Immunotherapy with immune checkpoint inhibitors (ICI) is widely used to treat cancers, and reports of rare immune-related adverse events (irAEs) are increasing. Ear, nose, and throat (ENT) irAEs are often underestimated, as patients rarely report rhinorrhea and most cases of sinusitis are asymptomatic, detected only during tumor CT assessments. We report a rare case of severe rhinosinusitis with hearing loss after ipilimumab and nivolumab combination therapy for melanoma. Due to steroid dependency, the patient was successfully treated with intravenous infliximab but was left with residual deafness. Physicians should be aware of these potentially serious ENT complications, which can affect quality of life, to allow timely referral to an ENT specialist. In severe cases, multidisciplinary care is needed to consider steroid-sparing treatments such as infliximab.

PURPOSE:Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS:Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS:Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco + bini, grade ≥ 3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco + bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco + bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION:EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

Background Specific data regarding Progression-Free Survival (PFS) and treatment maintenance estimated by Time To Next Treatment (TTNT) in patients with advanced melanoma responding to first-line treatments are scarce. Objective To evaluate and compare in a real-life setting PFS and overall TTNT in patients with advanced melanoma responding to first-line treatment within three therapeutic subsets: BRAF and MEK inhibitors (group 1), anti-PD1 (group 2) and anti-PD1/Anti-CTLA4 immunotherapies (group 3); and to perform comparative analyses of PFS and TTNT according to response depth (complete or partial response), brain metastases (BM), and per-treatment disease progression. Patients and Methods Patients with unresectable stage III or IV melanoma registered in the French nationwide multicenter Melbase database and responding to first-line immunotherapy or targeted therapy were retrospectively included. Overall and situation-specific PFS and TTNT were assessed and compared within and between therapeutic groups. Results Median PFS was 10.7 months, 84.6 months, and not reached in group 1, 2 and 3 respectively. No obvious difference was observed between PFS and TTNT for patients receiving targeted therapies (TT) and combined anti-PD1/CTLA4 immunotherapy. Conversely, TTNT largely exceeded PFS in patients receiving anti-PD1 alone, with an increasing gap over time. Similar trends were observed in patients with BM and in those experiencing per-treatment disease progression. Conclusion First-line combined anti-PD1/Anti-CTLA4 immunotherapy was associated with the most durable response in patients with advanced melanoma considered as responders, compared with anti-PD1 alone or targeted therapy, independently of BM status. Anti-PD1 monotherapy was frequently maintained beyond disease progression, in contrast to targeted therapy.

BACKGROUND:The Checkmate 067 randomized controlled trial, published in 2015, demonstrated improved progression-free survival (PFS) and numerically, although not statistically, superior overall survival (OS) for ipilimumab + nivolumab (I + N). OBJECTIVES:The objective of this study was to compare the efficacy and safety of N with I + N as first-line treatment for metastatic melanoma in a real-world setting. METHODS:Patients were prospectively included in the French MelBase cohort from 2013 to 2022. Eligible patients were those in first-line treatment for stage IIIc or IV melanoma, undergoing immunotherapy with N or I + N. The primary endpoint was OS at 36 months. The secondary endpoints included PFS at 36 months, best radiological response, and safety analyses. We conducted a propensity score using the inverse probability of treatment weighting (IPTW) method to overcome the various confounding factors and also a subgroup analysis (brain metastasis, lactate dehydrogenase levels and BRAF mutation status). RESULTS:Patients were treated with N (n = 406) or I + N (n = 416). OS at 36 months was higher in the I + N group at 57.1% [95% confidence interval (CI) 50.7-64.2] than in the N group [46.6% (95% CI 41.6-52.1)]; hazard ratio (HR) 1.4 (95% CI 1.1-1.8). PFS at 36 months was significantly improved in the I + N group (42.3%) compared with the N group (21.9%), with a HR of 1.6 (95% CI 1.4-1.9). The objective response rate (ORR) was similar for the two groups (44%). The overall incidence of side-effects was comparable (82% vs. 84%), and severe toxicity (grade ≥ 3) was more frequent, although not significantly so, in the I + N arm vs. the N arm (41% vs. 29%). CONCLUSIONS:Our results are consistent with those from the Checkmate 067 study, except for the ORR and the incidence of toxicities, which proved to be lower in our analysis.

BACKGROUND:Current first-line treatment for patients with metastatic melanoma with BRAFV600E or BRAFV600K mutations includes immunotherapy with immune checkpoint inhibitors and targeted therapy; however, the optimal sequencing of these treatments is unclear. We aimed to investigate the use of a targeted-therapy induction regimen before treatment with immune checkpoint inhibitors. METHODS:This open-label, randomised, controlled, phase 2 trial (EBIN) was conducted at 37 centres in eight European countries. Eligible patients were 18 years or older and had previously untreated, unresectable, stage III or IV melanoma with BRAFV600E or BRAFV600K mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to one of two groups. Those in the induction group received targeted therapy (oral encorafenib 450 mg once a day plus oral binimetinib 45 mg twice a day for 12 weeks) followed by immune checkpoint inhibitors (intravenous nivolumab 3 mg/kg plus intravenous ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by intravenous nivolumab 480 mg once every 4 weeks until unacceptable toxicity, disease progression, or 2 years of treatment). Patients in the control group received immune checkpoint inhibitors as above without any induction targeted therapy. Randomisation was conducted using a minimisation technique and was stratified by centre and a variable defined using stage and lactate dehydrogenase activity. The primary outcome was progression-free survival in the intention-to-treat population. Safety was assessed in all patients who initiated the protocol treatment. In this Article we report the primary analysis. The study is registered with ClinicalTrials.gov, NCT03235245, and is ongoing. FINDINGS:Between Nov 12, 2018, and July 11, 2022, 271 patients were randomly assigned: 136 to the induction group and 135 to the control group. 103 (38%) patients were female, 168 (62%) were male, and the median age was 55 years (IQR 43-66). The median follow-up time was 21 months (IQR 13-33). There was no evidence of a longer progression-free survival in the induction group than in the control group (hazard ratio 0·87, 90% CI 0·67-1·12; p=0·36). The median progression-free survival was 9 months (95% CI 7-13) in the induction group and 9 months (5-14) in the control group. Grade 3-5 treatment-related adverse events occurred in 57 (42%) of 136 patients who started treatment in the induction group and in 42 (32%) of 131 patients who started treatment in the control group. The most common grade 3-4 treatment-related adverse event was hepatitis (17 [13%] of 136 patients in the induction group and nine [7%] of 131 patients in the control group). Serious treatment-related adverse events occurred in 45 (33%) of 136 patients in the induction group and 33 (25%) of 131 patients in the control group. There were three treatment-related deaths: two from cardiac events (heart failure and arrhythmia) in the induction group and one from meningitis in the control group. INTERPRETATION:The targeted-therapy induction regimen did not improve progression-free survival compared with first-line treatment with immune checkpoint inhibitors in unselected patients with advanced melanoma with BRAFV600E or BRAFV600K mutations. FUNDING:Bristol Myers Squibb and Pierre Fabre.

Background: Nivolumab obtained approval in advanced melanoma (AM) with weight-adjusted dose (WAD) administration (3 mg/kg/2 weeks). In 2018, the dosage regimen was changed to flat dose (FD) administration (240 mg/2 weeks or 480 mg/4 weeks) based on a modeling study, without clinical data. Methods: AM patients have been prospectively included in the French national multicenter MelBase database since 2013. First-line patients treated with nivolumab monotherapy were included in the WAD or FD groups of this study. The primary end point was the incidence of grade >= 3 immune-related adverse events (irAEs). Secondary end points were incidence of any grade irAEs, and overall survival (OS) and progression-free survival (PFS). Inverse probability of treatment weighting was used to balance groups on their baseline characteristics. Results: Between 2015 and 2022, 348 patients were included: 160 in the WAD and 188 in the FD groups. In the FD group, 45% and 27% of patients weighed <75 kg and >85 kg, respectively. Grade >= 3 and any grade irAEs rates were 13.1% versus 11.7% (p = .8) and 63.1% versus 67.0% (p = .5) in the WAD and FD groups, respectively. After weighting, median PFS was 3.1 and 3.7 months (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.65-1.07), and median OS was 24.8 and 37.0 months (HR, 0.74; 95% CI, 0.54-1.01) in the WAD and FD groups, respectively. Conclusions: There was no difference in the incidence of severe irAEs and in median PFS between AM patients treated by WAD or FD nivolumab. The median OS between patient groups did not reach statistical significance.

Diagnosing atypical melanocytic proliferations (AMPs) is histologically challenging, and hence, these cases are referred to expert dermatopathologists for second opinions. The impact of such diagnoses varies depending on the case. Our study retrospectively analysed 6006 AMPs referred for second opinions over 13 years (the largest series to date), classifying them into the four Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis version 2.0 (MPATH-Dx-V2.0) classes. MPATH-Dx-V2.0 does not supplant existing nomenclature/classifications but is a complementary tool (based on the probabilistic tumour-progression risk) enabling clinicians to better prioritise problems and assess their impact on patient management. We propose a step-by-step ​integrative methodology using the 5th World Health Organization and MPATH-Dx classifications. MPATH-Dx classes I and II (76.4%), which carry favourable prognoses, presented the most frequent diagnostic problems. Invasive thick melanoma mimicking a naevus accounted for 50% of class IV melanomas and was the predominant differential diagnosis for class II melanocytomas. Low- and high-grade dysplastic naevi and melanoma in situ were problematic in 24.5% and 25.6% of class I and II lesions, respectively. Atypical Spitz/spitzoid tumours were the second major diagnostic challenge, representing 50% of class II compared with 11% for other melanocytomas. Other frequently encountered difficult histopathological diagnoses included inflamed tumours, combined naevi, special-site atypical naevi, and melanoma regression. Our results identified the most common problems encountered by pathologists in routine practice through the application of the MPATH-Dx v2.0 classification. We propose a step-by-step integrative methodology to interpret AMPs, aiming to optimise patient management by enhancing non-pathologists' understanding of diagnostic terminology.

PURPOSE:Patients with anti-PD-1-resistant melanoma (MEL) have no well-defined standard of care. BO-112 is a synthetic, double-stranded RNA (poly I:C) nanoplexed with polyethylenimine that when administered intratumorally has showed in patients with solid tumors potential to revert this resistance. We report efficacy and safety of the phase II clinical trial of intratumoral BO-112 plus intravenous pembrolizumab for patients with anti-PD-1-resistant MEL (ClinicalTrials.gov identifier: NCT04570332). METHODS:Forty-two patients were treated with intratumoral BO-112 once every week for 7 weeks and then once every 3 weeks (up to 2 mg and up to eight lesions per treatment) combined with 200 mg pembrolizumab once every 3 weeks until progressive disease, unacceptable toxicity, death, or up to 1 year. Primary end point was RECIST 1.1 objective response rate (ORR) by independent central radiology review in modified intention-to-treat population (mITT; patients evaluable for response) with 20% ORR positivity threshold. Secondary key end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. RESULTS:For mITT, there were 40 patients and the ORR was 25%, with 10% complete, 15% partial, and 40% stable disease, with nonachieved (NA) median DOR (95% CI, 8.3 to NA). For ITT, there were 42 patients, and the median PFS and OS were 3.7 months (95% CI, 2.2 to 9.2) and NA (95% CI, 9.9 to NA), respectively, with 54% patients alive at 24 months. The combination was well tolerated: 16 patients (38.1%) experiencing ≥G3-4 adverse events, four (9.5%) drug-related, and no deaths related to treatment. CONCLUSION:The clinical trial has met its primary end point (ORR) making BO-112 with pembrolizumab a potential strategy to revert anti-PD-1 resistance in patients with MEL. PFS results are in line with other clinical trials in anti-PD-1-resistant scenario, with promising OS data.

LBA9501 Background: Resected stage IIB/IIC melanoma has a high risk of recurrence. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-PD-1 significantly improve recurrence-free survival (RFS) vs. placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF&MEK inhibitor therapy showed benefit in high-risk stage III & advanced disease, but its role in patients with fully resected BRAF -mutated stage IIB/IIC melanoma is unknown. Encorafenib and binimetinib could be considered a valuable alternative with a lower risk of chronic toxicities. Methods: Adult patients with fully resected stage IIB or IIC cutaneous melanoma who harbored a BRAF mutation V600E or K were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients. It was designed to demonstrate superiority regarding the primary endpoint RFS defined as time from randomization to the earliest of recurrence, new melanoma that was either ulcerated, thick or requiring a treatment other than surgery, or death with a power of 97% to detect a hazard ratio (HR) of 0.55 and 91% to detect a HR of 0.6 with a level of statistical significance of 0.025 for a one-sided log-rank test. Following a premature termination of accrual, the study was amended to become a randomized trial with safety as the primary and RFS a secondary endpoint. Results: Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 were equally randomized between enco+bini and placebo arms. Median age was 59 yrs and 54% were male. Data cutoff was on 19 Nov. 2024, after the last patient was discontinued from the study. Among randomized patients, 87 (79%) had BRAF V600E and 23 (21%) V600K mutation, 71 (65%) AJCC8 stage IIB and 39 (35%) IIC. Median follow-up was 12 and 7 months for enco+bini and placebo arms. Among 54 patients who initiated enco+bini, grade ≥3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. A serious treatment-related adverse event occurred in 1 patient. No patients died. In the enco+bini and placebo arm, respectively, 4 and 9 patients had an RFS event and 3 and 5 developed distant metastases. Descriptive RFS at 12 months was 86% (95% CI: 65-95%) in the enco+bini and 70% (95% CI: 46-85%) in the placebo arm, Distant Metastasis-Free Survival (DMFS) at 12 months was 92% (95% CI: 77-97%) for enco+bini and 82% (95% CI: 55-93%) for placebo arms. Conclusion: EORTC 2139 - Columbus-AD demonstrated a consistent safety profile for enco+bini. Descriptive analyses of efficacy show encouraging results of the combination of enco+bini for adjuvant treatment of stage IIB/C BRAF V600E/K cutaneous melanoma. Clinical trial information: NCT05270044 .

Uveal melanoma (UM) is a rare malignancy originating from uveal melanocytes. Despite effective control of the primary tumour, metastatic uveal melanoma (MUM) occurs in approximately 20-30% of patients, primarily affecting the liver, with a poor prognosis and overall survival (OS). The unique molecular profile of UM, lacking BRAF, NRAS, and KIT mutations, limits targeted therapy efficacy. Chemotherapy and immune checkpoint inhibitors (ICIs) also show limited benefits, while tebentafusp has emerged as the first drug to improve OS, but this systemic treatment can be used only in HLA-A*02:01-positive patients. A French multidisciplinary panel developed evidence-based guidelines for MUM management presented in this review. Recommendations emphasise on comprehensive diagnosis, including liver biopsy and imaging, circulating tumour DNA (ctDNA) analysis, and high-definition HLA typing for HLA-A*02:01. Local therapies are proposed for patients with limited hepatic metastases, from liver surgery to isolated hepatic perfusion and chemoembolisation for patients with more extensive hepatic involvement. Systemic therapy with tebentafusp is the standard of care for HLA-A*02:01-positive patients. For HLA-A*02:01-negative patients with extensive disease, treatment options are limited. They are encouraged to participate in a clinical trial, alternatively, percutaneous hepatic perfusion, ICI alone or in combination can be proposed. Treatment efficacy assessment includes response evaluation criteria in solid tumours (RECIST), tumour growth rate (TGR) analysis, and ctDNA dynamics. This consensus provides practical guidelines for French oncologists to optimise MUM management, integrating locoregional interventions, systemic therapies, and biomarkers to enhance patient outcomes.

The link between palliative care and oncology must continue to develop, taking into account advances in treatment.Immune checkpoint inhibition (ICI) for metastatic melanoma is associated with different types of response, making it difficult to assess the benefits to the patient. Some clinical trials suggest a survival advantage of ICI even in the absence of an objective radiographic response. The aim of this study is to assess the impact of continuing ICI after progression of the disease on the overall survival (OS) in a cohort of final-line metastatic melanoma patients. Clinical data from 120 patients with metastatic melanoma were collected via Melbase, a French multicentric biobank, prospectively enrolling unresectable melanoma. Two groups were defined: patients continuing final-line ICI at progression (treated) and patients stopping ICI at progression (controls). The primary end-point is the OS from progression. Propensity score weighting was used to correct for indication bias. From the 120 patients, 72 (60%) continued ICI. Median OS from progression was 4.2 months [95% confidence interval (CI) 2.6-6.27] in the treated group and median OS was 1.3 months (95% CI 0.95-1.74) in the control group (P < 0.0001). The calculated hazard ratio was 0.20 (0.13-0.33). Continued ICI was discovered to have an association with a higher rate of hospitalization at the end of life; more treatments received in the last 15 days of life and less utilization of specialist palliative care. This study discovered that patients with metastatic melanoma show a significant decrease in the instantaneous probability of mortality when they continue with finale-line ICI after progression.

Cardiac metastasis from melanoma is a rare but clinically significant condition often underdiagnosed because of its asymptomatic nature. This retrospective case series examines six patients with metastatic melanoma treated at the University Hospital of Bordeaux who were incidentally found to have cardiac metastases during follow-up. The patients were treated with immune checkpoint inhibitors (ICIs) either alone or combined with surgical excision of cardiac lesions. Outcomes were mixed, with three (50%) patients achieving a complete response, one (16.7%) a partial response, and two (33.3%) experiencing disease progression. Cardiac metastasectomy, when combined with ICI, showed promising results in selected patients, highlighting a potential survival benefit and enhanced tumor control with a multimodal approach. This series emphasizes the importance of considering cardiac metastases in differential diagnosis and underscores the role of imaging in early detection. While ICI therapy shows effectiveness, further studies are needed to refine treatment strategies and improve outcomes for patients with cardiac involvement.

Diagnosing atypical melanocytic tumors can be challenging without molecular characterization, necessitating simple tools to enhance diagnostic accuracy in daily practice. This study retrospectively analyzed the utility of p16 immunohistochemistry (IHC) and 9p21 fluorescence in situ hybridization (FISH) on 206 tumors referred for expert second opinion. The performance of p16 and 9p21 was compared to histological diagnosis (both initial and final respectively without and with p16 and 9p21 status), histological subtype, and follow-up data. Negative p16 immunolabelling detected 90% of malignant cases, while only 11% of benign tumors were p16 negative. Homozygous 9p21deletion detected 42% of malignant tumors and excluded 95% of benign ones. Heterozygous deletion showed no diagnostic value. Homozygous 9p21 deletion significantly improved diagnostic confidence (P < 0.001), leading to tumor upgrading (n = 23) or melanoma confirmation (n = 22). Among 97 patients with follow-up, 17 had adverse outcomes. Kaplan-Meier analysis showed no significant difference in progression-free survival between groups (P = 0.64). Combining both techniques ultimately enhanced histological diagnostic confidence in daily practice. However, in cases where p16 is negative without homozygous deletion, or where histological malignancy is uncertain and p16 positive, other p16-inactivation mechanisms or molecular anomalies should be considered, necessitating further molecular investigations.

BACKGROUND:Merkel cell carcinoma (MCC) is an aggressive skin cancer causing distant metastases in 30 % of cases but rarely involving the brain. PD-1/PD-L1 inhibitors constitute the standard treatment of advanced MCC but their impact on brain metastases is unknown. METHODS:This retrospective study included MCC patients with central nervous system (CNS) metastases from the French CARADERM registry and the Groupe de Cancérologie Cutanée network. Primary objective was to assess CNS metastases incidence. Secondary objectives included response and survival. RESULTS:Among 1056 MCC patients, CNS metastases incidence was 0.3 % at baseline and 2.6 % throughout the disease course, reaching 7.0 % in stage IV patients. In 37 patients with CNS metastases, median time from diagnosis to CNS metastases was 15.7 months. Extra-CNS metastases preceded CNS involvement (n = 23) with a median delay of 7.3 months. PD-1/PD-L1 inhibitors were administered before (n = 20) and/or after (n = 23) CNS metastases onset. Intra-cranial responses (n = 15) occurred regardless of prior treatment before CNS metastases. Most (9/15) occurred following stereotactic radiosurgery (SRS) plus immunotherapy, with longer median response duration (15.3 months) versus other treatments (5.1 months). Of prior PD-1/PD-L1 complete responders, 4/6 achieved intracranial response. Median OS and PFS after CNS metastases were 6.6 months and 4.7 months, respectively. PD-1/PD-L1 inhibitors and SRS were associated with improved survival in univariate analysis. CONCLUSION:CNS metastases are rare, late, and often fatal. PD-1/PD-L1 inhibitors with SRS are likely to constitute the optimal treatment. The quality of response to PD-1/PD-L1 inhibitors prior to CNS metastases predicts intracranial disease control.

Immune checkpoint inhibitors (ICIs) present clinicians with the challenge of managing immune-related adverse events (irAEs), which can range from mild to severe due to immune system activation 1. While guidelines recommend discontinuing ICIs for grade 3 partial and all grade 4 irAEs, there is growing interest in rechallenging patients based on oncological outcomes, particularly for cardiovascular and neurological irAEs where data remains scarce 1,2. We retrospectively evaluated the safety of ICI rechallenge following grade 3-4 irAEs, specifically focusing on cardiovascular and neurological events, in patients discussed at our multidisciplinary immunotoxicity assessment board between 2019 and 2021. Fifteen patients were included, with a median time to severe irAE onset of 49 days. Among them, five patients experienced neurological adverse events (NAEs): aseptic meningitis (3), inflammatory polyradiculoneuropathy (1), and ophthalmoplegia (1), while one patient presented with myocarditis. Of the 15 patients retreated with ICIs after initial severe irAEs, 11 (73%) remained free of subsequent irAEs, two (13%) experienced recurrence of the initial irAE, and two (13%) developed new irAEs distinct from the initial event. The median time to event recurrence was 69 days, occurring no earlier than the initial severe irAE. In the subset analysis focusing on severe cardiovascular and neurological irAEs, rechallenge with ICIs was generally well tolerated. However, one patient treated with anti-PD1 experienced a relapse of grade 2 aseptic meningitis. Overall, our findings suggest that rechallenging with ICIs after severe irAEs, including those affecting the cardiovascular and neurological systems, may be safe, particularly after irAE regression and corticosteroid withdrawal.

9537 Background: Avelumab, an anti–PD-L1 antibody, has been approved in multiple countries for the treatment of mMCC based on the results of the pivotal phase 2 JAVELIN Merkel 200 trial (NCT02155647). In pts who received avelumab as 2L+ treatment in the trial (part A), median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 2.7 months. The French health technology assessment agency requested the collection of real-world data from pts with mMCC from a comprehensive registry; data are reported here. Methods: This retrospective, noninterventional, real-world study evaluated all pts with mMCC in France using combined data from 2 databases: CARADERM (French national database of rare dermatological cancers) and Système National des Données de Santé (SNDS; national healthcare database). For this analysis, eligible pts were diagnosed with mMCC and initiated 2L+ avelumab outside of a clinical trial between August 2016 and December 2019. Pts were followed for 24 months after initiation of avelumab. Probabilistic linkage was performed to identify pts registered in both databases. OS and PFS were analyzed using Kaplan-Meier methodology. Safety data were not collected. Results: A total of 180 pts who received 2L+ avelumab were identified, data were obtained for 112 pts from the CARADERM database and for 68 additional pts after SNDS linkage. Median age at diagnosis was 74.0 years, 66.7% were male, and 98.3% received chemotherapy as first-line treatment. Median follow-up was 13.1 months. 79.5% of CARADERM database pts had discontinued avelumab; the most common reasons specified were progressive disease (36.4%), complete response (17.0%), and death (13.6%). Median OS was 14.6 months (95% CI, 9.9-21.3 months) overall; in CARADERM database pts, median OS was 15.9 months (95% CI, 8.6-28.3 months) vs 13.3 months (95% CI, 6.7-19.1 months) in non-CARADERM database pts. 12- and 24-month OS rates in the overall population were 53.8% (95% CI, 46.2%-60.8%) and 40.5% (95% CI, 33.2%-47.6%), respectively. In CARADERM database pts (data not available in non-CARADERM database pts), median PFS was 3.6 months (95% CI, 2.7-7.5 months), and the objective response rate was 55.3% (95% CI, 45.3%-65.4%), including complete response in 31.9%. Median duration of response was 39.3 months (95% CI, 24.3 months-not estimable). Conclusions: In this real-world study of national data from France, outcomes with avelumab as 2L+ treatment for mMCC were similar to those observed in part A of the JAVELIN Merkel 200 trial. These findings confirm the effectiveness of avelumab in pts with mMCC that have progressed following first-line systemic treatment in routine clinical practice.

LBA9503 Background: The benefit of an induction treatment with targeted therapy (TT) with BRAF+MEK inhibitors prior to a combined immunotherapy (IT) with ipilimumab (ipi) + nivolumab (nivo) in patients (pts) with advanced BRAF-V600E/K mutant melanoma is still unclear. Methods: EBIN is an international randomized controlled phase II trial comparing upfront IT (arm A: nivo [3mg/kg] + ipi [1mg/kg] q3w x4 followed by nivo 480 mg q4w) with the sequential approach (arm B: 3 months induction with TT with encorafenib 450 mg QD + binimetinib 45 mg BID orally, followed by IT using the same regimen as in arm A), total treatment [Tx] duration in both arms: 2 years. In arm B, pts were allowed to be rechallenged with TT after progression. Pts with measurable BRAF-V600E/K unresectable stage III/IV melanoma, except pts with uveal melanoma, untreated or symptomatic brain or leptomeningeal involvement were randomly assigned 1:1 to arm A or B. Prior Tx for advanced melanoma was not allowed but adjuvant Tx completed at least 6 months before randomization was permitted. The primary objective was to show superiority of arm B in progression-free survival (PFS) using the log-rank test stratified by stage and lactate dehydrogenase (LDH) with a 1-sided alpha error set at 5%. The study had a power of 80% to detect a HR of 0.65. The study planned to randomize 135 pts in each arm. Results: All 136 pts randomized to arm B and 131 out of 135 in arm A started protocol Tx. At baseline, 170 (63%) pts had stage M1c, 129 (48%) had LDH above upper limit normal (ULN), 74 (27%) had a liver metastasis, and 19 (7%) received adjuvant therapy. The median follow-up was 21 months. In arm B, 135 (99%) pts were free of progression at week 12, when the end of TT was scheduled. In the intention-to-treat population, there was no evidence of a longer PFS in arm B (HR = 0.87, 90% confidence interval [CI] 0.67-1.12, p = 0.36). In a prespecified subgroup analysis, the HR for arm B vs arm A was 2.09 (95% CI 0.96-4.53), 0.74 (95% CI 0.43-1.29), 0.86 (95% CI 0.54-1.37), and 0.46 (95% CI 0.21-1.03) in pts with stage III with LDH≤ULN or M1a, M1b/M1c with LDH≤ULN, ULN < LDH≤2ULN, and LDH > 2ULN, respectively (p-value for interaction 0.045). In a post-hoc subgroup analysis, pts with ≥3 metastatic sites or a sum of target lesions ≥10cm at baseline did not have a longer PFS in arm B but in pts with liver metastasis the Tx HR was 0.48 (95% CI 0.28-0.80, p-value for interaction 0.008). The objective response rate was 53% in arm B and 45% in arm A. Complete response rate was 12% in arm B and 10% in arm A. Grade ≥3 adverse events occurred in 58% of pts in arm B and 51% in arm A. Conclusion: The EBIN trial shows there is no difference in PFS between the two treatment arms for unselected patients but supports the hypothesis that patients with very high LDH and those with liver metastases benefit from the sequential approach. Clinical trial information: NCT03235245 .

Introduction Immune checkpoint inhibitors-induced inflammatory arthritis (ICI-IA) affects about 5% of ICI recipients. We aimed (1) to characterize the resolution of ICI-IA during ICI treatment and after ICI discontinuation and (2) to assess how ICI-IA influences ICI management across time. Methods All ICI-treated patients referred to rheumatology at Bordeaux University Hospital were identified and patients with ICI-IA with a follow-up of≥6months after ICI-IA onset were included. Resolution of ICI-IA was defined by discontinuation of ICI-IA medications without recurrence of ICI-IA symptoms. Results Resolution of ICI-IA occurred in 13 of 80 patients (16%) while maintaining active ICI treatment, mainly in patients with polymyalgia rheumatica (PMR)-like clinical presentation (P=0.03). Synovitis was more frequent in those whose ICI-IA persisted throughout ICI treatment. In patients with persistent ICI-IA throughout ICI treatment, 34 (50%) and 47 (70%) resolved at 6- and 12-months post-ICI discontinuation, respectively. Reason for terminating ICI was more frequently cancer stable or in remission in those who still had active ICI-IA at 6- and 12-months post-ICI discontinuation. Both progression-free survival and overall survival were longer in the groups with active ICI-IA at 6- and 12-months after ICI discontinuation. Discussion In this cohort, ICI was safely continued in most patients experiencing ICI-IA. About one sixth of ICI-IA resolved despite maintaining active ICI treatment and allowing ICI-IA treatment discontinuation without recurrence of symptoms, mainly in those with PMR-like presentation. Larger studies are needed to determine predicting factors of resolving ICI-IA to minimize exposure to immunosuppressive treatment.

Introduction Les inhibiteurs de point de contrôle immunitaire ont révolutionné la prise en charge du carcinome épidermoïde cutané avancé (CECa), localement et métastatique. Le traitement par anti-PD-1 est désormais la référence thérapeutique pour les patients non candidats à un traitement local. Il a été montré que la qualité du microbiote intestinal est un facteur important de réponse tumorale et peut potentiellement interagir avec l’efficacité des immunothérapies. Il a été rapporté que les antibiotiques (AB) pouvaient avoir un impact négatif sur la réponse tumorale, mais cela n’a pas été étudié dans le contexte du CECa, malgré l’utilisation importante d’antibiotiques dans cette population.L’objectif est d’évaluer la prévalence de la prescription d’AB au début de l’immunothérapie dans le CECa et analyser leur impact sur la réponse au traitement. Matériel et méthodes Cette étude rétrospective monocentrique a inclus entre mars 2019 et juillet 2023 tous les patients ayant débuté un traitement anti-PD1 pour un CECa. Ils ont été suivis jusqu’en septembre 2023. La prise d’AB dans les trois mois précédant et suivant le début de l’immunothérapie a été enregistrée. La réponse au traitement, la survie globale, la survie spécifique et la survie sans progression ont été comparées chez ceux avec et sans AB. Résultats Parmi les 104 patients inclus, d’âge moyen de 76 ans dont 78 étaient des hommes, 47 avaient reçu des AB pendant la période étudiée, dont 21 durant la période d’un mois avant ou après le début de l’immunothérapie.Les patients ayant reçu des AB étaient plus jeunes que ceux n’en ayant pas reçu (p=0,005). Les stades TNM, l’état général et les comorbidités étaient semblables dans les 2 groupes.Les patients non exposés aux AB présentaient des taux de contrôle de la maladie significativement meilleurs après 3 mois de traitement que ceux exposés aux AB (70 % contre 49 %, p=0,02). La survie totale et la survie spécifique étaient significativement plus faibles dans le sous-groupe de patients ayant reçu des AB 1 mois avant et 1 mois après le début de l’immunothérapie, par rapport à ceux n’en ayant pas reçu (respectivement p=0,04 et p=0,01, test du log rank). De plus, la survie médiane sans progression était de 127 jours chez les patients traités par AB, significativement plus faible que chez les patients sans AB (médiane de survie non atteinte, p=0,003). Discussion Dans notre population, 45 % des malades étaient exposés à des AB dans la période du début de l’immunothérapie, ce qui paraît important, dont 20 % dans une période plus courte de 1 mois avant/1 mois après, ce qui paraît avoir un impact négatif. En effet, le taux de contrôle de la maladie ainsi que la survie globale et spécifique étaient plus faibles chez ces malades. Conclusion Il paraît important d’informer les médecins de l’effet potentiellement délétère des antibiotiques chez les patients atteints de CECa en attente de traitement systémique, et de bien évaluer leur pertinence.