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INTRODUCTION

Sarcomas are a heterogenous collection of malignancies found within the soft tissue or bone. The common element linking them is their precursor, the mesenchymal cell, which differentiates into numerous types of connective tissue within the body. At least 70 different tumors, both malignant and benign, can arise from these connective tissues. However, sarcomas make up fewer than 1% of all adult tumors and 15% of pediatric cancers, making them a very diverse mix of malignancies with different mutations, treatments and ultimately outcomes.^1,2

The tenosynovial giant cell tumor (TGCT) is one of the many types of sarcomas. Originally identified in 1941,³ earlier names included pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath, but the most recent World Health Organization (WHO) classification retired these names and designated them as TGCTs.⁴ TGCTs are rare and locally aggressive benign tumors arising from the lining of the synovium; these rarely transform into a malignant tumor that metastasizes.³ TGCTs affect people most often in their 20s to 50s with a slight predominance in females (~60%).^5,6

TGCTs usually affect a single joint, tendon sheath, or bursae. There is synovial proliferation with tumor development, made up of multinucleated giant cells, macrophages, histiocytes, and other pro-inflammatory cytokines such as tumor necrosis factor (TNF) alpha.^3,7 The mutated cells make up only a small portion of the cells within the tumor, the majority of which consists of inflammatory components that are recruited by colony stimulating factor-1 (CSF-1) receptors expressed on macrophages. This causes inflammation and leads to joint destruction with subsequent pain, swelling, stiffness, and decreased range of motion that affects the patient’s quality of life and is associated with a high healthcare cost burden.^1,7–9

Overexpression of CSF-1 facilitates growth of the tumor and is caused by a t(1;2) translocation, fusing the CSF-1 gene on chromosome 1p13 to the collagen type Via3 (COL6A3) promoter on chromosome 2q37 in the majority of cases. Other less frequent CSF-1 translocations have been identified, and some tumors have non-CSF-1–mediated growth.^3,10 Further research has demonstrated that CSF-1 translocation is not required for CSF-1 upregulation to occur, but the same resulting overexpression aids in the development of TGCTs.¹⁰

The 2 types of TGCTs are localized and diffuse tumors. Localized, or nodular, tumors —previously called giant cell tumor of the tendon sheath — are usually found in the digits of the hands and feet. They contain a single nodule that usually arises from the tendon sheath and less commonly from the synovial lining of the digital joints. Diffuse-type TGCTs (dt-TGCT), which have multiple nodules, were previously referred to as diffuse pigmented villonodular synovitis (PVNS) or synovitis (villo)nodularis pigmentosa (SVP). They account for about 10% of all TGCTs.^5,11 dt-TGCTs affect larger joints, most commonly the knee (~75%), but they can occur in the hip, ankle, elbow, jaw, wrist, or shoulder.⁵ These act more aggressively than localized tumors, with soft tissue masses developing along the synovial lining. All cases of tumors transforming to a malignant tumor (only about 0.1% of all TGCTs) were originally dt-TGCTs.³

The prevalence of TGCTs has traditionally been based on a single U.S. study from 1980 that reported an incidence of 11 cases per million person-years in localized and dt-TGCTs (9.2 and 1.8 cases per million person-years, respectively).¹¹ It is now being recognized that dt-TGCTs are more common than previously thought. In Denmark, researchers reviewed that country’s cases between 1997 and 2012, finding 30.3 and 8.4 cases per million person-years for localized and diffuse types, respectively.⁶ A study from the Netherlands reported 50 cases per million person-years, including both localized and diffuse types, with recurrence rates for dt-TGCTs about 2.6 times higher than in localized type.⁵

SYMPTOMS AND ASSESSMENT

Because TGCTs are slow growing, painless swelling of the joint is often the first symptom noticed, although that can depend on where the tumor is located. Other symptoms include joint stiffness, limited range of motion, or fatigue. Persistent disease can lead to long-term damage with cartilage destruction and bone erosion. Tests for inflammation—such as complete blood counts, C-reactive protein, and erythrocyte sedimentation rate — are usually negative.^7,12

Although TGCTs are benign tumors, they can affect overall quality of life through functionality and pain associated with the tumor. Studies that evaluate oncology drugs primarily look at the reduction in size of the tumor to determine efficacy. Instruments that could evaluate patient-reported outcomes for TGCT would provide additional ways to assess the overall impact of potential treatments. Gelhorn et al.⁹ conducted a study to assess available patient-reported outcome (PRO) instruments for evaluating the clinical efficacy of therapies that target TGCTs. Three PRO instruments were considered potentially relevant to this population and were evaluated further. Based on assessments by participants in the study who were interviewed and rated the relevance of the instruments, modifications were made. The study modified the Western Ontario McMaster Arthritis (WOMAC) scale that assesses pain, stiffness, and difficulty performing daily activities, focusing mainly on the lower extremities.

The new WOMAC-Pigmented Villonodular Synovitis and Giant Cell Tumor of the Tendon Sheath Index (PVNS-GCTTS) instrument asked the same questions as the original instrument but adapted them to specifically consider symptoms at the joint/tumor location. They used limited symptom numeric rating scale (NRS) items to evaluate pain, stiffness, swelling, immobility, and limited motion. The Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) assessment is an item bank that includes 121 self-administered elements that evaluate physical functioning. Of those, 15 items from the PROMIS-PF system were found to be relevant to the TGCT population for measuring physical function specific to patients with either upper or lower extremity tumors.⁹

Evaluating these newly developed PRO assessments in the study population, these investigators were able to confirm that pain, swelling, and stiffness are the most common and important symptoms from the patient perspective in those with TGCT. In interviews with study participants with TGCT, other symptoms mentioned often were reduced range of motion, instability, giving out, and catching in joints. These PRO instruments for TGCT followed the U.S. Food and Drug Administration and European Medicines Agency guidance on developing these types of instruments. They were then assessed in the phase 1 pexidartinib study and used to measure secondary outcomes in the phase 3 pexidartinib study.⁹

TREATMENT

Treatment of TGCTs is primarily surgery with a chief goal of preventing total joint replacement or amputation while preserving range of motion and functionality as much as possible. Patients often undergo multiple surgeries over time in an effort to control their disease because this condition is poorly responsive to systemic chemotherapy. Localized TGCT can often be managed through direct excision of the nodule. dt-TGCT is harder to resect; interventions can include total synovectomy, joint replacement or as a last resort, amputation. Surgery is usually performed arthroscopically or as an open synovectomy. Arthroscopic resection reduces morbidity but is associated with a higher risk of incomplete resection compared with open synovectomy. Open synovectomies are preferred if the tumor is locally advanced.^1,7

Overall, risk of recurrence varies based on the type of TGCT as well as the tumor characteristics and resection but can be as high as 45% despite complete resection.¹⁰ Factors that demonstrated a decreased risk of recurrence after surgery were new diagnosis, tumor size less than 20 mm, macroscopically complete resection, and female gender.¹³ Factors found to contribute to risk were incomplete resections, mitotic activity, bone involvement, and knee versus hip location.

In a multivariate analysis, a history of previous relapse was independently associated with local recurrence.¹³ Non-CSF-1 gene fusions may be associated with a greater risk of recurrence as well.^7,10 Risk of recurrence was assessed in a systematic review of localized TGCT and found to be 15% after an average follow up of 37–79 months.¹⁴ In dt-TGCTs, recurrence rates of 30%–40% can occur, potentially because surgeries may be incomplete and require additional resections.^1,7 In a systematic review, investigators found an average recurrence rate of 6% after arthroscopic surgery versus 4% with open resection in patients with localized disease, compared with 40% versus 14%, respectively, in those with diffuse disease.¹⁵ In extensive disease, perioperative radiation may reduce this risk.⁵

A number of therapeutic agents are providing needed options for patients with inoperable TGCTs. These include imatinib and nilotinib, emactuzumab and cabiralizumab, and pexidartinib.

Imatinib and Nilotinib

The tyrosine kinase inhibitors imatinib and nilotinib are nonselective CSF-1 inhibitors with similar potency. Imatinib was studied in a multi-institutional retrospective review of 29 patients with locally advanced or metastatic dt-TGCT. Of the 9 patients without previous surgery, 4 were given neoadjuvant imatinib. All others received imatinib 400 mg daily except for 1 patient who received 600 mg. Overall response rate was 19% in 27 evaluable patients (1 complete response and 4 partial responses). Stable disease was seen in 20 of 27 patients (74%). Symptomatic improvement was seen in 16 of 22 patients (73%) who were assessed for symptoms. However, 6 patients discontinued therapy due to toxicity, and 4 additional patients discontinued therapy for unknown reasons. Toxicities were similar to the known adverse effect profile of imatinib, with edema and fatigue seen most commonly.¹⁶ A long-term follow-up study of patients on imatinib showed that 17 of 58 (29%) evaluable patients achieved a complete response (CR) or partial response (PR) with a 1-year progression free survival rate of 71%. The 5-year progression-free survival rate was 48%.⁴

Nilotinib was evaluated in a phase 2, multicenter, open-label trial of 56 patients with unresectable dt-TGCT. All patients were given nilotinib 400 mg twice daily and assessed at week 12. Five patients did not complete the 12 weeks of therapy. Of the 51 evaluable patients, 92.6% had not progressed at the 12-week assessment. Overall, 54 of the 56 (96%) patients had a treatment-related adverse event that matched nilotinib’s usual adverse effect profile. At 1 year, responses were observed in only 3 of 51 (6%) patients.¹⁷

Emactuzumab and Cabiralizumab

Two monoclonal antibodies, emactuzumab (RG7155) and cabiralizumab (FPA008), have been identified as more potent selective inhibitors of CSF-1 than imatinib and nilotinib. Emactuzumab has been evaluated in a phase 1 clinical trial, with 26 of the 28 evaluable patients obtaining an objective response as early as 1–2 weeks into treatment. Significant symptomatic improvement was seen with a manageable safety profile.¹⁸ A phase 1/2 study using cabiralizumab in dt-TGCT is ongoing, as are continuations of studies with emactuzumab.¹⁹

Pexidartinib

Pexidartinib (PLX3397) is a potent selective CSF-1 tyrosine kinase inhibitor that also inhibits KIT and FLT3-ITD. A phase 1 study of 23 evaluable patients with recurrent and inoperable TGCT were included in the expansion cohort. Of those, 12 (52%) had a partial response and 7 (30%) had stable disease. Four patients had previously received imatinib or nilotinib but still responded to pexidartinib. It was well-tolerated and improved overall joint functionality and decreased pain and stiffness.²

Based on the phase 1 results, the phase 3 multinational, randomized ENLIVEN trial was conducted. Part 1 included 120 patients with measurable disease who were not eligible for surgery. They were randomized 1:1 to receive a loading dose of pexidartinib 400 mg in the morning and 600 mg in the evening for the first 2 weeks, followed by 400 mg twice daily, or a matching placebo. At week 25, central imaging was used to evaluate the primary endpoint of overall response (CR plus PR) and 2 secondary endpoints of overall response rate by tumor volume score (TVS) and duration of response. The TVS is specific to TGCT, which considers the overall size of the often irregularly shaped tumor relative to the normal synovial cavity. Additional secondary endpoints assessed functionality and pain using modified instruments for patients with TGCT. Range of motion (ROM) was evaluated by an independent, blinded third party.

The results at week 25 revealed that the pexidartinib arm achieved an overall response of 39% versus 0% with placebo (P <0.0001). Nine patients (15%) had a CR compared with none in the placebo arm (P <0.0001). All patients who responded to pexidartinib by week 25 had no progression 6 months later. A total of 12 patients in each group were considered unevaluable for the primary outcome. When all patients in the pexidartinib arm had completed week 25, median duration of response had not been reached as few patients had disease progression (median follow-up of 22 months) and the overall response was calculated at 53%, demonstrating additional reduction in size with longer pexidartinib treatment. Similarly, the overall response rate by TVS was increased from 56% at week 25 to 64% at the conclusion of part 1. All secondary endpoints demonstrated statistically significant improvement in outcomes, including improved range of motion, physical functioning, and stiffness. The only symptom to not meet statistical significance was pain.²⁰

Adverse effects occurred in 60 of the 61 patients in the pexidartinib arm and 55 of 59 patients in the placebo arm (98% vs. 93%, respectively). The most common adverse effects in the pexidartinib and placebo groups, respectively, were hair color changes (67% vs. 3%), fatigue (54% vs. 36%), nausea (38% vs. 41%), diarrhea (20% vs. 25%), dysgeusia (25% vs. 2%), and arthralgia (23% vs. 3%). Grade 3 or 4 events occurred in 27 (44%) receiving pexidartinib and 7 (12%) receiving placebo. The most common grade 3 or 4 adverse effects were aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase elevations, and hypertension.²⁰

Discontinuations within the first 25 weeks of the study due to adverse effects in the pexidartinib arm occurred in 13% of participants (8 of 61). For 7 of the 8 patients, discontinuation was linked to liver-related effects. A total of 11 patients in the placebo arm (n = 59) also discontinued therapy for various reasons not related to toxicity. Treatment interruption or dose reduction due to adverse effects occurred in 23 (38%) participants in the pexidartinib arm and 6 (10%) participants in the placebo arm. In the pexidartinib group, adverse effects were most commonly related to AST or ALT increases or cholestatic hepatotoxicity. Two cases of mixed and cholestatic hepatotoxicity in addition to other case reports of liver toxicity with pexidartinib caused the Data Monitoring Committee to recommend stopping further enrollment (6 patients shy of the total 126 planned). In all, 3 patients had AST and ALT≥3x upper limit of normal (ULN) with total bilirubin (Tbili) and alkaline phosphatase ≥2x ULN. One patient required 2 liver dialysis procedures for elevated bilirubin lasting for about 7 months. In the other 2 patients, hyperbilirubinemia persisted for 1–2 months after discontinuation of pexidartinib.²⁰

Patients in part 1 of this trial were allowed to enter part 2, which was open-label pexidartinib, if they were responding to pexidartinib at unblinding. Patients found to be on placebo had the option to crossover to pexidartinib until the study was halted enrollment due to hepatotoxicity. A total of 30 patients crossed over to pexidartinib at 400 mg twice daily. Of the 30 patients who had crossed over, 9 (30%) patients had an overall response at week 25 of part 2 and 17 (57%) had an overall response rate by TVS. Again, other secondary endpoints in part 2 demonstrated positive patient-reported outcomes. Hepatotoxicity was not as severe in part 2, potentially because of the lower dose of 800 mg/day vs the 1000 mg/day starting dose in part 1.²⁰

Pexidartinib use in patients with TGCT who cannot have definitive surgery can decrease tumor size as well as increase motility and functionality.²⁰ This is the first FDA-approved drug for the treatment of this rare tumor. However, research is far from complete with many remaining questions. What are the long-term effects, both positive and potentially negative, of pexidartinib? The duration of response in unresectable disease is still unknown. Can patients remain on the agent indefinitely? Can therapy be stopped and then resumed at a later point? Would neoadjuvant therapy allow complete resections to be possible with continued pexidartinib as adjuvant therapy to decrease risk of recurrence? Could pexidartinib then potentially be used in earlier stages of disease in these settings? As more patients are placed on this drug in the real-world setting, will liver toxicity remain a common theme? Can we better identify which patients would have lower risks? Might there be other rare adverse effects seen with pexidartinib with increasing numbers of patients on treatment? Additional research is needed to find answers to these questions.

Additional information on TGCTs is being pursued as well. Research will likely provide a better understanding of the impact of CSF-1 inhibition and the role of macrophages in wound healing. CSF-1 antagonism also affects angiogenesis, which could affect surgical complications. The use of local therapies to halt the growth of the tumor continues to be an exciting proposition with a potential for limited toxicity. Intra-articular bevacizumab as well as intra-articular yttrium 90 and TNF-alpha have shown some benefit in small series.⁷ The discovery of new biologic markers may facilitate identification of patients with higher risks of recurrence. The instruments developed to specifically assess issues that affect quality of life in patients with TGCT will also be important for future studies to measure clinical benefit and quality of life in addition to tumor benefits.

Implications for Pharmacists

Pexidartinib was approved in August 2019 for adult patients with symptomatic TGCT that is associated with severe morbidity or functional limitations and who are not candidates for surgery.²¹ As this and other therapies increase in usage, targeted therapies are becoming a chronic daily medication for patients. Providing patient and provider education is important to ensure its safe and effective use as well as aid in adherence to therapy. Beyond education of adverse effects, recommendations for dose modifications and symptom management will play a large role in the management of patients with TGCT. The toxicities and effects of pexidartinib are a concern, and with the approved Risk Evaluation and Mitigation Strategy (REMS) program, the pharmacist can be involved in many of these roles to provide safe and effective care for patients with TGCT.

Adverse Effects

The common adverse effects of pexidartinib have been seen repeatedly, including hair depigmentation, fatigue, eye edema, rash, and taste changes (Table 1). Other adverse effects of clinical or patient concern that occur in fewer than 20% of patients are hypertension (15%; grade ≥3, 4.9%), mouth ulcers (10%), decrease in appetite (16%), cognitive disorders (<10%, including memory impairment, amnesia, confusional state, disturbance in attention, and attention-deficit/hyperactivity disorder), neuropathy (10%, including peripheral neuropathy, paresthesia, hypoesthesia, burning sensation), vision changes (<10%, including blurred vision, photophobia, diplopia, reduced visual acuity), and changes in skin pigment (<10%). The most common clinical adverse effects that cause dose reductions or interruption include nausea, vomiting, dizziness, and abdominal pain. Liver function tests, bilirubin, and gamma-glutamyl transferase (GGT) elevations have also caused dose reductions or discontinuation. Due to the potential for hepatotoxicity with this agent, a REMS program was developed for close monitoring. No QTc interval issues have been identified in studies to date.²¹

Dose Modifications

The approved starting dose of pexidartinib is 400 mg twice daily. Any dose modifications should begin with 600 mg/day (200 mg in the morning and 400 mg in the evening). A second dose reduction would decrease to 400 mg/day (200 mg twice daily). Any further necessary reductions in dose should require discontinuation of therapy. These dose modifications should be used for any adverse effect, excluding hepatotoxicity, which should be handled in a specific way (Table 2).²¹

In the setting of mild-to-severe renal impairment at baseline (15–89 mL/min), reduce the dose to 200 mg in the morning and 400 mg in the evening. The properties of the drug, including protein binding of >99% and a volume of distribution of 187 liters, suggest that it is most likely not dialyzable.²¹

If there is mild liver impairment at baseline, defined as a Tbili ≤ULN with AST >ULN or Tbili >1–1.5x ULN with any AST, no adjustment is needed. No dosage has been established for moderate-or-severe impairment prior to treatment.²¹

Monitoring

Pexidartinib initiation requires strict monitoring parameters. Negative pregnancy status must be verified before starting therapy for any female of reproductive potential. Liver tests should be obtained before therapy begins, then weekly for the first 8 weeks, every 2 weeks for 1 month, and then continue every 3 months. If rechallenging, monitor liver tests weekly for the first month. Liver tests include AST, ALT, Tbili, Dbili ALP, and GGT.²¹

Reproductive Concerns

In animal models, pexidartinib has been shown to cause fetal harm and to impair both male and female fertility. Women who have the potential to become pregnant should use an effective nonhormonal method of contraception during and for 1 month after stopping pexidartinib. For men who could potentially impregnate a partner of childbearing potential, effective contraception should be used during treatment and for 1 week after stopping. It is important to use nonhormonal contraception as pexidartinib may decrease the efficacy of hormonal contraceptives. Breastfeeding should be avoided during treatment and for at least 1 week after ending therapy.²¹

Food and Drug Interactions

Pexidartinib interacts with food and various drugs. Pharmacists should be aware of these interactions and counsel patients about them.

Food increases drug exposure of pexidartinib by 100%. Pexidartinib should be taken on an empty stomach, either 1 hour before or 2 hours after a meal or snack. Grapefruit and grapefruit juice should also be avoided due to its effect on the cytochrome P450 (CYP) 3A system.²¹

Pexidartinib is a major substrate and moderate inducer of CYP3A as well as a substrate of UDP-glucuronosyltransferase (UGT). The CYP3A4 enzyme system is most affected by pexidartinib. It is critical to note that these interactions include hormonal contraceptives as pexidartinib can decrease their efficacy. Moderate or strong CYP3A inhibitors should be avoided, as should inhibitors of UGT. If interacting drugs must be used, the dose of pexidartinib should be reduced; doses of 600–800 mg/day should be reduced to 200 mg twice daily. For doses of 400 mg/day, reduce the dose to 200 mg once daily. If the inhibitor is discontinued, increase pexidartinib back to the previous dose after 3 half-lives of the inhibitor have passed.

Strong CYP3A inducers should be avoided as well. Concomitant CYP3A4 substrates should only be avoided if small changes in therapeutic concentrations can cause significant issues, such as with hormonal contraceptives.²¹

Proton pump inhibitors also should not be used concomitantly with pexidartinib. When given concomitantly with esomeprazole, pexidartinib’s maximum concentration and area under the serum concentration–time curve are decreased by about 50%. Antacids can be used instead, as long as these are not taken within 2 hours of the pexidartinib dose. A histamine-2 receptor antagonist may also be used as long as it is at least 10 hours before or 2 hours after the pexidartinib dose.²¹

Adherence

Adherence is a major issue for patients on long-term oral anticancer therapy. For some patients, the benefits of agents are not always seen or felt, but the adverse effects can severely impact quality of life. Some adverse effects will cause physical symptoms, while others can affect how a patient feels about themselves and their appearance. Working with patients to minimize the impact of these effects on their daily life can aid in adherence to therapy.

For patients with TGCT, both the tumor itself and the drugs used to treat it can produce frustrating changes in daily life; these patients are often young and healthy other than the tumor. The other side of adherence is the concern for overadherence, particularly with pexidartinib because of the risk of hepatotoxicity with higher doses. If a patient forgets a dose or vomits after one is taken, they should not try to make up the dose but rather should wait to take the next scheduled dose at the appropriate time. Making up missed doses by taking doses too close together or doubling up can elevate drug concentrations in the blood, leading to toxicities, especially liver damage; it is important that patients understand this and are motivated to stay on schedule.²¹

Pharmacists and the medical team should help patients find an appropriate aid to help them with adherence. Pill boxes are not good options because pexidartinib should remain in the stock bottle with the desiccant.²¹ Alarms, calendars, and phone apps are all potential resources that patients should explore. Communicating with patients so that they know what to expect and how they will be monitored can help them understand and remain adherent to this therapy while being open and honest about their concerns and any adverse effects.

REMS

Because of the potential for hepatotoxicity with this agent, a REMS program was developed. As outlined in the prescriber education, pexidartinib should be avoided in patients who already have increases in AST, ALT, Tbili, or Dbili above the ULN. This includes patients with active liver or biliary tract disease or with an increased ALP. The Turalio™ REMS program was developed to closely monitor liver toxicity in patients taking pexidartinib. To be certified, a prescriber must review the product labeling, as well as the Prescriber Training information slides and the Program Overview. They must acknowledge that they are required to report any serious or potentially fatal liver injuries by submitting the Liver Adverse Event Reporting Form, if needed. The prescriber fills out the Prescriber Enrollment Form and then must take and pass a Prescriber Knowledge Assessment (multiple choice and true/false questions). The prescriber has 3 attempts to pass the assessment. This can all be done online or may be printed and faxed. The prescriber will be notified when the certification is complete and prescribing of pexidartinib can begin.²²

When a prescriber is initiating treatment, they must first counsel the patient on the risk of serious and potentially fatal liver injury, the liver test monitoring that is required during treatment, and how the patient can identify and report any signs or symptoms of liver injury. They provide a Patient Guide to the patient that is located online and required with each refill. The prescriber must also enroll the patient into the patient registry, some of which can be done online, and by submitting the Patient Enrollment Form. This enrollment form includes the signatures of the patient and prescriber. It also includes information on the patient’s medication insurance that should be obtained from the patient. The patient’s signature on the form is their consent that they allow their information to be collected for tracking purposes. The prescriber should write a prescription for a 30-day supply for each of the first 3 months of therapy. While the patient is on treatment, the prescriber is required to complete and submit a Patient Status Form monthly for the first 3 months, then every 3 months for a total of 12 months. Thereafter, the form is submitted every 6 months as long as the patient remains on therapy.²²

REMS and Pharmacy

Pharmacies must designate an Authorized Representative who will ensure that the certification implementation is done and oversee compliance by the pharmacy staff. After reviewing the Program Overview, the Authorized Representative of the pharmacy should submit a signed copy of the Pharmacy Enrollment Form via fax or email. The Authorized Representative will be notified when the pharmacy can begin dispensing the drug.²²

Before pexidartinib can be dispensed by a certified pharmacy, the Authorized Representative must ensure training of all pertinent pharmacy staff using the Program Overview. They will also maintain the records of staff training with the pharmacy processes and procedures relevant to the REMS program. They must also comply with any audits by the drug company or their representative. For each prescription, the pharmacy must contact the Turalio™ REMS program to verify that the prescriber is certified and that the patient is enrolled and is authorized to receive drug in order to obtain an authorization for dispensing. No more than a 30-day supply can be dispensed for each of the first 3 months. The pharmacy is also responsible for reporting any serious or potentially fatal liver injury of which they are aware by submitting the Liver Adverse Event Reporting Form. The pexidartinib supply on hand cannot be distributed, transferred, loaned, or sold to anyone except a certified dispenser.

At this time, Biologics is the only pharmacy certified to dispense pexidartinib. This pharmacy ships the medication to the patient’s home. All information regarding the Turalio™ REMS program is online at www.turaliorems.com/#main.²²

Patient Support

There is a Turalio QuickStart program for any delays in starting therapy due to issues obtaining drug. For patients who experience a delay of 5 days or more in obtaining their prescription, the program will provide a 14-day supply of pexidartinib at no cost while the necessary insurance authorizations and any patient assistance approvals are being managed. To qualify, the patient must be new to therapy, have commercial or government insurance, and be experiencing a delay of 5 or more business days after submission of the completed prior insurance authorization. All REMS components must have been completed.²³

A patient financial support program is available through the drug manufacturer that provides access and financial support for patients prescribed pexidartinib. It is provided as a 200 mg capsule at almost $200 per capsule average wholesale price (AWP). If taking full dose, that becomes $800/day or about AWP $24,000 per month.²⁴

CONCLUSION

As can be seen by the different names used for this disease over time, our understanding of TGCTs has evolved with better diagnosis, classification, and therapies. Treatment of TGCTs is primarily surgery with a chief goal of preventing total joint replacement or amputation while preserving range of motion and functionality as much as possible. This can involve multiple surgeries over time to control localized tumors or diffuse-type conditions. This process is supported by systemic chemotherapy, to which not all patients respond.

A number of therapeutic agents are providing needed options for patients with inoperable TGCTs. With the identification of the CSF-1 receptor and its role in the development of TGCT, systemic treatment of TGCT has been developed that can reduce tumor size as well as increase functionality and range of motion. Systemic agents include the tyrosine kinase inhibitors imatinib and nilotinib, the monoclonal antibodies emactuzumab and cabiralizumab, and the selective CSF-1 tyrosine kinase inhibitor pexidartinib. As a more selective agent, pexidartinib has the potential to improve the treatment of nonresectable TGCTs associated with severe morbidity and functional limitations. Additional research will build upon these advances made as understanding and knowledge increase with the use of pexidartinib.

Update: May 3, 2021 Updated results from the phase 1 clinical trial evaluating emactuzumab in 63 patients with diffuse-type tenosynovial giant-cell tumor have been published. The independently reviewed best overall objective response rate (ORR) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrollment into the study. Reference: Cassier PA, Italiano A, Gomez-Roca C, et al. Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. European Journal of Cancer. 2020;141:162-170.

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