First-line, fixed-duration nivolumab plus ipilimumab followed by nivolumab in clinically diverse patient populations with unresectable stage III or IV melanoma: Checkmate 401

PURPOSE: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤ 24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months\u27 median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

PURPOSE To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer

Background In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available. Methods Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies. Results All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1. Conclusions Long-term darolutamide treatment was well tolerated; no new safety signals observed

Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

INTRODUCTION: Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. METHODS: The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. RESULTS: Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR(-)Lin(- )cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR(-)Lin(- )cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid. CONCLUSION: These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest

A PROPOS D'UN CAS DE SCHWANNOME MALIN A DIFFERENCIATION RHABDOMYOBLASTIQUE OU TUMEUR DITE DU TRITON (REVUE DE LA LITTERATURE)

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Prévalence des mutations des gènes Ckit, BRaf, NRas et MITF dans les mélanomes cutanés, oculaires et muqueux (distribution et valeurs pronostiques et prédictives dans les formes avancées)

Contexte: Les 1ères thérapies ciblées des mélanomes ont été validées en 2011 suite à la mise en évidence de mutations oncogéniques spécifiques de certains sous-types histologiques. Ces mutations ont été décrites essentiellement sur des populations nord-américaines et austrolo-pacifiques. Nous nous interrogeons sur la prévalence et les impacts prédictifs et pronostiques de ces mutations au sein de la population bretonne. Patients et méthodes: les mutations des gènes BRaf, NRas, CKit et MITF (E318K) ont été recherchées chez 126 patients dans une phase rétrospective et celles de BRaf, NRas et CKit chez 102 patients supplémentaires lors d'une phase prospective. Les mutations étaient recherchées par pyroséquençage pour BRaf et NRas et par séquençage direct pour CKit et MITF (E318K). La description de corrélations entre statut mutationel et facteurs pronostiques histologiques et cliniques ainsi que l'évaluation des impacts pronostiques et prédictifs étaient les objectifs principaux de cette étude. La mise en évidence d'une stabilité entre tumeurs primitives et lésions secondaires, du caractère mutuellement exclusif de ces mutations et de l'existence d'une corrélation entre aberrations de CKit et surexpression de CD 117 représentaient des objectifs secondaires. Résultats: les prévalences des mutations BRaf, NRas et CKit dans les phases rétrospective et prospective étaient respectivement de 23,0 et 31,2%, 11,9 et 22,1% et de 4,0 et 1,8%. Elles étaient plus faibles que les données disponibles de la littérature pour les mutations de BRaf et pour les mélanomes classiquement liés à des aberrations de CKit: aucun mélanome muqueux ni sur peau chroniquement insolée n'était muté et seuls 7,4% des acro-lentigineux l'étaient. Aucune mutation MITF E318K n'a été identifiée. Les mélanomes mutés sur BRaf étaient significativement liés à une forme SSM (p=0,02), à un âge au diagnostic plus jeune (p<0,05), à un envahissement ganglionnaire au diagnostic (p=0,03). Les mélanomes mutés sur NRas étaient liés aux formes nodulaires (p<0,05). La présence de ces mutations était prédictive de réponse aux inhibiteurs spécifiques mais ne présentait pas d'impact pronostique sur les survies globales et en phase métastatique. Conclusion: Les mutations des gènes BRaf, NRas et CKit sont retrouvées dans les mélanomes cutanés des patients bretons avec une prévalence inférieure aux populations nord-américaines ou australo-pacifiques. Les formes mutées BRaf se caractérisent au sein de cette population par leur survenue chez des sujets jeunes et par leur lymphophilie marquée.RENNES1-BU Santé (352382103) / SudocSudocFranceF

Radiation-induced spinal cord glioma subsequent to treatment of Hodgkin's disease: case report and review.: Radiation-induced spinal cord glioma subsequent to treatment of Hodgkin's disease: case report and review

article cliniqueRadiation-induced neoplasms of the central nervous system generally present as meningioma or sarcoma. Spinal cord glioma after radiation therapy is rare and half of the cases documented occurred after treatment of Hodgkin's disease.A 39-year-old male presented with a 1-month history of gradually worsening neck ache and paraparesis. The patient had been treated for stage IB Hodgkin's disease 9 years previously with combined therapy: MOPP-ABV and a 40-Gray mediastinal radiotherapy from T1 to T10. Magnetic resonance imaging disclosed an intramedullary lesion from C6 to T2 and histopathological examination from biopsy demonstrated a malignant glioma. Despite chemotherapy and additional radiotherapy, the patient's neurological status worsened and he died 11 months after initial presentation.We suggest a strategy aimed solely at obtaining a tissue diagnosis to differentiate myelitis from tumor, and, in the event of tumor, confirming the strong likelihood of a high histopathological grade. The very limited survival associated with these tumors regardless of therapy advocates palliative therapies without attempting complete resection

Intérêt de la MGMT dans les gliomes. [MGMT analysis in gliomas].

International audienceMGMT status is now regarded as a strong predictive factor of response to standard treatment of newly diagnosed glioblastomas involving temozolomide (TMZ) and radiotherapy. MGMT promoter methylation is also a prognostic factor - independent of treatment - in anaplastic gliomas. The predictive function can be explained by the role of the DNA repair enzyme MGMT, which antagonizes the effects of alkylating agents such as TMZ. MGMT promoter methylation could also reflect a particular molecular phenotype with its own specific prognostic significance. Since MGMT status determination is becoming a crucial biological marker in new clinical glioma trials, and is beginning to be used in day-to-day clinical practice, there is currently a strong need to determine the best technique for MGMT analysis. A French multicenter study has been set up for this purpose

Carcinome à cellules de Merkel : prise en charge et place de la radiothérapie. [Merkel cell carcinoma: outcome and role of radiotherapy].

International audienceMerkel cell carcinoma (MCC) are rare neuroendocrine malignant tumor of the skin, occurring in elderly patients. It affects primarily the sun-exposed areas of the skin, with approximately 50% of all tumors occurring in the face and neck and 40% in the extremities. Immunohistochemical markers (CK20+, CK7- and TTF1-) are used to distinguish between MCC and other tumors. MCC have a tendency to rapid local progression, frequent spread to regional lymph nodes and distant metastases. Due to the rarity of the disease, the optimal treatment has not been fully defined. Localized stages (stages I and II) are treated by surgical excision of the primary tumor (with 2 to 3 cm margin) and lymphadenectomy in case of node-positive disease, followed by external beam radiotherapy (EBRT) to a total dose of 50 to 60Gy in the tumor bed. Adjuvant EBRT has been shown to decrease markedly locoregional recurrences and to increase survival in recent studies. Treatment of lymph nodes area is more controversial. Chemotherapy is recommended only for metastatic disease

Immune checkpoint inhibitors in patients aged 80 or older with advanced non-small cell lung cancer or melanoma: a real-life multicentre study

International audienceBackground Data regarding characteristics, safety and survival outcomes of patients aged 80 or older treated with immune checkpoint inhibitors (ICI) in routine oncology practice are limited. Materials and methods We retrospectively collected data of patients aged 80 and older with advanced non-small cell lung cancer (NSCLC) or melanoma treated with anti-PD1, anti-PD-L1 or anti-CTLA-4 regardless of the treatment line, in 14 institutions, between January 2014 and June 2017. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan Meier method. Toxicity was assessed according to CTCAE 5.0. Multivariate analyses were performed with the Cox model. Results Eighty-two patients were included (36 with NSCLC, 45 with melanoma). Their median age was 82 years (range 80-93). Nivolumab and pembrolizumab were mainly used. In the NSCLC group, median PFS and OS were 2.3 months (95%CI 1.8-6.1) and 8.8 months (95%CI 5.5-18.1), respectively. In the melanoma group, median PFS and OS were 10.2 months (95%CI 4.5-20.0) and 24.5 months (95%CI 14.1-NR), respectively. The albumin level was found to be independently associated with a better OS in both groups. Grade 3-4 toxicities occurred in 15 patients (18.5%). One patient died from ICI-induced pulmonary toxicity. Conclusion Our study findings suggest that treatment with ICI in elderly patients with NSCLC and melanoma has a risk-benefit ratio that supports its use. However, we report in this cohort that one in five patients has a grade 3-4 IRAEs leading to treatment discontinuation. Geriatric assessment prior to initiation of therapy and during therapy should be routine in patients aged 80 years and older