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Late-onset adverse events (AEs) of anti-programmed cell death 1 (anti-PD1) antibodies have not been systematically described.The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered for at least 2 years in a real-life setting.Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow up of unresectable stage III or IV melanoma. The study included 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019. Median follow up was 41.7 months (range, 25.2-57.5 months). Fifty-three patients received nivolumab and 66 patients received pembrolizumab.AEs occurred in 99 patients (83%) with a median time of 13.3 months (range, 0-53.9 months), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grades 1 or 2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations, of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first 2 years of treatment) and treatment duration (P = .02 and P = .03, respectively).Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy. Late-onset AEs appear frequently and were mostly mild or moderate. Early-onset AEs and prolonged anti-PD1 treatment may increase the risk of late-onset AEs.

International audience; Aim: To describe real-world pembrolizumab administration and outcomes for advanced melanoma in France. Materials & methods: Using the MelBase longitudinal database, this multicenter historical-prospective study examined treatment and outcomes of patients with nonuveal, unresectable stage III/IV melanoma initiating pembrolizumab from April 2016 to September 2017, with follow-up to September 2019. Kaplan–Meier time-to-event analyses were conducted. Results: Of 223 patients (median age 67; 51% men), 134 (60%), 36 (16%) and 53 (24%) initiated pembrolizumab in first-, second- and third-line, respectively. Median overall survival (months) was 32.6 (95% CI: 20.3–not reached [NR]), 14.4 (8.6–NR) and 9.3 (6.4–NR), respectively. Best real-world tumor response of complete or partial response was recorded for 49, 39 and 26% of patients, respectively. Conclusion: Study results support benefits of pembrolizumab therapy for advanced melanoma.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma.Patients and methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation.Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences.Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes. & ordf;2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.None.

Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients. BRAFV600mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC0–τ and Ctrough) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed. Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib Ctrough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE. In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

International audience; Background: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. Methods: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. Results: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of −0.027 (95% CI, −0.03, −0.02) in the utility score, −1.82 (95% CI, −1.88, −1.76) in the FACT-General score, and −2.98 (95% CI, −3.05, −2.91) in the FACT-Melanoma score compared with first-line treatment. Conclusions: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.

ObjectiveTo quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma.MethodsCase–control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression.Results110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs.ConclusionIn our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy.

9575 Background: Both anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. For patients with V600 BRAF-mutated melanoma who recur with resectable disease on or after adjuvant, many may be suitable for ‘second adjuvant' treatment after surgery. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi in patients who recurred despite adjuvant PD-1 based immunotherapy. Methods: Patients with V600 BRAF-mutated melanoma treated with adjuvant PD-1 based immunotherapy for resected stage III/IV disease who recurred, underwent resection of recurrence and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres. Demographics, disease characteristics, treatment details, and outcome data were examined. Results: 55 patients were included; median age at commencement of PD-1 was 53y, most were V600E (91%) and had IIIB (42%) or IIIC (44%) melanoma. PD-1 based adjuvant therapy included nivolumab (71%), nivolumab plus ipilimumab (14%), pembrolizumab (13%) and pembrolizumab plus mRNA-4157 vaccine (2%). Patients had initial recurrence after mean 8.4 months (95% CI 7.4-10.6), mainly while on treatment (65%), in regional nodes (42%), in-transit metastases (ITMs; 38%), both regional nodes and ITMs (7%) and distant metastases (13%). Surgical management included CLND (36%), selected nodal resection (11%), ITM resection (33%) and resection of distant metastasis (13%). A minority had adjuvant radiotherapy (17%). Stage at start of second adjuvant BRAF/MEKi included IIIB (29%), IIIC (53%) IIID (4%) and IV (15%). Patients received dabrafenib and trametinib (95%, N = 52) and encorafenib and binimetinib (5%, N = 3). After a median follow up of 21.4 months (19.7-25.4), 17 (31%) patients have recurred again. Mean duration of treatment was 9 months (95% CI 7.4-10.6); 20% ceased for toxicity, 7% for recurrence and 35% were on treatment at last follow up. The most common toxicity was pyrexia (43%) and 21% patients experienced a severe (G3-4) adverse event. Median RFS was 33.4 months (14.3.7-NR) and median DMFS was not reached. At 12 months, 72% (59-88) of patients were recurrence free and 90% (81-100) were free of distant recurrence. For those whose disease recurred again, most recurred after cessation of second adjuvant BRAF/MEKi (13/17, 76%). 7 (41%) recurred locally and 8 (47%) recurred with new metastatic disease but none had brain metastases. Conclusions: This is the first study examining outcomes of patients receiving second adjuvant targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. While RFS appears shorter compared to first line trials, second adjuvant treatment with BRAF/MEKi appears safe and active in preventing further recurrence. Further data on sequencing adjuvant therapies are needed.

PURPOSE Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti–PD-1 monotherapy. METHODS The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, –1.05; chronic sun-exposed area, 1.12; P value for the location, < 10–5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB (P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice., The location of the primary melanoma in a sun-exposed area can help choosing first-line advanced melanoma treatment.

Immune checkpoint inhibitors for melanoma improve adaptive T cell immunity during COVID-19 without exacerbating inflammation., The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.

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BackgroundPatients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy and safety of PD1 versus IPI +PD1 after BRAF/MEK inhibitors (BRAF/MEKi).MethodsPatients with V600BRAF mutant metastatic melanoma treated with BRAF/MEKi who had subsequent PD1 versus IPI+PD1 at eight centers were included. The endpoints were objective response rate (ORR), PFS, OS and safety in each group.ResultsOf 200 patients with V600E (75%) or non-V600E (25%) mutant metastatic melanoma treated with BRAF/MEKi (median time of treatment 7.6 months; treatment cessation due to progressive disease in 77%), 115 (57.5%) had subsequent PD1 and 85 (42.5%) had IPI+PD1. Differences in patient characteristics between PD1 and IPI+PD1 groups included, age (med. 63 vs 54 years), time between BRAF/MEKi and PD1±IPI (16 vs 4 days), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 (62% vs 44%), AJCC M1C/M1D stage (72% vs 94%) and progressing brain metastases at the start of PD1±IPI (34% vs 57%). Median follow-up from PD1±IPI start was 37.8 months (95% CI, 33.9 to 52.9). ORR was 36%; 34% with PD1 vs 39% with IPI+PD1 (p=0.5713). Median PFS was 3.4 months; 3.4 with PD1 vs 3.6 months with IPI+PD1 (p=0.6951). Median OS was 15.4 months; 14.4 for PD1 vs 20.5 months with IPI+PD1 (p=0.2603). The rate of grade 3 or 4 toxicities was higher with IPI+PD1 (31%) vs PD1 (7%). ORR, PFS and OS were numerically higher with IPI+PD1 vs PD1 across most subgroups except for females, those with 3 years OS (area under the curve, AUC=0.74), while ECOG PS ≥1, progressing brain metastases and presence of bone metastases predicted primary progression (AUC=0.67).ConclusionsIPI+PD1 and PD1 after BRAF/MEKi have similar outcomes despite worse baseline prognostic features in the IPI+PD1 group, however, IPI+PD1 is more toxic. A combination of clinical factors can identify long-term survivors, but less accurately those with primary resistance to immunotherapy after targeted therapy.

Introduction En raison de l’oncogenese induite par les rayons ultraviolets, la charge mutationnelle tumorale est classiquement elevee dans les melanomes cutanes. Elevee, elle est un biomarqueur predictif de reponse aux anti-PD-1, mais une telle richesse mutationnelle peut au contraire faciliter l’emergence precoce de clones resistants sous therapies ciblees. Nous avons emis l’hypothese que la survie post immunotherapie vs therapies ciblees en 1e intention dans le melanome avance peut varier selon du profil de photo exposition du site de survenue du melanome primitif. Materiel et methodes Dans le cadre de Melbase, biobanque multicentrique francaise dediee au suivi prospectif des melanomes non resecables de stade III/IV, tous les patients atteints d’un melanome cutane primitif connu, ayant recu un traitement systemique de 1e intention par immunotherapie ou therapie ciblee entre 2013 et 2019 ont ete inclus. Les criteres de jugement etaient la survie sans progression (SSP) et la survie globale (SG). Resultats Neuf cent soixante treize patients ont recu une monotherapie anti-PD-1 (n = 466), anti-CTLA-4 (n = 143), l’association des deux (n = 118), dabrafenib + trametinib (n = 187) ou vemurafenib + cobimetinib (n = 59). Les caracteristiques des patients au debut du traitement etaient : sexe masculin (62 %), âge median 62 ans, BRAFwt (58 %), stade AJCC IV (84 %), metastases cerebrales (18 %), ECOG 0-1 (84 %) et LDH normaux (52 %). Le suivi median etait de 15,5 mois. Le melanome primitif etait localise en peau chroniquement photo-exposee (G1 : tete cou, n = 175), en peau exposee par intermittence (G2 : tronc, bras, jambes, n = 615), ou en zone non photo-exposee (G3 : paumes, plantes, n = 65). La mediane de SSP etait significativement meilleure pour le groupe G1 sous anti-PD-1 (8,7 mois vs 3,3 et 3,4 mois pour G2 et G3, respectivement) (p = 0,011), tandis que la SSP semblait meilleure pour le groupe G3 sous therapies ciblees (19,2 mois vs 8,1 et 6 mois pour G2 et G1) (p = 0,31), non significativite possiblement liee au faible effectif G3 traite par therapie ciblee (n = 8). La SSP ne differait pas significativement entre groupes sous ipilimumab. De meme, la mediane de SG etait significativement plus elevee pour le groupe G1 post anti PD-1 en 1e ligne (45,6 mois vs 31,6 et 21,4 mois pour G2 et G3) (p = 0,04), par opposition a la mediane de SG observee post therapies ciblees (19,5 mois vs 16,3 et 21,1 mois pour G1, G2 et G3 respectivement). Discussion Notre etude suggere que les anti-PD-1 en premiere intention sont particulierement recommandes en contexte de melanome primitif survenu en zone chroniquement exposee au soleil. En revanche, les patients dont le melanome provient d’une zone non-photo-exposee pourraient beneficier davantage d’une therapie ciblee de 1e intention lorsque cela est possible (presence de mutation BRAF), mais ce resultat reste a confirmer par des recherches ulterieures.

Introduction Le diagnostic de melanome est l’un des points les plus cruciaux de la prise en charge dermatologique. Recemment, le developpement d’algorithmes de deep learning pour le diagnostic de tumeurs cutanees malignes et en particulier de melanome amorce une revolution dans le diagnostic par le dermatologue. Cependant, la plupart des algorithmes des etudes publiees ont ete developpes sur des bases de donnees publiques. Nous avons developpe un algorithme destine au diagnostic de tumeurs cutanees malignes a partir des photographies de vie reelle, prises dans le cadre de soin. Materiel et methodes Les donnees utilisees pour le developpement et la validation de l’algorithme sont la banque d’images dermoscopiques constituees dans le cadre du soin a l’hopital Saint-Louis, comprenant 985 images dermoscopiques annotees pour le diagnostic par 2 medecins diplomes (aspect clinique, et resultat histologique pour les tumeurs malignes). La seconde base est la base publique de photos dermoscopiques ISIC comprenant 24 464 images dermoscopiques. Nous avons entraine un algorithme (un reseau de neurones convolutif de type EfficientNet-B1) a l’identification des tumeurs malignes (TM) (melanome, carcinomes) versus benignes (naevus, HCF, tumeurs vasculaires benignes) (TB), et au diagnostic de lesions melanocytaires ou non melanocytaires, au sein de la base locale. Nous avons evalue la performance de l’algorithme entre differentes bases de donnees en l’entrainant sur la base de donnees ISIC et en le testant sur la base locale. Resultats Notre algorithme entraine sur la base ISIC a une precision diagnostique (aire sous la courbe ROC) de 0,90 sur la base ISIC, et de 0,79 pour le diagnostic de TM vs TB sur notre base locale. Pour identifier les facteurs participant a cette baisse de performance, nous avons analyse 33 photos « mal classees » pour le diagnostic de tumeurs melanocytaires ou non par l’algorithme. Les principales sources d’erreur sont les lentigos (classes en non melanocytaire) et les CBC tatoues et les keratoses seborrheiques (classe en melanocytaire). L’analyse de 33 photos mal classees a permis d’identifier des erreurs recurrentes: biopsies anterieures remaniant la lesion (7), trait de crayon sur la photo (4), erreur d’annotation dans l’image (4), localisation muqueuse (1), erreur de diagnostic identique a celle du medecin prescripteur (8). Discussion Le developpement d’un algorithme sur une base de photos issues de la vie reelle permet d’identifier les facteurs pouvant alterer ses performances, et qu’il faudra prendre en compte lors du developpement de ce type d’outils aupres des dermatologues. Le developpement de l’algorithme va etre poursuivi par un apprentissage federe entre differentes bases de donnees hospitalieres pour ameliorer ses performances.

Introduction La restauration immunitaire induite par les inhibiteurs de checkpoints immunitaires ont révolutionné le pronostic des cancers métastatiques [1]. La contribution de cette stratégie thérapeutique pour la prise en charge des infections reste toutefois controversée, malgré quelques études en faveur de leur utilisation, notamment dans le contexte de paralysie immunitaire au décours d’un sepsis sévère [2], [3], ou dans les situations d’épuisement immunitaire au cours des infections virales chroniques [4], [5]. Au cours de la COVID-19, des études suggèrent qu’un état d’épuisement immunitaire en lien avec une anergie et/ou une déplétion des lymphocytes T serait partiellement responsable de la virulence du SARS-CoV-2 [6], [7], [8], [9], [10]. Certains proposent donc l’utilisation des anti-PD1 comme stratégie thérapeutique tandis que d’autres suggèrent qu’au contraire, elle pourrait aggraver l’hyperinflammation [11], [12]. Patients et méthodes Nous avons suivi de façon prospective 292 patients atteints de mélanome lors de la première vague de COVID-19 (de mars à juin 2020) dont la moitié était traitée par immunothérapie (anti-PD1 ± anti-CTLA4). Les patients présentant des symptômes de COVID-19 étaient dépistés par PCR. Une sérologie SARS-CoV-2 était recherchée de façon systématique. Les patients présentant une infection symptomatique active ( 21 jours du début des symptômes, PCR négative, sérologie positive) ont été inclus pour une étude approfondie de la réponse immunitaire par une analyse transcriptionnelle (Nanostring), protéomique (SIMOA, Luminex) et cellulaire (cytométrie de masse). Résultats Quinze patients atteints de COVID-19 ont été identifiés (infection active ou convalescente) avec une estimation de la séroprévalence à 8,6 % de la cohorte. Quatre patients sur 15 ont nécessité une hospitalisation (26,7 %). Les données cliniques ne retrouvaient pas d’éléments en faveur d’une forme plus sévère de COVID-19 lors d’un traitement par anti-PD1, seul un patient ayant également une leucémie lymphoïde chronique, a développé une forme sévère de la COVID-19 et est décédé de défaillance respiratoire. L’analyse de la réponse immunitaire, en comparaison avec une cohorte de patients non traités par immunothérapie, retrouvait une réponse immunitaire innée semblable dans les deux cohortes. De même, le taux d’anticorps anti-Spike (IgG et IgA), la capacité neutralisante ainsi que la longévité des anticorps (suivi du taux sur une période d’1 an) étaient similaires en présence ou non d’un traitement par immunothérapie. En revanche, l’analyse de la réponse cellulaire mettait en évidence, chez les patients traités par immunothérapie, une expansion de la population de lymphocytes T CD8+ effecteurs mémoires, une augmentation de l’activation des lymphocytes T CD4+ et CD8+, et une augmentation la production d’IFN-gamma lors d’une stimulation ex-vivo par des peptides issus du SARS-CoV-2. Conclusion Nos résultats sont en faveur d’une augmentation de la réponse cellulaire T anti-SARS-CoV-2 lors d’un traitement par anti-PD1 chez les patients suivis pour mélanome, et de l’absence d’une exacerbation de la réponse inflammatoire. Il est nécessaire de confirmer ces résultats avec un plus grand nombre de patients, dans d’autres types de cancers et dans d’autres centres.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were 3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

9556 Background: Melanoma of unknown primary (MUP) account for 3% of all melanomas. Clinical outcome of advanced MUP in the era of novel therapies including immunotherapies (ICI) and targeted therapies (TT) have been only scarcely studied, whereas a possibly different biologic background might introduce changes in its management. Recent retrospective studies suggested that patients with advanced MUP could benefit at least as much from novel therapies as patients with known primary cutaneous melanoma (cMKP). Methods: Based on the nationwide MelBase prospective database (NCT02828202) this retrospective study included patients with advanced melanoma treated with first-line ICI, TT or CT. MUP was defined by upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. Patients with primary mucosal or ocular melanoma were excluded. Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary variables in MUP vs cMKP, stratified by treatment subset (ICI vs TT vs CT vs whole cohort). Secondary variable was treatment-related toxicity. Multivariate analyses and propensity score analysis were performed. Objective: To investigate the efficacy and safety of systemic treatments (ICI, TT and chemotherapy (CT)) in patients with advanced MUP comparatively to stage-matched cMKP. Results: A total of 1882 patients were analyzed, including 265 (14.1%) MUP. Most patients were treated with first-line ICI. Median follow-up was 16 months. Patients in the MUP cohort more often displayed unfavorable initial prognostic factors (Table). PFS and OS did not significantly differ in MUP compared to MKP patients (p=0.73 and p=0.93 respectively). Stratification of cohorts by treatment type and application of propensity score did not lead to data modification. Treatment-related toxicity rate and severity did not differ between MUP and MKP, regardless of treatment type. Conclusions: Our results suggest that advanced MUP should be managed with similar strategies as advanced MKP. In our cohort, MUP patients benefited from novel therapies as much as MKP patients despite less favorable baseline prognostic factors. Exploratory studies investigating mutational burden and host immunity are needed to identify the underlying mechanisms. [Table: see text]

International audience; Background: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy.Patients and methods: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out.Results: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI.Conclusion: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Background Anti-PD1–based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown. Methods We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR. Results For group A, median duration of treatment (mDoT) was 22 months (range 5–49) and median time to CR 9 months (range 2–47). Accordingly, mDoT for group B was 3 months (range 0–36) and median time to CR 7 months (range 1–32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0–42) and 25 months (range 0–66), respectively. For MBM, mOTRt was 17 months (range 7–41) and 28 months (range 9–39), respectively. After a median follow-up of 38 months (range 9–70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma. Conclusions Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.

Importance: Few data are available on patients with leptomeningeal disease (LM) from melanoma treated with new systemic therapies. Objective: To gain a better understanding of patients, disease characteristics, and therapeutic interventions in melanoma patients with LM in the era of new systemic treatment. Design: Clinical characteristics, treatments, and survival of melanoma patients diagnosed with LM, isolated or associated with brain metastases, were collected. The Cox regression model assessed the influence of patient and melanoma characteristics on survival. Setting: Monocentric, retrospective, real-life cohort of patients with LM from melanoma. Participants: All patients followed up at Saint-Louis University Hospital and diagnosed with LM between December 2013 and February 2020 were included. For each patient identified, a central review by dermato-oncologist and neuro-oncologist experts was performed to confirm the diagnosis of LM. Exposure: Impact of new systemic therapies and radiotherapy. Results: Among the 452 advanced melanoma patients followed at St Louis Hospital between 2013 and 2020, 41 patients with LM from melanoma were identified. Among them, 29 patients with a diagnosis of LM &ldquo, confirmed&rdquo, or &ldquo, probable&rdquo, after central neuro-oncologists reviewing were included. Nineteen patients had known melanoma brain metastases at LM diagnosis. Among the 27 patients treated with systemic therapy, 17 patients were treated with immunotherapy, 5 patients received targeted therapy, 1 was treated with chemotherapy, and 4 patients were treated with anti-PD-1 in combination with BRAF inhibitor. The median overall survival (OS) from LM diagnosis was 5.1 months. Median OS was 7.1 months for the 9 patients receiving systemic therapy combined with radiotherapy, and 3.2 months for the 20 patients not receiving combined radiotherapy. Elevated serum lactate dehydrogenase (LDH) (HR 1.44, 95% CI 1.09&ndash, 1.90, p &lt, 0.01) and presence of neurological symptoms at LM diagnosis (HR 2.96, 95% CI 1.25&ndash, 6.99, p = 0.01) were associated with poor survival. At the time of data analysis, five patients were still alive with a median follow-up of 47.4 months and had persistent complete response. Conclusion: Targeted therapy and immunotherapy are promising new treatment options in LM from melanoma that can increase overall survival, and may induce long lasting remission in some patients.

Summary Background Immune-related hepatitis (IRH) occurs in 1 to 18% of immune checkpoint inhibitor (ICI)-treated patients. Steroids are usually recommended for grade ≥ 3 IRH, but their impact on IRH resolution and patient survival remains unclear. Methods We retrospectively analyzed a prospective cohort of 339 patients treated at Saint-Louis Hospital (Paris, France) with ICIs for advanced melanoma. Cases of grade ≥ 3 IRH were collected and analyzed. Two groups were compared for their biological features and time for IRH resolution and survival: patients who received steroids (steroids group: SG) and patients who did not (nonsteroids group: NSG). Findings Grade ≥ 3 IRH was observed in 21 patients. Thirteen were treated with steroids (SG), and 8 were not (NSG). The median time for toxicity resolution was 49 days in SG and 24 days in NSG (P = 0.62). All but one patient showed a favorable outcome. Two-year survival was 56% in SG and 54% in NSG (P = 0.83). Higher transaminase (P = 0.002) and bilirubin (P = 0.008) and lower prothrombin (P = 0.035) levels were observed in SG than in NSG. For 8 (4 SG/4 NSG) patients, ICI was resumed without any hepatitis relapse. Interpretation Favorable outcomes may be achieved spontaneously and with no steroids in patients with severe IRH. Steroid initiation should be discussed in cases of high bilirubin levels and decreased prothrombin levels. ICI could be resumed without hepatitis relapse. We propose a management algorithm for grade ≥ 3 IRH that should be validated in larger and prospective cohorts.

In patients with ipilimumab (IPI)-refractory melanoma, the anti-programmed cell death proteins 1 (PD1s) nivolumab (NIV) and pembrolizumab (PEM) are considered to be a new standard of treatment. Few data are available on anti-PD1 safety in patients who develop IPI-related severe adverse events (AEs) (grade≥3). The aim of this study was to compare the anti-PD1 safety and efficacy in patients with previous severe toxicity to IPI versus in those showing moderate and no previous IPI-related AEs. This single institution-based observational study included all patients treated with anti-PD1 (PEM or NIV) and previously treated with IPI for unresectable stage III or IV melanoma. The patients enrolled were classified according to the occurrence of IPI-related AEs: group A: no previous IPI-related AEs; group B: mild to moderate IPI-related AEs; and group C: severe to life-threatening IPI-related AEs. The main outcome measure was safety of the anti-PD1 among the three groups. The secondary endpoints included response parameters. Groups A, B, and C included, respectively, 16, 13, and 10 patients. The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in groups A, B, and C, respectively. One-year estimates of survival were 52.2, 73.4, and 66.7% among the patients in groups A, B, and C, respectively. The number of patients was too small to enable a meaningful statistical comparison. We did not observe any difference in anti-PD1 toxicity onset incidence according to the occurrence of previous IPI AEs. These reassuring real-life data should be confirmed in a wider analysis.

Introduction Les anti-PD1 sont associes a la survenue d’effets indesirables (EI) specifiques, en partie medies par l’immunite. Les patients atteints de melanomes avances inclus dans des essais cliniques ont ete traites par anti-PD1 pour une duree de deux ans ou moins et il n’existe pas de recommandation concernant la duree optimale de traitement. Il y a peu de donnees concernant les EIs tardifs des anti-PD1 (apres deux ans de traitement). L’objectif de cette etude etait de decrire les EIs (incluant les EIs tardifs) des anti-PD1 chez des patients atteints de melanomes avances traites en vie reelle pendant au moins deux ans. Materiel et methodes Les patients de la cohorte MELBASE (cohorte francaise multicentrique de suivi prospectif de patients atteints de melanomes de stades III non resecable ou IV de l’AJCC) traites par anti-PD1 pendant deux ans ou plus, entre janvier 2013 et novembre 2019, etaient inclus. Tous les EIs (dont les EIs tardifs, definis comme survenant au-dela de 2 ans de traitement) etaient colliges. Les facteurs potentiellement associes a la survenue d’EI etaient recherches. Resultats Parmi les 1849 patients atteints de melanomes avances inclus dans Melbase, 119 patients traites par anti-PD1 pendant au moins deux ans etaient inclus. La mediane de suivi de ces patients etait de 41,7 mois (25,2–57,5). Les principales caracteristiques initiales des patients etaient: sexe masculin (61 %), âge moyen 63 ans, antecedent de maladie auto-immune (11 %), mutation BRAF V600 (25 %), stade IV de l’AJCC (84 %), metastases cerebrales (22 %), ECOG 0-1 (88 %), et LDH eleves (18 %). Les patients avaient ete traites par nivolumab (n = 53, 45 %) ou pembrolizumab (n = 66, 55 %), et la maladie etait controlee par le traitement (reponse complete, partielle ou maladie stable dans 59 %, 34 % et 7 % des cas respectivement). La duree mediane de traitement etait de 35 mois (28,7–40,5). Des EIs etaient survenus chez 99 patients (83 %) apres une duree mediane de traitement de 13,3 mois (0–53,9) dont au moins un EI severe (grade 3–4) chez 30 patients (30 %). Les EIs tardifs, survenus au-dela de 2 ans de traitement par anti-PD1, etaient observes chez 51 patients (43 %). Ils etaient principalement de grade 1–2 mais severes chez 4 patients (3 %) et avaient conduit a l’hospitalisation de 5 patients (4 %). Parmi les patients ayant presente ces EIs tardifs, 45 (87 %) avaient deja presente un EI au cours des deux premieres annees de traitement et 29 (56 %) en avaient presente plusieurs. Les facteurs associes a la survenue d’EIs tardifs etaient les toxicites multiples avant 2 ans et la duree de traitement (p Discussion La poursuite du traitement par anti-PD1 au-dela de 2 ans s’accompagne frequemment d’EIs tardifs, le plus souvent benins. La survenue de plusieurs EIs au cours des 2 premieres annees etait un facteur de risque independant de survenue d’EIs tardifs.

Introduction L’obesite est un facteur de risque de nombreux cancers et peut conferer un pronostic plus pejoratif. Ces donnees restent debattues en ce qui concerne le melanome. Le concept du « paradoxe de l’obesite » a recemment emerge et plusieurs etudes, dont celle de McQuade JL et al., qui avancent qu’un IMC eleve serait associe a un taux de survie superieur chez les patients traites par immunotherapie et therapie ciblee pour un melanome metastatique. Nous avons etudie l’association entre l’IMC et la survie sans progression (SSP) ainsi que la survie globale (SG) chez les patients atteints de melanome metastatique sous traitement systemique. Materiel et methodes Cette etude retrospective a ete menee a partir de la cohorte prospective francaise MelBase. Les patients atteints de melanome metastatique traites en premiere ligne par immunotherapie, therapie ciblee et chimiotherapie etaient inclus. L’IMC etait defini selon les criteres de l’OMS. Les patients maigres (IMC Resultats Un total de 1214 patients ont ete inclus. La majorite etait traitee par immunotherapie, puis par therapie ciblee. Les patients obeses representaient 22 % de la cohorte. La mediane de suivi etait de 13,5 mois. Les patients en surpoids ou obeses ne presentaient pas de beneficie de SSP (p = 0,88) ni de SG (p = 0,25) par rapport aux patients avec un IMC normal. L’analyse univariee et multivariee, stratifiees sur l’âge, le sexe, et certains parametres pronostiques (LDH, nombre de metastases) ne trouvaient par de difference de survie pour les patients en surpoids ou obeses. Discussion Il s’agit de la seconde plus grande cohorte sur le sujet, qui, a l’inverse de celle publiee par Mc Quade et al., ne trouve pas d’association ni positive ni negative entre IMC et SSP/SG chez les patients traites pour un melanome metastatique, quel que soit le traitement. Parce que l’IMC ne reflete pas dans son integralite la composition corporelle (pas de distinction entre masse maigre/masse grasse), il s’agit d’une approche inadaptee, comme l’atteste d’ailleurs l’heterogeneite des resultats et l’absence de reproductibilite entre les etudes. Nous mettons en garde sur l’utilisation de l’IMC comme marqueur predictif de la survie chez les patients traites pour un melanome metastatique.

Introduction L’association nivolumab et ipilimumab (NIVO + IPI) a considerablement ameliore le pronostic des patients avec melanome metastatique, en particulier en cas de metastases cerebrales. Neanmoins, elle est responsable d’effets indesirables severes dans environ 55 % des cas. L’objectif de cette etude etait d’evaluer en vraie vie une population traitee par NIVO + IPI pour melanome metastatique afin d’identifier les facteurs associes a la survie, la reponse et aux arrets de traitement. Materiel et methodes Les patients etaient identifies via Melbase, une bio-banque multicentrique francaise dediee au suivi prospectif des patients adultes avec melanome avance. Tous les patients traites par NIVO + IPI dans notre centre entre mai 2016 et mars 2020 ont ete inclus. Les caracteristiques des patients et du melanome a l’initiation de NIVO + IPI ont ete recueillies: âge > 65 ans, sexe, stade metastatique (M1c versus M1b-c), presence de metastases cerebrales, taux de LDH (lactate deshydrogenase), type de melanome (muqueux versus autre), statut BRAF et l’ECOG (Eastern Cooperative Oncology Group). Les parametres cliniques et biologiques associes a la survie globale (SG), la survie sans progression (SSP), la reponse et les arrets de traitements ont ete identifies par analyse multivariee de Cox. Resultats Cette etude a inclus 81 patients, avec une mediane de suivi de 10,9 mois. A l’inclusion, 51 % des patients presentait un taux de LDH augmente, 42 % des metastases cerebrales et 19 % un stade M1c. Sur les 81 patients, les medianes de SG et de SSP etaient respectivement de 13,8 mois (9,4-NA) et 2,7 mois (2,0-4,7). La mediane de SG etait de 17,2 mois (12,6-NA) chez les patients en 1re ligne (N = 31) versus 3,8 mois (1,9-NA) en 2me ligne de traitement (N = 50). En analyse univariee, le taux de LDH (p Discussion Le benefice en survie de NIVO + IPI pour melanome avance en conditions de vie reelle semble inferieur aux donnees des essais therapeutiques, probablement en lien avec les caracteristiques plus pejoratives de cette population. Neanmoins, l’interet de NIVO + IPI en cas de metastases cerebrales est confirme en conditions de vie reelle.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increas

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

International audience; The prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable.Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma.Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017.Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (24 months).Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment.Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival.

International audience; Background: Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy.Patients and methods: Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias.Results: Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4-0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively.Conclusion: This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy.

Immunotherapy greatly improves clinical outcomes in treated patients with cancer. However, the long-lasting immune response and long duration of therapy could induce long-term adverse effects owing to the chronic inflammation induced. Type 2 diabetes is now recognized as an inflammatory disease. In addition, immunotherapy is concerned with increase in the production of tumor necrosis factor-α, interleukin-2, and interferon-γ, which are involved in the inflammatory process. Based on these observations, we hypothesized that anti-programmed cell death-1 (anti-PD-1) and/or anticytotoxic T-lymphocyte-associated protein-4 therapy could contribute to type 2 diabetes genesis in treated patients. Therefore, to evaluate this hypothesis, we studied HbA1c levels during follow-up in patients treated with anti-PD-1 and/or anticytotoxic T-lymphocyte-associated protein-4 therapy. A prospective and observational study was performed in an oncodermatology department (Saint-Louis Hospital, Paris, France) from March 2015 to February 2017. Sixty-two patients meeting the inclusion criteria were enrolled. Forty-three patients had paired HbA1c measurements during their follow-up period and were analyzed. The median follow-up was 3 months. We noted an increase in HbA1c levels from 5.3% [interquartile range (IQR): 5.1-5.5; range: 4.5-6.2) to 5.45% (IQR: 5.2-5.7; range: 4.7-6.2; P=0.037). This observation was confirmed in the subgroup of patients who did not receive concomitant glucocorticoids; their median HbA1c levels increased from 5.3% (IQR: 5.1-5.5; range: 4.7-6.2) to 5.5% (IQR: 5.2-5.7; range: 4.7-6.3; P=0.025). Variables such as age, BMI, and sex were not associated with the HbA1c level increase, but a tendency toward rising HbA1c levels was observed in treatments longer than 12 months. This study demonstrates that treatment with anti-PD-1 antibodies may impair glucose metabolism, as measured by increasing HbA1c levels.

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.

9533 Background: First line IPI+PD1 induces long-term response in 36% of MM patients (pts); however, the majority of pts will progress and may require further treatment, which is yet to be established. We studied the patterns of progressive disease (PD) on 1st line IPI+PD1, and the management and outcomes in MM pts. Methods: Demographics, disease characteristics, nature of PD, subsequent treatments and outcomes were examined in MM pts with PD on 1st line IPI+PD1. Multivariable analyses (MVA) identified factors associated with patterns of PD: innate resistance (IR) = PD as best response or stable disease (SD) < 6 mo; acquired resistance (AR) = PD after initial response or SD ≥ 6 mo. Results: 310 MM pts from 14 melanoma centres were included; 208 (67%) had PD during and 102 (33%) after ceasing IPI+PD1. Overall med. progression-free survival (mPFS) was 2.8 mo (CI 95% 2.7 – 3.0); 187 pts (60%) had IR (mPFS 2.2 [2.1 – 2.5]), 112 pts (36%) had AR (mPFS 8.5 [7.2 – 10.2]) and 11 pts (4%) had pseudoprogression, i.e. PD followed by response without changing treatment (mPFS 2.7 mo [1.4 – NA]). On MVA, pts with ECOG PS ≥ 1 were more likely to have IR vs AR; and within IR pts, those with head & neck primary melanomas and lung metastases were more likely to have PD < 1.5 mo. Most pts with IR (68%) had PD in multiple sites, while 61% AR pts had PD in a single site. Brain was most common site of single organ PD; 49% of IR and 41% of AR. Med. follow-up from PD was 32.7 mo (28.1 – 36.8). After PD, 61 pts (20%) had best supportive care (26% of IR and 11% of AR pts). 259 pts (80%) received further treatment: 39% IR pts had systemic treatment (ST) only and 27% had ST + local; 31% AR pts had ST only and 39% had ST + local. Of 200 pts (65%) who had ST(+/-local), 54% had 1 line of ST and 46% had ≥ 2; 1st line ST (ST1) was BRAF/MEKi in 36% of pts, PD1 in 32%, IPI+PD1 in 7%, investigational drugs in 11%, chemotherapy in 9% and others in 5%. ORR in IR pts was lower than in AR pts for every type of ST1 (see Table). Med. OS from PD was 11.4 mo (CI 95% 9.6 – 16.1); IR 6.4 mo (CI 95% 5.6 – 10.2) and AR 26.1 mo (CI 95% 17.1 – NA). Conclusions: These data suggest longer OS from PD for AR vs IR pts independent of ST type. BRAF/MEKi, rechallenge with PD1+/-IPI and investigational drugs showed activity after PD on IPI+PD1, while chemotherapy has no role in this context.[Table: see text]

BackgroundClinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases.MethodsWe performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients.ResultsOf the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23–83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab.Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren’s syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet’s syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare.The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005).ConclusionsIn patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.

Introduction Le diagnostic d’atteinte leptomeningee (LM) de melanome est associe a un pronostic sombre avec une mediane de survie historique de 4 a 10 semaines. Bien que le developpement de la therapie ciblee et de l’immunotherapie ait considerablement ameliore le pronostic des patients avec metastases cerebrales de melanome (MCM), peu de donnees existent concernant le benefice en cas de LM. La radiotherapie cerebrale (RTc) combinee a ces nouveaux traitements systemiques a montre un benefice en survie globale en cas de MCM mais l’efficacite de cette strategie combinee n’a pas ete evaluee en cas d’atteinte LM. L’objectif de cette etude etait d’evaluer les caracteristiques et le devenir d’une population presentant une LM de melanome a l’ere de ces nouvelles therapeutiques. Materiel et methodes Les caracteristiques clinico-radiologiques et les sequences therapeutiques (traitements systemiques et RTc concomitante) des patients suivis pour un melanome metastatique avec diagnostic de meningite carcinomateuse entre 2013 et 2020 dans notre centre ont ete recueillies retrospectivement. Une relecture centralisee des dossiers et imageries de chaque cas de LM identifie via Melbase etait effectue par 4 neuro-oncologues et 1 onco-dermatologue. Seuls les LM « confirmee » ou « probable » selon les criteres EANO-ESMO apres relecture etaient inclus. Les facteurs influencant la survie ont ete evalues par modele de Cox. Resultats Parmi les 452 patients suivis dans notre centre pour un melanome metastatique entre 2013 et 2020, une LM a ete diagnostiquee chez 41 patients. Apres relecture centralisee, 29 patients dont le diagnostic de LM etait considere comme « confirme » ou « probable » ont ete inclus. Des MCM concomitantes etaient presentes chez 19 patients au diagnostic de LM. Vingt-sept patients ont recu un traitement systemique apres le diagnostic de LM : immunotherapie (n = 17), therapie ciblee (n = 5), chimiotherapie (n = 1) ou anti-BRAF + anti-PD1 (n = 4). La mediane de survie globale apres le diagnostic de LM etait de 5,1 mois dans la population globale. La mediane de survie globale etait de 7,1 mois chez les 9 patients recevant une RTc combinee a un traitement systemique versus 3,2 mois chez les 20 patients n’ayant pas recu de RTc combinee. Un taux de LDH eleve (HR 1,44, 95 % CI 1,09–1,90, p Discussion Les therapies ciblees et l’immunotherapie, eventuellement combinee a la RTc, sont des options therapeutiques prometteuses en cas de melanome avec LM, pouvant prolonger la survie et induire des remissions persistantes chez certains patients.

10026 Background: Clinical trials of immunotherapy exclude patients (pts) with pre-existing AD. While retrospective data exist regarding the efficacy and safety of single agent ipi and anti-PD1 antibodies (PD1) in pts with AD, no data are available regarding the safety and efficacy of combination therapy in pts with AD, which has a higher toxicity risk. Methods: Pts with melanoma and pre-existing AD treated with combination ipi/PD1 were retrospectively identified from 10 international centres. Data regarding AD, treatment, toxicity and outcomes were examined. Results: Fifty-five pts were included, 46 were treated with ipi/nivolumab and 9 with ipi/pembrolizumab. 40 had an ipi dose of 3mg/kg while 15 had a lower dose regimen. 9 pts received prior PD1 therapy; 3 suffered moderate immune-related adverse events (irAE) with no flares of AD on single agent PD1. Pre-existing AD included inflammatory bowel disease (IBD), thyroiditis, rheumatoid arthritis (RA), multiple sclerosis and psoriasis. 10 pts had active symptoms of AD and 13 were immunosuppressed at commencement of ipi/PD1. Eighteen pts (33%) experienced a flare of their AD including 4/7 with RA, 3/6 with psoriasis, 5/9 with IBD, 3/18 with thyroiditis, 1/1 with Sjogren’s syndrome, 1/1 with polymyalgia, 1/1 with Behcet’s syndrome. Median time to flare was 19 days (range 4 – 167). 13 pts were managed with steroids, 5 required additional immunosuppressants. 7 pts were hospitalised for management of flare (5 with IBD, 2 with RA). 2 pts required intensive care and vasopressors for severe IBD flare, quiescent prior to ipi/PD1. One for diarrhoea and shock and one for duodenal perforation. 8 pts ceased treatment due to flare (3 with IBD, 2 with RA, 1 with Behcet’s, 1 with Sjogren’s). Thirty-seven pts (67%), experienced an irAE unrelated to their AD, 38% G3 or G4. The most frequent irAEs were colitis (n = 16), hepatitis (n = 12), endocrinopathies (n = 12), with 13 pts experiencing an irAE in ≥ 2 organs. 9 pts experienced both AD flare and an irAE. 20 pts (36%) ceased immunotherapy due to irAEs. ORR was 55% (54% in PD1 naive pts), at a median follow up of 14 months, 77% of responses ongoing. ORR in pts who had a flare of their AD was 44% and in pts on immunosuppression was 46%. Median PFS was shorter in pts who had a flare of AD compared with those who did not (2.6 vs 9 months; P-value 0.047). Conclusions: Combination ipi/PD1 shows efficacy comparable to clinical trial populations in pts with pre-existing AD and advanced melanoma. Whilst there was a substantial risk of flare of AD, no increased frequency of irAE’s was observed.

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.

International audience; Purpose Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. Methods Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. Results Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. Conclusion This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Introduction Depuis 2011, sept nouveaux medicaments ont ete approuves pour le traitement du melanome metastatique (MM), augmentant significativement la survie des patients et le cout de prise en charge en 1re ligne de traitement. Avec 52 % des patients atteignant aujourd’hui une deuxieme ligne de traitement, la sequence optimale de traitement chez les patients atteints de MM BRAF mute n’est pas encore bien definie. Afin d’informer les decideurs publics sur l’efficience de ces sequences, nous avons realise une analyse cout-efficacite comparant les sequences de traitement pour le MM BRAF mute en vie reelle, en France. Materiel et methodes Lors de l’evaluation de l’efficience la totalite des traitements disponibles doivent etre inclus dans l’analyse, ainsi cinq sequences ont ete comparees : anti-PD1- bitherapies ciblees (BI-TC), BI-TC-Anti-PD1, ipilimumab+ nivolumab-BI-TC, monotherapies ciblees (MONO-TC)-BI-TC et MONO-TC-anti-PD1. Les donnees cliniques (efficacite et utilite) et economiques ont ete extraites de la cohorte prospective MelBase, recueillant des donnees individuelles de 1 435 patients atteints de MM issus de 26 hopitaux francais, du diagnostic jusqu’au deces. Afin de rendre les patients, traites par differentes sequences, comparables il est necessaire de s’affranchir du biais de confusion et ainsi de pouvoir estimer l’effet traitement, pour cela il a ete utilise la ponderation inverse sur le score de propension (IPTW). La survie a ete estimee par la methode de Kaplan-Meier. Les couts ont ete calcules du point de vue de l’assurance maladie sur la base des tarifs francais. La survie et les couts ont ete extrapoles en utilisant un modele multi-etats, decrivant l’evolution de la maladie chez les patients sur un horizon temporel de 10 ans. Resultats Parmi les 1 435 patients, l’efficacite a ete evaluee sur les 608 patients BRAF mutes inclus entre 2013 et 2019. Par rapport a la sequence MONO-TC-Anti-PD1 (la moins chere), trois sequences (BI-TC-Anti-PD1, ipilimumab + nivolumab-BI-TC, MONO-TC-BI-TC) ont ete exclues de la frontiere d’efficience car elles etaient plus cheres et moins efficaces. Il reste la sequence Anti-PD1-Bi-TC, qui a ete associee a des couts supplementaires de 66 343€ et 0,7 annee de vie ponderee par la qualite de vie (QALYs), soit un ratio differentiel cout resultat de 94 776€/QALY. Au regard de la courbe d’acceptabilite, a un seuil de 150 000€, la sequence Mono-TC-Anti-PD1 a pres de 100 % de chance d’etre efficiente, a 300,000€ la sequence Anti-PD1-Bi-TC a 60 % de chance d’etre efficiente. Conclusion Pour les patients presentant un MM BRAF mute, les sequences Anti-PD1-BI-TC et MONO-TC-Anti-PD1 semblent etre les plus efficientes, en France, a partir des donnees observationnelles de la cohorte MelBase.