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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.

10057 Background: PD-1 inhibitors (anti-PD1) are frequently associated with immune-related adverse events (IRAE). Since melanoma patients included in clinical trials were frequently treated during two years, data on IRAE occurring after 2 years of treatment are lacking. This study aimed to describe IRAE in melanoma patients treated with anti-PD1 for longer than 2 years in a real-life setting. Methods: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. All patients who received anti-PD1 for at least 2 years between January 2013 and November 2019 were included. Among them, patients who experienced IRAE and long-term IRAE defined as IRAE occurring after 2 years of anti-PD1 were identified. Results: Among 1849 patients with advanced melanoma included in Melbase, 119 patients received anti-PD1 monotherapy during at least 2 years, from January 2013 to November 2019, with a median follow-up of 41.7 months (25.2-57.5). Patients characteristics at treatment initiation were: male gender (61%), mean age of 63 years old, past history of autoimmune disease (11%), BRAF WT (72%), AJCC stage IV (84%), brain metastases (22%), ECOG 0-1 (88%) and normal LDH (56%). Patients were treated with Nivolumab (n = 53) or Pembrolizumab (n = 66). IRAE occurred in 99 patients (83%) with a median time of 13.3 months (0-53.9), including severe IRAE (grade 3 or 4) in 30 patients (30%). Long-term IRAE, mostly grades 1-2, occurred in 52 patients (43%). Long-term IRAE led to 5 hospitalizations (4%) of which 4 were grades 3-4. Among patients with long-term IRAE, 45 patients (87%) previously experienced IRAE within the first 2 years of anti-PD1 and 29 patients (56%) experienced multiple IRAE. Conclusions: Our data demonstrate that long-term IRAE are frequent especially in patients who already experienced IRAE within the first two years of treatment. These data should be taken into account to establish formal recommendations on the duration of anti-PD1 therapy.

10031 Background: Obesity is an established risk factor for several cancers and higher body mass index (BMI) is associated with poor prognosis. These data are still debated in melanoma. Furthermore, recently the concept of “obesity paradox” has emerged. In a large cohort published by McQuade JL et al, higher BMI was associated with better survival in patients with metastatic melanoma (MM) especially for those treated with targeted therapy (TT) and immune checkpoint inhibitors (ICI). We studied the association between BMI and progression-free survival (PFS) and overall survival (OS) in patients with MM treated with systemic therapies. Methods: This study was conducted from the prospective MelBase cohort (NCT02828202). Patients with MM treated with first-line ICI, TT, or CT were included. BMI was categorized by WHO criteria. Underweight patients were excluded. The co-primary outcomes were the associations between BMI and PFS or OS, stratified by treatment, sex and age. Multivariate analyses were performed. Results: A total of 1214 patients were analyzed. The majority of them were treated with ICI, followed by TT. Obese patients represented 22% of cohort (Table). Median follow-up was 13.5 months. The patients who were overweight or obese did not have different PFS (p = 0.88) or OS (p = 0.25) than patients with normal BMI. Stratifying this cohort by treatment received, age, sex and others parameters (such as LDH, number of metastatic site) did not revealed any difference. Multivariate analysis did not change the results. Conclusions: BMI was not associated with clinical outcomes in our cohort, especially in ICI and TT groups. Thus, we did not confirm the results presented by McQuade Jl et al. with a cohort quite similar in term of size. Because BMI is too simplistic and then an imperfect measure of body composition, the published data are not reproducible. We caution the oncologists, about BMI as valuable predictive marker of survival for melanoma patients. [Table: see text]

e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In vitro, it has been shown that ingenol mebutate can induce the apoptosis of melanoma cells, but robust clinical data are missing with only few case reports reported.The objectives of the current study was to assess the efficacy and safety of ingenol mebutate for the treatment of lentigo maligna (LM). Methods: We conducted a prospective, multicentre, and single-arm phase 2 trial (NCT02723721), from June 2016 to November 2017. This trial was planned according to Simon’s optimal two-stage design for a total sample size of 23 subjects. Adults with LM of the head were included. Ingenol mebutate gel 150 µg/g was applied daily for 3 consecutive days (one cycle). For patients having no remission or only partial remission at 2 months, a second cycle was done. Patients were evaluated 2 months after the (re)treatment and then every 3 months for 36 months if a complete response (CR) was obtained. The primary endpoint was the CR, defined as the complete clearing of the LM evaluated at 2 months clinically and histologically. Results: Twelve patients with a median age of 73 years were recruited. Only 2 achieved a CR; one patient relapsed during the first year following the treatment. Forty-seven adverse events related to ingenol mebutate were declared. Most were grade 3-4 (66%), but all were resolved without any sequelae. The mean maximum local skin reaction score was 12 (min: 3 – max: 22). These results should be interpreted with caution, because this study has limitations, such as the lack of a comparative arm and the heterogeneity of LM (size and localization). Conclusions: To our knowledge, we report the first prospective study evaluating the efficacy and safety of IM in patients with LM of the head. Unfortunately ingenol mebutate is not an effective treatment of LM in this indication at the concentration of 150 µg/g. Its use with a more intense regimen (more cycles and/or highest concentration (500 µg/g)) is also limited by a poor safety profile. Clinical trial information: NCT 02723721.

e21021 Background: Primary progression (PP) and secondary progression (SP) to anti-PD1 therapy (APD) are poorly described in advanced melanoma in real life practice. Hyperprogression with a deleterious effect is reported in many cancers but is poorly assessed in advanced melanoma. Methods: Characteristics of 793 patients treated by APD (nivolumab or pembrolizumab) between July 2014 and May 2018 were collected from MelBase, a prospective French biobank (NCT02828202).We considered: group A (progressive disease as best response), group AHP (hyperprogression) within group A patients (progression/death within 3 months with normal initial LDH and ECOG at baseline, and either ECOG increased from 0 to 3-4, either LDH increased from normal to elevated or both), group B SP (response or stable disease then progression). Characteristics for all and survival for patients alive at progression (AAP) were also described. Results: Median follow-up was 11.3 months (Q1-Q3 4.8–23.6). Characteristics at baseline are in the table. In group A, 14% patients died at progression; within 262 patients AAP, 17% continue APD (the same or switch), 15.1% (CI95 11.1-20.6) were alive 1-year after progression (1YAP); 20.5% for patients in first line and 11.5% for pretreated. In group AHP, 41% patients died at progression; within 48 patients AAP, 12% continue APD, 11.1% (CI95 7.8-13.6) were alive 1YAP. In group B, 11% patients died at progression; within 88 patients AAP, 36% continue APD, 10.3% (CI95 5.2-20.1) were alive 1YAP, 15.9% for patients in first line and 7.0% for pre-treated. Conclusions: Our study shows that PP and SP to APD differ at baseline, but have similar survival rates at progression, while mechanisms involved might be different, providing important landmarks to build second line trials. This study thus highlights the existence of hyperprogressors among which 41% patients died within 3 months, as well as describes their associated characteristics. [Table: see text]

9551Background: Anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) antibody ipilimumab has been proved efficacy in treatment of metastatic melanoma, but with immune-related adverse events (irAE). Anti-...