PD-1 blockade with pembrolizumab in classic or endemic Kaposi's sarcoma: a multicentre, single-arm, phase 2 study.

BACKGROUND: Although the treatment of iatrogenic and HIV-related Kaposi sarcoma is well defined and mostly based on restoring immune function, the treatment of classic and endemic Kaposi sarcoma is less well established. Chemotherapy or interferon α is used for patients with extensive cutaneous or visceral Kaposi sarcoma, but tolerance might be poor and long-term remission is rare. We aimed to evaluate the activity of pembrolizumab in classic and endemic Kaposi sarcoma with cutaneous extension requiring systemic treatment. METHODS: We did a multicentre, single-arm, proof-of-concept, phase 2 trial in adults aged 18 years or older with histologically proven classic or endemic Kaposi's sarcoma with progressive cutaneous extension requiring systemic treatment and an Eastern Cooperative Oncology Group performance status of 0-1 in three hospitals in France. The patients were treated with 200 mg pembrolizumab intravenously every 3 weeks for 6 months (eight cycles) or until severe toxicity. The primary endpoint was the best overall response rate within the 6-month timeframe, defined by the occurrence of a complete response or partial response and assessed by an investigator using the modified AIDS Clinical Trial Group (ACTG) criteria. Three or more responses among a total 17 patients were needed for the primary endpoint to be met, using a Simon's two-stage optimal design assuming a 30% response rate as desirable. For this final study analysis, all patients were included following the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03469804, and is closed to new participants. FINDINGS: 30 patients were screened for eligibility and 17 patients (eight [47%] with classic and nine [53%] with endemic Kaposi's sarcoma) were enrolled between July 2, 2018, and Dec 16, 2019. The median follow-up was 20·4 months (IQR 18·1-24·1). Two (12%) patients had a complete response, ten (59%) had a partial response, and five (29%) had stable disease as the best response within the 6-month treatment timeframe, with a best overall response rate of 71% (95% CI 44-90), meeting the predefined primary outcome (ie, exceeding a response rate of 30%). Treatment-related adverse events occurred in 13 (76%) of 17 patients, including two grade 3 adverse events (one [6%] acute cardiac decompensation and one [6%] granulomatous reaction). Treatment was prematurely discontinued in two (12%) patients due to grade 3 acute reversible cardiac decompensation and grade 2 pancreatitis, and one other patient had a grade 3 granulomatous reaction in mediastinal lymph nodes requiring steroids and methotrexate treatment. There were no serious adverse events or treatment-related deaths. INTERPRETATION: In this prospective trial, which to our knowledge is the first to assess the role of PD-1 blockade in patients with classic and endemic Kaposi's sarcoma, pembrolizumab showed promising anti-tumour activity with an acceptable safety profile. If this result is supported by further studies, treatment with anti-PD-1 could be part of the therapeutic armamentarium for patients with classic and endemic Kaposi's sarcoma. FUNDING: MSD France.

Sonidegib in the Treatment of Locally Advanced Basal Cell Carcinoma: a Retrospective Study.

Sonidegib, a hedgehog pathway inhibitor, is indicated for treatment of locally advanced basal cell carcinoma, based on the results of the BOLT study. However, to date, no real-world study of sonidegib has been reported. An observational, retrospective, single-centre study (PaSoS study) was conducted. The primary objective was to evaluate the efficacy of sonidegib for treatment of locally advanced basal cell carcinoma in a real-world setting. Secondary objectives included modalities of use, tolerability, tumour evolution, and management after discontinuation. A total of 21 patients treated with sonidegib were included from March 2018 to January 2021. The median follow-up was 18.7 months and median exposure 7.0 months. Objective response (OR) rate was 81.0% (n = 17) including 6 (29%) patients with a complete response (CR). Disease control rate was 100%. First tumour response was rapid, with a median time of 2.3 months. Nine (43%) patients underwent surgery after sonidegib discontinuation, and no relapse was observed. All the patients experienced at least 1 adverse event (AE). Muscle spasms were the most frequent AE (n = 14; 67%), followed by dysgeusia (n = 8; 38%) and alopecia (n = 12; 57%). The efficacy and safety profile of sonidegib in this first-to-date real-life trial are consistent with prior results. Overall, real-world evidence corroborated sonidegib efficacy and tolerability as a first-line treatment for locally advanced basal cell carcinoma.

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.

Outcome of pretransplant melanoma after solid organ transplantation: an observational study.

The number of patients with a history of melanoma who are awaiting a solid organ transplantation (SOT) is increasing. Few recommendations exist on the timing to transplantation after melanoma diagnosis. The aim of this study was to assess the melanoma recurrence-free survival after pretransplant melanoma (PTM). We conducted a multicenter ambispective observational study. Organ transplant recipients (OTR) with a history of PTM and complete AJCC staging were included. Thirty-seven patients (predominantly men with a renal allograft) were included. Five melanomas were in situ, 21 stage IA, 4 stage IB, 5 stage II, and 2 stage IIIB. The median post-transplantation follow-up time was 4 years. Sixty-two percent of patients were followed up more than 2 years. Recurrence-free survival since melanoma reached 89.9%, but varied significantly according to AJCC staging (P = 0.0129). Three patients presented a recurrence. Despite the rather limited sample size and a wide range of follow-up, our findings concerning the recurrence-free survival appear reassuring for in situ and stage IA PTM; accordingly, we suggest that a waiting time to transplantation is not mandatory in patients with in situ or stage IA PTM, especially whenever SOT is urgently needed. Caution is, however, needed for patients with higher stage.

Targeted therapies in melanoma beyond BRAF: targeting NRAS-mutated and KIT-mutated melanoma.

PURPOSE OF REVIEW: Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which is a model of effective targeted therapy in cancer. However, patients with BRAF wild type cannot benefit for such treatments. In this review, we will focus on the current clinical development of targeted therapies beyond BRAF, in NRAS-mutated and KIT-altered melanoma. RECENT FINDINGS: In NRAS-mutated melanoma, targeted therapies based on MEK inhibition are being developed as monotherapy or in combination with MAPK, PI3K or CDK4/6 inhibitor. Targeted therapies of KIT-altered melanoma patients is based in KIT inhibitor (mostly imatinib, nilotinib), although for both melanoma subtypes, results are for now disappointing as compared with BRAF and MEK inhibitors in BRAF-mutated melanoma. SUMMARY: Combined therapeutic targeted strategies are awaited in NRAS-mutated and KIT-altered melanoma and could provide additional benefit.

Deep cutaneous fungal infections in solid-organ transplant recipients.

BACKGROUND: Deep cutaneous fungal infections (DCFIs) are varied in immunosuppressed patients, with few data for such infections in solid-organ transplant recipients (s-OTRs). OBJECTIVE: To determine DCFI diagnostic characteristics and outcome with treatments in s-OTRs. METHODS: A 20-year retrospective observational study in France was conducted in 8 primary dermatology-dedicated centers for s-OTRs diagnosed with DCFIs. Relevant clinical data on transplants, fungal species, treatments, and outcomes were analyzed. RESULTS: Overall, 46 s-OTRs developed DCFIs (median delay, 13 months after transplant) with predominant phaeohyphomycoses (46%). Distribution of nodular lesions on limbs and granulomatous findings on histopathology were helpful diagnostic clues. Treatments received were systemic antifungal therapies (48%), systemic antifungal therapies combined with surgery (28%), surgery alone (15%), and modulation of immunosuppression (61%), leading to complete response in 63% of s-OTRs. LIMITATIONS: Due to the retrospective observational design of the study. CONCLUSIONS: Phaeohyphomycoses are the most common DCFIs in s-OTRs. Multidisciplinary teams are helpful for optimal diagnosis and management.

[An unusual digestive complication under anti-PD-1 (pembrolizumab)]. / Une complication digestive rare sous anti-PD-1 (pembrolizumab).

The most commonly reported pattern of anti-PD-1 induced colitis is an active colitis characterized by neutrophilic inflammation and prominent apoptosis. On the other hand, reports of collagenous colitis (which is a microscopic colitis) are exceptional. In this report, we describe an unusual case of anti-PD1-associated collagenous colitis in a 76-year-old man, treated with pembrolizumab for a stage IV cutaneous melanoma. Fourteen months after the start of pembrolizumab, the patient developed a grade 3 diarrhea (up to 9 stools per day) associated with profound hypokalemia. No bacterial, viral or parasitological infectious agents were found from stool analysis. The rectosigmoidoscopy showed colonic diffuse congestion with no ulceration. Systematic biopsies were performed during endoscopy. Histologically, the fragments analyzed revealed a moderately thickened subepithelial collagen layer (20-30µm thick) associated with a mild mixed inflammatory infiltrate within the lamina propria. There were no granuloma lesions, ulcerations or viral inclusion bodies. The patient was initially successfully treated with corticosteroids (prednisone) and temporary interruption of pembrolizumab. However, during corticosteroids tapering, a relapse was observed. The treatment was switched to budesonide, leading to a complete and definitive resolution of diarrhea. To date, budesonide has been stopped and pembrolizumab has not been restarted. Currently, there is a bone progression treated by radiotherapy alone. In case of a more important progression, a systemic treatment will be secondarily discussed.

[Cardiotoxicity of immune checkpoint inhibitors used in cancer treatment]. / Cardiotoxicité des inhibiteurs de points de contrôle immunitaire utilisés dans le traitement des cancers.

Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, by reshaping the prognosis of many cancers and are progressively becoming the standard of care. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), of which cardiovascular irAEs are particularly feared. ICI-induced myocarditis is often a diagnostic challenge because of the vast heterogeneity of clinical presentations, and it is associated with a high mortality rate of around 50%. The present article summarizes the cardiac manifestations, the diagnostic strategy and the therapeutic management of patients with ICI-induced myocarditis used in the treatment of cancer.

Les inhibiteurs de points de contrôle immunitaire (ICI), ou immune checkpoint inhibitors (ICI), ont révolutionné la prise en charge de nombreux cancers en améliorant significativement la survie des patients et en devenant progressivement la norme de soins. Cette efficacité a néanmoins pour prix un taux élevé d'effets indésirables immunomédiés avec un large spectre d'organes touchés. Les toxicités cardiaques, dominées par la myocardite induite par les ICI, sont particulièrement redoutées du fait des difficultés diagnostiques et du risque d'évolution rapidement défavorable associée à une mortalité élevée, de l'ordre de 50 %. Le présent article s'intéresse aux manifestations cardiaques, à la stratégie diagnostique ainsi qu'à la prise en charge des patients présentant une myocardite induite par les ICI utilisés dans le traitement du cancer.

Management of Kaposi sarcoma after solid organ transplantation: A European retrospective study.

BACKGROUND: Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, or a combination of these. OBJECTIVE: To obtain an overview of clinical strategies about the current treatment of KS. METHODS: We conducted a multicenter retrospective cohort study including 145 solid organ transplant recipients diagnosed with KS between 1985 and 2011 to collect data regarding first-line treatment and response at 6 months. RESULTS: Overall, 95%, 28%, and 16% of patients had reduction of immunosuppression, conversion to mTOR inhibitor, and chemotherapy, respectively. Patients treated with chemotherapy or mTOR inhibitor conversion were more likely to have visceral KS. At 6 months, 83% of patients had response, including 40% complete responses. LIMITATIONS: The retrospective design of the study. CONCLUSION: Currently available therapeutic options seem to be effective to control KS in most patients. Tapering down the immunosuppressive regimen remains the cornerstone of KS management.

EMMPRIN regulates ß1 integrin-mediated adhesion through Kindlin-3 in human melanoma cells.

EMMPRIN is known to promote tumor invasion through extracellular matrix (ECM) degradation. Here we report that EMMPRIN can regulate melanoma cell adhesion to the ECM through an interaction with ß1 integrin involving kindlin-3. In this study, EMMPRIN knockdown in the human melanoma cell line M10 using siRNA decreased cell invasion and significantly increased cell adhesion and spreading. A morphological change from a round to a spread shape was observed associated with enhanced phalloidin-labelled actin staining. In situ proximity ligation assay and co-immunoprecipitation revealed that EMMPRIN silencing increased the interaction of ß1 integrin with kindlin-3, a focal adhesion protein. This was associated with an increase in ß1 integrin activation and a decrease in the phosphorylation of the downstream integrin kinase FAK. Moreover, the expression at both the transcript and protein level of kindlin-3 and of ß1 integrin was inversely regulated by EMMPRIN. EMMPRIN did not regulate either talin expression or its interaction with ß1 integrin. These results are consistent with our in vivo demonstration that EMMPRIN inhibition increased ß1 integrin activation and its interaction with kindlin-3. To conclude, these findings reveal a new role of EMMPRIN in tumor cell migration through ß1 integrin/kindlin-3-mediated adhesion pathway.

Low-dose methotrexate-induced skin toxicity: Keratinocyte dystrophy as a histologic marker.

BACKGROUND: Skin toxicity during low-dose methotrexate therapy is rare, ill described, and reported to have nonspecific histologic characteristics. Thus, misdiagnosis is common in patients with mucosal ulcers and/or skin erosions related to low-dose methotrexate. OBJECTIVE: We sought to describe the features of skin toxicity induced by low-dose methotrexate. METHODS: We evaluated the clinical and histologic features in 5 patients who experienced skin toxicity induced by low-dose methotrexate between 2011 and 2013. RESULTS: All 5 patients had acute mucosal ulcers, 4 had moderately abnormal blood cell counts, and 3 had skin erosions. In 3 patients, methotrexate dosage or dosing-schedule errors were identified. No other contributing factors (eg, renal dysfunction or interacting drugs) were identified. Mucocutaneous biopsy specimens consistently showed multiple dystrophic keratinocytes. LIMITATIONS: We studied only 5 patients and obtained no sensitivity or specificity data on the diagnostic value of keratinocyte dystrophy. CONCLUSION: Keratinocyte dystrophy may help to diagnose skin toxicity of low-dose methotrexate, even in the absence of known risk factors or methotrexate administration errors. Studies of the diagnostic performance of this histologic sign are needed.

Endemic Kaposi's Sarcoma.

Kaposi's sarcoma (KS) is a common neoplasm in Eastern and central Africa reflecting the spread of human gammaherpesvirus-8 (HHV-8), now considered a necessary causal agent for the development of KS. The endemic KS subtype can follow an aggressive clinical course with ulcerative skin lesions with soft tissue invasion or even bone or visceral involvement. In the latter cases, a thorough imaging work-up and better follow-up schedules are warranted. As KS is a chronic disease, the therapeutic goal is to obtain sustainable remission in cutaneous and visceral lesions and a good quality of life. Watchful monitoring may be sufficient in localized cutaneous forms. Potential therapeutic modalities for symptomatic advanced KS include systemic chemotherapies, immunomodulators, immune checkpoint inhibitors, and antiangiogenic drugs.