eIF4F translation initiation complex, a predictive marker of response to immunotherapy in mucosal melanoma.

Immune checkpoints inhibitors (ICIs) constitute a therapeutic revolution in cutaneous melanoma with 40% and 60% of durable response obtained with anti-programmed cell death 1 (PD1) monotherapy and combination of anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and anti-PD1, respectively [ [1] Hodi F.S. O'Day S.J. McDermott D.F. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363 (Epub 2010 Jun 5): 711-723https://doi.org/10.1056/NEJMoa1003466 Crossref PubMed Scopus (11545) Google Scholar , [2] Robert C. Schachter J. Long G.V. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372 (Epub 2015 Apr 19): 2521-2532https://doi.org/10.1056/NEJMoa1503093 Crossref PubMed Scopus (4208) Google Scholar ]. Mucosal melanoma (MM) is a rare subtype with high metastatic potential and a poor prognosis [ [3] Moya-Plana A. Aupérin A. Obongo R. et al. Oncologic outcomes, prognostic factor analysis and therapeutic algorithm evaluation of head and neck mucosal melanomas in France. Eur J Cancer. 2019; 123: 1-10 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar ]. Anti-tumour effects of ICI are lower in MM due to a particular molecular profile, unrelated to ultraviolet exposure, with a much lower mutational burden [ [4] Hayward N.K. Wilmott J.S. Waddell N. et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017; 545 (Epub 2017 May 3): 175-180https://doi.org/10.1038/nature22071 Crossref PubMed Scopus (806) Google Scholar ]. The rate of response of MM to ICI is between 25% and 35% [ [5] Shoushtari A.N. Wagstaff J. Ascierto P.A. et al. CheckMate 067: long-term outcomes in patients with mucosal melanoma. J Clin Oncol. 2020; 38 (10019–10019)https://doi.org/10.1200/jco.2020.38.15_suppl.10019 Crossref PubMed Google Scholar ]. The combination of anti-PD1 with anti-CTLA4 seems to be more effective than anti-PD1 monotherapy with 5-year survival rates of 43% and 30%, respectively [ [5] Shoushtari A.N. Wagstaff J. Ascierto P.A. et al. CheckMate 067: long-term outcomes in patients with mucosal melanoma. J Clin Oncol. 2020; 38 (10019–10019)https://doi.org/10.1200/jco.2020.38.15_suppl.10019 Crossref PubMed Google Scholar ]. In addition, since BRAF mutations are rare in MM, ICI are often the first-choice therapy [ [4] Hayward N.K. Wilmott J.S. Waddell N. et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017; 545 (Epub 2017 May 3): 175-180https://doi.org/10.1038/nature22071 Crossref PubMed Scopus (806) Google Scholar , [5] Shoushtari A.N. Wagstaff J. Ascierto P.A. et al. CheckMate 067: long-term outcomes in patients with mucosal melanoma. J Clin Oncol. 2020; 38 (10019–10019)https://doi.org/10.1200/jco.2020.38.15_suppl.10019 Crossref PubMed Google Scholar ].