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9556 Background: Melanoma of unknown primary (MUP) account for 3% of all melanomas. Clinical outcome of advanced MUP in the era of novel therapies including immunotherapies (ICI) and targeted therapies (TT) have been only scarcely studied, whereas a possibly different biologic background might introduce changes in its management. Recent retrospective studies suggested that patients with advanced MUP could benefit at least as much from novel therapies as patients with known primary cutaneous melanoma (cMKP). Methods: Based on the nationwide MelBase prospective database (NCT02828202) this retrospective study included patients with advanced melanoma treated with first-line ICI, TT or CT. MUP was defined by upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. Patients with primary mucosal or ocular melanoma were excluded. Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary variables in MUP vs cMKP, stratified by treatment subset (ICI vs TT vs CT vs whole cohort). Secondary variable was treatment-related toxicity. Multivariate analyses and propensity score analysis were performed. Objective: To investigate the efficacy and safety of systemic treatments (ICI, TT and chemotherapy (CT)) in patients with advanced MUP comparatively to stage-matched cMKP. Results: A total of 1882 patients were analyzed, including 265 (14.1%) MUP. Most patients were treated with first-line ICI. Median follow-up was 16 months. Patients in the MUP cohort more often displayed unfavorable initial prognostic factors (Table). PFS and OS did not significantly differ in MUP compared to MKP patients (p=0.73 and p=0.93 respectively). Stratification of cohorts by treatment type and application of propensity score did not lead to data modification. Treatment-related toxicity rate and severity did not differ between MUP and MKP, regardless of treatment type. Conclusions: Our results suggest that advanced MUP should be managed with similar strategies as advanced MKP. In our cohort, MUP patients benefited from novel therapies as much as MKP patients despite less favorable baseline prognostic factors. Exploratory studies investigating mutational burden and host immunity are needed to identify the underlying mechanisms. [Table: see text]

e21545 Background: The tumor mutational burden (TMB) is usually high in Cutaneous melanomas owing to ultraviolet radiation-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that the response pattern to immunotherapy and targeted therapy in advanced melanoma may vary depending on the sun-exposure profile of the site of primary melanoma. Methods: Patients were screened from MelBase, a French multicenter biobank dedicated to the prospective follow-up of unresectable stage III/IV melanoma. Within Melbase, all patients with a known cutaneous primary melanoma who received a first-line systemic treatment by immunotherapy or combined targeted therapy between January 2013 and November 2019 were included. Outcomes were progression-free survival (PFS ) and overall survival (OS). Results: 973 patients received either anti PD-1 monotherapy (n=466), anti CTLA-4 monotherapy (n=143), a combination of both (n=118), dabrafenib plus trametinib (n=187) or vemurafenib plus cobimetinib (n=59). Patients’ characteristics at treatment initiation were: male gender (62%), median age of 62 years old, BRAF WT (58%), AJCC stage IV (84%), brain metastases (18%), ECOG 0-1 (84%) and normal LDH (52%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 175 patients (G1: head neck), on intermittently sun-exposed skin in 615 patients (G2: trunk, arms, legs), and on sun-protected areas in 65 patients (G3: palms, soles, nails). Median PFS was significantly higher in G1 under anti PD-1 treatment (8,7 months vs 3,3 and 3,4 months for G2 and G3, respectively) (p=0.011), (19,2 months vs 8,1 and 6 months for G2 and G1) (p=0. although it is worthwhile to note that the number of G3 patients treated with targeted therapy was relatively low (n=8). PFS did not significantly differ between all groups under ipilimumab. Similarly, median OS was significantly higher in G1 receiving first-line anti PD-1 treatment (45,6 months vs 31,6 and 21,4 months for G2 and G3) (p=0.04), while OS was higher in G3 under targeted therapy (21,1 months vs 16,3 and 19,5 months for G2 and G1) (p=0.97). Conclusions: Our study suggests that first-line immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas. On the other hand, melanomas originating from sun-protected areas may benefit more from first-line targeted therapy when possible (presence of BRAF mutation), but this finding needs to be confirmed by further research.

9533 Background: First line IPI+PD1 induces long-term response in 36% of MM patients (pts); however, the majority of pts will progress and may require further treatment, which is yet to be established. We studied the patterns of progressive disease (PD) on 1st line IPI+PD1, and the management and outcomes in MM pts. Methods: Demographics, disease characteristics, nature of PD, subsequent treatments and outcomes were examined in MM pts with PD on 1st line IPI+PD1. Multivariable analyses (MVA) identified factors associated with patterns of PD: innate resistance (IR) = PD as best response or stable disease (SD) < 6 mo; acquired resistance (AR) = PD after initial response or SD ≥ 6 mo. Results: 310 MM pts from 14 melanoma centres were included; 208 (67%) had PD during and 102 (33%) after ceasing IPI+PD1. Overall med. progression-free survival (mPFS) was 2.8 mo (CI 95% 2.7 – 3.0); 187 pts (60%) had IR (mPFS 2.2 [2.1 – 2.5]), 112 pts (36%) had AR (mPFS 8.5 [7.2 – 10.2]) and 11 pts (4%) had pseudoprogression, i.e. PD followed by response without changing treatment (mPFS 2.7 mo [1.4 – NA]). On MVA, pts with ECOG PS ≥ 1 were more likely to have IR vs AR; and within IR pts, those with head & neck primary melanomas and lung metastases were more likely to have PD < 1.5 mo. Most pts with IR (68%) had PD in multiple sites, while 61% AR pts had PD in a single site. Brain was most common site of single organ PD; 49% of IR and 41% of AR. Med. follow-up from PD was 32.7 mo (28.1 – 36.8). After PD, 61 pts (20%) had best supportive care (26% of IR and 11% of AR pts). 259 pts (80%) received further treatment: 39% IR pts had systemic treatment (ST) only and 27% had ST + local; 31% AR pts had ST only and 39% had ST + local. Of 200 pts (65%) who had ST(+/-local), 54% had 1 line of ST and 46% had ≥ 2; 1st line ST (ST1) was BRAF/MEKi in 36% of pts, PD1 in 32%, IPI+PD1 in 7%, investigational drugs in 11%, chemotherapy in 9% and others in 5%. ORR in IR pts was lower than in AR pts for every type of ST1 (see Table). Med. OS from PD was 11.4 mo (CI 95% 9.6 – 16.1); IR 6.4 mo (CI 95% 5.6 – 10.2) and AR 26.1 mo (CI 95% 17.1 – NA). Conclusions: These data suggest longer OS from PD for AR vs IR pts independent of ST type. BRAF/MEKi, rechallenge with PD1+/-IPI and investigational drugs showed activity after PD on IPI+PD1, while chemotherapy has no role in this context.[Table: see text]

10026 Background: Clinical trials of immunotherapy exclude patients (pts) with pre-existing AD. While retrospective data exist regarding the efficacy and safety of single agent ipi and anti-PD1 antibodies (PD1) in pts with AD, no data are available regarding the safety and efficacy of combination therapy in pts with AD, which has a higher toxicity risk. Methods: Pts with melanoma and pre-existing AD treated with combination ipi/PD1 were retrospectively identified from 10 international centres. Data regarding AD, treatment, toxicity and outcomes were examined. Results: Fifty-five pts were included, 46 were treated with ipi/nivolumab and 9 with ipi/pembrolizumab. 40 had an ipi dose of 3mg/kg while 15 had a lower dose regimen. 9 pts received prior PD1 therapy; 3 suffered moderate immune-related adverse events (irAE) with no flares of AD on single agent PD1. Pre-existing AD included inflammatory bowel disease (IBD), thyroiditis, rheumatoid arthritis (RA), multiple sclerosis and psoriasis. 10 pts had active symptoms of AD and 13 were immunosuppressed at commencement of ipi/PD1. Eighteen pts (33%) experienced a flare of their AD including 4/7 with RA, 3/6 with psoriasis, 5/9 with IBD, 3/18 with thyroiditis, 1/1 with Sjogren’s syndrome, 1/1 with polymyalgia, 1/1 with Behcet’s syndrome. Median time to flare was 19 days (range 4 – 167). 13 pts were managed with steroids, 5 required additional immunosuppressants. 7 pts were hospitalised for management of flare (5 with IBD, 2 with RA). 2 pts required intensive care and vasopressors for severe IBD flare, quiescent prior to ipi/PD1. One for diarrhoea and shock and one for duodenal perforation. 8 pts ceased treatment due to flare (3 with IBD, 2 with RA, 1 with Behcet’s, 1 with Sjogren’s). Thirty-seven pts (67%), experienced an irAE unrelated to their AD, 38% G3 or G4. The most frequent irAEs were colitis (n = 16), hepatitis (n = 12), endocrinopathies (n = 12), with 13 pts experiencing an irAE in ≥ 2 organs. 9 pts experienced both AD flare and an irAE. 20 pts (36%) ceased immunotherapy due to irAEs. ORR was 55% (54% in PD1 naive pts), at a median follow up of 14 months, 77% of responses ongoing. ORR in pts who had a flare of their AD was 44% and in pts on immunosuppression was 46%. Median PFS was shorter in pts who had a flare of AD compared with those who did not (2.6 vs 9 months; P-value 0.047). Conclusions: Combination ipi/PD1 shows efficacy comparable to clinical trial populations in pts with pre-existing AD and advanced melanoma. Whilst there was a substantial risk of flare of AD, no increased frequency of irAE’s was observed.

10057 Background: PD-1 inhibitors (anti-PD1) are frequently associated with immune-related adverse events (IRAE). Since melanoma patients included in clinical trials were frequently treated during two years, data on IRAE occurring after 2 years of treatment are lacking. This study aimed to describe IRAE in melanoma patients treated with anti-PD1 for longer than 2 years in a real-life setting. Methods: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. All patients who received anti-PD1 for at least 2 years between January 2013 and November 2019 were included. Among them, patients who experienced IRAE and long-term IRAE defined as IRAE occurring after 2 years of anti-PD1 were identified. Results: Among 1849 patients with advanced melanoma included in Melbase, 119 patients received anti-PD1 monotherapy during at least 2 years, from January 2013 to November 2019, with a median follow-up of 41.7 months (25.2-57.5). Patients characteristics at treatment initiation were: male gender (61%), mean age of 63 years old, past history of autoimmune disease (11%), BRAF WT (72%), AJCC stage IV (84%), brain metastases (22%), ECOG 0-1 (88%) and normal LDH (56%). Patients were treated with Nivolumab (n = 53) or Pembrolizumab (n = 66). IRAE occurred in 99 patients (83%) with a median time of 13.3 months (0-53.9), including severe IRAE (grade 3 or 4) in 30 patients (30%). Long-term IRAE, mostly grades 1-2, occurred in 52 patients (43%). Long-term IRAE led to 5 hospitalizations (4%) of which 4 were grades 3-4. Among patients with long-term IRAE, 45 patients (87%) previously experienced IRAE within the first 2 years of anti-PD1 and 29 patients (56%) experienced multiple IRAE. Conclusions: Our data demonstrate that long-term IRAE are frequent especially in patients who already experienced IRAE within the first two years of treatment. These data should be taken into account to establish formal recommendations on the duration of anti-PD1 therapy.

e21042 Background: Immunotherapy (IT) has demonstrated an improved overall survival (OS) in advanced melanoma with 15% complete responses (CR) in treatment-naïve patients (pts) with brain metastases (met) in the anti-PD1/anti-CTLA4 combination. However, data on brain-met pts who discontinue treatment (EoT) after achieving a CR are lacking. Methods: Disease characteristics and clinical outcome were retrospectively collected from 6 centers on advanced melanoma pts treated with anti-PD1 or anti-PD1/anti-CTLA4. Pts were followed for at least 10 weeks (10.8 – 242). Off-treatment survival (OTS) was defined as time between last IT dose to disease progression or death. Results: Out of 890 pts, 62 achieved a CR; 40 pts stopped treatment due to CR, while 22 due to an adverse event (AE) (n = 19) or investigator decision (n = 3) with subsequent CR. 14 were treated with anti-PD1/anti-CTLA4 and 48 with anti-PD1. 24 had a BRAF mutation, of which 10 had previously received targeted therapy (TT). The median time to first CR was 31 weeks (6 – 138), median duration of response and OTS was 91.1 and 60.7 (10.6 – 242) weeks respectively. OTS was numerically longer for those pts with EoT after AE (85 weeks, 13-242) versus those with EoT due to CR (60 weeks, 11-130). Median OS was not reached. 6/62 (3%) progressed after EoT; 4 locoregionally while 2 were subsequently treated with IT. All pts were alive at last follow-up. 19 pts had brain mets. 8 were BRAF mutated. 10 were treatment naïve, 6 received previously anti-CTLA4, 1 chemotherapy and only 2 TT. Data on reasons for EoT and responses in brain mets are seen in the table. Conclusions: Early data suggest that OTS is numerically longer in patients with EoT due to AE with subsequent CR. EoT due to sustained CR is a feasible option also in brain mets. EoT due to AE with subsequent CR was a more frequent event in the combination treatment. [Table: see text]

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.

9556Background: Melanoma brain metastases (BM) are associated with poor prognosis. Although novel therapies such as ipilimumab (IPI) and anti-PD1 (aPD1: nivolumab and pembrolizumab) have shown thei...

9072 Background: The BRAF inhibitor Vemurafenib (V) improves survival in BRAFV600 mutated metastatic melanoma patients, with a 59% response rate (BRIM-3). The aim of this retrospective study is to ...