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Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at plt; 0.05.Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOGgt;1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

International audience; This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

Immunotherapy has dramatically improved the prognosis of patients with metastatic melanoma (MM). Yet, there is a lack of biomarkers to predict whether a patient will benefit from immunotherapy. Our aim was to create radiomics models on pretreatment computed tomography (CT) to predict overall survival (OS) and treatment response in patients with MM treated with anti-PD-1 immunotherapy.We performed a monocentric retrospective analysis of 503 metastatic lesions in 71 patients with 46 radiomics features extracted following lesion segmentation. Predictive accuracies for OS 1 year versus 1 year and treatment response versus no response was compared for five feature selection methods (sequential forward selection, recursive, Boruta, relief, random forest) and four classifiers (support vector machine (SVM), random forest, K-nearest neighbor, logistic regression (LR)) used with or without SMOTE data augmentation. A fivefold cross-validation was performed at the patient level, with a tumour-based classification.The highest accuracy level for OS predictions was obtained with 3D lesions (0.91) without clinical data integration when combining Boruta feature selection and the LR classifier, The highest accuracy for treatment response prediction was obtained with 3D lesions (0.88) without clinical data integration when combining Boruta feature selection, the LR classifier and SMOTE data augmentation. The accuracy was significantly higher concerning OS prediction with 3D segmentation (0.91 vs 0.86) while clinical data integration led to improved accuracy notably in 2D lesions (0.76 vs 0.87) regarding treatment response prediction. Skewness was the only feature found to be an independent predictor of OS (HR (CI 95%) 1.34, p-value 0.001).This is the first study to investigate CT texture parameter selection and classification methods for predicting MM prognosis with treatment by immunotherapy. Combining pretreatment CT radiomics features from a single tumor with data selection and classifiers may accurately predict OS and treatment response in MM treated with anti-PD-1.

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.

International audience

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%, partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS &lt, 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Immune checkpoint inhibitors (ICI), most commonly anti-PD-1 (programmed cell death 1) and anti-PD-L1 (programmed cell death ligand 1) therapies, have revolutionized the treatment of many cancers. ICI may activate the immune system response even in healthy tissues, which can cause immune-related adverse events (irAEs).(1) Several cases of bullous pemphigoid (BP) triggered by anti-PD-1/PD-L1 therapy have been reported.

International audience; Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan–Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. Results: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33–8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with

Importance Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies. Objectives To evaluate the risk of a recurrence of immune toxic effects associated with anti–programmed cell death 1 antibody (anti–PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs. Design, Settings, and Participants This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti–PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017. Exposures Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti–PD-1 (nivolumab or pembrolizumab) therapy. Main Outcomes and Measures The primary outcome was the rate of immune-related AEs associated with anti–PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti–PD-1 immune–related AEs and overall response rate and overall survival associated with anti–PD-1 therapy. Results Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti–tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti–PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing). Conclusions and Relevance The findings suggest that anti–PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.

PURPOSE To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS Patients, predominantly men, with their CSSCs’ immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort’s objective response rate at week 15 (ORRW15). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy–General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORRW15 difference between PD-L1+ and PD-L1– patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS Median age of all patients was 79 years. The primary cohort’s ORRW15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORRW15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1– patients (17%; P = .02). Responders’ W15 total FACT-G score had improved ( P = .025) compared with nonresponders. CONCLUSION First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Introduction L’immunotherapie est utilisee en soins courants dans le traitement du melanome et peut etre a l’origine d’effets indesirables telle qu’une colite auto-immune (CAI). Les CAI partagent des similarites cliniques, histologiques, biologiques et therapeutiques avec les maladies inflammatoires chroniques de l’intestin (MICI) tout en s’en distinguant. L’infection a Clostridium difficile (CD) complique classiquement les MICI. Par analogie, le but de ce travail etait d’etudier le lien entre CAI et infection a CD sous immunotherapie pour un melanome. Materiel et methodes Les patients de ce travail ont ete inclus de maniere retrospective a partir de 9 centres hospitaliers francais. L’objectif principal etait d’etudier la frequence d’une CAI parmi les patients presentant une infection a CD sous immunotherapie par anti-PD1 ou anti-CTLA4 pour un melanome. Les objectifs secondaires etaient de decrire les caracteristiques de l’infection a CD. Resultats Un total de 18 patients ont ete analyses. Parmi ces 18 patients, 12 ont eu une CAI et 6 ont eu une infection a CD isolee. Quand la CAI etait associee a une infection a CD, elle pouvait la preceder (n = 8), etre concomitante (n = 3) ou la suivre (n = 1). La majorite des CAI est survenue sous anti-CTLA-4. Le delai de survenue de l’infection a CD par rapport au debut de l’immunotherapie etait variable avec une moyenne de 130 jours (±166). Lorsque l’infection a CD compliquait la CAI, elle survenait dans un delai egalement variable avec une moyenne de 84 jours (±41). Trois infections a CD etaient fulminantes et celles-ci etaient precedees de la prise d’une antibiotherapie. Les caracteristiques endoscopiques et histologiques de l’infection a CD etaient aspecifiques. 9 patients sur 12 ont necessite un traitement immunosuppresseur lorsque l’infection a CD etait associee a une CAI. 3 patients ont ete traites par transplantation de microbiote fecal. 9 patients ont arrete l’immunotherapie pour toxicite digestive. Discussion Sous immunotherapie, l’infection a CD peut etre isolee, compliquer ou declencher une CAI. En effet, la CAI semble etre un facteur de risque de developper une infection a CD et l’infection a CD semble pouvoir declencher une poussee de CAI. Les caracteristiques de l’infection a CD dans les CAI sont proches de celles dans les populations de MICI : severite de l’infection a CD, patients peu exposes a une antibiotherapie avant la survenue de l’infection a CD et traitement necessitant majoritairement l’association d’un immunosuppresseur et d’une antibiotherapie. En conclusion, l’infection a CD, potentiellement grave, doit toujours depistee lors d’une diarrhee sous immunotherapie car elle peut etre isolee mais semble egalement pouvoir compliquer ou declencher une CAI.

BACKGROUND Isosulfan blue dye peripheral injection is used in preoperative sentinel lymph node (SLN) identification alone or, to increase sensitivity, in conjunction with radiocolloid mapping. However, isosulfan blue dye has certain drawbacks and limitations. OBJECTIVE This study assesses the authors' experience of SLN biopsy using only radiocolloid tracer. MATERIALS AND METHODS Between 2000 and 2008, 218 patients underwent SLN biopsy with radiocolloid mapping, preoperative localization by lymphoscintigraphy and intraoperative confirmation by gamma probe in primary malignant cutaneous melanoma. RESULTS Mean Breslow index was 2.1 mm. The SLN biopsy success rate was above 98% at all sites and 87% in head and neck locations. The 5-year overall survival rate was 90% and that of 5-year disease-free survival was 80%. False-negative rate, with a mean follow-up time of 41 months, was 5.5%. CONCLUSION Sentinel lymph node biopsy can be successfully performed in patients with melanoma using only radiocolloid tracer without blue dye staining. In circumstances where blue dye cannot be used such as head and neck tumors, allergic reactions and pregnancy, radiocolloid tracer mapping alone is not a loss of chance for patients with melanoma.

Introduction Les anti-PD-1 (programmed cell death 1) et les anti-PDL-1 (programmed cell death ligand 1) ont revolutionne la prise en charge de nombreux cancers. Une soixantaine de pemphigoides bulleuses (PB) associees a un traitement par anti-PD-1/PDL-1 ont ete decrites dans la litterature, mais leurs caracteristiques restent mal connues. Nous avons decide de collecter les cas francais et d’en decrire les caracteristiques. Materiel et methodes Etude retrospective multicentrique nationale, incluant tous les patients traites par un anti-PD-1/PD-L1, avec une PB survenant pendant le traitement, de 2014 a 2019. Les donnees demographiques, cliniques et biologiques etaient collectees grâce a un questionnaire envoye a tous les membres du Groupe Bulle et du Groupe de cancerologie cutanee. Resultats Au total, 85 cas ont ete observes dans 34 services de dermatologie en France. Il s’agissait principalement d’hommes (80 %). L’âge moyen etait de 73 ans (50–93). Les 2 principaux anti-PD-1 etaient le nivolumab (65 %) et le pembrolizumab (27 %) et les principaux cancers primitifs un melanome (52 %) et un cancer bronchopulmonaire (27 %). Le delai median d’apparition de la PB etait de 6 mois. Au diagnostic, 9 % des patients ne presentaient aucune bulle, 49 % moins de 10 nouvelles bulles par jour, 30 % entre 10 et 50, 6 % entre 50 et 100 et 6 % plus de 100. Une atteinte muqueuse survenait chez 38 % des patients. Seuls 3 patients (4 %) presentaient des troubles cognitifs. L’analyse histopathologique montrait une bulle sous-epidermique dans 81 % des cas, avec un infiltrat a eosinophiles dans 82 % des cas. L’immunofluorescence directe etait positive dans 80 % des cas. Les anticorps anti-BP180 et anti-BP230 etaient positifs dans respectivement 61 % et 13 % des cas. Une hypereosinophilie superieure a 0,5 G/L etait presente chez 43,5 % des patients. La majorite des patients etait traitee en premiere ligne par des dermocorticoides tres forts (84 %), avec une evolution favorable chez 65 % d’entre eux. Concernant les 44 patients atteints d’un melanome, la meilleure reponse tumorale etait : une remission complete pour 41 % des patients et une remission partielle pour 29 %. Discussion Il s’agit de la plus grande cohorte de PB associee a un traitement par anti-PD-1/PDL-1. Cette etude permet de definir le phenotype particulier de ces PB. En effet, elles surviennent majoritairement chez les hommes, plus tot que dans la PB classique, et chez des patients sans trouble cognitif. Elles sont plus souvent pauci bulleuses et avec plus frequemment une atteinte muqueuse. Parmi les patients dont l’immunotherapie a ete poursuivie et un traitement par dermocorticoides tres forts utilise, la PB a ete controlee dans 74 % des cas. Conclusion Une pemphigoide bulleuse doit etre evoquee devant un prurit resistant ou une eruption bulleuse survenant au decours d’un traitement par antiPD-1/PDL-1, et ce traitement ne doit pas etre systematiquement stoppe.

Objective Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. Methods A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. Results The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. Conclusion Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

International audience; Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participating centers were included. Relative incidence was calculated according to the total number of patients treated with ICI in network centers during the period of inclusion. The possible impact of anti-TNFα treatment on disease outcome was evaluated through comparison of objective response rate, progression-free survival, and OS with pivotal literature data. Twenty-seven patients from 13 tertiary referral centers were included. Overall, severe ICI-related colitis treated with anti-TNFα occurred in 1% of patients with advanced melanoma, mostly with ipilimumab. Infliximab was successfully used in all patients but 1, mostly after 1 infusion. OS and progression-free survival of 12 and 3 months, respectively, were observed in these patients, along with an objective response rate of 41% at 12 months. This survey shows a low real-life incidence of severe colitis requiring anti-TNFα. Response rates to immunotherapy and survival data do not appear to significantly differ from those observed in pivotal studies. Severe ICI-induced colitis requiring anti-TNFα treatment appears to be a rare event in advanced melanoma, and infliximab does not seem to adversely affect disease outcome.

Background Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. Patients and methods In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. Results Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). Conclusion(s) The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Background Thirty to 60% of stage unresectable AJCC III and IV melanoma patients (pts) develop brain metastases (BM). This population has been excluded from most clinical trials. Using a large prospective trial including pts with advanced BRAFV600-mutant melanoma and allowing for BM, we assessed in the BM population factors associated with disease progression and stratified the population into risk groups using regression tree analysis (RTA). Methods This phase IIIb single arm, open label, multicenter, non randomized French study included pts with unresectable stage IIIc or IV BRAFV600-mutant melanoma. Selection criteria allowed for BM, ECOG ≤2, previous advanced melanoma treatments. Pts received dabrafenib (D) + trametinib (T) until progression. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modeled with a multivariate Cox regression model. Risk subgroups were identified using an exponential RTA. Significance was set at p Results Between March 2015 and November 2016, 856 pts were included and 275 (32%) had BM. Median PFS was 5.68 months (95% CI, 5.29-6.87) in the BM population. Significant independent factors associated with lower PFS were ECOG ≥1, elevated serum LDH, ≥3 metastatic sites, and non naive status (Table). Pts with ECOG 0, Table: 1332P . Multivariate Cox proportional hazards analysis of PFS by prognostic factors N (%) HR 95% CI p value LDH at baseline * 115 (41.8) 1 (=reference) - - [1 - 2[ ULN 50 (18.2) 1.30 [0.83 - 2.04] 0.2473 ≥2 ULN 21 (7.6) 2.50 [1.37 - 4.58] 0.0030 Missing 89 (32.4) 1.44 [0.99 - 2.10] 0.0571 ECOG PS * O 144 (52.4) 1 (=reference) - - 1 91 (33.1) 1.36 [0.94 - 1.96] 0.0995 ≥2 40 (14.6) 2.17 [1.37 - 3.44] 0.0010 Metastatic sites * 84 (30.6) 1 (=reference) - - ≥3 191 (69.5) 1.58 [1.10 - 2.28] 0.0142 Status Naive 121 (44.0) 1 (=reference) - - Non naive 154 (56.0) 1.60 [1.14 - 2.25] 0.0061 * Factors included in the RTA. Conclusions To our knowledge, this is the first analysis from the largest prospective study in BRAF-mutated melanoma pts with BM. The study was carried out in difficult-to-treat pts and in conditions that were close to the real-world setting. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in pts without BM. Regression trees will be presented. Editorial acknowledgement Jone Iriondo-Alberdi (PhD) from ITEC Services. Legal entity responsible for the study Novartis Pharma S.A.S. (France). Funding Novartis Pharma S.A.S. (France). Disclosure C. Dutriaux: Honoraria (self), Advisory / Consultancy: Novartis. C. Robert: Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme ; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Participation to Boards and Steering Committees: Pierre Fabre. J.J. Grob: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Incyte. L. Mortier: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: GSK/Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Leo; Honoraria (self): Sanofi; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Honoraria (self): Merck Serono. C. Lebbe: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Incyte. S. Mansard: Advisory / Consultancy: Novartis. F. Grange: Advisory / Consultancy: Novartis. E. Neidhardt: Honoraria (self): BMS. T. Lesimple: Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: Incyte; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (self): Roche. C. Bedane: Advisory / Consultancy: Novartis. S. Dalac-Rat: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre. C. Nardin: Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme . A. Szenik: Full / Part-time employment: Novartis. A. Denden: Full / Part-time employment: Novartis. P. Saiag: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme ; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche-Genentech; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.

Background Tilsotolimod (IMO-2125) is a Toll-like receptor (TLR) 9 agonist with potent immunostimulating activity. In an ongoing phase I/II clinical study in patients with advanced melanoma who progressed on or after anti-PD-1 therapy (NCT02644967), intratumoral (IT) tilsotolimod with ipilimumab was well-tolerated, demonstrating durable responses (including complete response >21 months), dendritic cell activation, type I interferon response, CD8+ T-cell proliferation in responders, and an abscopal effect.1-2 Trial design ILLUMINATE 301 (NCT03445533) is a randomized phase III global, multi-center, open-label study of IT tilsotolimod (8 mg) in combination with ipilimumab (3 mg/kg) versus ipilimumab monotherapy in patients with advanced melanoma and progression on or after anti-PD-1 therapy. Eligible patients are ≥18 years with histologically confirmed unresectable Stage III or Stage IV melanoma, ≥1 measurable lesion accessible for injection (superficial or visceral, the latter with image guidance), ECOG PS ≤ 1, and adequate organ function. Exclusion criteria include prior TLR agonists, prior ipilimumab (except adjuvant ≥12 weeks before progression), and CNS disease other than stable brain metastases. Patients are randomized 1:1 and stratified by duration of prior antiPD-1 (≥12 weeks vs Clinical trial identification NCT03445533. Editorial acknowledgement Ted Everson, Idera Pharmaceuticals, Inc. Legal entity responsible for the study Idera Pharmaceuticals, Inc. Funding Idera Pharmaceuticals, Inc. Disclosure M.O. Butler: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Immunovaccine; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: Genzyme; Honoraria (self): Roche; Research grant / Funding (self): Takara Bio. C. Robert: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Amgen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Merck Serono. S. Negrier: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. G.K. In: Advisory / Consultancy: Bristol-Myers Squibb. J. Walker: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck Serono; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Merck/MSD. V.G. Atkinson: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck/MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: OncoSec. J. Hansson: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb. E. Kapiteijn: Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Roche. C. Loquai: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Idera. H.M. Shaw: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (institution), Travel / Accommodation / Expenses: Idera; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: Iovance Biotherapeutics. T. Cheng: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD. S. Mansard: Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Pierre Fabre. J.J. Grob: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Merck Serono. M. Mehta: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Array BioPharma; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: MedImmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore.A. Diab: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Nektar; Advisory / Consultancy: CureVac; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Idera; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.

International audience; Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma.

Summary Background BRAF was identified as an oncogene in skin melanoma in 2002, and since 2011 has been a therapeutic target in the treatment of metastatic melanoma. The role of BRAF mutation in tumour initiation and the disease course remains to be elucidated. Objectives The main objective of our study was to determine whether there is a relationship between BRAF status and overall survival in patients with a melanoma and a positive sentinel lymph node. We also sought an association between BRAF status and the clinicopathological features of the melanoma. Finally, we looked for a potential heterogeneity of BRAF status in primary and metastatic tumours. Methods All patients (n = 72) treated for melanoma and with a positive sentinel lymph node at the University Hospital of Clermont-Ferrand, France, between January 2000 and January 2010 were enrolled in the study. We investigated BRAF status in primary melanoma and lymph node metastatic tissue in our molecular pathology laboratory and collected the clinical and survival data. Results Of the 72 patients, 32 had at least one BRAF mutation. There was a statistically significant difference in overall survival between the BRAF-mutated and wild-type populations. The only clinical feature related to BRAF status was metastatic burden. Of the 25 patients in whom we obtained the status in both locations, five had a discordant result. Conclusions BRAF mutation is an indicator of poor prognosis in patients with stage III melanoma with a positive sentinel lymph node. BRAF status could be used in the staging of this population. BRAF has a role not only in cellular immortalization but also in metastatic spread.

Background BRAF and MEK inhibitors dabrafenib (D) and trametinib (T) have transformed BRAFV600-mutant melanoma patients’ (pts) treatment. In a large prospective trial of pts treated with combination D+T, which also included pts with brain metastasis (BM), we assessed factors associated with progression and stratified the population into risk groups using regression tree analysis (RTA). Methods This phase IIIb single arm, open label, multicenter, French study included in 40 centers pts with histologically confirmed unresectable stage IIIc or IV BRAFV600-mutant melanoma. Selection criteria allowed presence of BM, ECOG ≤2, previous advanced melanoma treatments (except BRAFi+MEKi combination). Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modeled with multivariate Cox regression model. Risk subgroups were identified using an exponential RTA. Significance was set at p Results Between March 2015 and November 2016, 914 pts were screened and 856 received at least 1 dose of D+T. Overall, 92% of pts had AJCC stage IV melanoma, 38% ECOG ≥1 and 32% BM. Among the 587 pts with known LDH at baseline, 38% had >ULN. Median PFS was 8.02 months (95%CI, 7.33-8.77). Significant independent factors associated with lower PFS were ECOG ≥1, elevated serum LDH, ≥3 metastatic sites, and presence of BM (Table). Pts with Table . 1338P Multivariate Cox proportional hazards analysis of PFS by prognostic factors - All Subjects Treated Population (N = 856) N (%) HR 95% CI p value LDH at baseline * 366 (42.8) 1 (=reference) - - [1 - 2[ ULN 160 (18.7) 1.64 [1.26 - 2.14] 0.0003 ≥2 ULN 61 (7.1) 2.45 [1.70 - 3.53] Missing 269 (31.4) 1.34 [1.05 - 1.71] 0.0167 ECOG * 0 531 (62.0) 1 (=reference) - - 1 242 (28.3) 1.49 [1.19 - 1.87] 0.0005 ≥2 83 (9.7) 2.32 [1.69 - 3.19] Metastatic sites * 344 (40.2) 1 (=reference) - - ≥3 445 (52.0) 1.61 [1.28 - 2.02] Missing 67 (7.8) 1.05 [0.63 - 1.74] 0.8494 Presence of brain metastasis * No 579 (67.6) 1 (=reference) - - Yes 275 (32.1) 1.38 [1.11 - 1.71] 0.0043 Missing 2 (0.23) - - - * Factors included in the RTA. Conclusions This is to date the largest prospective study in advanced BRAFV600-mutant melanoma pts treated with D+T. The study was carried out in conditions close to the real-world. We confirm findings of registration trials that LDH, ECOG and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor. Editorial acknowledgement Jone Iriondo-Alberdi (PhD) from ITEC Services. Legal entity responsible for the study Novartis Pharma S.A.S. (France). Funding Novartis Pharma S.A.S. (France). Disclosure P. Saiag: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme ; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche-Genentech; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Novartis. C. Robert: Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme ; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Participation to Boards and Steering Committees: Pierre Fabre. J.J. Grob: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Incyte. L. Mortier: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: GSK/Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Leo; Honoraria (self): Merck Serono; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre; Honoraria (self): Novartis. C. Lebbe: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Incyte. S. Mansard: Advisory / Consultancy: Novartis. F. Grange: Advisory / Consultancy: Novartis. E. Neidhardt: Travel / Accommodation / Expenses: BMS. T. Lesimple: Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: Incyte; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (self): Roche. C. Bedane: Advisory / Consultancy: Novartis. S. Dalac-Rat: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre. C. Nardin: Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. A. Szenik: Full / Part-time employment: Novartis. A. Denden: Full / Part-time employment: Novartis. C. Dutriaux: Honoraria (self), Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.

TPS9599 Background: Tilsotolimod (IMO-2125) is a Toll-like receptor (TLR) 9 agonist with potent immunostimulating activity. In an ongoing Phase 1/2 clinical study in patients with advanced melanoma who progressed on or after anti-PD-1 therapy (NCT02644967), intratumoral (IT) tilsotolimod with ipilimumab was well-tolerated, demonstrating durable responses (including complete response > 21 months), dendritic cell activation, type I interferon response, CD8+ T-cell proliferation in responders, and an abscopal effect. Methods: ILLUMINATE 301 (NCT03445533) is a randomized phase 3 global, multi-center, open-label study of IT tilsotolimod (8 mg) in combination with ipilimumab (3 mg/kg) versus ipilimumab monotherapy in patients with advanced melanoma and progression on or after anti-PD-1 therapy. Eligible patients are ≥18 years with histologically confirmed unresectable Stage III or Stage IV melanoma, ≥1 measurable lesion accessible for injection (superficial or visceral, the latter with image guidance), ECOG PS ≤1, and adequate organ function. Exclusion criteria include prior TLR agonists, prior ipilimumab (except adjuvant ≥12 weeks before progression), and CNS disease other than stable brain metastases. Patients are randomized 1:1 and stratified by duration of prior anti-PD-1 (≥12 weeks vs

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.

Introduction L’immunotherapie permet d’allonger la survie globale des patients atteints de melanome avance. Cependant, des effets secondaires severes peuvent survenir notamment des colites inflammatoires justifiant, dans les formes les plus graves, la prescription d’un anti-TNFα. Compte tenu du role potentiellement aggravant des anti-TNF sur les cancers, l’objectif de ce travail etait d’etudier l’incidence de ces colites en vie reelle et l’impact des anti-TNF sur le pronostic. Materiel et methodes Il s’agit d’une etude retrospective multicentrique recueillant les caracteristiques des melanomes traites par anti-TNFα pour colite severe sous immunotherapie. L’incidence etait calculee a partir du recueil exhaustif des delivrances d’inhibiteurs de check point par les pharmacies hospitalieres de chaque centre. L’impact etait mesure par l’etude de la survie globale, survie sans progression et du taux de reponse objective. Resultats Vingt-cinq patients provenant de 13 centres etaient inclus (sex-ratio 0,92, âge moyen 65 ans). Le melanome etait en stade IVM1c dans 72 % des cas ; 3 patients etaient porteurs d’une mutation BRAF, 1 d’une mutation cKIT et 9 (36 %) d’une mutation NRAS. Deux mille six cent deux malades avaient recu une immunotherapie. Les colites severes justifiant un traitement par anti-TNFα (grade 3/4 en echec de la corticotherapie generale) survenaient chez 0,96 % des patients. Elles etaient observees majoritairement avec l’ipilimumab en 1 re ligne ( n = 14) ou apres echec d’un anti-PD1 ( n = 3) et avec l’association ipilimumab + nivolumab ( n = 4). Toutes molecules confondues, elles survenaient en moyenne apres 2 mois de traitement. Tous les patients avaient recu une corticotherapie generale puis un traitement par infliximab a la dose de 5 mg/kg. Dans 64 % cas, une reponse complete sur la colite etait obtenue apres une seule injection. La mediane de survie globale apres immunotherapie etait de 12 mois et la mediane de survie sans progression de 3 mois. Le taux de reponse objective a 6 mois etait de 36 %. Discussion Dans la litterature, les colites grade 3/4 sont observees chez 1 a 2 % des patients sous anti-PD1 et 3 a 11 % des patients sous ipilimumab seul ou en association. Cette etude apporte, pour la premiere fois, des donnees en vie reelle. Les resultats montrent une incidence faible de ces colites severes. Comme attendu, elles sont surtout liees a l’ipilimumab (84 %). Cette toxicite doit etre prise en charge precocement par corticotherapie generale. En cas d’echec, l’infliximab est rapidement efficace. Les taux de reponses observes sous immunotherapie dans ce groupe de malades sont comparables a ceux observes dans les etudes pivots. Le traitement par anti-TNFα ne semble pas modifier le pronostic. Conclusion Il n’existe pas de facteur predictif de survenue de ces colites severes. Les patients a risque doivent etre mieux identifies. L’infliximab peut etre utilise en securite dans cette indication.

Introduction Les inhibiteurs de point de controle (checkpoint) immunitaire, en inhibant des molecules immunosuppressives surexprimees dans l’environnement tumoral comme CTLA4 ou PD1, augmentent la reponse immunitaire anti-tumorale, mais au risque d’effets secondaires auto-immuns (ESAI). Les patients atteints de maladie auto-immune (MAI) ont donc ete exclus des essais cliniques testant ces molecules. Le but de cette etude est d’evaluer leur securite d’emploi en pratique courante chez les patients atteints de MAI pre-existante, ainsi que la reponse anti-tumorale dans cette population. Materiel et methodes Il s’agit d’une etude retrospective multicentrique nationale, realisee grâce a la collaboration du groupe de cancerologie cutanee (GCC), du groupe francais de pneumo-cancerologie (GFPC) et du club rhumatisme et inflammation (CRI). Resultats Parmi les 31 patients inclus (19 hommes (61 %), âge median 66 ans), les MAI les plus frequentes etaient la PR (n = 9 ; 29 %), le psoriasis (n = 6 ; 19 %), le lupus (n = 4 ; 13 %), la RCH (n = 3 ; 10 %) et la SpA (n = 3 ; 10 %). 11 patients (35 %) etaient sous traitement immunosuppresseur au debut de l’immunotherapie, 10 avaient une maladie consideree active. Les types de cancers etaient des melanomes (n = 16 ; 52 %), des cancers pulmonaires non a petites cellules (n = 12 ; 39 %) et des cancers urologiques (n = 3 ; 9 %), avec une duree mediane d’evolution de 19 mois. La majorite des patients (30/31) ont recu un anti-PD1, pour une duree mediane de 4 mois. Les poussees de MAI sous immunotherapie etaient frequentes (n = 18 ; 58 %) mais moderees pour la plupart, CTCAE grade 1–2 (n = 12 ; 67 %), grade 3–4 (n = 3 ; 17 %). Pour ces poussees, 14 patients (78 %) ont recu des corticoides ou AINS, et 3 (17 %) du methotrexate ou acitretine. Des effets secondaires auto-immuns sans lien avec la MAI sont apparus chez 10 patients (32 %) : arthralgies (n = 5), colite (n = 2), thyroidite (n = 2) et vitiligo (n = 2), de severite moderee egalement. Aucun patient n’a recu d’anti-TNF, autant pour une poussee de MAI que pour un ESAI autre. L’immunotherapie a ete stoppee chez 5 patients pour effet secondaire immunologique. Concernant le taux de reponse du cancer, 4 patients sur 11 sous immunosuppresseurs etaient repondeurs (36 %) contre 12 des 20 autres patients (60 %). Discussion Les poussees de MAI sous immunotherapie sont frequentes. Des ESAI autres sont aussi possibles, controlables sous corticotherapie seule. La reponse anti-tumorale pourrait etre moindre lorsqu’il existe un traitement immunosuppresseur au debut de l’immunotherapie, dans la limite du faible effectif de l’etude. Conclusion La tolerance des immunotherapies chez les patients atteints de MAI semble donc acceptable, mais un suivi multidisciplinaire avec le medecin referent de la MAI semble approprie.

Purpose To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS). Patients and Methods Thirty-six patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated. Results Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes. Conclusion As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.

The relationships of pregnancy and melanoma have been debatable. Our aim was to assess the influence of gestation on the course of melanoma in a classic murine model of tumor progression and in women. B16 mouse melanoma cells were injected in nonpregnant or pregnant mice on day 5 of gestation. Animals were evaluated for tumor progression, metastases, and survival. Tumor sections were analyzed for lymphatic and blood vessel number and relative surface and expression of angiogenic growth factors. Finally, primary melanomas from pregnant and nonpregnant women, matched for age and tumor thickness, were also considered. Tumor growth, metastasis, and mortality were increased in B16-injected pregnant mice. Tumors displayed an increase in intratumoral lymphangiogenesis during gestation. This increased lymphatic angiogenesis was not observed in normal skin during gestation, showing its specificity to the tumor. An analysis of melanoma from pregnant and matched nonpregnant women showed a similar increase in lymphatic vessels. Tumors from pregnant mice had increased expression of vascular endothelial growth factor A at the RNA and protein levels. The increased vascular endothelial growth factor A production by melanoma cells could be reproduced in culture using pregnant mouse serum. In conclusion, pregnancy results in increased lymphangiogenesis and subsequent metastasis. Caution should be applied in the management of patients with advanced-stage melanoma during gestation.

e21598Background: Nivolumab was the first anti-PD1 therapy to receive a European marketed authorization for the treatment of advanced (unresectable or metastatic) melanoma. To collect and evaluate ...

Resume Introduction La valeur pronostique de la presence de signes histologiques de regression dans la tumeur primitive de melanome est discutee. Objectif Determiner s’il existe une association entre la presence de signes de regression dans la tumeur primitive de melanome et la presence de micrometastases ganglionnaires. Malades et methode Il s’agissait d’une etude monocentrique, retrospective, portant sur 84 tumeurs primitives de melanome d’epaisseur superieure a 1 mm et le ganglion sentinelle correspondant. L’analyse des signes de regression a ete effectuee par deux examinateurs independants. L’indice de Breslow, l’âge, le sexe, la localisation du melanome ont ete notes pour chaque tumeur. Resultats Parmi les 84 melanomes etudies, 40 avaient des signes de regression et 24 etaient associes a des micrometastases ganglionnaires. Parmi ces derniers, seules 10 avaient des signes de regression. Il n’y avait pas d’association entre signes de regression et micrometastases (RR = 0,5 ; p = 0,5). Seuls un indice de Breslow superieur a 2 mm (RR = 4,6, p = 0,03) et le sexe masculin (RR = 7,6, p = 0,006) apparaissaient comme predictifs de l’atteinte du ganglion sentinelle. En analyse multivariee, ces deux derniers facteurs etaient independants avec, pour RR respectifs 3,2 (IC95 p. 100 : 1,1-9,1.) et 4,6 (IC95 p. 100 : 1,5-13,8.). Discussion Ces resultats suggerent qu’il n’y a pas une forte association entre la regression au sein de la tumeur primitive et la presence d’une micrometastase dans le ganglion sentinelle. Ils confirment que l’indice de Breslow est significativement predictif de la presence de micrometastases.

Resume Introduction La dermatose pustuleuse erosive des jambes est une entite recemment decrite, rare, d’etiologie inconnue touchant les sujets âges. Elle se caracterise par des erosions symetriques des jambes resultant de la confluence de pustules steriles survenant, le plus souvent, apres un traumatisme minime. Le traitement par dermocorticoides est rapidement efficace mais il n’est pas codifie et les rechutes sont frequentes. Observations Trois malades âges respectivement de 74, 84 et 92 ans avaient des erosions des jambes et des chevilles associees a des pustules en peripherie apparues a la suite d’un traumatisme minime. Il s’agissait de pustules steriles d’aspect spongiforme a l’examen histologique. Aucun n’avait d’antecedent de psoriasis. Tous avaient une carence en zinc. Un traitement par dermocorticoides associe a du gluconate de zinc oral a permis, pour deux des malades, une resolution totale en quelques jours et a ete efficace lors d’une rechute chez le troisieme. Discussion La dermatose pustuleuse erosive des jambes est une dermatose benigne vraisemblablement de frequence sous-estimee a integrer dans le cadre des dermatoses neutrophiliques inflammatoires. Nos observations suggerent le role declenchant ou favorisant de la carence en zinc.

Resume Introduction Les melanomes du penis sont des tumeurs rares et de mauvais pronostic. Methodes Six cas de melanome du penis repertories entre 1975 et 2002 ont ete etudies retrospectivement. Nous avons recueilli les donnees cliniques, anatomopathologiques, epidemiologiques, les antecedents, ainsi que les traitements et l’evolution. Resultats L’âge moyen des malades etait de 44 ans. Le delai jusqu’au diagnostic etait de 2 ans. Deux malades avaient des facteurs favorisants generaux et 3 malades des facteurs favorisants locaux de melanome. Deux malades ont eu une penectomie partielle, les 4 autres un traitement conservateur. Un malade a eu une recidive locale, un malade a eu des metastases entrainant le deces. Cinq malades sur 6 etaient en vie et en remission au moment de l’etude avec un delai moyen de 24 mois. Discussion Les seuls facteurs de risque connus de melanome du penis sont les melanoses et les naevus preexistants. Le pronostic est habituellement mauvais en raison du retard au diagnostic. Le traitement chirurgical classique est radical, mais les techniques conservatrices sont actuellement proposees. A titre de depistage, l’exerese des melanoses peniennes operables parait indiquee et toute lesion atypique du penis doit etre biopsiee.

Summary There is a growing body of evidence to support the efficacy of topical imiquimod in the treatment of primary skin carcinomas. Conflicting data exist concerning the use of imiquimod for the treatment of skin melanoma metastases. To date, only the impact of imiquimod on cytokines involved in immunological processes has been studied extensively. We report a woman successfully treated with imiquimod (once daily for 8 weeks) for skin melanoma metastases in whom we investigated the expression of molecules involved in metastasis and angiogenesis. Before and after treatment, a skin lesion was biopsied and the expression of the following molecules was investigated using real-time reverse transcription–polymerase chain reaction: matrix metalloproteinase (MMP)-1, 2 and 9 and their inhibitors KiSS-1 and tissue inhibitor of metalloproteinase (TIMP)-1, vascular endothelial growth factor (VEGF), fibroblast growth factor-2, and angiogenesis inhibitors (thrombospondin-1 and 2). Interferon (IFN)-α was also investigated as an in vivo marker of imiquimod activity. IFN-α was upregulated by the treatment. Under imiquimod, the following molecules were upregulated: TIMP-1, KiSS-1 and MMP-1. MMP-2 expression was not modified. MMP-9 expression was dramatically decreased. The expression of angiogenesis inhibitors was slightly increased but VEGF expression remained at a basal level. These results suggest that imiquimod could downregulate metastasis invasion and angiogenesis. However, these data were obtained at a transcriptional level and from a single case, and further investigations should include migration assays and additional cases in order to confirm that imiquimod may be safely used for treatment of melanoma metastases.

Psoriasis has a chronic and relatively benign course. However, severe complications are possible. One rare complication is acute interstitial pneumonitis. This entity should be suspected when a patient presents with dyspnoea and high fever. Knowledge of this pathology is crucial, for although it is essential to rule out aetiologies requiring specific management such as microbial infection or drug-related syndromes, diagnosis should not be delayed as its severe clinical course is improved by corticosteroids. We report two patients with an acute respiratory distress syndrome arising during the course of pustular psoriasis. Repeated bacteriological testing in lungs and blood remained negative. In both cases lung involvement was severe, requiring artificial ventilation. Dramatic clinical resolution was obtained by using corticosteroids. Besides infectious causes and drug hypersensitivity to methotrexate or acitretin, acute respiratory distress syndrome, sometimes due to a pulmonary capillary leak syndrome, is a rare cause of pneumonitis in the course of psoriasis, and may be fatal. Its pathogenesis is unknown. However, animal models suggest a role for T-helper (Th) 1 lymphocytes, known to be activated in psoriasis, and a role for tumour necrosis factor-alpha, a major Th1 cytokine, in alveolar damage.

Introduction Les therapies ciblees et immunotherapies ont bouleverse la prise en charge des patients atteints de melanome avance. Neanmoins, les reponses sont encore inconstantes et transitoires du fait de resistances primaires ou secondaires. La necessite de decouvrir de nouveaux traitements reste pleinement d’actualite. Materiel et methodes A partir de donnees preliminaires fondamentales suggerant un effet in vitro de la metformine sur des lignees cellulaires de melanome, nous avons voulu evaluer de facon prospective et multicentrique l’efficacite et la tolerance de la metformine per os (1g 3 × /jour) chez des patients atteints de melanome avance en echec d’au moins un traitement type chimiotherapie, inhibiteur de BRAF (BRAFi) ou ipilimumab. L’evaluation tumorale etait faite selon les criteres Recist 1.1 et l’analyse de survie selon la methode de Kaplan-Meier. Resultats Dix-sept patients etaient inclus, avec un âge median de 74 ans (49–88). Les caracteristiques de la population sont detaillees dans le Tableau 1. Le taux de reponse (critere principal, reponse complete [RC] + reponse partielle [RP]) a 6 mois etait de 0 %. L’evaluation a M6 n’etait realisee que chez 1 patient. Pour les autres, il etait observe avant le 4e mois, 11 progressions, 3 deces dus a une progression et 2 interruptions de traitement dues a des effets indesirables (EI). Parmi les criteres secondaires, le meilleur taux de reponse globale etait de 5,9 % (95 CI, 0,3–30,8, methode de Wilson), la survie globale de 72,5 % (95 CI, 32,0–91,5), le taux de survie sans progression a M6 de 6,25 % (95 CI, 0,41–24,7) et la mediane de 1,94 mois. Parmi les EI rencontres (61 EI), les plus frequents etaient la diarrhee (16,4 %), les nausees (13,1 %) et la fatigue (9,8 %). Les EI de grade 3–4 concernaient 11,8 % des patients. Aucun deces lie au traitement n’etait observe. La moitie des EI ont ete consideres comme possiblement lies au traitement (Fig. 1). Discussion Il s’agit de la premiere etude prospective evaluant l’effet de la metformine chez des patients atteints de melanome metastatique. Malheureusement, les resultats sont negatifs et montrent l’absence d’efficacite de la metformine dans cette indication, du moins a cette dose et per os. D’autre part, le profil de tolerance peut aussi constituer un frein a son utilisation. Neanmoins, le rationnel scientifique a son utilisation avec de bons resultats in vitro incite a ne pas abandonner cette piste. Un derive avec une meilleure biodisponibilite et/ou son utilisation par voie intraveineuse permettraient peut-etre d’observer en clinique des resultats similaires et aussi encourageants que ceux observes in vitro. Par ailleurs, l’effet synergique avec les BRAFi demontre in vitro constitue egalement un axe de recherche particulierement interessant. Conclusion La metformine per os en monotherapie n’est pas une bonne alternative therapeutique chez les patients atteints de melanome avance. Son interet devrait etre etudie en association avec les inhibiteurs de kinases.

Resume Les reactions cutanees d’hypersensibilite retardee aux heparines, longtemps confondues avec les necroses cutanees au site d’injection sont actuellement bien individualisees. Nous rapportons une serie de 9 cas ayant presente des manifestations cutanees sous traitement heparinique. L’exploration allergologique de chacun des patients a permis un diagnostic positif et a montre l’importance des reactions croisees entre les differentes heparines mais aussi les heparinoides. Cette etude met en evidence l’interet et les limites des tests allergologiques. Bien conduits, ils permettent de proposer des alternatives therapeutiques en cas de necessite d’un traitement anticoagulant urgent ou a venir, ce d’autant plus que ce type d’hypersensibilite semble se perenniser dans le temps.

International audience; The prognostic value of the sentinel lymph node in Merkel cell carcinoma (MCC) has been examined previously in heterogeneous retrospective studies. The current retrospective study included a homogeneous population of patients with a localized MCC, all staged with sentinel lymph node biopsy. Factors associated with 3-year progression-free survival were analysed using logistic regression. The sentinel lymph node was positive in 32% of patients. The recurrence rate was 26.9%. In first analyses (n = 108), gender (p = 0.0115) and the presence of immunosuppression (p = 0.0494) were the only significant independent factors. In further analyses (n = 80), excluding patients treated with regional radiotherapy, sentinel lymph node status was the only significant prognostic factor (p = 0.0281). Immunosuppression and positive sentinel lymph node are associated with a worse prognosis in patients with MCC. Nodal irradiation impacts on the prognostic value of the sentinel lymph node status.

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-...

Background Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. Objective We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). Methods We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. Results The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Limitations The study was not population based. Conclusions This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.