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Introduction L’immunotherapie est une avancee majeure dans le traitement du melanome metastatique mais la recherche de biomarqueurs predictifs de son efficacite est necessaire. Une charge mutationnelle elevee serait un marqueur de bonne reponse aux anti-PD-1. Le programme Experience FoundationOne® (partenariat CHU-Roche®) propose un sequencage de nouvelle generation par NGS avec un panel de 315 genes et de 28 introns, afin de determiner le profil genomique de la tumeur. Nous rapportons l’analyse de la charge mutationnelle (tumor mutational burden [TMB], exprimee en nombre de mutations par megabase d’ADN sequence) et la reponse a l’immunotherapie de patients inclus dans 2 services hospitalo-universitaires. Materiel et methodes Etude prospective de la TMB et de la reponse aux immunotherapies dans 32 cas de melanomes sequences par NGS avec le test FoundationOne® a partir d’un prelevement inclus en paraffine. La TMB etait consideree comme basse entre 1 et 5 mutations par megabase (Muts/Mb), intermediaire entre 6 et 19 et eleve a partir de 20 Muts/Mb. Les cas selectionnes etaient prioritairement ceux non mutes pour les cibles theranostiques habituelles (BRAF, NRAS et KIT), afin d’identifier de nouvelles possibilites therapeutiques. Resultats Les melanomes de 32 patients âges de 24 a 85 ans ont ete inclus dans le programme d’octobre 2017 a mai 2018. Trois sequencages (9 %) etaient non contributifs du fait de la mauvaise qualite de l’ADN extrait. Parmi les 8 patients avec une TMB elevee (28 % de la cohorte analysable), 5 recevaient un traitement par anti-PD-1 avec une reponse partielle ou complete pour 4 (80 %) (TMB [25–60]) et une stabilite pour un (TMB = 20 Muts/Mb). Tous les melanomes choroidiens (n = 3) avaient une TMB basse et n’ont repondu ni aux anti-PD-1 ni a l’anti-CTLA-4. Un patient avec une TMB basse (melanome acrolentigineux ; 2 Muts/Mb) a eu une reponse spectaculaire et immediate a l’ipilimumab apres avoir progresse sous anti-PD-1 et radiotherapie ( Tableau 1 ). Discussion Nos donnees confirment que la TMB est tres variable dans le melanome et sont en accord avec Goodman et al. qui ont analyse retrospectivement la TMB de 1638 patients et montre une association etroite et independante entre reponse a l’immunotherapie et TMB elevee versus intermediaire et basse (58 % vs 20 %, p = 0,0001). Dans notre cohorte un seul patient avec une TMB basse a presente une reponse spectaculaire a l’ipilimumab. Il avait recu prealablement une radiotherapie sur une masse ganglionnaire axillaire qui pourrait avoir favorise de cette reponse. Conclusion L’analyse de la TMB a permis de mettre en evidence des profils differents chez nos patients avec des reponses differentes a l’immunotherapie. Dans le contexte actuel ou le choix therapeutique de la 1re ligne est primordial en particulier chez les patients BRAF sauvage, l’analyse de la TMB pourrait etre un indicateur dans la decision du clinicien, a developper en pratique courante.

Introduction Le melanome metastatique a connu des avancees therapeutiques majeures depuis 2011, avec la mise sur le marche des immunotherapies et des therapies ciblees. Notre objectif etait de decrire, a partir du systeme national des donnees de sante de l’Assurance maladie (SNDS-SNIIRAM), l’evolution de la prise en charge du melanome metastatique sur la periode 2010–2016. Materiel et methodes Les cas incidents de melanome metastatique traites, en France entre 2010 et 2016, ont ete identifies. Nous avons compare les parcours et le devenir des patients initiant une premiere ligne de traitement systemique en 2011, 2013 ou 2015. Les sequences therapeutiques ont ete decrites avec des diagrammes de Sankey. La survie globale (date de point : 31 decembre 2017) a ete analysee par la methode de Kaplan–Meier. Resultats Parmi 8956 cas incidents de melanome metastatique, 3157 patients etaient traites par therapie ciblee, 2009 par ipilimumab et 3138 par anti-PD1. Le recours a la chimiotherapie diminuait de facon continue sur la periode, au fur et a mesure de la disponibilite des nouveaux traitements. La comparaison des parcours des patients initiant une prise en charge en 2011, 2013 ou 2015 objectivait des differences majeures. La survie globale etait amelioree pour les patients dont le traitement avait debute en 2015 (survie globale a 2 ans : 48 %, IC95 % [0,46 ; 0,50] versus 40 % [0,37 ; 0,43] pour les patients debutant une 1re ligne de traitement en 2011) ( Fig. 1 ). Discussion Les donnees de l’Assurance maladie permettent de decrire les evolutions en « vie reelle », de facon exhaustive a l’echelle nationale, et sans perdu de vue. Meme si les donnees cliniques ne sont pas disponibles (caracteristiques du melanome, rechute, etc.), les traitements le sont de facon detaillee ; les sequences therapeutiques et le deces permettent d’evaluer la prise en charge et le pronostic. Il n’existe pas de donnees equivalentes dans un autre pays. Cette etude est toutefois restreinte aux melanomes traites, population non parfaitement superposable a l’ensemble des stades IV. Par ailleurs, au sein d’un parcours individuel, les periodes d’essais cliniques ne sont pas facilement identifiables. Conclusion Ce travail objective les changements majeurs de la prise en charge du melanome metastatique et permet de quantifier l’amelioration de la survie globale, en « vie reelle », a l’echelle nationale.

9520Background: Brain metastasis commonly occur in patients with metastatic melanoma (MM) and are managed with surgery or stereotactic radiosurgery (SRS) and/or systemic treatment based on BRAF sta...

e21536Background: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since more than 50% of melanoma arise in > 65 years-old (yo). Combined BRAF and MEK targeted...

Purpose Thymosin α 1 (Tα1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Tα1 with dacarbazine (DTIC) and interferon alfa (IFN-α) in patients with metastatic melanoma. Patients and Methods Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-α+Tα1 (1.6 mg); DTIC+IFN-α+Tα1 (3.2 mg); DTIC+IFN-α+Tα1 (6.4 mg); DTIC+Tα1 (3.2 mg); DTIC+IFN-α (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months. Results Ten and 12 tumor responses were observed in the DTIC+IFN-α+Tα1 (3.2 mg) and DTIC+Tα1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P0 ≤ .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Tα1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Tα1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Tα1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Tα1 to DTIC and IFN-α did not lead to any additional toxicity. Conclusion These results suggest Tα1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.

The master regulator of the melanocyte lineage Mitf is intimately involved in development as well as melanoma, controlling cell survival, differentiation, proliferation and metastasis/migration. Consistent with its central role, Mitf expression and Mitf post-translational modifications are tightly regulated. An additional potential level of regulation is afforded by differential splicing of Mitf exon-6 leading to the generation of two isoforms that differ by the presence of six amino-acids in the Mitf (+) isoform and which have differential effects on cell cycle progression. However, whether the ratio of the two isoforms is regulated and whether their expression correlates with melanoma progression is not known. Here, we show that the differential expression of the Mitf 6a/b isoforms is dependent on the MAPKinase signalling, being linked to the activation of MEK1-ERK2, but not to N-RAS/B-RAF mutation status. In addition, quantification of Mitf 6a/b splicing forms in 86 melanoma samples revealed substantially increased levels of the Mitf (-) form in a subset of metastatic melanomas. The results suggest that differential expression of the Mitf 6a/b isoforms may represent an additional mechanism for regulating Mitf function and melanoma biology.

Object In this article, the authors report their experience in the management of adult patients with medulloblastoma at their institution to identify prognostic factors important for survival and disease control. Methods Between 1977 and 2005, 27 patients who were ≥ 16 years old and had medulloblastoma were treated consecutively. There were 16 women and 11 men with a median age of 21 years (range 16–54 years). Gross-total resection was performed in 21 patients, subtotal (≥ 90%) in 2, incomplete in 1, and biopsy in 3 patients. Six patients had the desmoplastic variant, and 21 patients presented with classic medulloblastoma. Staging according to the Chang classification showed 4 patients with tumors invading the brainstem (2 with Stage T3b and 2 with Stage T4), 3 patients with metastases (2 with Stage M2 and 1 with Stage M3), and 1 patient in whom the stage was unknown (Stage MX) who died 10 days postoperatively. Twenty patients were assigned to the standard-risk group and 7 to the high-risk group. All patients except the one whose status was classified as Stage MX underwent craniospinal radiotherapy at our institution. Seven patients received chemotherapy before radiotherapy. Results The 5- and 10-year overall survival rates for the present study were 81 and 62%, respectively. The median overall survival time was 17.7 years. The 5- and 10-year event-free survival rates were 72 and 57%, respectively. The median event-free survival time was 17.9 years. Univariate analysis showed that survival was significantly correlated with sex (women had a better prognosis than men) and M stage (patients without metastases had a better outcome). Patient age, duration of symptoms, Karnofsky Performance Scale score at presentation, hydrocephalus, tumor location, brainstem invasion, extent of resection, histological subtype, preradiotherapy chemotherapy, risk group, and period of presentation were not significant variables. Multivariate analysis identified sex and M stage as well as the period of presentation as independent prognostic factors for overall and event-free survival times. Eleven patients suffered tumor recurrence within a median time of 4.2 years. The posterior fossa was not the most common site of recurrence, and delayed recurrence was not rare. All patients in whom the tumor recurred have died despite aggressive treatments. The median survival time after diagnosis of recurrence was 2.5 years. Questionnaires on quality of life and cognition showed high scores in favor of limited negative effects in the perception of mental and physical health after treatment. The authors observed 1 supposed second malignancy (thyroid carcinoma) and no evidence of pituitary dysfunction. Conclusions Long-term survival is possible in adults treated for medulloblastoma. Although rare, metastasis seeding at presentation is a poor prognostic factor. The possibility of delayed recurrence necessitates close follow-up of all patients. Tumor recurrences should be treated with aggressive therapies as some patients may have sustained response. Adjuvant chemotherapy should be given to high-risk patients, but its role in reducing recurrences, particularly distant ones, remains unclear in the standard-risk group.

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.

Merkel cell carcinoma (MCC) are rare neuroendocrine malignant tumor of the skin, occurring in elderly patients. It affects primarily the sun-exposed areas of the skin, with approximately 50% of all tumors occurring in the face and neck and 40% in the extremities. Immunohistochemical markers (CK20+, CK7- and TTF1-) are used to distinguish between MCC and other tumors. MCC have a tendency to rapid local progression, frequent spread to regional lymph nodes and distant metastases. Due to the rarity of the disease, the optimal treatment has not been fully defined. Localized stages (stages I and II) are treated by surgical excision of the primary tumor (with 2 to 3 cm margin) and lymphadenectomy in case of node-positive disease, followed by external beam radiotherapy (EBRT) to a total dose of 50 to 60Gy in the tumor bed. Adjuvant EBRT has been shown to decrease markedly locoregional recurrences and to increase survival in recent studies. Treatment of lymph nodes area is more controversial. Chemotherapy is recommended only for metastatic disease.

Malignant melanoma of soft parts (MMSP) (or "clear cell sarcoma") is a very rare tumour that shows up without primitive skin involvement (except in subcutaneous prolongations of deep tumours), mostly predominant in the extremities of young adults. Eight files of MMSP were studied retrospectively. The mean patient is a male of 35 years old affected in an extremity (four upper, three lower and one gluteal), according to classical descriptions. The importance of radical surgery in these cases has been extensively established. Confronted with these cases, the plastic surgeon must be aware of the specifics of this rare entity to ensure its proper inclusion in his clinical suspicion. Just in case.

Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results.

Contexte La validite des recommandations repose sur leur actualisation au meme titre que sur la rigueur du developpement initial. Dans ce contexte, les Standards, options et recommandations (SOR) de la Federation nationale des centres de lutte contre le cancer (FNCLCC) ont mis en place un programme de veille dont l’objectif est de surveiller l’appartition de nouvelles donnees.

The purpose of this study was to investigate the biodistribution of mature dendritic cells (DCs) injected by various routes, during a cell therapy protocol.In the context of a vaccine therapy protocol for melanoma, DCs matured with Ribomunyl and interferon-gamma were labelled with( 111)In-oxine and injected into eight patients along various routes: afferent lymphatic vessel (IL) (4 times), lymph node (IN) (5 times) and intradermally (ID) (6 times).Scintigraphic investigations showed that the IL route allowed localisation of 80% of injected radioactivity in eight to ten nodes. In three cases of IN injection, the entire radioactivity stagnated in the injected nodes, while in two cases, migration to adjacent nodes was observed. This migration was detected rapidly after injection, as with IL injections, suggesting that passive transport occurred along the physiological lymphatic pathways. In two of the six ID injections, 1-2% of injected radioactivity reached a proximal lymph node. Migration was detectable in the first hour, but increased considerably after 24 h, suggesting an active migration mechanism. In both of the aforementioned cases, DCs were strongly CCR7-positive, but this feature was not a sufficient condition for effective migration. In comparison with DCs matured with TNF-alpha, IL-1beta, IL-6 and PGE2, our DCs showed a weaker in vitro migratory response to CCL21, despite comparable CCR7 expression, and higher allostimulatory and TH1 polarisation capacities.The IL route allowed reproducible administration of specified numbers of DCs. The IN route sometimes yielded fairly similar results, but not reproducibly. Lastly, we showed that DCs matured without PGE2 that have in vitro TH1 polarisation capacities can migrate to lymph nodes after ID injection.

Introduction Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. Methods The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. Results Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR-Lin- cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR-Lin- cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid. Conclusion These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest.

Contains fulltext : 49133ravic.pdf (Publisher’s version ) (Closed access) E7070 is a synthetic chloro-indolyl sulphonamide that is being developed as an anti cancer agent. In this phase II study, 28 patients with metastatic melanoma received 700 mg/m(2) of E7070 as a 60-min infusion repeated every 3 weeks. Although therapy was well tolerated, with one patient receiving 14 courses of treatment, there were only minor responses on independent radiological review. E7070 does not warrant further development as a single agent for the treatment of metastatic melanoma.

Epithelioid hemangioendothelioma (EHE) is an uncommon vascular neoplasm. Its intracranial occurrence is rare, and the literature review revealed only 23 cases (14 adults and 9 children). To our knowledge, this is the first case of EHE arising in the infundibular-hypothalamic region. A 53-year-old man presented with headaches and loss of libido. Magnetic resonance imaging revealed a supra-sellar mass, which homogeneously absorbed the contrast agent. A trans-sphenoidal craniotomy and a biopsy were performed. Adjuvant radiotherapy was administered due to intolerance to interferon. Epithelioid hemangioendothelioma is a hemorrhagic tumor. Total resection is mandatory where possible, otherwise radiotherapy seems necessary. The prognosis of intracranial location has not yet been well defined, despite the favorable outcome noted in the majority of cases.

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m 2 twice daily, days 1–14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0–6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20–36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5–19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatmentrelated grade 3/4 adverse events. The most common adverse events were hand–foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting. # 2003 Elsevier Ltd. All rights reserved.

The objective of this study was to examine and compare two core measures of Quality Of Life (QOL) used in cancer clinical trials: the European Organisation for Research and Treatment of Cancer QOL Core Questionnaire 30 (EORTC QLQ-30) and the Functional Assessment of Chronic Illness Therapy (FACIT), in order to identify which one patients have the strongest preference for using. 68 patients suffering from Carcinomas of an Unknown Primary site (CUP) were recruited in a multicentric study; all of them completed both questionnaires, administered in a randomised manner. The criteria were the percentage of preferences, and four indicators of acceptability. The results indicated that an equal proportion of patients preferred the QLQ-C30 (19%) and FACIT (19%). 54% of patients felt both questionnaires were acceptable. All the indicators of acceptability favoured the QLQ-C30. Analysis of open-ended questions shed light on the difficulties encountered by the patients. As no significant preference was observed for one of the questionnaires, the QLQ-C30 was chosen on the basis of its significantly better acceptability criteria.

Introduction Immunotherapies (I) et therapies ciblees (TC) ont bouleverse le pronostic du melanome metastatique et s’evaluent actuellement en adjuvant (prise en charge de la maladie micrometastatique). Ceci repose sur le concept tres debattu que les cellules dormantes des micrometastases aient un « statut biologique » (proliferation/immunogenocite du microenvironnement) comparable a la macrometastase. Ainsi, un lien fort devrait exister entre le delai exerese du primitif-recidive a distance et la survie, ce que suggerent 2 etudes (Karakousis ; Balch, 1983). Nous avons souhaite explorer cette hypothese dans le cadre de la cohorte MelBase. Materiel et methodes MelBase est une base nationale clinicobiologique prospective ( n = 914). Les donnees de 206 patients traites en 1 e ligne par I (gA) ou TC (gB) ont ete extraites (31/12/2015). L’analyse porte sur la survie sans progression (PFS) en fonction du delai de rechute en variable continue (VC) ou dichotomisees en 2 classes (inferieur/superieur ou egal a 24 mois). Sont exclus les patients de primitif inconnu, d’emblee metastatique. L’association entre le delai de rechute et la PFS a ete analysee par des modeles de Cox et les resultats exprimes en termes de rapport des risques instantanes (HR). Resultats Dans gA : pour le delai (VC, en annees) : HR 0,996 (IC95 % 0,943–1,051) ; pour un delai superieur ou egal a 24 mois : HR 0,97 (IC95 % 0,66–1,43). Dans gB : pour le delai (VC, en annees) : HR 0,996 (IC95 % 0,953–1,042) ; pour un delai superieur ou egal a 24 mois : HR 1,28 (IC95 % 0,71–2,28). Discussion Ces premiers resultats ne montrent pas d’association entre les delais exerese : 1 e rechute a distance (divise en 2 classes inferieur/superieur ou egal a 24 mois) et la PFS au j1 de traitement pour les patients traites par I ou TC en 1 e ligne. Le meme resultat est retrouve en prenant le delai entre exerese-rechute a distance (donnees non montrees). Nous souhaitons confirmer ces donnees par une analyse poolee mais stratifiee sur le type de strategie therapeutique et la valeur de l’indice de Breslow. Conclusion Nos donnees ne montrent pas de lien entre le temps de « dormance » de la maladie micrometastatique et la cinetique evolutive metastatique. Il est possible que notre etude manque de puissance. Neanmoins, nos resultats confortent des donnees recentes (cancer du sein), suggerant que la progression de l’etat de dormance a la maladie metastatique evolutive n’est pas lineaire mais depend d’evenements genetiques ou immunologiques secondaires modifiant l’etat de quiescence cellulaire et/ou l’equilibre croissance/apoptose (Willis, 2013). De telles approches sont importantes pour la reflexion sur les futurs traitements adjuvants.

Introduction Les anticorps anti-PD1 (APD) ont bouleverse la prise en charge du melanome metastatique, permettant d’obtenir une mediane de survie superieure a 24 mois. Cependant, la PFS a 2 ans est d’environ 30 %, traduisant un echappement chez beaucoup de patients pour lesquels il existe aujourd’hui peu de donnees demographiques et de reponse aux strategies ulterieures. C’est le but de ce travail effectue a partir de la cohorte MelBase. Materiel et methodes MelBase, base de donnees clinicobiologique labellisee INCA (25 centres), est dediee au suivi prospectif de patients avec melanome avance naifs de tout traitement systemique non adjuvant. Depuis mars 2013, 914 ont ete inclus. Les donnees de 195 patients traites par APD au 31/12/15 ont ete extraites (06/06/16) parmi lesquels 36 patients ont echappe apres avoir ete controles (reponse complete, partielle, stable) par les APD. Leurs donnees ont ete analysees a l’initiation des APD (g1, n = 36) et a l’echappement (g2, n = 36) en termes demographique, de strategies therapeutiques apres progression et de survie. Resultats Les donnees demographiques sont presentees dans le Tableau 1. On note, comme attendu, dans la population du g2 des patients de pronostic plus defavorable (LDH, metastases cerebrales) mais dont 89 % gardent un bon etat general (ECOG 0,1). Le delai entre le J1 de traitement par APD et la progression est en mediane de 6 (4 ; 8) mois. Le delai entre la 1 re reponse aux APD et la progression est en mediane de 3 (2 ; 6) mois. Les patients recoivent, apres progression en mediane, 1 ligne de traitement systemique (1–3). De facon interessante, on note 28 % de reponse a la ligne therapeutique suivante et 61 % de taux de controle. Dans les strategies postprogression, 20 patients poursuivent le meme APD (dont 2 en bitherapie avec cobimetinib ou temodal) ; 2 patients arretent l’APD et recoivent de l’ipilimumab, 4 une association d’anti-BRAF et anti-MEK, 5 une chimiotherapie. Parmi les patients sous chimiotherapies, 2 sont repondeurs et encore sous traitement (a 5 et 6 mois) et 3 sont decedes (a 3, 3,5 et 6 mois). Cinq parmi les 36 progresseurs sous APD ne recoivent pas de traitement dans les deux mois qui suivent l’arret de l’APD, dont un qui decede rapidement. La mediane de survie globale du groupe 2 n’est pas atteinte (Fig. 1). Discussion Notre etude suggere que la progression post-APD selectionne des patients un peu plus graves (LDH, metastases cerebrales) qu’en premiere ligne mais en bon etat general et susceptibles de repondre a des lignes ulterieures beaucoup mieux et plus durablement qu’attendu, notamment aux chimiotherapies usuelles. Conclusion Nous aimerions poursuivre ce travail en augmentant la taille de la population developpant une resistance secondaire aux APD et le recul postprogression et en etudiant les mecanismes moleculaires de ces echappements. Nous souhaitons aussi analyser les facteurs predictifs de rechute et de longue reponse aux anti-PD1.

Introduction L’ipilimumab (IPI), anticorps monoclonal anti-CTLA-4, a largement demontre son efficacite dans le traitement du melanome metastatique. Des donnees preliminaires d’efficacite en « vie reelle » via la cohorte MelBase montraient des resultats similaires a l’essai pivot et aux cohortes europeennes. Nous rapportons, ici, des donnees actualisees d’efficacite, de tolerance et de qualite de vie de patients traites par IPI en « vie reelle » en France. Materiel et methodes MelBase, base de donnees clinicobiologique labellisee INCA (25 centres), est dediee au suivi prospectif des patients avec melanome de stade III inoperable ou IV naifs de tout traitement systemique non-adjuvant. Depuis mars 2013, 914 patients ont ete inclus. Les donnees de 237 patients (hors essai clinique) ont ete extraites (25/11/2015) en 2 groupes : traites en 2e ligne ou plus (g2), et traites en 1re ligne (g1). La qualite de vie a ete mesuree par des questionnaires (FACT-M, EQ-5D) proposes a l’initiation du traitement et tous les 3 mois. Resultats Les caracteristiques demographiques et les suivis medians sont presentes dans le Tableau 1. Les donnees d’efficacite de g1 etaient : mediane de survie globale (SG) 14,6 mois (IC 95 % 11 ; non atteinte NA), SG a 2 ans estimee a 45,2 % (IC 95 % 33,0;62,0), survie sans progression (PFS) de 3,2 mois (IC 95 % 2,9;3,5). Les taux de reponse et de controle etaient respectivement de 19 % et 36 % (154 patients evalues). Concernant g2 : SG de 8,3 mois (IC 95 % 6,1;NA), PFS de 2,8 mois (IC 95 % 2,5;3,4), SG a 2 ans estimee a 34,3 % (IC 95 % 20,0;59,0). Les taux de reponse et de controle etaient respectivement de 9 % et 26 % (55 patients evalues). Le profil de toxicite est presente dans le Tableau 2. Aucun deces imputable n’etait rapporte. La qualite de vie ne semblait pas etre modifiee selon la ligne de traitement. Aucune modification notable n’etait relevee au cours du traitement par IPI. Discussion Les donnees presentees sont comparables en terme de survie aux essais actualises. De plus, un meilleur benefice en 1re ligne de traitement precedemment suggere par les donnees preliminaires semble se confirmer avec cependant une population moins severe pour g1. Conclusion Avec une population enrichie et une mediane de suivie plus importante, les donnees preliminaires d’efficacite de IPI en « vie reelle » sont confirmees avec des valeurs ajustees, proches des tendances des essais actualises, bien que les standards therapeutiques aient ete modifies par l’arrivee des anti-PD1, notamment en 1re ligne de traitement.

Objectifs Cette analyse sur base de donnees visait a decrire en vie reelle l’efficacite, la tolerance et l’utilisation du vemurafenib en monotherapie chez des patients atteints d’un melanome metastatique ou inoperable. Methode Les donnees ont ete extraites de la cohorte prospective, nationale, multicentrique, non interventionnelle Melbase, geree par l’AP–HP. Les donnees analysees ont ete recueillies entre le 12/03/2013 et le 08/09/2015. Dix-huit centres ont inclus au moins un des 101 patients retenus. La robustesse des resultats a ete controlee (nombre de patients analyses suffisant, controles sur les donnees recueillies, duree de traitement similaire a celle observee sur l’ensemble des prescriptions de vemurafenib au cours de la periode). Resultats Lors du diagnostic initial de melanome, les patients presentaient les caracteristiques suivantes : 60 % d’hommes, âge median 59 ans (Q1–Q3 : 50–71), antecedents d’un autre melanome chez 7 patients (7 %). Les caracteristiques de la maladie etaient les suivantes a l’instauration du traitement par vemurafenib : delai median depuis le diagnostic initial de melanome de 20 mois (6–68), ECOG 0–1 dans 74 % des cas, stade IV chez 93 % des patients et M1c dans 66 % des cas, mutation V600E chez 71 % des patients et de type V600 sans precision chez 19 %. Le taux de LDH est superieur a la normale pour 32 % des patients (manquant pour 39 patients). Il n’existe pas de melanome primitif identifie pour 10 % des patients. Quatre-vingt-neuf patients (88 %) avaient debute vemurafenib en monotherapie en premiere ligne. Pour un suivi median de 15,5 mois (8,0–26,4), 79 patients (78 %) ont arrete definitivement le traitement pour progression de la maladie (n = 35, 44 %) et/ou toxicite (effets secondaires lies ou non au vemurafenib) (n = 33, 42 %). La dose moyenne initiale etait de 1 900 ± 140 mg/jour (1 920 mg dans 96 % des cas). La mediane de survie globale [IC 95 %] etait de 12,0 mois [9,5–18,3] sur l’ensemble des patients, de 14,8 mois [11,2-non atteinte] en premiere ligne de traitement et de 7,5 mois [4,8-non atteinte] en seconde ligne ou plus. La mediane de survie sans progression etait de 5,4 mois [4,4–6,6] au total, de 5,8 mois [4,8 ; 7,8] en premiere ligne et de 3,3 mois [2,0 ; non atteinte] au-dela. Trois facteurs pronostiques de la survie globale des patients ont ete identifies : stade M1c de la maladie, metastases cerebrales symptomatiques et instauration du vemurafenib en seconde ligne ou plus. Au cours du traitement par vemurafenib, 408 toxicites ont ete reportees chez 88 patients (87 %) dont 330 toxicites reliees au traitement (87 patients, 86 %) incluant 24 toxicites qualifiees de graves par le notificateur (18 patients, 18 %). Vingt-neuf patients (29 %) ont arrete definitivement vemurafenib pour toxicite reliee. Vingt-six cancers secondaires (10 patients, 10 %) ont ete reportes jusqu’a la fin du suivi (21 carcinomes epidermoides cutanes, 3 carcinomes basocellulaires et 2 melanomes). Aucune toxicite n’a entraine de deces. Conclusion L’analyse des donnees extraites de la cohorte Melbase, sur des patients traites par vemurafenib en monotherapie pour un melanome metastatique ou inoperable a confirme en vie reelle les donnees de survie et de tolerance issues des essais cliniques.

Introduction Dans un contexte croissant de traitements inities en secteur hospitalier et dispenses en ville, le pharmacien d’officine doit connaitre ces medicaments et les pathologies associees afin d’accompagner au mieux les patients concernes, meme s’ils sont peu nombreux. Materiel et methodes Depuis 2012, Roche a coordonne un groupe de cliniciens et de pharmaciens pour concevoir et mettre en place un dispositif d’accompagnement des pharmaciens d’officine avec un double objectif : favoriser la coherence des messages delivres aux patients entre l’hopital et la ville et assurer une formation pratique adaptee aux besoins des pharmaciens d’officine. Ce dispositif comprend pour le pharmacien : – une formation interactive a distance sur le traitement ; – la mise a disposition de 2 sites Internet (pathologie et role du pharmacien) elabores par des cliniciens et des pharmaciens ; – un outil permettant d’identifier les risques d’interactions medicamenteuses. Nous presentons le bilan a plus de 3 ans de ce dispositif pour 2 produits (vemurafenib et vismodegib) ainsi que les resultats d’une etude menee en novembre 2015 aupres de 40 pharmaciens d’officine representatifs sur leurs patients en oncologie (20 entretiens face-face et 20 semi-directifs en ligne). Resultats Au total, 2348 officines ont dispense entre le 02/02/2013 et le 17/05/2016 du vemurafenib a 2694 patients atteints de melanome non resecable ou metastatique avec BRAF V600 mute. Pour ces 2348 officines, 2186 e-visites (dans 93 % des cas) ont ete realisees jusqu’au 17/05/2016. Trois cent soixante-huit officines ont dispense entre le 04/09/2015 et le 08/05/2016 du vismodegib a 379 patients atteints de carcinome basocellulaire (CBC) metastatique ou localement avance. Pour ces 368 officines, 227 e-visites (dans 62 % des cas) ont ete realisees jusqu’au 17/05/2016. Pour ces 2 traitements, les pharmaciens ont evalue leur satisfaction vis-a-vis du dispositif d’accompagnement par des notes respectives de 9,0 et 8,8 sur 10 (questionnaires retournes dans 84 et 81 % des cas respectivement). L’etude conduite aupres de 40 pharmaciens a montre que les patients atteints de melanome ou CBC avances recherchaient aupres des pharmaciens ecoute et disponibilite (97 %) et conseils sur les traitements de support (62 %), prioritairement a des informations sur le traitement anticancereux et ses effets secondaires (36 %). Discussion Ce dispositif d’accompagnement contribue a l’atteinte de deux objectifs du plan cancer (garantir la qualite et la securite des prises en charge, accompagner les evolutions technologiques et therapeutiques) en securisant l’utilisation des chimiotherapies orales. Conclusion Ce dispositif d’accompagnement des pharmaciens d’officine repond aux attentes des cliniciens et des pharmaciens comme a celles des patients atteints de cancer et confirme son utilite.

A phase I study was performed to determine the maximum tolerated dose and the recommended dose of continuous intravenous infusion of topotecan in combination with radiotherapy (RT) in patients with previously untreated glioblastoma multiforme (GBM). Twenty patients with histologically proven GBM and 1 with rhabdoid tumor were enrolled. After surgery or stereotactic biopsy, patients received cranial RT (60 Gy/30 fractions/40 days) and 3 cycles of topotecan as continuous infusion (CIV) from day 1 to 5 on weeks 1, 3, and 5 during RT. The dose of topotecan was escalated from 0.6 to 1.0 mg/m2/day. Four dose levels were tested. One grade 4 thrombocytopenia was seen at level 1 (topotecan dose 0.6 mg/m2/day; 6 patients). No dose-limiting toxicity was seen at level 2 (0.8 mg/m2/day; 3 patients) or an intermediate level of 2 bis (0.9 mg/m2/day; 6 patients). Six patients were included at level 3 (1.0 mg/m2/day), 4 of whom experienced dose-limiting toxicities, including 3 episodes of grade 4 thrombocytopenia, 1 platelet transfusion, 1 febrile neutropenia, and 1 grade 4 neutropenia of more than 7 days. Eighty percent of patients with GBM were alive at 12 months. The dose-limiting toxicity of topotecan administered as CIV for 5 days every 2 weeks is hematological. The maximum tolerated dose is 1.0 mg/m2/day and the recommended dose is 0.9 mg/m2/day. A phase II trial using the recommended dose of topotecan is ongoing.

Purpose: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site. Patients and Methods: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done. Results: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively. Conclusion: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

Carcinomas of unknown primary site are metastatic malignant epithelial tumours whose primary site cannot be identified during pretreatment assessment. They are characterised by their slow local development and their high metastatic potential. The primary site remains unknown in 20–50% of the patients, but the results from autopsies show that the primary tumours are most often located in the pancreas, lung, gut or kidney. In France, the incidence of carcinomas of unknown primary site is eight out of 100 000 per year, corresponding to between 5 and 7% of the solid tumours in adults. The average age at detection is 60 years old, with slightly more men being affected. The median survival time is only a few months. The heterogeneity of carcinoma of unknown primary site is due to the different histopathological types and anatomical localisations, making this a difficult topic to cover. In this document, we present the diagnostic strategy based on these two parameters, with the first entry point being the histopathological type. The therapeutic strategies to be used depend on the prognostic factors: specific anatomoclinical entities (neuroendocrine tumours, cervical lymph node metastases from squamous cell carcinoma, axillary lymph node metastases from an adenocarcinoma in women, undifferentiated carcinoma of the mediastinum in young men) and other nonspecific situations. Although primary papillary serous carcinoma is no longer included in the classification of peritoneum carcinomas of unknown primary site, we covered the management in women here in an attempt to be exhaustive.

Resume Objectif de l'etude. – L'objectif de cette etude prospective, multicentrique et randomisee de phase III etait de comparer l'association de la fotemustine et d'une irradiation encephalique totale a la fotemustine seule en termes de reponse cerebrale et de duree de survie sans progression cerebrale chez des patients atteints de metastases cerebrales de melanome. Patients et Methodes. – Soixante-seize patients, au lieu des 106 patients prevus car l'essai a ete interrompu apres une analyse intermediaire, ont ete randomises pour recevoir la fotemustine seule (groupe A, n = 39) ou la fotemustine associee a une irradiation encephalique (groupe B, n = 37). La fotemustine a ete administree par voie intraveineuse a la dose de 100 mg m –2 aux jours 1, 8 et 15. Apres un repos therapeutique de 5 semaines, les patients dont le cancer n'a pas progresse ont recu toutes les 3 semaines 100 mg m –2 de fotemustine. Dans le groupe B, une irradiation encephalique a ete realisee concomitamment a la dose totale de 37,5 Gy en 15 fractions de 2,5 Gy et 3 semaines consecutives. Resultats. – Malgre l'existence de facteurs pronostiques plus defavorables chez les patients traites par la fotemustine seule, aucune difference significative n'a ete observee en termes de taux de reponse cerebrale objective (groupe A : 7,4 %, B : 10,0 %), de controle cerebral (reponses objectives et stabilisations) (groupe A : 30 %, B : 47 %) apres 7 semaines et de survie globale (groupe A : 86 j, B : 105 j). La duree de survie sans progression cerebrale etait significativement plus longue dans le groupe B ( p = 0,028, test de Wilcoxon). Conclusion. – L'association de la fotemustine et d'une irradiation encephalique a retarde la progression cerebrale par rapport a la fotemustine seule, mais n'a pas significativement ameliore le taux de controle objectif ou de survie globale chez des patients atteints de metastases cerebrales de melanome.

not available. Disclosures: Study sponsored by Novartis. Copyright 2018 SKIN

Introduction Les metastases cerebrales (MC) de melanome ont un pronostic tres sombre, surtout en cas de metastases symptomatiques. Des donnees issues des essais cliniques ont montre l’efficacite des therapies ciblees seules (vemurafenib V, dabrafenib D) dans le traitement des MC et plus recemment en association (dabrafenib + trametinib DT), offrant des perspectives encourageantes. Cette etude presente des resultats originaux d’efficacite et de tolerance des patients avec MC traites en vie reelle par therapies ciblees (TC) seules (V, D) ou en combinaison (DT, vemurafenib + cobimetinib), via MelBase. Materiel et methodes MelBase est une base de donnees clinicobiologique labellisee INCa (26 centres), dediee au suivi prospectif des patients avec melanome de stade III inoperable ou IV naifs de traitement systemique non adjuvant. Depuis mars 2013, 1168 patients sont inclus. Les donnees des patients avec MC traitees par toutes TC ont ete extraites (juin 2017) et analysees en 2 groupes, monotherapie V/D (gA) et bitherapie VC/DT (gB). Resultats Les caracteristiques initiales sont : gA ( n = 58) : âge moyen 58 ans (48–70), ECOG 0–1 81 %, LDH > ULN 36 %, ≥ 3 sites metastatiques (SM) 60 %, avec traites en 1 re ligne 67 %, asymptomatiques 47 %, symptomatiques ou avec corticotherapie 53 %, avec toxicites grade 3/4 43 % ; gB ( n = 64) : âge moyen 56 ans (45–64), ECOG 0–1 90 %, LDH > ULN 39 %, ≥ 3 SM 63 %, traites en 1 re ligne 70 %, asymptomatiques 61 %, symptomatiques ou avec corticotherapie 39 %, avec toxicites grade 3/4 36 %. Apres un suivi median de 7,3 mois, la survie globale (OS) moyenne est 8,3 mois (IC95 % : 6,8–11,8 ; gA) et 15,1 mois (IC95 % : 7,7–NA ; gB) ; la survie sans progression (PFS) moyenne est 4,0 mois (IC95 % : 3,5–5,6 ; gA) et 6,6 mois (IC95 % : 5,5–8,1 ; gB). La meilleure reponse (BORR) est 31 % (gA) et 41 % (gB) ; le taux de controle (DCR) est 64 % (gA ; gB). Les facteurs testes en analyse univariee sont âge, LDH, ECOG, nombre MC, radiotherapie (RT). Dans les analyses multivariees sur population globale (stratifiees sur traitement) LDH (HR ajuste 1,9, IC95 % : 1,2–3,3), ECOG (HRa 3,6, IC95 % : 1,9–6,8), RT (HRa 2,3, IC95 % : 1,3–4,2) sont significativement associes a OS ; ECOG (HRa 3,0, IC95 % : 1,6–5,5), MC (HRa 1,5, IC95 % : 1,0–2,4) sont significativement associes a PFS. Discussion Les resultats d’efficacite d’OS et de PFS paraissent sensiblement similaires aux resultats issus des essais cliniques recemment publies (Davies et al., 2017) dans les 2 groupes. Le rajout d’anti-MEK augmente BORR mais pas DCR. Il augmente PFS et OS mais dans des proportions moindres que chez les patients sans MC. Conclusion Il s’agit de la 1 re etude qui permet d’evaluer les facteurs pronostiques et souligne une RT associee comme bon facteur en analyse multivariee. L’association a la RT stereotaxique concomitante doit etre systematiquement envisagee.

Introduction Lors de la suspicion d’un melanome metastatique, une confirmation histologique peut etre recommandee par la Reunion de concertation pluridisciplinaire. La biopsie est indiquee lors de presentation clinicoradiologique atypique, ou d’un contexte concomitant d’autre cancer. Cette biopsie n’est pas toujours aisement realisable et represente un geste invasif pouvant retarder le traitement specifique et entrainer des complications. Les cellules tumorales liberent de l’ADN dans la circulation sanguine par phenomene de necrose. La detection d’un profil mutationnel specifique sur un panel de genes a partir d’ADN tumoral circulant, permet d’affirmer la presence de cellules de melanome dans l’organisme et d’ecarter un profil mutationnel specifique d’un autre cancer. Nous rapportons la confrontation des resultats de biopsie profonde versus « biopsie liquide » chez 4 patients en situation diagnostique complexe. Materiel et methodes Entre fevrier et mai 2017, nous avons confronte le resultat anatomopathologique de la biopsie profonde et le resultat de la « biopsie liquide » chez 4 patients ayant un antecedent de melanome primitif et une suspicion de maladie metastatique. L’analyse se faisait par biologie moleculaire sur 4 mL de plasma. L’ADN etait extrait avec le kit QIAGEN et analyse par NGS (sequencage nouvelle generation). Le panel de genes suivant etait analyse : ALK, BRAF, CTNNB1, EGFR, ERBB2, ERBB4, FGFR2, FGFR3, GNA11, GNAQ, H3F3A, HIST1H3B, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MAP2K2, MAPK1, MAPK3, MET, MITF, NRAS, PDGFRA, PIK3, PTEN, RAC1, TERT et TYRP1. Resultats Les situations cliniques et les resultats sont presentes dans le ( Tableau 1 ). Dans les 4 cas, le resultat etait concordant. Discussion Chez ces patients, la recherche d’ADNtc etait concordante avec l’analyse des biopsies profondes sur le diagnostic de melanome metastatique. Du fait de l’heterogeneite intrinseque de la tumeur, une biopsie profonde peut ramener un pourcentage de cellules tumorales faible responsable d’une absence de detection d’alteration genetique. La localisation tumorale peut etre difficile d’acces, voire inaccessible, rendant le prelevement a risque. La biopsie « liquide » peut aider a affirmer le diagnostic de maladie metastatique de facon non invasive, rapide et abordable. Sa performance dans le diagnostic differentiel vis-a-vis d’un autre cancer primitif depend du panel de genes etudies. Son apport semble limite a l’etude des cellules tumorales et n’apporte pas d’informations sur le microenvironnement tumoral, notamment immunitaire. Enfin, Sherwood et al. ont montre une degradation rapide par des nucleases de l’ADNtc suite a la prise de sang et soulevent le probleme de la sensibilite et de standardisation de ce test.

9551 Background: With increasing armamentarium in advanced melanoma management, the impact of various strategies remains to be determined including the importance of time to switch from one treatment to another. We report the impact of time to IPI/APD non-planned switch on APD efficacy in real life patients within MelBase (MB). Methods: MB is a French multicentric biobank dedicated to the prospective follow-up (FU) of unresectable stage III or IV melanoma with 1102 patients included since March 2013. Data were collected (Sept.2016) and analyzed (demography, overall survival (OS), progression-free survival (PFS), response rate, multivariate analysis, safety). Results: 71 patients were treated with IPI/APD sequence. 72% received 4 IPI injections. The median time to switch was 1.7 months (0.36-3). The characteristics at the initiation of APD are: mean age 64 yrs, PS 0-1 80%, elevated LDH 34%, BRAF WT 90%, brain metastasis 25%, ≥ 3 metastatic organ sites (MOS) 49%, median FU 11.9 months, OS 20 months (95%CI:12.6-NR), PFS 3.5 months (95%CI:2.9-6.2). The best overall response was 25%, disease control rate was 54% with a low toxicity profile (17% grade 3/4). In a multivariable analysis, longer time to switch was significantly associated with better OS (adjusted HR 0.38 per 1 more month, 95%CI:0.14-0.93), as well as ECOG 0-1 (aHR 3.11, 95%CI:0.99-9.72) and LDH < ULN (aHR 3.32, 95%CI:1.26-8.75). In addition, the association of time to switch with OS vary significantly according to the number of MOS ( < 3 MOS aHR 0.25, 95%CI:0.10-0.62; ≥3 MOS aHR 0.99 95%CI:0.41-2.39) and AJCC stage (M0/1a/1b aHR 0.06, 95%CI:0.01-0.43 ; M1c aHR 0.77, 95%CI:0.39-1.54). Conclusions: In patients who failed IPI treatment, longer survival after APD was associated to time to switch only in patients with favorable baseline factors. Such results are probably more related to the slow kinetics of the disease than to the delay itself. Our results are different from Blank et al.(ESMO 2016) who tested a planned switch, immediately after 2 IPI perfusions, and showed overall response rate close to IPI+APD association. We are currently conducting a similar study on the reverse sequence (APD/IPI) and the role on IPI efficacy.

9538 Background: In the past decade, the prognosis of advanced melanoma has been greatly improved by new therapeutic agents such as immune and targeted therapies, which are now being evaluated as adjuvant therapies. Although the kinetic of metastatic disease is correlated to patient survival, the unfolding of the dormant disease remains hardly predictable and data from the literature on the topic is controversial (Karakousis, Francken). We hypothesized that the course of the advanced disease could be predicted from time to distant recurrence. Methods: Melbase is a French multicentric cohort dedicated to the prospective follow-up of adults with unresectable stage III or IV melanoma. Date of primary excision, time to recurrence, progression free survival (PFS) and overall survival (OS) of 298 patients treated in first line by immune therapies (IT, n = 148), targeted therapies (TT, n = 68) or within clinical trials (n = 73) were collected on September 5th, 2016. Patients with unknown primary or de novo metastatic melanoma were not included. Time to distant recurrence was analyzed as a continuous variable and as a categorical variable ( < 12 months; 12 to 24 months; ≥ 24 months). Results: Patients’ characteristics at baseline are: mean age 62 years, PS 0-1 84%, elevated LDH 32%, BRAF mutated 39%, brain metastases 18%. Time to recurrence studied as a continuous variable was not correlated to PFS (HR = 0.96; 95%CI: 0.85-1.07) or OS (HR = 0.89; 95%CI: 0.77-1.03). These results remained insignificant after stratification upon treatment or even when time to recurrence was analyzed as a categorized variable. Conclusions: Our data showed no correlation between the time from primary to distant recurrence and PFS or OS in patients treated with TT or IT. Therefore, kinetics of advanced disease cannot be predicted by the history of dormant disease. Dormancy and metastasis proliferation are thus probably driven by different molecular and cellular mechanisms.

Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72-21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P.05).

The objective of this study was to evaluate the efficacy of belinostat, a histone deacetylase inhibitor, when added to paclitaxel/carboplatin in the empiric first-line treatment of patients with carcinoma of unknown primary site (CUP).In this randomized phase 2 trial, previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re-evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single-agent belinostat, whereas patients in group B stopped treatment. The primary endpoint was progression-free survival (PFS): The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months.In total, 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months [95% confidence interval, 3.0-6.0 months]; group B, 5.3 months [95% confidence interval, 2.8-6.6 months]; P = .85). Overall survival was 12.4 months for group A versus 9.1 months for group B (P = .20). The response rate favored the belinostat group (45% vs 21%; P = .02). Belinostat resulted in a modest increase in treatment toxicity.The addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first-line therapy, although the patients who received belinostat had a higher investigator-assessed response rate. Future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities.

Background Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. Objectives To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. Methods Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. Results This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). Conclusion Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAFor NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.

Purpose: We have previously reported a clinical trial on the intravenous injection of autologous activated macrophages (AAM) in 15 patients with renal carcinoma [11]. The present paper concerns scintigraphic investigations performed in 11 of these patients after injection of 111indium oxinate-radiolabeled AAM. Methods: AAM were prepared from mononuclear cells (MNC) collected by apheresis from patients treated simultaneously with granulocyte–macrophage colony-stimulating factor (GM-CSF). MNC were cultured for 6 days in the presence of GM-CSF and exposed for 18 h to gamma-interferon, the AAM were then separated by elutriation and injected. Results: After intravenous infusion, radiolabeled AAM were transiently retained in the lungs, where they predominated in the first hour. Later on, radioactivity accumulated in liver and spleen and then decreased from the first and second day, respectively. In one patient, two foci of radioactivity were detected in the lungs 1 h after injection, and persisted thereafter. Their association with tumor lesions was uncertain. This observation possibly resulted from the presence of granulocytes in the radiolabeled AAM populations of this patient. It seems that MNC collected from GM-CSF-treated patients and cultured in the presence of GM-CSF enables the differentiation of granulocytes. Conclusions: A series of 11 investigations confirms the previously reported distribution pattern of intravenously injected AAM. It is possible that in patients treated with hematopoietic cell-mobilizing agents, granulocytes develop in cultures designed to produce monocyte-derived antigen-presenting cells.

Fifteen patients with progressive metastatic renal cell carcinoma were treated with granulocyte-macrophage colony-stimulating factor and intravenous infusions of activated autologous macrophages (AAMs). The latter were prepared from leukapheresis-separated mononuclear cells cultured in the presence of granulocyte-macrophage colony-stimulating factor, exposed to gamma interferon, and submitted to elutriation to separate AAMs. Three intravenous injections of AAMs were performed within a 2-week interval. This treatment cycle was repeated once or twice, in cases of tumor response or stabilization. Ninety-seven preparations containing a mean 3 x 10(9) AAMs were administered and usually well tolerated. One partial response, eight stabilizations and six progressions were observed. The median time to progression and median overall survival time after inclusion were 7 and 9 months, respectively. The cells injected did not accumulate substantially in tumor lesions, as shown by scintigraphic imaging of indium-111-labeled AAMs. Thus, combined granulocyte-macrophage colony-stimulating factor and AAM treatment was well tolerated and resulted in transitory stabilization (n = 8) or partial regression (n = 1) in 9 of 15 patients.

The objective of this phase II multicenter study was to assess the efficacy and tolerance of triptorelin (a sustained-release LHRH agonist) in advanced or recurrent endometrial cancer. A total of 101 monthly intramuscular injections were administered to 24 eligible patients (median number/patient = 3; range 1-12). Mainly due to progression, only 16 patients received 3 or more injections. Among the 23 evaluable patients, 1 complete and 1 partial response (response rate of 8.7%) and 5 disease stabilizations were observed, often of long duration, but never in an irradiated area or after progestogens treatment failure. Median survival for eligible patients was 7.2 months (range: 1-36 months). Only grade 1 toxicities possibly related to the treatment were observed in 4 patients. In conclusion, triptorelin was safe, well tolerated, and easily manageable, and the very low toxicity did not impair the quality of life in these patients with a very poor prognosis. Although the response rate was disappointing, several patients showed early evidence of efficacy which may be of long duration. Response rates range between 0 and 45% in different published studies. Additional studies with stricter inclusion criteria and a larger sample size are necessary to better evaluate the role of LHRH agonists in endometrial adenocarcinomas.

Introduction L’ipilimumab (IPI) a obtenu une AMM a la dose de 3 mg/kg toutes les 3 semaines, pour un total de 4 doses, en 2 e ligne dans le traitement du melanome avance, puis en 1 re ligne sur la base de donnees retrospectives. Sa mise a disposition est limitee au remboursement chez les patients BRAF non mutes. Nous presentons les premieres donnees de vie reelle de patients francais traites par IPI recueillies dans la cohorte MelBase. Materiel et methodes MelBase, base de donnees clinico-biologique (25 centres, labellisee INCA) est dediee au suivi prospectif des patients avec melanome de stade III inoperable ou IV naifs de tout traitement systemique non adjuvant. Depuis mars 2013, 563 patients ont ete inclus. Les donnees de 143 patients (hors essai clinique) ont ete extraites (12/02/2015) en 2 sous-groupes : traites en 2 e ligne ou plus (g2), et traites en 1 re ligne (g1). Resultats Les caracteristiques demographiques et les suivis medians sont presentes dans le tableau. Les donnees d’efficacite de g1 sont : mediane de survie globale (SG) non atteinte, SG a 1 an estimee a 62,2 % (IC 95 % 49,3–78,5), survie sans progression (PFS) de 3,7 mois (IC 95 % 3,1–4,7). Les taux de reponse et de controle sont respectivement de 21 % et 52 % (56 patients evalues). Concernant g2 : SG de 7,2 mois (IC95 % 5,7–NA), PFS de 3,5 mois (IC95 % 3–5,3), SG a 1 an estimee a 36,4 % (IC95 % 22,7–58,5). Les taux de reponse et de controle sont respectivement de 11 % et 44 % (27 patients evalues). Le nombre de doses recues en moyenne est de 3,3 (1–4) pour sg1 (14 patients en cours de traitement) et 3,2 (1–4) pour sg2 (4 patients en cours de traitement). Les toxicites sont detaillees dans le tableau. Dans g1 : 54 % des patients ont presentes des toxicites imputables (tous grades) dont 17 % de grade ≥ 3 (17 patients hospitalises). Dans g2 : 53 % des patients ont eu des toxicites imputables (tous grades) et 24 % de grade ≥ 3 (12 patients hospitalises pour toxicite et aucun deces). Discussion Nos resultats sur cette population traitee en premiere et seconde ligne sont comparables a ceux rapportes dans les autres etudes europeennes (Italie, Royaume-Uni). Cependant, du fait d’un acces retarde a IPI en 1 re ligne, peu de donnees de vie reelle ont ete decrites en Europe. Nos resultats suggerent un benefice plus important en premiere ligne (meilleure efficacite et moins de toxicites severes) alors que les caracteristiques demographiques sont comparables, a l’exception du taux de melanomes mutes BRAF (33 % g2 versus 9 % g1) et de l’ECOG. En France, les patients mutes BRAF ont eu un acces limite a IPI. Conclusion Nos resultats montrent l’importance de la cohorte MelBase, tant du point de vue scientifique pour une reflexion sur les strategies therapeutiques et la recherche de biomarqueurs (en cours), que medico-reglementaire pour optimiser l’acces aux soins de nos patients.

Introduction Le traitement du melanome de stade avance a connu un bouleversement avec l’arrivee de therapies ciblees chez les patients avec mutations activatrices BRAF V600. Le vemurafenib (V), premier inhibiteur de BRAF approuve au niveau national, a considerablement augmente la survie globale mediane (13,2 mois) (essai BRIM-3 : V versus dacarbazine). Nous rapportons des resultats d’efficacite et de tolerance chez des patients mutes BRAF V600 traites par V en vie reelle, suivis au-travers de la cohorte nationale MelBase. Patients et methodes Banque clinico-biologique labellisee INCa, MelBase est dediee au suivi prospectif des patients de melanome stade III inoperable ou IV naifs de tout traitement systemique non adjuvant (25 centres). Depuis mars 2013, 559 patients majeurs consentants ont ete inclus. En date du 22/10/14, les donnees des 60 patients traites par V en AMM (hors essai clinique) ont ete extraites et rapportees. Resultats La population comportait 52 patients traites par V en premiere ligne et 8 en deuxieme ligne ou plus. Les caracteristiques demographiques etaient : âge moyen 61 ans (dont 9 ≥ 75 ans), 72 % de mutations V600E, 13 % de primitifs inconnus, 87 % stade IV, 68 % de stade M1c dont 34 % avec metastases cerebrales, 86 % ECOG 0 ou 1 et 31 % avec un taux eleve de LDH. La mediane de survie sous V etait de 11,9 mois (IC95 % : 7,4;NA). La survie globale a 12 mois etait estimee a 45,4 % (IC95 % : 28,1;73,3). La survie sans progression (PFS) etait de 4,9 mois en mediane (IC95 % : 4;6,8). Les taux de reponse et de controle etaient de 37 % et 67 % (47 patients evalues). Quarante-neuf patients (82 %) ont presente des toxicites imputables a V. Les plus frequentes etaient : photosensibilite (18 %), arthralgies (17 %), asthenie, diarrhees et syndromes mains-pieds (13 % chaque). Vingt et un patients (35 %) ont presente des toxicites de grade ≥ 3 imputables a V, dont les plus frequentes etaient des cancers secondaires lies au traitement (15 %). Trente-trois patients ont definitivement arrete V (12 pour toxicite, 11 pour progression) et aucun deces relie n’a ete rapporte. Discussion Les donnees d’efficacite sont comparables aux donnees publiees dans les essais cliniques (phase 2, phase 3 etendue) et aux premieres etudes en vie reelle dans une population de patients severes avec forte representation des stades M1c et des patients avec metastases cerebrales. Le profil de tolerance est comparable aux donnees de la litterature, mais avec une prevalence plus faible. Conclusion Bien que necessitant une confirmation avec un plus grand echantillonnage, ces premiers resultats mettent en lumiere la faisabilite et les potentialites de la banque clinico-biologique MelBase et s’inscrivent dans une demarche plus globale d’etude de l’impact des diverses strategies therapeutiques ciblees en vie reelle.

PURPOSE A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.

Background Several case reports suggested that tumour necrosis factor-α (TNF) inhibitors might increase the incidence and/or alter the natural course of melanoma towards a more aggressive behaviour. Objective Our objective was to point if history of melanoma in patients exposed to TNF inhibitors could present with a particular pattern at diagnosis or during follow-up. Methods We performed a retrospective multicentre study settled in the West part of France to collect and analyse all cases of patients with melanoma who received anti-TNF therapy. Results Fifteen cases were included. First, 10 patients (mean age: 55.6 years; sex ratio: 1) had a melanoma diagnosed after TNF inhibitors initiation. The mean duration between initiation of treatment and melanoma was 48.7 months. Two patients died of metastatic disease. Second, four patients had a past history of melanoma before anti-TNF therapy (mean duration of treatment: 10.8 months). None experienced a progression of melanoma disease. Last, one woman had a past history of melanoma before and then developed a second melanoma when exposed to biotherapy. Conclusion Our case series does not reveal a distinct profile of melanoma in the patients exposed to TNF inhibitors. Additional prospective trials including larger number of patient are needed to demonstrate the possible link between biological therapy with TNF inhibitors and development of melanoma.

Steroid sulfatase (STS) inhibition may have a therapeutic role in suppression of endocrine-responsive breast cancer. This study aimed to determine the optimal biological dose and recommended dose (RD) of the STS inhibitor irosustat. A three-part, open-label, multicenter, dose escalation study of irosustat in estrogen receptor-positive breast cancer patients involved administration of a single dose of irosustat with a 7-day observation period; followed by a daily oral dose of irosustat for 28 days; and an extension phase, in which the daily oral dose of irosustat was continued at the discretion of the investigator and as long as the patient was benefitting from the treatment. Five doses of irosustat were tested (1, 5, 20, 40, and 80 mg) in 50 patients. After 28 days of daily administration of irosustat, all the evaluated patients in the 5, 20, 40, and 80 mg cohorts achieved ≥95 % STS inhibition in peripheral blood mononuclear cells and corresponding endocrine suppression. The maximum tolerated dose was not reached, and the 40 mg dose was established as the RD. The median time to disease progression in the 40 mg cohort was 11.2 weeks. Disease stabilization was achieved in 10 % of patients potentially indicative of drug activity. Dry skin was the most frequent adverse event. The RD of irosustat is 40 mg. Disease stabilization occurred in 10 % of this heavily pretreated patient population. A larger study is required to define an accurate response rate to irosustat as a single agent and whether co-administration with an aromatase inhibitor is needed.

Introduction Pres de 10 a 20 % des patients presentent des metastases cerebrales (MC) lors du diagnostic initial de melanome metastatique (MM) et jusqu’a 73 % des patients souffrant d’un MM developpent des MC. On retrouve des mutations BRAF V600 dans environ 50 % des melanomes cutanes. Le vemurafenib, un inhibiteur de BRAF, est un traitement de premiere ligne standard du MM avec mutation BRAF V600 en Europe. Des donnees recentes indiquent qu’il apporte un benefice aux patients avec MC. Cependant, la resistance a la monotherapie par inhibiteur de BRAF est frequente. Les resultats d’un essai de phase III comparant l’association cobimetinib + vemurafenib (inhibiteur de MEK) au vemurafenib, chez des patients atteints d’un MM avec mutation BRAF, montrent une amelioration de la PFS et de l’OS. Les patients avec MC symptomatique etaient toutefois exclus de cette etude. L’objectif de l’etude CONVERCE, etude interventionnelle de phase II, est de determiner si l’association cobimetinib + vemurafenib est efficace pour le traitement du melanome avec mutation BRAF V600 et MC. Sa methodologie est presentee ci-apres. Materiel et methodes Des patients avec melanome cutane metastatique confirme a l’histologie, melanome muqueux ou melanome d’origine primitive inconnue et avec MC pour lesquelles une resection chirurgicale ne constitue pas une possibilite raisonnable seront inclus dans 3 cohortes ( n = 137) : patients sans symptomes neurologiques avec MC precedemment non traitees localement (cohorte A) ou precedemment traitees localement (cohortes B) et patients avec symptomes neurologiques et MC precedemment traitees ou non traitees localement (cohorte C). Les patients seront traites par vemurafenib 960 mg per os , deux fois par jour de J1 a J28, de facon continue, et par cobimetinib 60 mg per os , une fois par jour, de J1 a J21 (1 cycle = 28 jours) jusqu’a progression (intracrânienne ou extracrânienne), toxicite inacceptable, retrait du consentement, deces ou decision de l’investigateur. Le critere d’evaluation principal est le taux de reponse intracrânienne partielle ou complete dans la cohorte A, fonde sur l’evaluation de la meilleure reponse tumorale du patient evaluee par un comite d’evaluation centralise conformement aux criteres Recist 1.1 modifies. Les criteres d’evaluation secondaires incluent les taux de reponse intracrânienne objective dans les cohortes B et C, la duree de la reponse intracrânienne, la survie sans progression, le taux de reponse globale et la survie globale dans toutes les cohortes, la tolerance, l’etude de pharmacocinetique incluant le liquide cephalorachidien, l’etude cinetique du taux de mutation BRAF dans l’ADN tumoral circulant et l’etude de pharmacogenetique. Les resultats preliminaires sont attendus pour 2018.

Introduction L’augmentation du taux de survie grâce aux nouvelles therapies pourrait favoriser l’apparition de melanomes a primitifs multiples. Plusieurs etudes rapportent que 1 a 10 % des patients presentent au moins un second melanome primitif. Cependant, l’incidence des melanomes primitifs multiples sur la survie globale reste sujette a debat. Le present travail a partir de la base nationale RIC-Mel (recherche et investigation clinique sur le melanome) a pour objectif de decrire les caracteristiques cliniques des patients presentant des melanomes primitifs multiples (MPM) compares aux patients avec un melanome primitif unique (MPU). Materiel et methodes La population etudiee est la cohorte nationale francaise recensee dans RIC-Mel. Les patients melanome tous stades confondus ont ete inclus depuis mars 2012 par les 49 centres du reseau. Les caracteristiques cliniques ont ete obtenues sur l’ensemble de la population et la probabilite de survie a 10 ans analysee. Les analyses ont ete realisees grâce a un modele logistique mono et multivarie. Resultats L’etude a porte sur 14 307 patients ayant des donnees completes et exploitables dont 712 MPM (4,98 %) et 13 595 MPU (95,02 %). Parmi les patients MPM, 83 % avaient 2 primitifs, 12 % 3 primitifs et 5 % plus de 3 primitifs. Les types histologiques des MPU et MPM etaient respectivement : SSM (59,8 vs 97,33 %), Dubreuilh (8,16 vs 17,56 %), nodulaires (12,72 vs 9,27 %), ALM (4,85 vs 5,48 %) et muqueux (0,73 vs 0,7 %). L’âge median a l’exerese du premier primitif MPU vs MPM etait de 59 vs. 58 ans, p = 0,19. L’indice de Breslow moyen des MPU et MPM etait de 2,15 mm vs. 1,98 mm, p = 0,023. L’analyse multivariee montrait que les hommes sont plus susceptibles de developper des primitifs multiples (p Discussion Cette etude presente pour la premiere fois les caracteristiques des patients a melanomes primitifs multiples de la cohorte nationale francaise. L’analyse des donnees cliniques et histologiques montre un profil significativement moins agressif ainsi qu’une meilleure survie des patients a MPM, confirmant les resultats d’autres cohortes internationales (Savioaet al., 2012, Bower et al,. 2010). Neanmoins, une etude recente montre plutot un pronostic defavorable dans les cas de MPM (Youlden et al., 2016). Ce pronostic paradoxalement plus favorable des patients MPM souleve la question d’un profil immunologique particulier de ces patients, soumis a une stimulation antigenique repetee vis-a-vis des antigenes de melanome. Conclusion Cette premiere analyse des donnees de la base RIC-Mel confirme l’interet de la mise en place de la cohorte melanome nationale ainsi que l’apport epidemiologique et medical d’une telle cohorte dans la recherche sur le melanome au niveau international.

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-...