August 2, 2019, with PAPhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211810s000lbl.pdf
On August 2, 2019, the U.S. Food and Drug Administration granted approval to Pexidartinib (turalio) capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not responsive to improvement with surgery.
“TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement. The tumor can significantly affect a patient’s quality of life and cause severe disability,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure. Today’s approval is the first FDA-approved therapy to treat this rare disease.”
TGCT is a rare tumor that affects the synovium (thin layer of tissue that covers the surfaces of the joint spaces) and tendon sheaths (layer of membrane that covers tendons, which are fibrous tissue that connect muscle to bone). The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, causing damage to surrounding tissue.
The approval of Turalio was based on the results of a multi-center international clinical trial of 120 patients, 59 of whom received placebo. The primary efficacy endpoint was the overall response rate (ORR) analyzed after 25 weeks of treatment. The clinical trial demonstrated a statistically significant improvement in ORR in patients who received Turalio, with an ORR of 38%, compared to no responses in patients who received placebo. The complete response rate was 15% and the partial response rate was 23%. A total of 22 out of 23 responders who had been followed for a minimum of six months following the initial response maintained their response for six or more months, and a total of 13 out of 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months.
The prescribing information for Turalio includes a Boxed Warning to advise health care professionals and patients about the risk of serious and potentially fatal liver injury. Health care professionals should monitor liver tests prior to beginning treatment and at specified intervals during treatment. If liver tests become abnormal, Turalio may need to be withheld, the dose reduced, or permanently discontinued, depending on the severity of the liver injury. Turalio is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program.
Common side effects for patients taking Turalio were increased lactate dehydrogenase (proteins that helps produce energy in the body), increased aspartate aminotransferase (enzymes that are mostly in the liver but also in muscles), loss of hair color, increased alanine aminotransferase (enzymes that are primarily in the liver and kidney) and increased cholesterol. Additional side effects included neutropenia (low level of white blood cells that help the immune system defend against disease and infection), increased alkaline phosphatase (enzymes that are mostly in the cells of bone and the liver), decreased lymphocytes (white blood cells that help the immune system defend against disease and infection), eye edema (swelling around the eyes), decreased hemoglobin (protein in red blood cells that carry oxygen), rash, dysgeusia (altered sense of taste) and decreased phosphate (electrolytes that help with energy).
The FDA advises health care professionals to tell females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Turalio. Women who are pregnant or breastfeeding should not take Turalio because it may cause harm to a developing fetus or newborn baby. Turalio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
The FDA granted this application Breakthrough Therapy designation and Priority Review designation. Turalio also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Turalio to Daiichi Sankyo.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist’s Applications to Practice
Pexidartinib for the Treatment of Advanced Tenosynovial Giant Cell Tumor (TGCT) in Adults
Author: Sarah E. Hoffman, PharmD BCOP
Oncology Clinical Specialist Pharmacist
The James Cancer Hospital at The Ohio State University
What is the potential role for pexidartinib in the treatment of tenosynovial giant cell tumor (TGCT)?
- Pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) tyrosine kinase inhibitor (TKI), was approved by the U.S. Food and Drug Administration (FDA) for adult patients with symptomatic TGCT (also known as pigmented villonodular synovitis [PVNS]) that is not amenable to improvement in morbidity or functionality with surgery.1
- Prior to the approval of pexidartinib, no systemic therapies for TGCT/PVNS had been approved by the FDA. Historically, TKIs such as imatinib and nilotinib had been used off-label for unresectable TGCT because of their inhibitory effects on CSF1R.2,3 However, responses to these TKIs were low, with the majority of patients achieving stable disease.
- FDA approval of pexidartinib was based on data from the phase 3 multinational ENLIVEN trial, which randomized patients with advanced, symptomatic TGCT in which surgical resection was likely to cause increased morbidity or worsening functional status to either pexidartinib (n = 61) or placebo (n = 59).4
- The overall response rate (ORR) at 25 weeks was significantly improved in the pexidartinib group compared to the placebo group (39% vs. 0% [95% confidence interval (CI) 27–52]; p < .0001).
- Patients receiving pexidartinib also experienced significant improvement in tumor volume score and relative range of motion and stiffness based on patient-reported symptoms.
- Grade 3 or 4 adverse events occurred in 44% of pexidartinib patients, compared to 12% of patients receiving placebo. The most common grade 3 or 4 adverse events in the pexidartinib group included increased aspartate aminotransferase (AST) (10%), increased alanine aminotransferase (ALT) (10%), increased alkaline phosphatase (7%), and hypertension (5%). Serious adverse events occurred in 8 (13%) of patients in the pexidartinib group and included mixed or cholestatic hepatotoxicity.
- The enhanced response rate seen with pexidartinib compared to historical TKIs is likely because pexidartinib is a more selective inhibitor of CSF1R than are imatinib and nilotinib.2
- As a result of the ENLIVEN trial and subsequent FDA approval, pexidartinib was added to the National Comprehensive Cancer Network guidelines for soft tissue sarcoma in 2019 and was given a category 1 recommendation for TGCT/PVNS.5
What role can the pharmacist play in the management of patients on pexidartinib?
- The pharmacist should be an essential member of the team caring for patients with TGCT and can provide patient education, ensure appropriate dosing, monitor for drug interactions, and manage various toxicities associated with pexidartinib treatment.
- Pexidartinib for TGCT is administered at a dose of 400 mg orally twice daily.1
- The dose of pexidartinib should be reduced to 600 mg/day (200 mg in the morning and 400 mg in the evening) if the creatinine clearance (CrCl) is between 15 and 89 mL/min.
- No dose adjustments are provided for baseline hepatic impairment; however, pexidartinib should be avoided in patients with active liver or biliary tract disease, including increased alkaline phosphatase.
- Drug interactions1
- Concomitant use of strong cytochrome P450 3A4 (CYP3A4) or uridine 5'-diphospho-glucuronosyltransferase (UGT) inhibitors should be avoided, including grapefruit or grapefruit juice. If use of a strong CYP3A4 or UGT inhibitor cannot be avoided, the recommendations for dose reductions in the package insert should be followed. Strong CYP3A4 inducers, including St John’s wort, should be avoided.
- Patients should also avoid proton pump inhibitors (PPIs) during treatment with pexidartinib. Antacids and histamine 2-receptor antagonists (H2RAs) may be used if they are appropriately spaced from pexidartinib administration.
- Because of the black-box warning for hepatotoxicity, pexidartinib is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program.6
- Prescribers, pharmacies, and patients must all be enrolled in the REMS program.
- Prior to initiating treatment with pexidartinib, patients should be counseled on the risk of serious and potentially fatal liver injury.
- Patients must also complete a patient enrollment form, receive a patient guide, and have baseline liver tests.
- A patient status form must be completed at designated intervals. Liver tests should be monitored at baseline, monthly for the first 3 months, then every 3 months until 1 year of treatment has been completed, and every 6 months thereafter.
- Liver tests include AST or serum glutamic-oxaloacetic transaminase (SGOT); ALT or serum glutamic pyruvic transaminase (SGPT); gamma-glutamyl transferase (GGT); total bilirubin; direct bilirubin; alkaline phosphatase; albumin; and prothrombin time/international normalized ratio.
- Detailed dose modifications and criteria for holding or discontinuing the drug because of hepatotoxicity are outlined in the package insert.1
- Other adverse events (any grade) associated with pexidartinib include increased lactate dehydrogenase (92%), hair-color changes (67%), fatigue (64%), decreased neutrophils (44%), increased cholesterol (44%), decreased lymphocytes (38%), nausea (38%), decreased hemoglobin (30%), eye edema (30%), rash (28%), dysgeusia (26%), and hypophosphatemia (25%).1,4
- Currently, Biologics is the only specialty pharmacy that dispenses pexidartinib. A patient assistance program is available through Daiichi Sankyo Access Central in coordination with Biologics pharmacy.7
- Pexidartinib is supplied as a 200-mg capsule available in 28- and 120-count desiccant-containing bottles. Capsules should be swallowed whole.
- Many patients will likely require upfront renal dose adjustments, given the relatively high CrCl cutoff for mild–moderate impairment (15–89 mL/min).
- The ENLIVEN trial included a small number of geriatric patients (> 65 years old). Elderly patients should be monitored closely for safety and efficacy while they are receiving pexidartinib.
- Pexidartinib may cause harm to embryos and fetuses if administered during pregnancy. Patients of reproductive potential should use effective contraception during treatment and for 1 week (males) or 1 month (females) after the last dose.
- Diligent monitoring of liver tests to maintain compliance with the FDA-mandated REMS program is essential to ensure patients’ safety while they are receiving pexidartinib, especially during the first 8 weeks of treatment.
- Turalio (pexidartinib) [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2019.
- Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer. 2012;118(6):1649-1655.
- Gelderblom H, Crope C, Chevreau C, et al. Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2018;19(5):639-648.
- Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019:394(10197):478-487.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 5.2019 (January 23, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed January 30, 2020.
- Turalio Risk Evaluation and Mitigation Strategy. Available at https://www.turaliorems.com/#Main. Accessed January 2, 2020.
- Daiichi-Sankyo Access Central. Turalio pexidartinib 200 mg capsules. Available at https://dsiaccesscentral.com/patient/turalio/start. Accessed January 2, 2020.