A targeted genomic alteration analysis predicts survival of melanoma patients under BRAF inhibitors.

Several mechanisms have been described to elucidate the emergence of resistance to MAPK inhibitors in melanoma and there is a crucial need for biomarkers to identify patients who are likely to achieve a better and long-lasting response to BRAF inhibitors therapy. In this study, we developed a targeted approach combining both mRNA and DNA alterations analysis focusing on relevant gene alterations involved in acquired BRAF inhibitor resistance. We collected baseline tumor samples from 64 melanoma patients at BRAF inhibitor treatment initiation and showed that the presence, prior to treatment, of mRNA over-expression of genes' subset was significantly associated with improved progression free survival and overall survival. The presence of DNA alterations was in favor of better overall survival. The genomic analysis of relapsed-matched tumor samples from 20 patients allowed us to uncover the largest landscape of resistance mechanisms reported to date as at least one resistance mechanism was identified for each patient studied. Alterations in RB1 have been most frequent and hence represent an important additional acquired resistance mechanism. Our targeted genomic analysis emerges as a relevant tool in clinical practice to identify those patients who are more likely to achieve durable response to targeted therapies and to exhaustively describe the spectrum of resistance mechanisms. Our approach can be adapted to new targeted therapies by including newly identified genetic alterations.

Anti-PD1-induced collagenous colitis in a melanoma patient.

Targeted immunotherapy has markedly improved the survival of melanoma patients. We report the case of a melanoma patient who developed a collagenous colitis under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a thickened apical subepithelial collagen layer with irregular collagen deposition of more than 25 µm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to a decrease in the number of stools to grade 2. Because of the prognosis of the disease, the efficacy of pembrolizumab in this patient and the lack of other efficient treatments, pembrolizumab was restarted, with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type of drug-induced colitis has emerged because of monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract immune-mediated adverse effects are now well described with ipilimumab. To the best of our knowledge, this is the first report of a collagenous colitis in a patient treated with pembrolizumab, thus suggesting a new mechanism of toxicity. Classically, collagenous colitis first-line treatment is based on discontinuation of the suspected treatment. However, there may be a strong benefit to maintaining an anti-PD1 regimen in our patients. In this case, symptomatic management associated with budesonide and cholestyramin enabled continuation of pembrolizumab.