1133P Skin photoaging around the site of occurrence of primary melanoma as a clinical predictive biomarker of response to PD-1 inhibitors

Abstract

Background: Cutaneous melanomas have a high tumor mutational burden (TMB) because of mutations induced by ultraviolet radiations (UVR). TMB is a predictive biomarker of response to PD-1 inhibitors but it is unfortunately not yet routinely available. Considering photoaging as a result of repeated and cumulative exposure to UVR, we hypothesized that signs of photoaging around primary melanoma could predict response to PD-1 inhibitors.Methods: We conducted a retrospective bicentric study including 34 patients with stage IV melanoma treated with first-line immunotherapy. Five independent dermatologists assessed the grade of photoaging for each patient using two clinical scales, one descriptive and the second photo-analogic (McKenzie Photographic Scale), in a blinded, photographic assessment. The reliability of the clinical scales was statistically assessed by intraclass correlation coefficients (ICC). Outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).Results: The clinical scales, graded from 0 to 3, were reproducible, with an ICC of 0.68 for the descriptive scale and 0.72 for the photo-analogic scale. PFS was significantly higher in case of severe photoaging with both the descriptive scale and the photoanalogic scale (HR¼0.32, p<10-3, and HR 0.41, <10-3, respectively). Similarly, OS was higher when photoaging was assessed severe. Three-month ORR was better in cases of severe photoaging than in cases of mild/no photoaging, both with the descriptive and photo-analogic scales (77% vs. 24% and 61% vs. 25% respectively).Conclusions: Our study suggests that reliable determination of photoaging around a melanoma or its scar can be used as a predictive clinical biomarker of response to PD-1 inhibitors, higher grades being associated with better response rate and progression-free survival.

Positive Association Between Location of Melanoma, Ultraviolet Signature, Tumor Mutational Burden, and Response to Anti–PD-1 Therapy

“…30 To go even further, we recently proposed pericicatricial sunexposure pattern of the skin around the primary melanoma, as a directly accessible surrogate marker for TMB, to predict response to systemic treatments, in two independent studies including more than 900 patients. 31,32 Another important finding of this study is the positive association between advanced age and higher TMB (P = .002). A few studies reported an association between age and TMB, but these studies encompassed smaller cohorts and covered multiple solid tumors.…”

“… 30 To go even further, we recently proposed pericicatricial sun-exposure pattern of the skin around the primary melanoma, as a directly accessible surrogate marker for TMB, to predict response to systemic treatments, in two independent studies including more than 900 patients. 31 , 32…”

Gradient differences of immunotherapy efficacy in metastatic melanoma related to sunlight exposure pattern: A population-based study

“…MM patients with high TMB have more improvement in OS and progression-free survival (PFS) after receiving ICIs (18,19). UV exposure is thought to be the main cause of increased TMB in melanoma (20,21). Dousset et al measured TMB in chronically sun-exposed areas (face and neck), intermittently sun-exposed areas (trunk arms and legs), and sun-protected areas (mucosal, uveal, foot, toes, etc), found that the values of TMB were 37.2 muts/Mb, 13.6 muts/Mb, and 4 muts/Mb successively, and indicated that TMB was significantly associated with sunlight exposure (20).…”

“…MM patients with high TMB have more improvement in OS and progression-free survival (PFS) after receiving ICIs ( 18 , 19 ). UV exposure is thought to be the main cause of increased TMB in melanoma ( 20 , 21 ). Dousset et al.…”