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Background: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms., Objectives: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database., Methods: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models., Results: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS., Conclusions: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.) more...

BACKGROUND Trichoblastic carcinoma (TC) is a rare adnexal tumor that usually occurs on the scalp and the face. Clinical presentation is nonspecific and can simulate basal cell carcinoma (BCC). Optimal treatment and outcomes remain unclear. Surgery remains the main treatment but can be difficult or impossible in locally-advanced situations. Thus, conservative options must be developed as TC affects elder populations, and radiotherapy may be a good conservative option but its use in TC is poorly documented. CASE REPORT We report a case of an 86-year-old man with an asymptomatic 5-cm tumor of the nose, extending to the right cheek and inner canthus. He was immunodeficient on kidney transplant and was treated by prednisone and tacrolimus. Biopsy confirmed the TC diagnosis. Surgery and brachytherapy were not possible due to clinical extension, advanced age, and comorbidities. External beam radiation with intensity modulated radiotherapy on tomotherapy was attempted. Seventy Gy was delivered in 35 fractions over 2 months 5/7 days. A bolus with ball (Seemed®) was used each treatment day to deliver an adequate dose of radiotherapy to the skin. Clinical examination at 1 month did not reveal any residual lesion and the patient remains in complete remission after 9 months of follow-up. Tolerance was characterized by grade 2 (NCI CTC AE V4) radiodermatitis, mucositis, and conjunctivitis, managed by local medications. CONCLUSIONS We report a rare case of locally-advanced TC, successfully treated by external beam radiation, which may be an acceptable alternative treatment for unresectable tumors. more...

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.) more...

The ever-increasing use of immune checkpoint inhibitors (ICIs) has significantly improved cancer management, but at the cost of frequent immunologic side effects. Among them, neurologic immune-related adverse events (nirAEs) are less common but pose a challenge to clinicians due to their severity, heterogeneous nature and nonspecific clinical presentation, making diagnosis complex. The prognosis of these nirAEs, especially those related to the central nervous system (CNS), correlates with their rapid recognition and therapeutic management. Indeed, the therapeutic options are sometimes unfamiliar and may be further complicated by the lack of recommendations in the event of failure of a well-managed first-line treatment. Finally, the attribution of ICIs to certain CNS disorders is controversial and may lead to an incorrect decision to discontinue or contraindicate treatment, resulting in an irremediable loss of opportunity for the patient. Therefore, the aim of this review is to present known/suspected CNS nirAEs induced by ICI, their diagnostic approach and management through therapeutic advices for optimal treatment and rechallenge opportunities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) more...

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., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.) more...

Background: Immune checkpoint inhibitors (ICIs) have demonstrated their efficacy with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials provides for treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after treatment cessation shows sustained response and a low risk of relapse in the months following cessation. To date, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI administration., Methods: We emulated target trials using the cloning, weighting and censoring approach. Each emulation trial aimed to compare the effect of discontinuing versus continuing ICIs at a specific timepoint, among patients still under treatment and with disease control at that time. Patients were from MelBase between 2015 and 2021., Findings: 435 participants in the MelBase cohort were eligible and were included in the 6-month discontinuation emulated trial. The results showed significantly lower OS when treatment was discontinued, than when treatment was prolonged for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8-60.5), and the corresponding restricted mean survival time difference was 8.3 months (95% CI: 4.1-12.7). Neither the 12-month nor the 18-month discontinuation emulated trials showed evidence of benefit of either discontinuing or continuing ICIs at either of these timepoints. The 24-month discontinuation emulated trial results were more in favor of discontinuing than continuing treatment at that time point, with an absolute 48-month survival rate that was 10.5% higher (95% CI 4.4-18.1)., Interpretation: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental., Funding: This work was supported by a grant from Bristol Myers Squibb, Merck Sharp Dhome, Pierre Fabre, Novartis, Sun Pharm, Regeneron, Sanofi, Nektar, Therapeutics and Oncyte., Competing Interests: LM reports advisory board and travel expenses from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, Novartis and Sun Pharm. SD reports advisory board and travel expenses from Bristol Myers Squibb and Merck Sharp, and Dhome; research fundings from Bristol Myers Squibb, Merck Sharp and Dhome, and Pierre Fabre. FBP reports financial support outside the submitted work from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre and Novartis. JDQ reports advisory board from Merck Sharp and Dhome, Pierre Fabre, Novartis and Bristol Myers Squibb. CGM reports advisory board and travel expenses from Pierre Fabre, Bristol Myers Squibb and Merck Sharp and Dhome. PS reports advisory board and travel expenses from Bristol Myers Squibb, Merck Sharp and Dhome and Pierre Fabre and Novartis; consulting fees from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, Regeneron, Sanofi, Damae and Novartis. TL reports advisory board and travel expenses from Bristol Myers Squibb, Merck Sharp and Dhome, Pierre Fabre and Novartis. HM reports advisory board from Pierre Fabre, Bristol Myers Squibb, Merck Sharp and Dhome, Novartis, Regeneron and Sun Pharma; research funding from Pierre Fabre, Bristol Myers Squibb, Merck Sharp and Dhome, Novartis, Regeneron, Nektar Therapeutics, 4SC and Incyte; and research grant from Leo Pharma and Merck Sharp and Dhome. All other authors declare no completing interests., (© 2024 The Authors.) more...

Background: The Checkmate 067 randomized controlled trial, published in 2015, demonstrated improved progression-free survival and numerically, although not statistically, superior overall survival for ipilimumab + nivolumab. The objective of this study was to compare the efficacy and safety of nivolumab to ipilimumab + nivolumab 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 nivolumab or ipilimumab + nivolumab. The primary endpoint was overall survival at 36 months. The secondary endpoints included progression-free survival at 36 months, best radiological response, and safety analyses. We conducted a propensity score using the IPTW method to overcome the various confounding factors and also a subgroup analysis (brain metastasis, LDH levels, and BRAF mutation status)., Results: A total of 406 patients were treated with nivolumab, and 416 with ipilimumab + nivolumab. Overall survival at 36 months was higher in the ipilimumab + nivolumab group (57.1%, ([95%CI 50.7-64.2]) than in the nivolumab group (46.6% [95%CI 41.6-52.1]), HR 1.4[1.1;1.8]. Progression-free survival at 36 months was significantly improved in the ipilimumab + nivolumab group (42.3%) compared to the nivolumab group (21.9%), with a HR 1.6[1.4;1.9]. The objective response rate 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, though not significantly so, in the ipilimumab + nivolumab arm (29% vs. 41%)., Conclusions: Our results are consistent with those from the Checkmate 067 study, except for the objective response rate and the incidence of toxicities, which proved to be lower in our analysis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) more...

Immune-mediated sinusitis is poorly described and may easily go undiagnosed. We conducted a retrospective, multicenter, national study focusing on symptomatic immune-mediated sinusitis in patients receiving immune checkpoint inhibitors (ICIs) for melanoma treatment. Twelve patients were included (50% women, median age 58 years). Overall, the paraclinical assessment, the inefficacy of antibiotic/antihistaminic treatment, the improvement of symptoms on immunosuppressants and/or after ICI discontinuation, and the presence of multiple concomitant immune-related adverse-events, suggested a noninfectious etiology. Recognizing this toxicity is imperative for limitation of diagnostic wandering and appropriate treatment. However, additional epidemiological studies are needed to assess its prevalence as a potential immune-related adverse-event, and its prognostic value in patients treated with ICIs. more...

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., (© 2023. The Author(s).) more...

Radiation recall reactions are inflammatory reactions confined to previously irradiated tissues, often of drug-induced etiology, particularly with anticancer therapies. Other drugs, in particular COVID-19 vaccines, may also be involved. To describe radiation recall reactions under non-anticancer drugs more precisely, we extracted the cases of radiation recall reactions associated with non-anticancer drugs from WHO pharmacovigilance database VigiBase®. We performed two analyses from this extraction: a global analysis and an analysis focusing on vaccination-related issues. We extracted 120 cases corresponding to 269 drugs, of which 130 were non-anticancer (22 vaccines). Among the non-anticancer drugs, tozinameran was the most reported treatment (4.46% of cases), followed by levofloxacin (2.97%) and folinic acid (2.60%), dexamethasone (2.23), and ChAdOx1 nCoV-19 vaccine and prednisone (1.86% each). Among vaccines, tozinameran (54.55% of cases) was the most reported, followed by ChAdOx1 nCoV-19 (22.73%), HPV and inactivated influenza vaccine (9.09% each), and elasomeran (4.55%). Our study first describes the occurrence of radiation recall reactions during non-anticancer treatment. It also highlights a potential safety signal with COVID-19 vaccines., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.) more...

Background: Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied., Objective: To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP)., Methods: Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed., Results: Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type., Limitations: No record of standard diagnostic criteria of MUP used in the participating centers., Conclusions: Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies., Competing Interests: Conflicts of interest Dr Dalle received research grants by BMS and MSD, travel costs covered by BMS, spouse working for Sanofi; Dr Dereure reported a Consulting or Advisory Role with Bristol-Myers Squibb, Genevrier, Kiowa Kirin, Leo Pharma, MSD, Novartis, Pierre Fabre, and Recordati, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Pierre Fabre, and Recordati; Dr Saiag has received outside of this study personal fees from Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, and Novartis; Dr Arnault consulting for NOVARTIS, Dr Lebbé reported honoraria from Amgen, Bristol-Myers Squibb, Incyte, MSD, Novartis, Pfizer, Pierre Fabre, and Roche, reports a Consulting or Advisory Role with Amgen, Bristol-Myers Squibb, Merck Serono, MSD, Novartis, Roche, and Sanofi, is on the Speakers' Bureau for Amgen, Bristol-Myers Squibb, MSD, Novartis, and Roche, received Research Funding from Bristol-Myers Squibb, and Roche, reports travel, accommodations, and expenses from Bristol-Myers Squibb and MSD, and reports other relationship with Avantis Medical Systems; and Dr Montaudié reported a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, received Research Funding from Leo Pharma and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, and Pierre Fabre., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.) more...

Introduction: Axillary and inguinal lymph node dissection (LND) are performed in metastatic skin tumors with several local complications, such as lymphorrhea, lymphoceles, and lymphedema. The purpose of this study is to determine whether negative pressure wound therapy (NPWT) applied as a preventive measure could improve outcomes., Materials and Methods: A monocentric study included patients who underwent axillary or inguinal LND from May 2010 to March 2020, with a retrospective evaluation of prospectively collected data. Patients were divided into two groups: the conventional wound care (CWC) and the NPWT groups. Patients were systematically reviewed at D7, D30, and at 1 year postoperative, and data regarding lymphorrhea, lymphoceles, and lymphedema were collected., Results: A total of 109 axillary and inguinal LND were performed. NPWT was applied on 68 LND and CWC on 41 LND. The variables, diabetes, smoking, gender, associated treatments, and primary pathology (melanoma, squamous cell carcinoma, or Merkel tumors) were similar in both groups. Analyses have shown a significant difference in the rate of scar disunion during the first month between the two groups (p=0.045 between D1 and D7; p=0.011 between D8 and D30), as well as the presence of lymphorrhea (p=0.000 between D1 and D7; p=0.002 between D8 and D30). The rate of lymphoedema was significantly reduced in the NPWT group versus CWC (p=0.000 between D8 and D30; p=0.034 between D31 and 1 year)., Conclusion: NPWT reduces local complications (scar disunion, lymphorrhea, and lymphedema) during the first year following LND in the management of node metastatic skin tumors., Competing Interests: Conflict of interest statement None., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.) more...

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients' characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained. more...

Objective: To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma., Methods: Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression., Results: 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs., Conclusion: In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy., Competing Interests: Competing interests: DL: fees from Novartis, BMS et MSD. PS: consulting fees from Roche, Novartis, BMS, Pierre FABRE, MSD. FB-P: consulting fees from BMS and Sanofi. TL: consulting fees from MSD, BMS, Pierre Fabre, Novartis. J-JG : consulting fees from MSD, Roche, Novartis, Amgen, Pierre-Fabre, Sanofi, Philogen, Merck, Pfizer. CA: grants from Amgen, BMS, Roche. LM: grants from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre and consulting fees from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre. CL: grants from BMS, MSD, Novartis, Sanofi, Pierre Fabre; consulting fees from BMS, MSD, Novartis, Amgen, Roche, Merck, Serono, Sanofi, Pierre Fabre and teaching fees from Roche, BMS, Novartis, Amgen, MSD., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Background: Late-onset adverse events (AEs) of anti-programmed cell death 1 (anti-PD1) antibodies have not been systematically described., Objectives: The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered for at least 2 years in a real-life setting., Methods: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow up of unresectable stage III or IV melanoma. The study included 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019. Median follow up was 41.7 months (range, 25.2-57.5 months). Fifty-three patients received nivolumab and 66 patients received pembrolizumab., Results: AEs occurred in 99 patients (83%) with a median time of 13.3 months (range, 0-53.9 months), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grades 1 or 2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations, of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first 2 years of treatment) and treatment duration (P = .02 and P = .03, respectively)., Conclusions: Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy. Late-onset AEs appear frequently and were mostly mild or moderate. Early-onset AEs and prolonged anti-PD1 treatment may increase the risk of late-onset AEs., Competing Interests: Conflicts of interest Dr Nardin has a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre. Dr. Dalle is an employee of Sanofi, has Stock and Other Ownership Interests in Sanofi, has a Consulting or Advisory Role with Bristol-Myers Squibb, received Research Funding from Bristol-Myers Squibb, and reports travel, accommodations, and expenses from Bristol-Myers Squibb and Pierre Fabre. Dr Leccia has No Relationships to Disclose. Dr Mortier received honoraria from Bristol-Myers Squibb and MSD Oncology, received Research Funding from MSD Oncology and Pierre Fabre, and received travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Roche/Genentech, and Roche/Genentech. Dr Dalac-Rat received honoraria from Bristol-Myers Squibb, MSD, and Novartis, reports a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, and Novartis, is on the Speakers' Bureau for Bristol-Myers Squibb, reports Research Funding from Bristol-Myers Squibb, MSD, and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb. Dr Dutriaux received honoraria from Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre reports a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre. Dr Legoupil received honoraria from Bristol-Myers Squibb and MSD, reports a Consulting or Advisory Role with Bristol-Myers Squibb and Pierre Fabre, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, MSD, and Pierre Fabre. Dr Montaudié reports a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, received Research Funding from Leo Pharma and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, and Pierre Fabre. Dr Dereure reports a Consulting or Advisory Role with Bristol-Myers Squibb, Genevrier, Kiowa Kirin, Leo Pharma, MSD, Novartis, Pierre Fabre, and Recordati, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Pierre Fabre, and Recordati. Dr De Quatrebarbes is on the Speakers' Bureau for Bristol-Myers Squibb and Janssen-Cilag and reports travel, accommodations, and expenses from BMS and MSD Oncology. Dr Granel-Brocard has no relationships to disclose. Dr Le-Bouar has no relationships to disclose. Dr Charles has no relationships to disclose. Dr Brunet-Possenti reports a Consulting or Advisory Role with Bristol-Myers Squibb and Sanofi. Dr Dreno received honoraria from Bristol-Myers Squibb, Merck, Pierre Fabre, Roche, and Sanofi, reports a Consulting or Advisory Role with Bristol-Myers Squibb, Pierre Fabre, Roche, and Sanofi, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Pierre Fabre, and Roche. Dr Lefevre has no relationships to disclose. Dr Allayous reports travel, accommodations, and expenses from Amgen, Bristol-Myers Squibb, and Roche. Dr Lebbe reports honoraria from Amgen, Bristol-Myers Squibb, Incyte, MSD, Novartis, Pfizer, Pierre Fabre, and Roche, reports a Consulting or Advisory Role with Amgen, Bristol-Myers Squibb, Merck Serono, MSD, Novartis, Roche, and Sanofi, is on the Speakers' Bureau for Amgen, Bristol-Myers Squibb, MSD, Novartis, and Roche, received Research Funding from Bristol-Myers Squibb, and Roche, reports travel, accommodations, and expenses from Bristol-Myers Squibb and MSD, and reports other relationship with Avantis Medical Systems., (Copyright © 2021. Published by Elsevier Inc.) more...

Background: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib., Materials and Methods: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment., Results: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months)., Conclusion: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms., Competing Interests: Disclosure EMN: Consulting or advisory role: Novartis, Pierre Fabre, Bristol-Myers Squibb, MSD. EM: Consulting or advisory role: MSD, Pierre Fabre, Novartis, Sanofi; research funding: MSD (Inst); travel, accommodations, expenses: MSD Oncology, Pierre Fabre, Novartis. NM: Consulting or advisory role or research funding: Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Merck, Sanofi, Sun Pharmaceutical Industries. MB-B: Research funding: Roche; consulting or advisory role: Sun Pharmaceutical Industries. NB-S: Consulting or advisory role: Sanofi, Sun Pharmaceutical Industries. LM: Consulting or advisory role: Sanofi, Sun Pharmaceutical Industries, MSD Oncology, Bristol-Myers Squibb, Novartis. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

The Sezary syndrome has been defined by a triad combining erythrodermia, generalized lymphadenopathy, and the presence of circulating Sezary cells > 1 × 10 9 /L characterized by a CD4+/CD8- phenotype with loss of one or more T antigens (mainly CD7 and/or CD26). We retrospectively reviewed the immunophenotypic profiles of 10 SS patients followed in our institution (University Hospital at Nancy, France). The application of the WHO criteria resulted in a diagnostic confirmation for 9 out of 10 cases. Since 2008, new diagnostic and staging criteria have been proposed, including the CD158k/KIR3DL2 receptor detection. The application of these new criteria to our cohort led us to notice a phenotypic heterogeneity of our cases but allowed to achieve a relevant diagnosis of Sezary syndrome in all cases, especially for patients with lymphopenia. The use of such a panel of monoclonal antibodies also optimized the follow-up of the patients. more...

Background: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy., Patients and Methods: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out., Results: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI., Conclusion: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution., Competing Interests: Disclosure StD reports institutional research funding from Roche; institutional research funding and nonfinancial support from Bristol-Myers Squibb (BMS); and an immediate family member who is employed by Sanofi and owns stock or other ownership interest in the company. LM reports personal fees and nonfinancial support from Roche, Novartis, BMS, and Merck Sharp & Dohme (MSD) outside the submitted work. OD reports personal fees and nonfinancial support from BMS, MSD, Pierre Fabre, Novartis, Leo Pharma, Genevrier, Kyowa Kirin, Recordati Rare Diseases outside the submitted work. SoD received research funding and travel costs covered by BMS and MSD. Travel costs covered by Pierre Fabre. CD reports personal fees from Roche, BMS, Novartis, MSD, and Pierre Fabre Laboratories outside the submitted work. PS reports research funding and personal fees from Roche; grants, personal fees, and nonfinancial support from BMS, MSD, Novartis, and Pierre Fabre Laboratories; and personal fees from Array, Sanofi, and Merck, all outside the submitted work. J-PA reports personal fees from BMS, grants from BMS, Novartis, and MSD, during the conduct of the study. EM reports grants, personal fees, and nonfinancial support from MSD; personal fees from Sanofi and Novartis; personal fees and nonfinancial support from BMS; and nonfinancial support from Pierre Fabre Laboratories, all outside the submitted work. JDQ reports nonfinancial support from BMS, MSD, and Janssen outside the submitted work. FA reports personal fees and nonfinancial support from Novartis, MSD, and Roche outside the submitted work. TL reports research funding and personal fees from Roche and personal fees from BMS, MSD, Novartis, Pierre Fabre Laboratories, and Incyte, all outside the submitted work. P-ES reports travel accomodations -meetings by BMS, Novartis, MSD, and Sanofi. J-JG reports personal fees and nonfinancial support from BMS, Roche, MSD, Novartis, Merck, Amgen, Pierre Fabre Laboratories, Sanofi, and Pfizer and nonfinancial support from Amgen, all outside the submitted work. CA reports travel accommodations-meetings by Roche, BMS, and Amgen. CL reports grants and personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, personal fees from Merck Serono, personal fees from Sanofi, outside the submitted work. HM reports institutional research funding from LeoPharma; institutional research funding, personal fees, and nonfinancial support from BMS; personal fees from Pierre Fabre Laboratories and MSD; and nonfinancial support from Novartis, all outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.) more...

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. more...

Background: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life., Methods: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates., Results: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of -0.027 (95% CI, -0.03, -0.02) in the utility score, -1.82 (95% CI, -1.88, -1.76) in the FACT-General score, and -2.98 (95% CI, -3.05, -2.91) in the FACT-Melanoma score compared with first-line treatment., Conclusions: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed., (© 2019 American Cancer Society.) more...