Autoimmune Skin Diseases and Immune Checkpoint Inhibitors.

Immune system escape is one of the major strategies required for cancer growths. In this scenario, the advent of immune checkpoint inhibitors (ICIs) revolutionized the landscape of treatment options for tumors. Despite their wide use, these agents are associated with a unique spectrum of toxicities known as immune-related adverse events (irAEs). IrAEs are cause of treatment suspension (up to 60% of all causes of treatment interruption) and potentially impact on patients' quality of life. These toxicities are the main limitations on the use of these innovative drugs. IrAEs are peculiar, due to the mechanism of actions of ICIs, and any body organs may be involved (skin, thyroid, colon, lungs, in particular). Thus, the management often requires a multidisciplinary approach. The aim of this manuscript is to review current literature on autoimmune skin diseases described in association with ICIs (i.e., vitiligo, lupus erythematosus, vasculitis, morphea/scleroderma, alopecia areata, bullous pemphigoid, dermatomyositis), in order to provide a comprehensive overview for the physician.

Intracranial Treatment in Melanoma Patients with Brain Metastasis Is Associated with Improved Survival in the Era of Immunotherapy and Anti-BRAF Therapy.

Metastatic melanoma patients are at high risk of brain metastases (BM). Although intracranial control is a prognostic factor for survival, impact of local (intracranial) treatment (LT), surgery and/or radiotherapy (stereotactic or whole brain) in the era of novel therapies remains unknown. We evaluated BM incidence in melanoma patients receiving immune checkpoint inhibitors (ICI) or anti-BRAF therapy and identified prognostic factors for overall survival (OS). Clinical data and treatment patterns were retrospectively collected from all patients treated for newly diagnosed locally advanced or metastatic melanoma between May 2014 and December 2017 with available BRAF mutation status and receiving systemic therapy. Prognostic factors for OS were analyzed with univariable and multivariable survival analyses. BMs occurred in 106 of 250 eligible patients (42.4%), 64 of whom received LT. Median OS in patients with BM was 7.8 months (95% CI [5.4-10.4]). In multivariable analyses, LT was significantly correlated with improved OS (HR 0.21, p < 0.01). Median OS was 17.3 months (95% CI [8.3-22.3]) versus 3.6 months (95% CI [1.4-4.8]) in patients with or without LT. LT correlates with improved OS in melanoma patients with BM in the era of ICI and anti-BRAF therapy. The use of LT should be addressed at diagnosis of BM while introducing systemic treatment.

Long-Term Outcome of Neoadjuvant Tyrosine Kinase Inhibitors Followed by Complete Surgery in Locally Advanced Dermatofibrosarcoma Protuberans.

In locally advanced dermatofibrosarcoma protuberans (DFSP), imatinib mesylate has been described as an efficient neoadjuvant therapy. This retrospective study included patients with locally advanced DFSP who received neoadjuvant TKI (imatinib or pazopanib) from 2007 to 2017 at Saint Louis Hospital, Paris. The primary endpoint was the evaluation of the long-term status. A total of 27 patients were included, of whom nine had fibrosarcomatous transformation. The median duration of treatment was 7 months. The best response to TKI treatment before surgery, evaluated according to RECIST1.1 on MRI, consisted of complete/partial response (38.5%) or stability (46.2%). DFSP was surgically removed in 24 (89%) patients. A total of 23 patients (85%) were disease-free after 64.8 months of median follow-up (95% confidence interval 47.8; 109.3). One patient developed distant metastases 37 months after surgical tumor resection and finally died. Two patients (7%) did not get surgery because of metastatic progression during TKI treatment, and one patient refused surgery even though the tumor decreased by 30%. Treatment-related adverse events (AE) occurred in 23 patients (85%). Only four patients (imatinib: n = 3, pazopanib: n = 1) had grade ≥3 AE requiring temporary treatment disruption. Neoadjuvant TKI followed by complete surgery with micrographic analysis is an effective strategy for locally advanced and unresectable DFSP, with durable local recurrence disease-free survival.

Systemic Treatment Initiation in Classical and Endemic Kaposi's Sarcoma: Risk Factors and Global Multi-State Modelling in a Monocentric Cohort Study.

BACKGROUND: Although several studies described the clinical course of epidemic and post-transplant Kaposi's Sarcoma (KS), the lack of large cohorts of classic/endemic KS, precluded such characterization. METHODS: We used multi-state modelling in a retrospective monocentric study to evaluate global disease evolution and identify risk factors for systemic treatment (ST) initiation. 160 classic/endemic KS patients consecutively diagnosed between 1990 and 2013 were included. RESULTS: 41.2% of classic/endemic KS patients required ST. Cumulative incidence of ST after 2 years of follow-up was 28.4% [95% CI: 20.5; 35.5]. Multivariate analysis identified six risk factors for ST initiation: time between first symptoms and diagnosis ≥1 year, endemic KS, total number of lesions ≥10, visceral, head or neck localization and presence of edema. Type of ST, type of KS, age and time between diagnosis and ST were not associated with response. Mean treatment-free time during the first 5 years following ST was 44 months for interferon and 44.6 months for chemotherapy treated patients (Mean difference: -0.5 months [95% CI: -9.5; 4.9]). CONCLUSIONS: Our study reveals ST risk factors in classic/endemic KS and highlights the clinical aggressiveness of the endemic KS subtype. No efficacy difference was observed between standard of care treatments, enabling treatment choice based on patient's fitness.

Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial.

PURPOSE: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. PATIENTS AND METHODS: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. RESULTS: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. CONCLUSIONS: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.

PD-1 inhibitors might limit the development of brain metastases in patients with advanced melanoma.

Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017 (Toulouse, N = 202; Limoges, N = 91). Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy [immune checkpoint inhibitor (ICI)] vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group [95% confidence interval (CI) 9.14-19.36] and 27.26% in the other group (95% CI 19.38-35.71), P = 0.004. The cumulative incidence was 9.49% in the anti-PD-1 group (95% CI 5.43-14.90) vs 30.11% in the other group (95% CI 22.59-37.97), P < 0.0001. In multivariable analysis (model with 277 patients), anti-PD-1 reduced the risk of brain metastases by almost 70% (hazard ratio = 0.29, 95% CI 0.15-0.56, P < 0.0001). The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.

Survival estimation of melanoma patients with brain metastasis using the Melanoma-molGPA score: external validation from a French cohort.

While immunotherapies and targeted therapies such as BRAF inhibitors have improved the prognosis, BM is still associated with poor outcome and a short survival. Metastatic melanoma patients are a heterogeneous subgroup with variable prognosis. As several prospective clinical trials have addressed the question of optimal therapy for these patients, an accurate validated selection tool is needed. Melanoma molecular graded prognostic assessment (Melanoma-molGPA) is a new prognostic score for BM melanoma patients. We decided to perform an external validation of this score. All consecutive patients treated between May 2014 and December 2017 for a newly diagnosed locally advanced or metastatic melanoma with available status for BRAF mutation were identified. Melanoma mol-GPA was applied in each patient with BM and correlated to overall survival. One hundred patients were included. Median follow-up was 27.8 months. Distribution for the Melanoma-molGPA groups GPA 0-1, GPA 1.5-2, GPA 2.5-3 and GPA 3.5-4 were as follows: 23, 51, 24 and 2.0%, respectively. Subgroups GPA 2.5-3 and 3.5-4 were combined. Median overall survival for groups GPA 0-1, 1.5-2 and 2.5-4.0 was 4.2, 6.9 and 18.4 months, respectively, P = 0.0032. Our study is the most recent, and with the largest cohort, to validate the Melanoma-molGPA score as an accurate and reproducible score for estimating overall survival. As several prospective clinical trials are addressing the issue of optimal therapy including the impact of local treatment for these patients, the Melanoma-molGPA is a useful tool in BM melanoma patients.

Advanced Cutaneous Squamous Cell Carcinoma Is Associated with Suboptimal Initial Management in a Cohort of 109 Patients.

BACKGROUND: Little is known about the epidemiological characteristics of patients with advanced cutaneous squamous cell carcinoma (A-cSCC). OBJECTIVE AND METHOD: A retrospective study was conducted on a routine care cohort of 109 patients to identify the epidemiological factors associated with A-cSCC. RESULTS: The median age was 83 years (IQR: 73.9-89.8), and the median ECOG was 1 (IQR: 1-2). Sixty percent of the patients had a history of cardiac disease and 22% had cognitive disorders. Seventy-four percent of patients were from rural/semi-rural areas (towns of <15,000 residents) and 17% were living in nursing homes. The cSCC lesions were on the head and neck in 72% of cases. Thirty-seven percent of patients were not diagnosed until the disease was in an advanced stage, indicating a lack of cSCC identification. In the remaining 69 patients, 7% did not received treatment within 3 months of the cSCC being identified, 62% had an incomplete histological report, and 37% had incomplete treatment. CONCLUSION: A-cSCC is associated with incomplete initial treatment in an elderly and rural population with good general condition. We hypothesize that a lack of access to good dermatological expertise may have led to underestimation of the aggressiveness of cSCC and/or therapeutic mismanagement.

Discoidin domain receptors: A promising target in melanoma.

The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1-IN-1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma.

Severe gastrointestinal toxicity of MEK inhibitors.

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

Diagnosis and treatment of Kaposi's sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC).

Kaposi's sarcoma (KS) is a multifocal neoplasm of lymphatic endothelium-derived cells infected with human herpesvirus 8. Four clinical subtypes are distinguished: the classic, the endemic, the epidemic subtype in HIV positive patients and the iatrogenic subtype. The diagnosis is primarily based on clinical features and confirmation by histology with immunohistochemistry. Cutaneous distribution and severity, mucosal, nodal and visceral involvement depend on the type of KS with in general indolent behaviour and chronic evolution in the classic subtype and the more severe forms in iatrogenic or epidemic subtypes. Management should aim at achieving disease control. For localised lesions, several local therapies have been developed without randomised trial comparisons. Radiotherapy, intralesional chemotherapies and electrochemotherapy have high response rates. Topical treatments-imiquimod or topical 9-cis-retinoid acid-can also be used. Systemic treatments are reserved for locally aggressive extensive and disseminated KS: the recommended first-line agents are pegylated liposomal doxorubicin (PLD) and paclitaxel. In CKS, PLD or low-dose interferon-alfa are the recommended first-line agents in younger patients. In AIDS-related KS, combination antiretroviral therapy is the first treatment option; specific systemic treatment is needed only in case of extensive disease and in the prevention and treatment of immune reconstitution inflammatory syndrome. In post-transplant KS, tapering down immunosuppressive therapy and switching to mammalian target of rapamycin (m-TOR) inhibitors are used. Follow-up schedules for patients with KS disease depend on aggressiveness of the disease.

Osteopenia and fractures associated with long-term therapy with MEK inhibitors.

Targeted therapies have markedly improved the survival of patients with melanoma. We report the case of two patients with advanced melanoma controlled by long-term MEK inhibitor or combination of BRAF and MEK inhibitors, who developed fractures related to severe osteopenia. A 48-year-old woman was treated by pimasertib after the failure of two lines of chemotherapy, and a 42-year-old man was treated by an association of BRAFi (dabrafenib) and MEKi (trametinib) after the failure of one line of chemotherapy. During follow-up, both complained of buttock pain, revealing primary fractures of the pelvis and lumbar vertebra. In both patients, none had osteoporosis risk factors; DEXA scan revealed osteopenia, and analysis ruled out metastatic bone lesion or secondary osteoporosis. Zoledronic acid, cholecalciferol (vitamin D3), oral calcium, and pain killers were introduced, leading to no further bone event. Numerous pathways are involved in the homeostasis of bone turnover, and the effect of tyrosine kinase inhibitors on those pathways is not well known yet. The absence of usual causes of osteoporosis or metastatic bone lesion and kinetics of symptoms lead us to suggest that MEK inhibitors were responsible for the development of osteoporosis. To the best of our knowledge, this is the first report of fractures associated with osteopenia in patients treated with MEKi. Long-term survival owing to new targeted treatment could be associated with yet underestimated adverse effects such as osteopenia/osteoporosis that could impair patient's quality of life and should be investigated.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Sentinel Lymph Node Biopsy in Cutaneous Squamous Cell Carcinoma Series of 37 Cases and Systematic Review of the Literature.

Cutaneous squamous cell carcinoma (cSSC) is one of the most common skin cancers and can lead to patient death. Early detection of node metastasis is a major goal for dermatologists and oncologists. The procedure sentinel lymph node biopsy has been proposed to improve early detection of node metastasis. The aim of this study was to evaluate the efficacy and impact of this technique on the prognosis of cSSC. A total of 37 patients (Saint Louis Hospital, Paris, France) who had undergone sentinel lymph node biopsy and 290 cases from the literature were analysed. The mean rate of positive sentinel lymph node biopsy was 0.14 [95% CI 0.09-0.22]. However, relapse-free survival and overall survival were not affected by sentinel lymph node status (log-rank test; p = 0.08 and p = 0.31, respectively), suggesting that this procedure is not mandatory in the management of cSSC.

Transient pituitary ACTH-dependent Cushing syndrome caused by an immune checkpoint inhibitor combination.

Immune checkpoint inhibitors have improved survival in numerous advanced malignancies, but are associated with a number of immune-related adverse events, including endocrinopathies. Endogenous Cushing's syndrome (CS) is a rare disorder resulting from exposure to high levels of circulating cortisol. CS can be caused either by adrenal cortex tumors or hyperplasia or by pituitary or extra-pituitary tumors over-secreting ACTH (known as ACTH-dependent CS). We report the first case of transient ACTH-dependent CS, which appeared after combined ipilimumab and nivolumab therapy. Our patient presented typical clinical features of CS after three infusions of combined therapy, high serum and daily urinary free cortisol, and high serum ACTH levels. Pituitary MRI showed an enlargement of the pituitary gland suggesting ACTH secretion of pituitary origin, which was confirmed by inferior petrosal sinus sampling. The pituitary findings were preceded by thyroiditis. The evolution was characterized by spontaneous CS regression and subsequent appearance of severe corticotroph deficiency consistent with destructive hypophysitis. Immunotherapy is a novel cause of CS.