Abstract Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related disorders. We here review the ...literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3.8% with anti-CTLA4 antibodies, 6.1% with anti-PD1 antibodies, and 12.0% with the combination of both. The clinical spectrum of neurological disorders was highly heterogeneous. Most of these nAEs were grade 1–2 and consisted of non-specific symptoms such as headache (55%). The incidence of high grade nAEs was below 1% for all types of treatment. Headaches, encephalopathies and meningitis were the most commonly reported (21%, 19% and 15%, respectively). Among the 27 case reports, the most common nAEs were encephalopathies, meningoradiculoneuritis, Guillain-Barré like syndromes and myasthenic syndromes. The median time of nAEs onset was 6 weeks. In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-Barré syndrome.
L’oncologie médicale connaît une révolution depuis l’introduction des inhibiteurs de checkpoints immunitaires (ICI) tels que les anticorps monoclonaux anti-CTLA-4 et anti-PD-1. Ces derniers ont été ...approuvés dans plus de 23 cancers et les approches combinant les immunothérapies ont démontré une efficacité redoutable. Ces bénéfices en termes de survie s’accompagnent d’une augmentation des effets indésirables liés à l’immunité (irAEs), conséquence d’une activation excessive du système immunitaire. Les irAEs représentent un nouveau type d’auto-immunité pouvant affecter presque tous les organes, responsable d’une morbi-mortalité importante. Actuellement, il n’existe pas de biomarqueurs permettant de prédire l’incidence et la gravité de ces toxicités. Nous avons mis au point une approche innovante pour l’identification de ces biomarqueurs avant l’initiation d’un traitement combinant anti-CTLA-4 et anti-PD-1. Notre approche consiste en la stimulation immunitaire ex vivo du sang total issu de patients ayant un mélanome éligible au traitement, en utilisant la technologie des tubes TruCulture en présence d’un activateur de lymphocytes T (cytostim) et d’anticorps monoclonaux (nivolumab±ipilimumab), avant l’initiation du traitement. Les prélèvements biologiques sont analysés en utilisant la technologie LUMINEX pour l’étude du profil protéomique des surnageants et la technologie NANOSTRING pour l’étude du profil transcriptomique des cellules sanguines. Les patients sont prospectivement suivis pendant 3 mois, puis 6 mois après l’initiation du traitement. Le suivi prospectif a mis en évidence une irAE sévère chez 60 % des patients (n=15), dont 67 % avec une atteinte digestive sévère, principalement des colites. L’étude immunologique a identifié plusieurs candidats biomarqueurs, dont la chimiokine MCP-1 et les cytokines IP-10 et IFN-g, permettant de prédire l’apparition d’une irAE sévère avant même l’initiation du traitement. L’analyse transcriptomique a confirmé l’implication de ces voies de signalisation et a mis en évidence l’activation la voie des interférons chez les patients qui développeront des colites sévères, ouvrant des perspectives mécanistiques sur la genèse des irAEs. Les irAEs représentent un défi majeur pour la médecine moderne, et des travaux intensifs sont nécessaires pour comprendre le développement des irAEs et identifier des biomarqueurs permettant leurs prédictions. La stimulation ex vivo du sang total, puis l’analyse intégrée des profils immunitaires ont permis d’identifier plusieurs biomarqueurs candidats qui pourraient prédire l’apparition d’irAEs sévères ainsi que des pistes mécanistiques.
Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in ...BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after≥36-month follow-up for all living patients.
This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150mg twice daily) plus trametinib (2mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.
Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.
These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for
-mutant metastatic melanoma.
SECOMBIT is a randomized, three-arm, noncomparative phase II trial ...(ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic
-mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib 450 mg orally once daily plus binimetinib 45 mg orally twice daily until progressive disease PD -> ipilimumab plus nivolumab ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks), arm B ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib, or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication.
A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged.
Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with
-mutant melanoma.
The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5–7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 ...leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
•A melanoma consensus conference, organised by the ESMO Guidelines Committee, was attended by 32 experts from 14 countries•The experts compiled recommendations (with supporting evidence) on controversial topics in melanoma management•Recommendations for metastatic melanoma in this manuscript include the following:○targeted versus immunotherapy○treatment sequencing and duration○management of brain metastases•A separate manuscript presenting results relating to the management of locoregional melanoma is also available
On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this ...phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.
After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety.
At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval CI, 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.
As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).
The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5–7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 ...leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
•A melanoma consensus conference, organised by the ESMO Guidelines Committee, was attended by 32 experts from 14 countries•The experts compiled recommendations (with supporting evidence) on controversial topics in melanoma management•Recommendations for locoregional melanoma in this manuscript include:○indications for sentinel lymph node biopsy and radical lymph node dissection○adjuvant targeted versus immunotherapy○adjuvant therapy in specific situations (after node dissection, stage IIIA, resected stage IV, in-transit metastasis)○adjuvant therapy toxicity management•A separate manuscript presenting results relating to the management of metastaticmelanoma is also available
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