Differential gradients of efficacy of immunotherapy according to the sun-exposure pattern of the site of occurrence of primary melanoma: A multicenter prospective cohort study (MELBASE).
Authors: Russo David , Dalle Stéphane , Dereure Olivier , Mortier Laurent , Dalac Sophie , Dutriaux Caroline , Leccia Marie Thérèse , Legoupil Delphine , Montaudie Henri , Maubec Eve , De Quatrebarbes Julie , Arnault Jean-Philippe , Granel Brocard Florence , Saiag Philippe , Dréno Brigitte , Allayous Clara , Oriano Bastien , Lefevre Wendy , Lebbe Celeste , Boussemart Lise 
Published: June 2021

e21545

Background: The tumor mutational burden (TMB) is usually high in Cutaneous melanomas owing to ultraviolet radiation-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that the response pattern to immunotherapy and targeted therapy in advanced melanoma may vary depending on the sun-exposure profile of the site of primary melanoma. Methods: Patients were screened from MelBase, a French multicenter biobank dedicated to the prospective follow-up of unresectable stage III/IV melanoma. Within Melbase, all patients with a known cutaneous primary melanoma who received a first-line systemic treatment by immunotherapy or combined targeted therapy between January 2013 and November 2019 were included. Outcomes were progression-free survival (PFS ) and overall survival (OS). Results: 973 patients received either anti PD-1 monotherapy (n=466), anti CTLA-4 monotherapy (n=143), a combination of both (n=118), dabrafenib plus trametinib (n=187) or vemurafenib plus cobimetinib (n=59). Patients’ characteristics at treatment initiation were: male gender (62%), median age of 62 years old, BRAF WT (58%), AJCC stage IV (84%), brain metastases (18%), ECOG 0-1 (84%) and normal LDH (52%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 175 patients (G1: head neck), on intermittently sun-exposed skin in 615 patients (G2: trunk, arms, legs), and on sun-protected areas in 65 patients (G3: palms, soles, nails). Median PFS was significantly higher in G1 under anti PD-1 treatment (8,7 months vs 3,3 and 3,4 months for G2 and G3, respectively) (p=0.011), (19,2 months vs 8,1 and 6 months for G2 and G1) (p=0. although it is worthwhile to note that the number of G3 patients treated with targeted therapy was relatively low (n=8). PFS did not significantly differ between all groups under ipilimumab. Similarly, median OS was significantly higher in G1 receiving first-line anti PD-1 treatment (45,6 months vs 31,6 and 21,4 months for G2 and G3) (p=0.04), while OS was higher in G3 under targeted therapy (21,1 months vs 16,3 and 19,5 months for G2 and G1) (p=0.97). Conclusions: Our study suggests that first-line immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas. On the other hand, melanomas originating from sun-protected areas may benefit more from first-line targeted therapy when possible (presence of BRAF mutation), but this finding needs to be confirmed by further research.