pexidartinib
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte atteint d’une tumeur à cellules géantes ténosynoviale symptomatique associée à une morbidité sévère ou à des limitations fonctionnelles et non susceptible d’être améliorée par la chirurgie.
Mises en garde cliniques
- Mise en garde encadrée · AVERTISSEMENT ENCADRÉ : peut provoquer une atteinte hépatique grave ou fatale, notamment un syndrome de disparition des canaux biliaires. Éviter de commencer si les transaminases, la bilirubine ou la phosphatase alcaline sont élevées ou en présence d’une maladie hépatobiliaire active. Contrôler AST, ALT, bilirubine totale et directe, phosphatase alcaline et GGT avant le traitement, chaque semaine pendant 8 semaines, toutes les 2 semaines le mois suivant puis tous les 3 mois. L’arrêt précoce n’élimine pas le risque. — DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- Mise en garde encadrée · Disponible uniquement dans le cadre du programme restreint TURALIO REMS en raison du risque d’hépatotoxicité. — DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- Mise en garde majeure · Un repas riche en graisses, environ 55 à 65 g de graisses totales, augmente l’exposition et peut accroître les effets indésirables et l’hépatotoxicité. Administrer uniquement avec un repas pauvre en graisses. — DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
Interactions médicamenteuses
- SévèreMédicaments hépatotoxiques
Mécanisme: Ils peuvent augmenter le risque d’atteinte hépatique grave.
Recommandation: Éviter l’association, surtout en cas d’anomalies hépatiques ou de maladie hépatobiliaire active.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- SévèreInhibiteurs modérés ou puissants du CYP3A ou inhibiteurs de l’UGT
Mécanisme: Ils augmentent l’exposition au pexidartinib et sa toxicité.
Recommandation: Éviter l’association ; si elle est indispensable, appliquer la réduction de dose spécifique.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- SévèreInducteurs puissants du CYP3A
Mécanisme: Ils réduisent l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- ModéréeInhibiteurs de la pompe à protons, antagonistes H2 et antiacides
Mécanisme: La réduction de l’acidité peut diminuer l’exposition au pexidartinib.
Recommandation: Éviter les IPP. Administrer le pexidartinib 2 heures avant ou après un antiacide local, ou au moins 2 heures avant ou 10 heures après un antagoniste H2.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- SévèreSubstrats du CYP3A à marge thérapeutique étroite
Mécanisme: Le pexidartinib est un inducteur modéré du CYP3A et peut réduire leur exposition et leur efficacité.
Recommandation: Éviter l’association, y compris les contraceptifs hormonaux ; si elle est inévitable, coordonner la surveillance et l’ajustement du substrat avec l’équipe prescriptrice.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
Effets indésirables
Communs (≥1%)
élévation de la LDH · élévation de l’AST · changement de couleur des cheveux · fatigue · élévation de l’ALT · neutropénie · élévation du cholestérol · élévation de la phosphatase alcaline · lymphopénie · œdème oculaire · diminution de l’hémoglobine · éruption cutanée · dysgueusie · diminution du phosphate
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse avant de commencer. Les femmes doivent utiliser une contraception non hormonale efficace pendant le traitement et pendant 1 mois après ; les hommes pendant le traitement et pendant 1 semaine après. Peut altérer la fertilité masculine et féminine. Ne pas allaiter pendant le traitement ni pendant 1 semaine après.
Bibliographie récente (PubMed)
Diffuse tenosynovial giant cell tumor (D-TGCT) is a benign neoplasm with locally aggressive potential of the synovium, bursae, and tendon sheaths. This review summarizes the current treatment landscape for D-TGCT, with a focus on systemic therapies. Surgery is the primary treatment option for tenosynovial giant cell tumor (TGCT), but there is a high risk of recurrence and associated morbidity, particularly for patients with advanced D-TGCT. Systemic therapies targeting the colony-stimulating factor 1 receptor (CSF1R) have resulted in positive tumor response, improved function, and decreased symptoms. For an alternative to surgery, the CSF1R inhibitors pexidartinib and vimseltinib are approved in the United States for TGCT, and other CSF1R inhibitors are in clinical development. CSF1R inhibitors represent a significant evolution in therapeutic strategies for D-TGCT. The potential risks and benefits of available treatments should be carefully considered in collaboration with a bone tumor-experienced, multidisciplinary team to determine the best course of care. Increased D-TGCT awareness and support through patient advocacy groups have helped to reshape the patient journey.
Colony-Stimulating Factor-1 Receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. Mutations of CSF1R have been implicated in neurodegeneration, skeletal anomalies, and cancers. Activation of CSF1R by endogenous cytokine ligation to the ectodomain triggers the autophosphorylation of the intracellular tyrosine kinase domain, and thereafter, activation of several downstream pro-survival kinase cascades, including PI3K, ERK1/2, and JNK. The immunological role of CSF1R in regulating tumor-associate macrophages (TAMs) have been well-documented. TAMs harboring activated CSF1R release tumorigenic cytokines, which further deconditioning tumor microenvironment to a protumoral phenotype. Pharmacological inhibition of CSF1R has emerged as a promising antitumor strategy, with PLX3397 (pexidartinib) been approved by the FDA for the treatment of tenosynovial giant cell tumor in 2019. Research around developing novel small-molecule CSF1R inhibitors, as well as expanding their potential indications, have drawn numerous attentions thenceforward. Herein, we've comprehensively reviewed the latest progression of CSF1R inhibitors under clinical and preclinical studies. Key findings of CSF1R targeted therapies either as monotherapy or combinatorial therapy have also been discussed.
Pexidartinib is approved in the US, Taiwan, and Korea for adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery based on the phase III ENLIVEN study (NCT02371369). We report the final long-term efficacy and safety results from ENLIVEN. Adults with symptomatic TGCT not eligible for surgery were enrolled and randomized to pexidartinib or placebo (part 1). The blinded phase (part 1) ended at week 25; patients received pexidartinib (800 mg/day) until progression, toxicity, or study completion (part 2). This analysis includes patients who received pexidartinib at any time during ENLIVEN. Centrally reviewed overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and tumor volume score (TVS), time to response, duration of response (DOR), patient-reported outcomes (PROs), and long-term safety were assessed. Overall, 91 patients received pexidartinib. With a median follow-up of 31.2 (range: 2-66) months, ORR was 60.4% and 68.1% by RECIST and TVS, respectively. Median DOR by RECIST was not reached (range: 0.03-63.4 months). Most responses were within the first 6 months of treatment; most responders were on 800 mg vs 600/400 mg dose levels, respectively. Throughout parts 1 and 2, 3 (3%) patients had progressive disease per RECIST without dose reduction/interruption. PROs improved or were maintained. The most common grade 3/4 treatment-emergent adverse events were aspartate aminotransferase (AST) increase (9%), alanine aminotransferase (ALT) increase (10%), and hypertension (8%). Twenty-eight (31%) patients had AST or ALT ≥3 times the upper limit of normal (ULN); 17 (19%) patients had AST or ALT ≥5 times the ULN. No new safety signals were observed after long-term pexidartinib treatment. Final long-term ENLIVEN results demonstrated that pexidartinib sustained clinical benefit, with increased ORR by RECIST and TVS compared to the end of
Tenosynovial giant cell tumors (TGCTs) are locally aggressive mesenchymal neoplasms that can cause chronic disability. Surgery is a mainstay of treatment but can carry a high risk of morbidity or can confer limited benefit. As such, effective alternative treatment options are needed, including systemic agents. Improved understanding of the pathophysiology of TGCTs has led to such drug development. Vimseltinib is a switch-control tyrosine kinase inhibitor designed to selectively inhibit CSF1R, which, along with CSF1, is responsible for the synovial inflammation that characterizes TGCTs. In this drug evaluation, we review the mechanism of action, pharmacologic properties, clinical efficacy and current role within the TGCT treatment landscape of vimseltinib. Vimseltinib demonstrated a significant response rate as well as meaningful symptomatic improvement in patients with TGCTs. Furthermore, there is an absence of severe toxicities that have arisen with other agents in the TGCT treatment space, specifically liver failure. Vimseltinib is a favorable option for patients with TGCTs and further efforts to determine its place in the sequence of overall management are needed.
Pexidartinib is effective in patients with tenosynovial giant cell tumor (TGCT) for whom surgery is not feasible. Durability of response after discontinuation of pexidartinib and the safety and efficacy of restarting pexidartinib have not been previously recorded. This phase 4 study was designed to mimic the real-world experience with pexidartinib to evaluate the effects of discontinuation of and retreatment with pexidartinib in patients with TGCT who previously benefited from the drug. This was a global, multicenter, phase 4 study that enrolled patients with TGCT who were experiencing clinical benefit from pexidartinib in one of four prior phase 1 or phase 3 studies investigating pexidartinib in the disease. Patients could choose to continue pexidartinib at the same dose (the treatment-continuation cohort) or discontinue treatment with the option to restart pexidartinib (the treatment-free/retreatment cohort). Tumor progression determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, patient-reported outcomes (the Patient-Reported Outcomes Measurement Information System-Physical Function [PROMIS-PF] questionnaire and the EuroQol 5-dimension, 5-level [EQ-5D-5L] visual analog scale), and safety were assessed every 3 months. The primary end point was the proportion of patients in the treatment-free/retreatment cohort who remained treatment-free at month 12 and 24; this did not depend on disease progression. Thirty-two patients were enrolled: 21 chose to enter the treatment-continuation cohort, and 11 entered the treatment-free/retreatment cohort. During the treatment-free period, six of 11 (54.5%) patients in the treatment-free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1, whereas no patient in the treatment-continuation cohort had disease progression. Over the 24-month study, three of 11 (27.3%) patients in the treatment-free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symptomati