixteen of these patients had BRAF-mutated melanoma and had also been previously treated with a BRAF inhibitor (vemurafenib or dabrafenib), while 26 had BRAF wild-type melanoma (no previous BRAF inhibitor). Patients with BRAF-mutant melanoma who were previously treated with BRAF inhibitors had a significantly lower median progression-free survival (3 versus not reached mo) and disease control rate (18.6% versus 65.4%;) than patients with BRAF wild-type, while there was also a trend toward a lower response rate (assessed using immune-related response criteria) although this was not significantly different between groups (12.5% versus 36.4%;). These data are consistent with previous reports that BRAF inhibitor therapy may affect subsequent response to immunotherapy.

Hmmm....  Not sure this is terribly elucidating.  I fear the "facts" in this report are much confounded!

1.   It would not surprise me to find that one day we consider mucosal melanoma and cutaneous melanoma to be two different diseases.  They are certainly not apples to apples.
2.  Pretreatment with ipi is KNOWN to decrease the response to anti-PD-1 (Pembro/Ketruda and Nivo/Opdivo)!  Remember this?  Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening???????
3.  Also, BRAF wild-type vs BRAF mutated - again, not apples to apples.
4.  What we need is a study in which one group of folks with cutaneous melanoma (or strictly mucosal melanoma) with BRAF positive status are treated with targeted therapy then given anti-PD-1 vs another BRAF positive group of folks are treated with anti-PD-1 followed by BRAFi.

It's just me, but... C'mon man!!!!  Hang in there, ratties!  - c