Differential gradients of immunotherapy vs targeted therapy efficacy according to the sun-exposure pattern of the site of occurrence of primary melanoma: a multicenter prospective cohort study (MelBase).

Background: The tumor mutational burden (TMB) is high in melanomas owing to UV-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 survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment.
Patients and Methods: Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS).
Results: 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). 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). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1 ^st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1 ^st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively).
Conclusion: Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.
Competing Interests: SD reported receiving financial support from and is a consultant for BMS, Roche, and is employed by Sanofi with stock ownership. LM reported receiving financial support from and is a consultant for BMS, Amgen, Merck, Incyte, MSD, Roche, and Novartis. OD reported receiving financial support from and is a consultant for BMS, MSD, Pierre Fabre, Recordati, Genevrier, Kiowa Kirin, Leo Pharma, and Novartis. CA reported receiving financial support from Amgen, BMS, and Roche. J-PA reported receiving financial support from BMS and MSD. SD-R reported receiving financial support from BMS, Novartis and MSD. HM reported receiving financial support from BMS, Novartis, Pierre Fabre, Leo Pharma and MSD. CD reported receiving financial support from BMS, MSD, Pierre Fabre, and Novartis. JQ reported receiving financial support from BMS, Jansen Cilag. DL reported receiving financial support from BMS, MSD, Novartis, Leo Pharma, and Merck. EM reported receiving financial support from BMS, MSD, and Novartis. PS reported receiving financial support from BMS, MSD, Novartis, Roche, and Pierre Fabre. CL reported serving as a consultant for BMS and receiving financial support from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer, and Incyte. LB reported receiving financial support from Novartis, Pierre Fabre, Roche, BMS, MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Russo, Dalle, Dereure, Mortier, Dalac-Rat, Dutriaux, Leccia, Legoupil, Montaudié, Maubec, De Quatrebarbes, Arnault, Brocard, Saïag, Dreno, Allayous, Oriano, Lefevre, Lebbé and Boussemart.)