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

BackgroundRP1 is an enhanced potency oncolytic HSV-1 which expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF).1 In pre-clinical studies, RP1 demonstrated potent GALV-GP R-enhanced anti-tumor activity and immunogenic cell death. This Phase 1/2 (Ph 1/2) study was designed to evaluate the safety and efficacy of RP1 ± nivolumab (nivo) in patients (pts) with advanced solid tumors, including pts whose disease failed prior anti-PD-1/PD-L1 therapy and has reported promising interim data in a number of tumor types including cutaneous squamous cell carcinoma (CSCC) and anti-PD1 failed melanoma to date.2MethodsThis is a multi-center, first-in-human, open label, multi-cohort, non-randomized Ph1 study of RP1 alone and combined with nivo followed by Ph2 in combination with nivo in pts with recurrent advanced solid tumors including those that progressed after prior anti-PD-1/PD-L1 therapy. The Ph 1 monotherapy dose escalation (n=14) and RP-1 combination expansion (n=22) cohorts are fully enrolled. Approximately 260 pts are expected to be enrolled in the ongoing Ph 2 portion across five cohorts; melanoma (n=30, enrollment complete), non-melanoma skin cancer (n=45, to include 15 pts with anti-PD-1/PD-L1 failed disease), anti-PD-1 failed MSI-H/dMMR tumors (n=30), anti-PD-1/PD-L1-failed non-small-cell lung cancer (n=30) and a registration-directed cohort in anti-PD-1 failed cutaneous melanoma (n=125). Pts in the Ph 2 portion receive up to 10 mL of RP1 intratumorally into one or more superficial or deep seated/visceral lesions at the recommended Ph 2 dose (1x10^6 PFU/mL × 1 followed by 1x10^7 PFU/mL × 7, Q2W). Following the first dose of RP1, nivo (240 mg IV Q2W for 4 months then 480 mg IV Q4W for up to 2 years) is subsequently administered in combination. Pts may receive up to 8 additional doses of RP1 if they meet protocol-specified criteria. Tumor assessments are performed Q8W. The primary objectives of the Ph 2 part of the study are to assess the safety, tolerability, and overall response rate (ORR) of RP1 in combination with nivo, by independent review for the anti-PD1 failed melanoma cohort. Secondary objectives include duration of response, complete response rate, disease control rate, PFS, 1-year and 2-year survival rates. Exploratory objectives include biodistribution and shedding analysis of RP1 and biomarker studies, including analyses of tumor biopsies and blood samples. Enrollment is currently ongoing in the UK and US, with additional sites in the EU (including France and Spain) are expected to open in 2021.Trial RegistrationNCT03767348ReferencesThomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, Smith H, Kaufman HL, Harrington KJ, Coffin RS. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer 2019;7(1):214.Coffin R, Astley-Sparke P, and Middleton M (2021, June 3rd). Retrieved from https://ir.replimune.com/static-files/f4fe3349-e082-4d41-94a1-106ce7e78a23Ethics ApprovalThe study was approved by institutional review board or the local ethics committee at each site. Informed consent was obtained from patients prior to enrollment.

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

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

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

9509Background: Surgery is the main treatment of basal cell carcinoma. In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damages. Neoadjuvant administratio...

e21571Background: Melanomas of unknown primary (MUP) are considered as metastatic disease. Epidemiologic features of MUP patients have been described in several studies, but never yet from the Fren...

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.

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.

Introduction L’utilisation de vismodegib dans le traitement neoadjuvant du carcinome basocellulaire localement avance (laBCC) non resecable pourrait reduire la taille de la tumeur, en faciliter la resection et potentiellement preserver la fonctionnalite et l’esthetique de la zone affectee. L’etude VISMONEO est realisee afin d’evaluer l’efficacite et la tolerance du vismodegib dans ce contexte. Materiel et methodes VISMONEO est une etude ouverte, non comparative, multicentrique, de phase II. Des patients presentant au moins une lesion de laBCC confirmee a l’histologie et une lesion d’un diametre ≥ 3 cm dans des zones ou le risque de recidive tumorale est intermediaire et un BCC d’un diametre ≥ 2 cm dans des zones ou le risque de recidive tumorale est plus eleve sont inclus. Le vismodegib etait administre par voie orale a une dose de 150 mg une fois par jour pendant 10 mois au maximum. Au total, 55 patients devraient etre suivis pendant 3 ans. Le critere d’evaluation principal est le pourcentage de patients atteints de BCC avec reduction du stade tumoral (down-staging) apres resection chirurgicale a l’issue d’un traitement par vismodegib durant au moins 4 mois. Les criteres d’evaluation principaux etaient les benefices cliniques evalues par un panel independant d’experts, l’impact medico-economique de cette strategie neoadjuvante, la tolerance (criteres NCI-CTCAE, v4.0) et la qualite de vie (questionnaire Skindex-16). Resultats Entre novembre 2014 et juin 2015, 55 patients ont ete inclus dans 17 centres en France. La moitie des patients etaient des hommes (51 %), l’âge moyen de 72 ans (± 12) et 73 % des patients (n = 40) avaient plus de 65 ans ; 58 % (n = 32) presentaient un indice de performance ECOG egal a 0, 35 % (n = 19) un ECOG de 1 et 7 % (n = 4) et un ECOG ≥ 2. La tumeur etait mesurable chez tous les patients et 3 (5,5 %) avaient un syndrome de Gorlin. Les sites affectes etaient principalement l’œil (35 %, n = 19), l’oreille (14 %, n = 8), la region temporale (14 %, n = 8), le nez (13 %, n = 7), le front (11 %, n = 6), la joue (5 %, n = 3), le cuir chevelu (4 %, n = 2) et d’autres sites (levres, region parietale : 4 %, n = 2). Pas de radiotherapie anterieure pour la plupart des patients, 98 % (n = 54). En decembre 2015, 8 patients etaient toujours sous traitement et 47 avaient termine le protocole (y compris patients toujours suivis et patients ayant beneficie d’une resection par une chirurgie moins lourde que prevue et avec reponse complete). Conclusion Les caracteristiques des patients atteints d’un laBCC traites par vismodegib en neoadjuvant et resection chirurgicale correspondent a celles des quelques patients avec laBCC resecable inclus dans les essais cliniques. Cette etude de phase II est en cours.