pexidartinib
Regulatory sources consulted
Approved indications
- In adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery.
Clinical warnings
- Boxed warning · BOXED WARNING: it can cause serious or fatal liver injury, including vanishing bile duct syndrome. Avoid starting if transaminases, bilirubin, or alkaline phosphatase are elevated or active hepatobiliary disease is present. Check AST, ALT, total and direct bilirubin, alkaline phosphatase, and GGT before treatment, weekly for 8 weeks, every 2 weeks for the next month, then every 3 months. Prompt discontinuation does not eliminate the risk. — DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- Boxed warning · It is available only through the restricted TURALIO REMS program because of hepatotoxicity risk. — DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- Major warning · A high-fat meal, approximately 55–65 g total fat, increases exposure and may increase adverse reactions and hepatotoxicity. Administer only with a low-fat meal. — DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
Drug interactions
- HighHepatotoxic medicines
Mechanism: They may increase the risk of serious liver injury.
Recommendation: Avoid the combination, especially with liver test abnormalities or active hepatobiliary disease.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- HighModerate or strong CYP3A inhibitors or UGT inhibitors
Mechanism: They increase pexidartinib exposure and toxicity.
Recommendation: Avoid the combination; if unavoidable, apply the specific dose reduction.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- HighStrong CYP3A inducers
Mechanism: They reduce exposure and may decrease efficacy.
Recommendation: Avoid the combination, including St John’s wort.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- ModerateProton pump inhibitors, H2 antagonists, and antacids
Mechanism: Reduced acidity may decrease pexidartinib exposure.
Recommendation: Avoid PPIs. Give pexidartinib 2 hours before or after a local antacid, or at least 2 hours before or 10 hours after an H2 antagonist.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
- HighCYP3A substrates with a narrow therapeutic index
Mechanism: Pexidartinib is a moderate CYP3A inducer and may reduce their exposure and efficacy.
Recommendation: Avoid the combination, including hormonal contraceptives; if unavoidable, coordinate substrate monitoring and adjustment with the prescribing team.
DailyMed, TURALIO set_id 7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b0ec4bf-b2ac-49ee-96af-7740ad3f2e16
Adverse events
Common (≥1%)
increased LDH · increased AST · hair color change · fatigue · increased ALT · neutropenia · increased cholesterol · increased alkaline phosphatase · lymphopenia · eye edema · decreased hemoglobin · rash · dysgeusia · decreased phosphate
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy before starting. Females must use effective non-hormonal contraception during treatment and for 1 month afterward; males during treatment and for 1 week afterward. It may impair male and female fertility. Do not breastfeed during treatment or for 1 week afterward.
Recent literature (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