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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 ...

9535 Background: Vismodegib is a Hedgehog Pathway inhibitor (HPI) indicated for treatment of inoperable locally advanced basal-cell carcinoma (laBCC). Previous studies showed an objective response (OR) rate of 67%, including 34% of complete response (CR). Discontinuation of vismodegib is very frequent, mostly due to intolerable side-effects. Long-term response and predictive factors of relapse after suspension of vismodegib have not yet been evaluated, but should play a crucial role in the management of laBCC patients. Methods: We conducted an observational retrospective study in 9 onco-dermatological French units. Medical charts of laBCC patients treated with vismodegib from March 2012 until June 2016 were reviewed and patients with CR who stopped treatment were selected. Relapse was diagnosed clinically and/or histologically. A survival analysis was conducted, and predictive factors, characterization and management of relapse were studied. Results: 119 laBCC patients achieved CR and stopped treatment. 21 were lost to follow-up and 6 died before relapse. Event-free survival median was 18.4 months (12.1 – 24.1) and cumulative incidence of relapse at 36 months was 59.04% (48.05 - 70.04), implying that more than 40% of patients do not relapse. Multiple BCC and BCC not localized on the head and neck were associated with a higher risk of relapse, independently of the existence of Gorlin syndrome (HR = 3.3 (IC95 = 1.6 - 6.7) and 2.01 (IC95 = 1.05 - 3.87) respectively). Total duration of treatment was not associated with relapse. 50% (n = 27) of patients who relapsed during follow-up were retreated with vismodegib, with an OR of 85.2% (n = 23). 42% (n = 24) were eligible to surgery only and other patients received local treatments. Conclusions: Long term responders after vismodegib treatment discontinuation are frequent independently of the time exposure to the drug before and after CR. Most patients who relapse are still responder to vismodegib rechallenge. Patients with multiple or laBCC not localized on the head and neck are more at risk of relapse after discontinuation. This study emphasizes the interest of treatment of laBCC with HPI.

9552 Background: Anti-PD1 are now pivotal in the treatment of metastatic melanoma (MM). Some concerns have emerged regarding the risk/benefit ratio of their combination with stereotactic radiosurgery. Methods: Retrospective assessment of the interaction between Gamma-Knife radiosurgery (GKRS) and anti-PD1 in terms of toxicity and OS in mm patients (pts) with BM. Patients were included if they were under anti-PD1 (PRE) at time of GKRS, or if they had started anti-PD1 concomitantly with GKRS (CO), or had received anti-PD1 within 3 months after GKRS (POST). Results: Among 47 pts who received GKRS and anti-PD1 during their disease course, 35 fulfilled PRE or CO or POST criteria (anti PD1 1st line therapy in 10 pts and 2d or more in 25 pts). One pt died before radiological evaluation. GKRS targeted a single BM in 10 pts and multiple BMs in 24 (max 19 BMs). Out of the 128 BMs treated, 6 cases of increase of preexisting edema (4.7%) and 8 hemorrhages (6.25%) occurred in 12 pts, but only 5 events (5%) were regarded as Adverse Radiation effects (ARE), being symptomatic in 3 pts (8% of pts). One BM had to be resected because of the occurrence of a symptomatic hemorrhage with hemiparesis 9 month after treatment. Median follow- up from GKRS was 13.7 mths. Median overall survival (OS) from GKRS and 1st BM were 14.8 and 26.5 mths respectively, with 6 and 12 mths 0S rates from GKRS of 65.7% and 57%, respectively. Local failure was observed in 5 pt. Median time to new BM was 12.6 mths. There was no significant difference in outcomes in pts, depending on PRE, CO and POST conditions. Conclusions: In this series, the largest to date of pts with BMs treated by GKRS and anti-PD1,ARE were within the expected range and survival rates appear promising. Given the natural propensity of MM-BMs for bleeding and edema our data do not support an increased risk with the combination of GKRS and anti-PD1. Regarding the timing between anti-PD1 administration and GKRS our data do not support a higher efficacy or higher toxicity among the 3 following potential mechanisms: immuno- sensitization to radiation (PRE), immuno-radio direct synergy (CO) or radiosensitization to immunotherapy (POST).

9525 Background: Anti-PD1 are now the backbone of immunotherapy (IT) of metastatic melanoma (MM). Although they are overall well- tolerated, a number of severe immune-related adverse events (IRAE) have been described, among which type 1 diabetes. We observed 3 cases of fulminant diabetes (FD) in our center, and also had the impression that diabetics patients became more difficult to manage when receiving anti-PD1. Methods: Retrospective analysis of blood glucose samples collected before, during and after anti-PD1 treatment (trt ) in all mm patients (pts) receiving anti-PD1 in our department over a 36-month period. Study of FD cases observed. Results: A total of 163 pts were treated with 1920 cures of anti-PD1 including 27 treated within clinical trials. Anti-PD1 was the 1st line of IT in 70% of cases. As a whole, 1470 glycaemia were available. There was no significant difference between the median pre and post-trt glycaemia (5.37 +/-1.6 vs 5.6 +/-1.3 mmol/L (p = 0.033)). In the 28 pts with a type I (n = 0) or II (n = 28) diabetes prior to trt, there was very slight drift toward an increase of glycaemia along with the successive trt infusions (+0.05mmol/L/Cure, p = 0.004 with linear regression tendency test) .Three pts (1.84%) developed a FD revealed by a severe episode of ketosis with acute polyuria polydipsia, hyperglycaemia until 50mmol/L and weight loss. Two additional cases of FD were observed in pts treated within clinical trial comparing anti-PD1 with anti-CTLA4 in adjuvant and metastatic situation (imputability of anti-PD1 likely but uncertain until unblinding). None of these pts had any glucose increase in weeks prior to FD diagnosis. Four out of 5 FD cases had an HLA group at risk for type 1 diabetes development (HLA DRB3/4), a rare group in general population (1%). Conclusions: We could not document any systematic tendency to glycemic disorder in mm pts treated by anti-PD1. In diabetic pts prior to trt, a slight drift toward increase of glycaemia may be explained by other interfering factors (diet, metastatic disease itself, corticosteroids, anxiety etc). FD is not exceptional (2% of patients in our series) and does not seem to be announced by any minor preliminary glycemic disorder. Despite apparently stochastic onset, FD may be associated with HLA DRB3/4 subgroup.

e21042 Background: Rate of growth (ROG) of the primary tumor is a known prognostic factor in melanoma (MM). Fast growing melanomas (FGMM) could account for an important part of the thick tumors which still exist despite earlier and earlier detection. Methods: All patients referred for a primary mm to two French Dermatology Department from the period 2012-2016 were prospectively enrolled in an observational case control study. ROG was calculated as the ratio of Breslow thickness to time to mm development according to patient, following a well-established process. FGMM were defined as those with a ROG > 0.5 mm/month and MMs with a ROG ≤05mm/month were used as controls. Differences in epidemiological, clinical and pathological features were evaluated with univariate and multivariate analysis. Results: 464 patients were enrolled. 149 mm (32.1%) were FGMM. Factors associated with FGMM in univariate analysis were age > 70 years (p = 0.006), tumor location (p = 0.032), histological subtype (p = 0.021), median thickness (p < 0.001), ulceration (p < 0.001), high mitotic rate ( > 1/mm2 )(p = 0.002), sentinel node involvement (p = 0.008), hair color at the age of 20 (p = 0.011), lower NSAIDS consumption (p = 0.012) and lower number of sunburns (p = 0.002). Age > 70 years (OR 1.88 95%CI 1.19-2.98, p = 0.007), ulceration (OR 3.70 95%CI 2.05-6.61) p < 0.001), sentinel node involvement (OR 1.93 95%CI 1.01-3.69 p = 0.046), regression (OR 0.37 95%CI 0.15-0.94) p = 0.037) and NSAIDS exposure (OR 0.29 95%CI 0.11-0.78, p = 0.014) remained associated with FGMM in multivariate analysis. OS and PFS were significantly lower in the FGMM group (HR 1.98 (95%CI 1.11-3.54, p = 0.02) and HR 1.79 (95%CI 1.17-2.73, p = 0.007), respectively). Conclusions: Fast growth characterizes a subset of primary mm which are intrinsically more aggressive and have different risk factors than other MM, namely more frequent in the elderly and with no association with skin type, nevus count or sun exposure. Association with ulceration could reflect a specific immune context. Negative association with NSAIDS exposure warrants more investigation, since it may have therapeutic implications.

9573Background: On demand Gamma - knife (OD -GK), ie repeated sessions as many times as required by the appearance of new lesion(s) upon imaging follow-up, is one of the best strategies to control ...

9562Background: A Hh pathway inhibitor, vismodegib (VISMO) is approved for the treatment of locally advanced (la BCC) and metastatic BCC (mBCC). While most patients respond to drug treatment, in th...

9083 Background: Both Gamma-Knife radiosurgery (GKRS) and BRAF-inhibitors (BRAF-I) have been shown to be useful in melanoma patients with brain metastases (BM), thus suggesting that it could be int...

8568 Background: Ipilimumab (Ipi) is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for the treatment of metastatic melanoma (MM) and currently under investigation in the adjuvant setting. Methods: Retrospective analysis of patients treated with ipi between June 2006 and September 2011 in our department in Marseille. As some patients are still blinded in trials, the exact number of patient under ipi is unknown. We present a minimal percentage (>%) assuming that the 120 patients received ipi. Results: A total of 120 patients were treated: 76 stages IV MM, from which 16 in the BMS clinical trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 or 10mg/kg IV dosage, while stages III MM were randomly assigned to receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 patients (>10%): 2/76 patients with stage IV MM (>2. 6 %) and 10/44 patients with stage III MM (>22.7). Diagnosis was performed at the 1st, 3rd and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients (33.3%). Clinical symptoms included headaches (n=11; 91.6%), asthenia (n=7; 58.3%) and decreased libido (n=2; 1.6%). Adrenal, thyroidal and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 patients (58.3%). MRI changes were observed in 7 patients (58.3%): pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids supplementation was required in 11 patients and thyroidian supplementation in 4 patients. Clinical symptoms regressed within one week in 8 patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only if clinicians are aware of these unspecific signs. Only MRI can make diagnosis in some patients without clinical and/or biological signs. Our data suggest that it develops especially for 10mg/kg dosage, after the third administration, and that the rate could be higher in patients with a normal immune system (adjuvant treatment), than in metastatic ones. Hormonal supplementation usually controls the disease.

8555 Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p

8578 Background: “Ugly duckling” (UD) sign is widely admitted as a major sign for melanoma (MM) detection. UD is based on the concept of intra-individual comparative analysis, which has never been validated. It is assumed that, in a given individual, variability of nevi is limited and represented by a few similarity clusters (SC) grouping all nevi sharing the same pattern, and that a nevus is suspicious when it does not fit with the SCs of this individual (UD). Objective: To validate the concept of UD and SC. Methods: 9 international experts (dermatologists) and 9 novices (untrained individuals) were blindly tested, using digital images of the nevi at clinical and dermoscospic scale successively in 80 patients, (2,089 nevi and 7 MM). Concordance was assessed by kappa statistics for UDs, and B-cubed metrics for SCs. Results: At clinical scale, experts had a better concordance for UDs (kappa= 0.53, [0.33 - 0.87]) and SCs (B-cubed = 0.65, [0.55, 0.73]), than novices (0.31, [0.03, 0.51] and 0.56 [0.49, 0.64], respectively). Experts identified a mean number of 1 UD and 2.7 SCs per patient, and agreed on consensual UD and SCs, whatever their natural propensity to see a high or a low number of UDs and SCs: among the 254 nevi considered as UDs by at least 1 expert, 54 were considered as such by at least 5, and from them, 20 by all 9 experts. The 20 consensual UDs included all the MMs (7/7) (sensitivity for MM: 100%). At dermoscopic scale, concordance tended to be lower for SCs than at clinical scale. Conclusions: We demonstrated the limited variability of nevi patterns in each patient, the consistency in the recognition of UD, and its clinical relevance, supporting evidence that it is useful for experts and to a lesser degree to general population to spot the skin lesions with the highest probability of being MM.