Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée).

BACKGROUND: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. MATERIALS AND METHODS: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). RESULTS: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. CONCLUSION: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.

Real-life practice of reflectance confocal microscopy in France: A prospective multicenter study.

BACKGROUND: Studies demonstrating the potential utility of reflectance confocal microscopy (RCM) have been performed under experimental conditions. OBJECTIVE: To provide an overview of RCM practice in real-life. METHODS: A multicenter, prospective study carried out in 10 university dermatology departments in France. RESULTS: Overall, 410 patients were enrolled. One-half of the patients (48%) were referred by private practice dermatologists. They were referred for diagnosis (84.9%) or presurgical mapping (13%). For diagnosis, the lesions were located on the face (62%), arms and legs (14.9%), and trunk (13.6%), and presurgical mapping was almost exclusively on the face (90.9%). Among those referred for diagnosis, the main indication was suspicion of a skin tumor (92.8%). Of these, 50.6% were spared biopsies after RCM. When RCM indicated surgery, histology revealed malignant lesions in 72.7% of cases. The correlation between RCM and histopathology was high, with a correlation rate of 82.76% and a kappa coefficient of 0.73 (0.63; 0.82). LIMITATIONS: This study was performed in the settings of French tertiary referral hospitals. CONCLUSION: This study shows that in real-life RCM can be integrated into the workflow of a public private network, which enables a less invasive diagnostic procedure for patients.

Personalized follow-up of circulating DNA in resected stage III/IV melanoma: PERCIMEL multicentric prospective study protocol.

BACKGROUND: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. METHODS: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence.

Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: a national multicentre study.

OBJECTIVES: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyse the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICIs) rechallenge. METHODS: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analysed in both groups. The modalities and outcomes of ICI rechallenge were reviewed. RESULTS: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favourable evolution, including one irM-related death, and required heavy immunosuppression. ICIs were safely reintroduced in nine patients presenting a moderate (n = 6) or a severe (n = 3) irM. CONCLUSION: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favour of a safe reintroduction of ICI following symptom resolution and creatin kinase (CK) normalization in moderate and severe forms of irM.

Characteristics of Pruritus in Bullous Pemphigoid and Impact on Quality of Life: A Prospective Cohort Study.

Pruritus is a common symptom of bullous pemphigoid (BP), but has been poorly studied. The aim of this study was to analyse the characteristics of pruritus in patients with BP and its impact on their quality of life. A multicentre prospective observational study (in 15 French hospitals) was performed. A total of 60 patients were included, with a mean age of 77.4 years. Pruritus occurred daily in 85% of patients, with a mean pruritus intensity of 5.2/10. Tingling sensations were present in 72.4% of patients and burning sensations in 68.9%. Pruritus was exacerbated by stress, fatigue and xerosis. The mean ItchyQol score was 56.2/110 and the mean 5-D Itch Scale score was 16.5/25. The severity of pruritus was not related to age, sex, BP activity score, eosinophilia, or anti-BP230 and anti-BP180 autoantibodies. This study revealed that pruritus in BP is poorly tolerated and is an important cause of impaired quality of life.

Drug-induced linear immunoglobulin A bullous dermatosis: A French retrospective pharmacovigilance study of 69 cases.

AIMS: Linear immunoglobin A (IgA) bullous dermatosis is a rare autoimmune dermatosis considered spontaneous or drug-induced (DILAD). We assessed all DILAD cases, determined the imputability score of drugs and highlighted suspected drugs. METHODS: Data for patients with DILAD were collected retrospectively from the French Pharmacovigilance network (from 1985 to 2017) and from physicians involved in the Bullous Diseases French Study Group and the French Investigators for Skin Adverse Reactions to Drugs. Drug causality was systematically determined by the French imputability method. RESULTS: Of the 69 patients, 42% had mucous membrane involvement, 20% lesions mimicking toxic epidermal necrolysis (TEN), 21% eosinophil infiltrates and 10% keratinocytes necrosis. Direct immunofluorescence, in 80%, showed isolated linear IgA deposits. Vancomycin (VCM) was suspected in 39 cases (57%), 11 had TEN-like lesions, as compared with three without VCM suspected. Among the 33 patients with a single suspected drug, 85% had an intrinsic imputability score of I4. Among them, enoxaparin, minocycline and vibramycin were previously unpublished. For all patients, the suspect drug was withdrawn; 15 did not receive any treatment. First-line therapy for 31 patients was topical steroids. Among the 60 patients with available follow-up, 52 achieved remission, 10 without treatment. Four patients experienced relapse, four died and five had positive accidental rechallenges. CONCLUSIONS: There is no major clinical difference between DILAD and idiopathic linear IgA bullous dermatosis, but the former features a higher prevalence of patients mimicking TEN. VCM, suspected in more than half of the cases, might be responsible for more severe clinical presentations. We report three new putative drugs.

Hidradenitis suppurativa (HS): An unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases.

BACKGROUND: Paradoxical hidradenitis suppurativa (HS) induced by biologic agents (BA) is scarcely reported. OBJECTIVE: We sought to describe the clinical characteristics and outcome of patients developing paradoxical HS under BA. METHODS: This was a multicenter nationwide retrospective study asking physicians to report all cases of HS, confirmed by a dermatologist, occurring during treatment of an inflammatory disease by a BA. RESULTS: We included 25 patients (15 inflammatory rheumatism, 9 Crohn's disease, 1 psoriasis) treated by 5 BA (adalimumab = 12, infliximab = 6, etanercept = 4, rituximab = 2, tocilizumab = 1). Median duration of BA exposure before HS onset was 12 (range 1-120) months. Patients were mostly Hurley stage I (n = 13) or II (n = 11). Simultaneously to HS or within 1 year, 11 patients developed additional inflammatory diseases, including paradoxical reactions (psoriasis = 9, Crohn's disease = 3, alopecia areata = 1, erythema elevatum diutinum = 1). Complete improvement of HS was more frequently obtained after BA discontinuation or switch (n = 6/10, 60%) rather than maintenance (n = 1/14, 7%). Reintroducing the same BA resulted in HS relapse in 3 of 3 patients. LIMITATIONS: Retrospective nature and lack of complete follow-up for some patients are limitations. CONCLUSION: HS is a rare paradoxical adverse effect of BA, but fortuitous association cannot be excluded in some cases. We observed a trend toward better outcome when the BA was discontinued or switched.

A Typical Vascular and Pigmentary Dermoscopic Pattern of Capillary Malformations in Capillary Malformation-Arteriovenous Malformation Syndrome: Report of Four Cases.

We report dermoscopic characteristics of cutaneous capillary malformations in four patients with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. We observed a mixed vascular and pigmentary pattern with branched linear vessels and an underlying homogeneous brown background. Disappearance of the vascular pattern on pressure revealed an underlying faint pigmentary reticular pattern. Our results suggest that this typical biphasic pattern on dermoscopy may be useful for the diagnosis of CM-AVM syndrome.

Clostridium difficile infection and immune checkpoint inhibitor-induced colitis in melanoma: 18 cases and a review of the literature.

Immunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor-induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficile infection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficile should be carried out for all patients with diarrhea who are being treated with immunotherapy.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

BACKGROUND: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. PATIENTS AND METHODS: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. RESULTS: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). CONCLUSION: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Cutaneous B-cell lymphoblastic lymphoma in children: a rare diagnosis.

BACKGROUND: Lymphoblastic lymphoma (LBL) is a rare malignant neoplasm usually occurring in the mediastinum of children and adolescents. The B-cell immunophenotype of LBL (B-LBL) accounts for less than 20% of all cases and may involve extramediastinal areas, such as the skin. Although highly aggressive, LBL is potentially curable if diagnosed early. OBJECTIVE: We sought to describe the clinical and histopathologic features of B-LBL in children presenting with cutaneous lesions, and to highlight the specific features of this rare and serious disease. METHODS: Seven children with a confirmed diagnosis of cutaneous B-LBL were identified by retrospective chart review. The clinical and histopathologic features were documented, analyzed, and compared with cases previously published in the literature. RESULTS: Six children developed nodules on the head, and one child presented with lesions on the back and abdomen. Histopathology showed a diffuse dermal and subcutaneous monomorphous infiltrate made up of atypical cells with an immature B-cell phenotype. The average duration of the lesions before diagnosis was 3.2 months. A staging workup revealed extracutaneous disease in 5 patients, including bone-marrow involvement in 4 children. LIMITATIONS: This was a retrospective study with a small number of patients. CONCLUSION: The cutaneous lesions of B-LBL typically manifest as rapidly growing erythematous firm nodules located on the head. Awareness of these clinical features is important for the diagnosis to be reached rapidly and treatment started without delay.

Endotracheal tube biofilm in critically ill patients during the COVID-19 pandemic : description of an underestimated microbiological compartment.

Biofilm (BF) growth is believed to play a major role in the development of ventilator-associated pneumonia (VAP) in the intensive care unit. Despite concerted efforts to understand the potential implication of endotracheal tube (ETT)-BF dispersal, clinically relevant data are lacking to better characterize the impact of its mesostructure and microbiological singularity on the occurrence of VAP. We conducted a multicenter, retrospective observational study during the third wave of the COVID-19 pandemic, between March and May 2021. In total, 64 ETTs collected from 61 patients were included in the present BIOPAVIR study. Confocal microscopy acquisitions revealed two main morphological aspects of ETT-deposited BF: (1) a thin, continuous ribbon-shaped aspect, less likely monobacterial and predominantly associated with Enterobacter spp., Streptococcus pneumoniae or Viridans streptococci, and (2) a thicker, discontinuous, mushroom-shaped appearance, more likely characterized by the association of bacterial and fungal species in respiratory samples. The microbiological characterization of ETT-deposited BF found higher acquired resistance in more than 80% of analyzed BF phenotypes, compared to other colonization sites from the patient's environment. These findings reveal BF as a singular microbiological compartment, and are of added clinical value, with a view to future ETT-deposited BF-based antimicrobial stewardship in critically ill patients. Trial registration NCT04926493. Retrospectively registered 15 June 2021.

BRAF inhibitor resistance of melanoma cells triggers increased susceptibility to natural killer cell-mediated lysis.

BACKGROUND: Targeted therapies and immunotherapies are first-line treatments for patients with advanced melanoma. Serine-threonine protein kinase B-RAF (BRAF) and mitogen-activated protein kinase (MEK) inhibition leads to a 70% response rate in patients with advanced melanoma with a BRAFV600E/K mutation. However, acquired resistance occurs in the majority of patients, leading to relapse. Immunotherapies that activate immune cytotoxic effectors induce long-lasting responses in 30% of patients. In that context, combination of targeted therapies with immunotherapy (IT) is a promising approach. We considered boosting natural killer (NK) cell tumor immunosurveillance, as melanoma cells express stress-induced molecules and activate NK cell lysis. METHODS: Here we have generated vemurafenib (a BRAF inihibitor)-resistant (R) cells from BRAFV600E SK28 and M14-sensitive (S) melanoma cell lines and investigated how resistance interferes with immunogenicity to NK cells. We determined the levels of several soluble molecules including NK ligands in 61 melanoma patients at baseline and 6 months M post-treatment with targeted therapies or immunotherapies. RESULTS: Vemurafenib resistance involved activation of p-AKT in SK28R and of p-MEK/p-ERK in M14R cells and was accompanied by modulation of NK ligands. Compared with S cells, SK28R displayed an increased expression of natural killer group 2 D (NKG2D) receptor ligands (major histocompatibility complex class (MHC) I chain-related protein A (MICA) and UL16-binding protein 2 (ULBP2)) whereas M14R exhibited decreased ULBP2 . SK28R and M14R cells induced higher NK degranulation and interferon gamma secretion and were more efficiently lysed by donor and patient NK cells. SK28R showed increased tumor necrosis factor-related apoptosis-inducing ligand receptor II (TRAIL-RII) expression and TRAIL-induced apoptosis, and TRAIL-induced apoptosis of M14R was decreased. Combined BRAF/MEK inhibitors abrogated the growth of SK28S, M14S, and M14R cells, while growth of SK28R was maintained. BRAF/MEK inhibition attenuated NK activity but R cell lines activated polyfunctional NK cells and were lysed with high efficiency. We investigated the relationship of soluble NK ligands and response to treatment in a series of melanoma patients. Soluble NKG2D ligands known to regulate the receptor function have been associated to cancer progression. Serum analysis of patients treated with target therapies or IT indicates that soluble forms of NK ligands (MICA, B7H6, programmed cell death ligand 1, and carcinoembryonic antigen cell adhesion molecule 1) may correlate with clinical response. CONCLUSION: These results support strategies combining targeted therapies and NK-based immunotherapies.

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma.

Importance: Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies. Objectives: To evaluate the risk of a recurrence of immune toxic effects associated with anti-programmed cell death 1 antibody (anti-PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs. Design, Settings, and Participants: This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti-PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017. Exposures: Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti-PD-1 (nivolumab or pembrolizumab) therapy. Main Outcomes and Measures: The primary outcome was the rate of immune-related AEs associated with anti-PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti-PD-1 immune-related AEs and overall response rate and overall survival associated with anti-PD-1 therapy. Results: Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti-tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti-PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing). Conclusions and Relevance: The findings suggest that anti-PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.

Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients.

PURPOSE: Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation. METHODS: An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy. RESULTS: One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%). CONCLUSION: Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.

Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey.

Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participating centers were included. Relative incidence was calculated according to the total number of patients treated with ICI in network centers during the period of inclusion. The possible impact of anti-TNFα treatment on disease outcome was evaluated through comparison of objective response rate, progression-free survival, and OS with pivotal literature data. Twenty-seven patients from 13 tertiary referral centers were included. Overall, severe ICI-related colitis treated with anti-TNFα occurred in 1% of patients with advanced melanoma, mostly with ipilimumab. Infliximab was successfully used in all patients but 1, mostly after 1 infusion. OS and progression-free survival of 12 and 3 months, respectively, were observed in these patients, along with an objective response rate of 41% at 12 months. This survey shows a low real-life incidence of severe colitis requiring anti-TNFα. Response rates to immunotherapy and survival data do not appear to significantly differ from those observed in pivotal studies. Severe ICI-induced colitis requiring anti-TNFα treatment appears to be a rare event in advanced melanoma, and infliximab does not seem to adversely affect disease outcome.

Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population.

Dipeptidyl peptidase-4 inhibitors have been suspected to induce bullous pemphigoid (BP). The objective of this study was to compare the observed frequency of gliptin intake in a large sample of 1,787 BP patients diagnosed between 2012 and 2015 in France, with the expected frequency after indirect age standardization on 225,412 individuals extracted from the database of the National Healthcare Insurance Agency. The secondary objective was to assess the clinical characteristics and the course of gliptin-associated BP, depending on whether gliptin was continued or stopped. The observed frequencies of intake of the whole gliptin class and that of vildagliptin in the BP population were higher than those in the general population after age standardization (whole gliptin class: 6.0%; 95% confidence interval = 4.9-7.1% vs. 3.6%, observed-to-expected drug intake ratio = 1.7; 95% confidence interval = 1.4-2.0; P < 0.0001; vildagliptin = 3.3%; 95% confidence interval = 2.5-4.1% vs. 0.7%, ratio = 4.4; 95% confidence interval = 3.5-5.7; P < 0.0001). The association of any gliptin+metformin was also higher than in the general population, ratio = 1.8 (95% confidence interval = 1.3-2.4; P < 0.0001). Gliptin-associated BP had no specific clinical characteristics. Gliptin was stopped in 48 (45.3%) cases. Median duration to achieve disease control, rate, and delay of relapse were not different whether gliptin was stopped or continued. This study strongly supports the association between gliptin intake, particularly vildagliptin, and the onset of BP.

Efficacy of Immunotherapy in Patients with Metastatic Mucosal or Uveal Melanoma.

BACKGROUND: The objective was to assess the response rate and survival of patients with metastatic mucosal melanoma (MM) and uveal melanoma (UM) treated with anti-CTLA-4 or anti-PD-1 monoclonal antibodies (mAbs). METHODS: A multicenter retrospective study was performed in 25 dermatology departments in France. All patients with stage III-C to IV MM or UM who were treated with anti-CTLA-4 or anti-PD-1 mAbs between 2008 and 2016 were included and compared after adjustment for main prognostic factors with a second cohort of patients treated with chemotherapy. Tumor response was evaluated according to RECIST v. 1.1 criteria at Week 12. RESULTS: Four-hundred-and-thirty-nine patients were included, 229 MM (151 immunotherapy, 78 chemotherapy) and 210 UM (100 immunotherapy, 110 chemotherapy). Response rates of MM patients treated with immunotherapy were 18/151 (11.9%; 95% CI:7.2%-18.2%), versus 11/78 (14.1%, 95% CI:7.3%-23.8%) in patients treated with chemotherapy (p=0.87). No tumor response was observed in UM patients treated with immunotherapy, versus 4/110 responses (3.6%, 95% CI:1.0-9.0%) in patients treated with chemotherapy (p=0.15). The adjusted overall survival (OS) of MM patients treated with immunotherapy was longer than that of patients treated with chemotherapy HR=0.62 (95% CI: 0.43-0.91), p=0.014, with an unadjusted median OS of 15.97 months [interquartile range (IQR)=6.89-27.11] and 8.82 months [IQR=5.02-14.92], respectively. The adjusted OS of UM patients treated with immunotherapy was not significantly different from that of patients treated with chemotherapy (HR=0.98, 95% CI: 0.66-1.44) p=0.92, with an unadjusted median OS of 13.38 months [IQR=6.03-29.57] and 11.02 months [IQR=6.13-23.93], respectively. CONCLUSION: Immunotherapy significantly improves OS for MM. The prognosis of metastatic UM remains poor.