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Abstract Background The anti-Programmed Death receptor 1 (anti-PD-1) antibodies nivolumab and pembrolizumab are new treatments in metastatic melanoma. Immunotherapies are best known to be responsible for thrombotic microangiopathy. However, immune interstitial nephritis has been described in a patient treated by nivolumab and ipilimumab concomitantly, and three cases of granulomatous interstitial nephritis have been reported with ipilimumab monotherapy. We report herein a case of acute interstitial immune nephritis in a patient treated with nivolumab after ipilimumab for pulmonary metastatic melanoma. Case presentation Interstitial nephritis was diagnosed after acute kidney injury following three cycles and was confirmed by kidney biopsy. Kidney injury responded rapidly to prednisolone, which was then gradually reduced. As a follow-up computed tomography scan indicated mixed response, with minimal size progression of a pulmonary nodule, but a significant reduction in the size of the other nodules, nivolumab was reintroduced after renal function improvement. Low-dose corticosteroids were first maintained during nivolumab treatment and subsequently discontinued. Only one month after prednisolone discontinuation, creatinine levels increased. A second kidney biopsy confirmed relapse of acute interstitial nephritis. Conclusions To our knowledge, this is the first case of nivolumab-induced acute interstitial immune nephritis. This case highlights that anti-PD-1 immunotherapy may be continued when renal function is adequate, and this requires close interaction between dermatologists and nephrologists. This adverse effect should be made known to prescribers as nivolumab is associated with significant improvement of survival in metastatic melanoma and may be used in many different types of cancer.

BackgroundThe tumor mutational burden (TMB) is high in melanomas owing to UV-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 survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment.Patients and methodsPatients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS).Results973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients’ characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). 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). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively).ConclusionOur study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.

Abstract Metastatic melanoma patients carrying a BRAFV600 mutation can be treated with a combination of BRAF and MEK inhibitors (BRAFi/MEKi), but innate and acquired resistance invariably occurs. Predicting patient response to targeted therapies is crucial to guide clinical decision. We describe here the development of a highly efficient patient‐derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI‐PDXTM). In this in vivo paradigm, we depict a fast and reproducible tumor engraftment of patient samples within the embryonic skin, preserving key molecular and phenotypic features. We show that sensitivity and resistance to BRAFi/MEKi can be reliably modeled in these AVI‐PDXTM, as well as synergies with other drugs. We further provide proof‐of‐concept that the AVI‐PDXTM models the diversity of responses of melanoma patients to BRAFi/MEKi, within days, hence positioning it as a valuable tool for the design of personalized medicine assays and for the evaluation of novel combination strategies.

Introduction: Nail diseases are often diagnosed late with a potential prognostic and functional im-pact. This could be partly due to knowledge gaps among primary care physicians (PCPs). Objectives: To evaluate the knowledge about diagnosis and management of ten common/important nailconditions in a population of French PCPs and its improvement after a 31-minute online training session. Methods: We submitted 10 pre-test and post-test clinical cases and an educative online course on the diagnosis and the management of nail diseases to 138 volunteer PCPs; 73 completed the whole training path. Results: Compared to pre-test, more PCPs in the post-test required an urgent second opinion to der-matologist for pigmented melanoma (100% versus 80.3%; P

Abstract Background Cytotoxic chemotherapy (CC) is currently used in metastatic melanoma after patients have developed resistance to immune checkpoint inhibitors (ICI) and/or Mitogen‐Activated Protein Kinase inhibitors (MAPKi). We sought to evaluate if a previous treatment by ICI or MAPKi influences clinical outcomes in patients treated by CC in metastatic melanoma. Methods Eighty‐eight patients with a metastatic melanoma, treated by CC after a previous treatment by ICI or MAPKi between January 2009 and October 2019, were retrospectively analyzed. Progression‐Free‐Survival (PFS), Overall Survival (OS), Overall Response Rate (ORR), and Disease Control Rate (DCR) were evaluated in patients treated by CC according to their prior treatment by ICI or MAPKi. Results Patients treated by CC after ICI tended to have a better median PFS (2.81 months (2.39–5.30) versus 2.40 months (0.91–2.75), p = 0.023), median OS (6.03 months (3.54–11.54) versus 4.44 months (1.54–8.59), p = 0.27), DCR (26.0% vs. 10.5%, p = 0.121) and ORR (22.0% vs. 7.9% p = 0.134) than those previously treated by MAPKi. Conclusions A prior treatment by an MAPKi may be associated with a worse response to CC than ICI, and further investigations should be performed to confirm if there is a clinical benefit to propose CC in this setting.

Immunotherapies blocking negative immune checkpoints are now approved for the treatment of a growing number of cancers. However, even in metastatic melanoma, where sustained responses are observed, a significant number of patients still do not respond or display resistance. Increasing evidence indicates that non-genetic cancer cell-intrinsic alterations play a key role in resistance to therapies and immune evasion. Cancer cell plasticity, mainly associated with the epithelial-to-mesenchymal transition in carcinoma, relies on transcriptional, epigenetic or translational reprogramming. In melanoma, an EMT-like dedifferentiation process is characterized by the acquisition of invasive or neural crest stem cell-like features. Herein, we discuss recent findings on the specific roles of phenotypic reprogramming of melanoma cells in driving immune evasion and resistance to immunotherapies. The mechanisms by which dedifferentiated melanoma cells escape T cell lysis, mediate T cell exclusion or remodel the immune microenvironment will be detailed. The expanded knowledge on tumor cell plasticity in melanoma should contribute to the development of novel therapeutic combination strategies to further improve outcomes in this deadly metastatic cancer.

(1) Background: Ipilimumab plus nivolumab (combo-ICI) improves overall survival (OS) in patients with advanced renal cell carcinoma (RCC) or melanoma. The impact of bone metastases (BM) on survival outcomes of combo-ICI-treated patients is unknown. (2) Methods: This single-center retrospective observational study involved 36 combo-ICI-treated patients with advanced RCC and 35 with melanoma. Clinical and laboratory data preceding the initiation of combo-ICI were collected. Univariate and multivariate Cox proportional hazard models were used to assess the effect of BM on overall survival (OS) and progression-free survival (PFS). (3) Results: zNine RCC and 11 melanoma patients had baseline BM. In unadjusted analysis, baseline BM was associated with a poorer OS in the RCC cohort. Baseline BM did not have any impact on survival outcomes in melanoma patients. After adjustment on baseline performance status and on neutrophil-to-lymphocyte ratio (NLR), the impact of BM was no longer significant, but a NLR ≥ 3 was significantly associated with a poorer OS in the RCC cohort. (4) Conclusions: The presence of baseline BM seems to be associated with worse outcomes in RCC combo-ICI-treated patients, while its effect might not be independent from the inflammatory state (approximated by the NLR). BM seems to have no impact on the outcomes of melanoma combo-ICI-treated patients.

Abstract Background Nivolumab is a fully human antibody which is routinely used at first therapy for metastatic melanoma. Usually, side effects are immune-related adverse events. We report a case of a man who developed bilateral anterior uveitis and macular serous retinal detachment during nivolumab treatment for metastatic melanoma. Case presentation A man on nivolumab treatment for a leg melanoma with duodenal and lymph nodes metastases developed a sudden bilateral visual acuity impairment and bilateral non-painfull redness eyes several days after the third infusion. The clinical examination showed a significant decreased of the visual acuity. Slit lamp examination revealed the presence of bilateral granulomatous keratic precipitates, anterior chamber cells +++, bilateral synechiae, bilateral papilledema and macular edema associated with serous retinal detachment in the left eye. The anti-Programmed cells Death-1 was stopped and a topical corticosteroid treatment was administrated. After 8 days of topical corticosteroid treatment visual acuity was worsening with similar optical coherence tomography examination. An oral corticosteroid treatment was started. Evolution was favorable with a decrease of ocular inflammation and a complete visual acuity recovery after 3 weeks. Nivolumab was re-initiated. Conclusions This is the second clinical report of bilateral anterior uveitis associated with macular serous retinal detachment related to anti-PD-1 treatment, and the first with nivolumab. Cases of uveitis were reported several times. Although rare, ophthalmologic manifestations that are rapidly recognized and adequately managed can be treated.

Abstract Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF‐mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV600‐mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem‐like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi.