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Introduction L’immunotherapie represente une avancee majeure dans la prise en charge du melanome. Elle s’associe a des effets indesirables auto-immuns lies a l’activation du systeme immunitaire. L’ototoxicite immuno-induite est peu decrite. Nous rapportons 2 cas d’hypoacousie survenus chez des patients traites par ipilimumab 3 mg/kg et nivolumab 1 mg/kg toutes les 3 semaines pour un melanome metastatique. Materiel et methodes Une patiente de 53 ans traitee par ipilimumab et nivolumab d’aout 2019 a novembre 2019 a presente une myodesopsie apres le 2e cycle. Le fond d’œil a montre un decollement posterieur du vitre bilateral. Une surveillance ophtalmologique rapprochee a ete recommandee. L’immunotherapie a ete poursuivie. Apres le 4e cycle, la patiente a eu une hypoacousie brutale, des acouphenes et une baisse de l’acuite visuelle. Le traitement d’entretien par nivolumab a ete arrete. L’evaluation ORL a mis en evidence une hypoacousie moderee bilaterale probablement immuno-induite. L’audiometrie trouvait un seuil auditif a 40 dB bilateralement. Un traitement oral par prednisone 1 mg/kg a ete debute en novembre 2019 avec decroissance progressive, ameliorant l’audition. Un appareil auditif bilateral a ete pose en septembre 2020 pour compenser l’hypoacousie residuelle. Une evaluation ophtalmologique parallele a retrouve une uveite bilaterale posterieure severe probablement immuno-induite, necessitant plusieurs traitements immunosuppresseurs (dexamethasone, anti-TNF adalimumab et methotrexate). L’evaluation tumorale apres 4 cycles d’ipilimumab et nivolumab a permis une reponse complete mais la tumeur a progresse en juin 2020, necessitant une deuxieme ligne par therapie ciblee. Un patient de 76 ans a recu ipilimumab et nivolumab de novembre 2019 a avril 2019. Apres le 2e cycle, il a presente une hypoacousie brutale et un vitiligo etendu. Le traitement a ete arrete. L’evaluation ORL a trouve une hypoacousie moderee bilaterale avec un seuil auditif a 50 dB bilateralement. Un traitement par prednisone 1 mg/kg a ete debute en avril 2019 sans amelioration clinique. Une injection bilaterale intratympanique de dexamethasone 4 mg a ete administree toutes les 3 semaines de mai 2019 a juin 2019. L’hypoacousie s’est amelioree apres 3 injections et des appareils auditifs prescrits en juillet 2021 pour compenser l’hypoacousie residuelle. A ce jour, le patient est en reponse partielle persistante. Discussion L’ototoxicite immuno-induite survient rarement. Associee a une uveite ou un vitiligo, sa pathogenese pourrait etre liee a une activation du systeme immunitaire ciblant les melanocytes de la cochlee, du labyrinthe et de l’uvee, semblable au syndrome de Vogt-Koaynagi-Harada. Une evaluation ORL avec audiometrie est recommandee avant de debuter l’immunotherapie a partir de 55 ans.

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

9550 Background: Since the development of immune checkpoint inhibitors (ICI) for advanced melanoma, a small group of patients with an excellent and durable response has emerged. Complete response (CR) is achievable in about 10-20% of the patients and seem to have an excellent prognosis. However, 10 to 15% of them might relapse eventually. Our main objective was to determine factors associated with relapse after a CR to ICI in advanced melanoma. The second objective was to describe relapse modalities and tumor response to subsequent treatments. Methods: We performed a single-center, retrospective study, in 141 patients with a CR to ICI for advanced melanoma, treated at Gustave Roussy (France) from January 2010 to June 2020. CR was confirmed on two consecutive CT-scanner or PET-CT at least 3 months apart. Characteristics of the patients at diagnosis, during and after treatment were compared in both groups: CR with relapse and CR without relapse. The LASSO analysis, a statistical analysis using lambda penalization coefficient for prognostic studies, was performed regarding the many statistical variables analysed. Results: At data analysis, immunotherapy was interrupted in 94.3% of the patients and the median follow-up was 3.5 years since immunotherapy discontinuation. Eventually, 18 of 141 patients (12.8%) had relapsed and 126 (87.2%) had not. The statistical analysis identified three factors associated with melanoma recurrence: prior lines of therapy, the type of melanoma and the mutation status. Indeed, relapse risk was higher in patients with wild type melanoma (as opposed to BRAF or NRAS mutant melanoma), with a mucosal, acral or unknown primitive melanoma and who received prior lines of treatment. Other factors such as demographical characteristics, tumor burden, metastasis localization, type or grade of toxicity, pseudo progression, type of ICI, treatment duration, use of a complementary local treatment and pursuit/discontinuation of immunotherapy were not statistically associated with the duration of the complete response. In case of melanoma recurrence, reintroduction of immunotherapy provided tumor response in half of our patients: 13 of the 18 relapsing patients received immunotherapy after melanoma recurrence; allowing 3 CR, 2 partial responses and 1 stable disease. One third of the relapsing patients eventually died of disease progression. Conclusions: This study confirmed the excellent prognosis of CR to ICI in advanced melanoma, even after treatment discontinuation and identified 3 baseline factors associated with a risk of relapse: absence of BRAF or NRAS mutation, primary of acral, mucosal or unknown origin, and previous lines of therapy. Rechallenge with ICI was effective in 50% of the patients.

Introduction L’avenement des nouveaux traitements du melanome metastatique, immunotherapies (IT) et therapies ciblees (TC), a permis d’ameliorer la survie des patients dont certains presentent des reponses completes (RC). Nous avons souhaite caracteriser les patients repondeurs complets sous IT et TC pour identifier si les facteurs associes a la RC different selon le traitement. Materiel et methodes Cette etude retrospective a porte sur les patients atteints de melanome stade III inoperable ou stade IV ayant ete mis en RC lors de leur suivi a l’institut Gustave-Roussy entre le 15/07/2007 et le 02/11/2016. Ils etaient traites par IT ou TC a l’occasion d’essais therapeutiques, ATU ou AMM, quelle que soit la ligne therapeutique ; en monotherapie ou en combinaison de traitements. La reponse etait consideree comme complete apres deux imageries successives en faveur de la RC (scanner ou TEP). Les distributions des variables d’interet dans les deux groupes IT et TC ont ete comparees par test exact de Fisher ou test de Kruskal–Wallis. Resultats Les caracteristiques des 71 patients inclus sont representees sur la ( Fig. 1 ) ; 53 patients etaient sous IT et 18 sous TC, avec un suivi median de 39,6 mois. La ( Fig. 2 ) represente par patient la survenue de reponse partielle (RP), reponse complete (RC), d’eventuelle interruption de traitement et/ou de recidive. Chez les patients traites par IT, le delai median jusqu’a RC etait de 8,3 mois et le temps median de RC de 25,6 mois. Sous TC, le delai median jusqu’a RC etait de 8,8 mois et le temps median de RC de 13,9 mois. Dans chaque groupe, 7 patients avaient recidive a la fin du suivi et un patient etait decede dans le groupe TC. Comparee a la TC, l’IT etait associee a des interruptions du traitement apres RC plus frequentes (91 % vs. 22 %, p Conclusion Apres plus de 3 ans de suivi, les durees de RC sont plus longues avec les IT que les TC (mediane 25,6 mois vs 13,9 mois) et les taux de recidive apres obtention d’une RC sont plus bas avec l’IT qu’avec les TC (13 % vs 38 %), cela malgre des interruptions de traitement plus frequentes avec les IT que les TC. Nous n’avons pas pu mettre en evidence de facteur associe a la RC pour les patients traites par IT ou TC sauf peut-etre le nombre de sites metastatiques a l’evaluation initiale. Des etudes de plus grande taille et des essais randomises seront necessaires pour le confirmer et pour tenter d’identifier des marqueurs predictifs de la reponse a l’IT et a la TC afin d’etablir des recommandations de sequences therapeutiques en fonction des caracteristiques des patients.

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.

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.

Background/Aims: Debate continues on whether serum and intrahepatic HCV viral loads are correlated and if HCV viral load correlates with the severity of liver disease. These difficulties may at least in part be linked to liver cell heterogeneity, when total liver extracts from HCV-infected individuals are tested for HCV RNA quantification. We have therefore investigated the feasibility of quantifying HCV replication using a laser-based microdissection technique. Methods: We compared the results with those obtained for serum HCV RNA quantification and immunochemistry in the case of HCV antigen detection in the liver. Twenty-one HCV-positive patients with chronic active hepatitis ( n =10) or cirrhosis ( n =11) were analyzed. Results: A positive correlation ( P =0.0019) was observed between HCV RNA quantifications in sera and microdissected cells. Immunohistochemistry demonstrated that HCV antigen hepatocytes were randomly distributed within liver lobules. Their percentage varied in different patients (0–40%), but did not correlate with the HCV viral load. Conclusions: We have designed a sensitive methodology to evaluate the intrahepatic HCV viral load by combining a standardized RNA quantification method with microdissected hepatocytes from frozen liver needle biopsies. Our results directly demonstrate a positive correlation between serum and intrahepatic viral loads, which therefore provides a reliable reflection of intrahepatic HCV replication.