cabozantinib
Sources réglementaires consultées
Indications approuvées
- Profil UE CABOMETYX : chez l’adulte, carcinome rénal avancé en monothérapie de première ligne à risque intermédiaire ou élevé, après traitement ciblant le VEGF ou en première ligne avec nivolumab ; carcinome hépatocellulaire après sorafénib ; cancer différencié de la thyroïde localement avancé ou métastatique réfractaire ou non éligible à l’iode radioactif après progression sous traitement systémique ; et tumeurs neuroendocrines pancréatiques ou extrapancréatiques bien différenciées, non résécables ou métastatiques, après au moins un traitement systémique autre que les analogues de la somatostatine.
- Profil États-Unis COMETRIQ : traitement du cancer médullaire de la thyroïde progressif et métastatique.
Contre-indications
Absolues
- Profil CABOMETYX : hypersensibilité au cabozantinib ou à ses excipients.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer des perforations ou fistules gastro-intestinales, une hémorragie sévère ou mortelle et une thrombose artérielle ou veineuse. Arrêter définitivement en cas de perforation, fistule sévère, hémorragie menaçant le pronostic vital ou événement thromboembolique nécessitant une intervention. — DailyMed, COMETRIQ set_id 1a0c3bea-c87b-4d25-bb44-5f0174da6b34
- Mise en garde majeure · Surveiller la pression artérielle, la fonction cardiaque, la protéinurie, les électrolytes, la toxicité hépatique, le syndrome main-pied, la diarrhée, l’ostéonécrose de la mâchoire et l’encéphalopathie postérieure réversible. Suspendre au moins 3 semaines avant une chirurgie programmée et ne reprendre qu’au moins 2 semaines après une chirurgie majeure et après cicatrisation adéquate. — DailyMed, COMETRIQ set_id 1a0c3bea-c87b-4d25-bb44-5f0174da6b34
- Mise en garde majeure · CABOMETYX et COMETRIQ ne peuvent pas être substitués milligramme pour milligramme : leurs comprimés et gélules ne sont pas bioéquivalents. — CIMA/AEMPS, ficha técnica CABOMETYX 1161136002
Interactions médicamenteuses
- SévèreInhibiteurs puissants du CYP3A4
Mécanisme: Ils augmentent l’exposition au cabozantinib.
Recommandation: CABOMETYX : utiliser avec prudence et surveiller la toxicité. COMETRIQ : réduire de 40 mg pendant l’association.
CIMA/AEMPS, ficha técnica CABOMETYX 1161136002https://cima.aemps.es/cima/dochtml/ft/1161136002/FT_1161136002.html
- SévèreInducteurs puissants du CYP3A4
Mécanisme: Ils réduisent fortement l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’usage chronique avec CABOMETYX. Avec COMETRIQ, si l’association est indispensable, la dose peut être augmentée de 40 mg sans dépasser 180 mg/jour et sous surveillance.
CIMA/AEMPS, ficha técnica CABOMETYX 1161136002https://cima.aemps.es/cima/dochtml/ft/1161136002/FT_1161136002.html
- ModéréeWarfarine et substrats de la P-gp
Mécanisme: Le cabozantinib peut modifier l’INR et augmenter l’exposition aux substrats de la P-gp.
Recommandation: Contrôler l’INR avec la warfarine ; surveiller la toxicité des substrats de la P-gp à marge thérapeutique étroite.
CIMA/AEMPS, ficha técnica CABOMETYX 1161136002https://cima.aemps.es/cima/dochtml/ft/1161136002/FT_1161136002.html
Effets indésirables
Communs (≥1%)
diarrhée · fatigue · nausées · diminution de l’appétit · syndrome main-pied · hypertension
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Les patients des deux sexes et leurs partenaires doivent utiliser une contraception efficace pendant le traitement et pendant au moins 4 mois après ; une méthode barrière doit compléter les contraceptifs oraux. Ne pas allaiter pendant le traitement ni pendant les 4 mois suivants. La fertilité peut être altérée.
Bibliographie récente (PubMed)
Approximately 43 720 new cases of thyroid carcinoma are expected to be diagnosed in 2023 in the US. Five-year relative survival is approximately 98.5%. This review summarizes current evidence regarding pathophysiology, diagnosis, and management of early-stage and advanced thyroid cancer. Papillary thyroid cancer accounts for approximately 84% of all thyroid cancers. Papillary, follicular (≈4%), and oncocytic (≈2%) forms arise from thyroid follicular cells and are termed well-differentiated thyroid cancer. Aggressive forms of follicular cell-derived thyroid cancer are poorly differentiated thyroid cancer (≈5%) and anaplastic thyroid cancer (≈1%). Medullary thyroid cancer (≈4%) arises from parafollicular C cells. Most cases of well-differentiated thyroid cancer are asymptomatic and detected during physical examination or incidentally found on diagnostic imaging studies. For microcarcinomas (≤1 cm), observation without surgical resection can be considered. For tumors larger than 1 cm with or without lymph node metastases, surgery with or without radioactive iodine is curative in most cases. Surgical resection is the preferred approach for patients with recurrent locoregional disease. For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma. Approximately 44 000 new cases of thyroid cancer are diagnosed each year in the US, with a 5-year relative survival of 98.5%. Surgery is curative in most cases of well-differentiated thyroid cancer. Radioactive iodine treatment after surgery improves overall survival
Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear. We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety. In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events. Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse e
Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.
HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells, with 80-85% originating in the adrenal medulla and 15-20% from extra-adrenal chromaffin tissues (paragangliomas). Approximately 30-40% of PPGLs have a hereditary component, making them one of the most genetically predisposed tumor types. Recent advances in genetic research have classified PPGLs into three molecular clusters: pseudohypoxia-related, kinase-signaling, and WNT-signaling pathway variants. Specifically, the detection of SDHB-related tumors indicates an increased risk of metastatic disease, which may impact decisions regarding functional imaging in patients with high suspicion of metastasis and influence targeted treatment strategies. Diagnosis of PPGLs primarily relies on biochemical testing, measuring catecholamines or their metabolites in plasma or urine. However, molecular testing, functional imaging, and targeted therapies have greatly enhanced diagnostic precision and management. Personalized treatment approaches based on genetic profiling are becoming integral to the clinical management of these tumors. In South American countries like Colombia, functional imaging techniques such as positron emission tomography/computed tomography (PET/CT) with tracers like 18F-DOPA, 18F-fluorodeoxyglucose (18F-FDG), and 68Ga-DOTA-conjugated somatostatin receptor-targeting peptides (68Ga-DOTA-SST) are used to guide follow-up and treatment strategies. Radionuclide therapy with lutetium-177 DOTATATE is employed for patients showing uptake in 68Ga-DOTA-SST PET/CT scans, while access to 131-MIBG therapy remains limited due to high costs and availability. Recent clinical trials have shown promise for systemic therapies such as sunitinib and cabozantinib, offering potential new options for patients with slow or moderate progression of PPGLs. These advancements underscore the potential of personalized and targeted therapies to improve outcomes in this challenging pati