Treatment goals for patients with TGCT include long-term tumor eradication or control of tumor burden and improvement of musculoskeletal symptoms [3]. The successful use of pexidartinib in this patient provides support for the use of this treatment modality as upfront therapy for TGCT, with consideration of symptoms, functional limitations, surgical prognosis, and treatment side effects.

Although the standard-of-care treatment for TGCT is surgery, this is not always possible, as observed in the present report. Furthermore, tumors often recur, and repeated surgeries may be required [9]. The ENLIVEN study showed that 39% of patients had stable disease with pexidartinib treatment, with an additional 39% achieving partial or complete response to therapy [7]. In a pooled analysis of patients treated with pexidartinib for a median of 19 months (range 1–76+ months), the response rate per RECIST v1.1 was 60% [10].

The patient described in this report experienced a complete tumor response after 2 years of pexidartinib treatment, which was accompanied by reduced pain and improved range of motion. The patient had CPK elevations that led to dose reduction. These elevations were discussed at length with the study sponsor, and it was determined that discontinuation was not necessary. During the time the patient started pexidartinib, CPK was routinely monitored. The treatment was well tolerated over 4 years of treatment, including CPK normalization after dose reduction to 200 mg. Importantly, the reduced dose was also effective with improved response over time.

Pexidartinib is associated with a serious risk of hepatotoxicity; in an analysis of patients treated with pexidartinib across four clinical studies, 95% of patients with TGCT experienced liver test abnormalities, 5 (4%) patients experienced serious mixed or cholestatic injury with all events occurring within the first 8 weeks of treatment [11]. The patient described here did not have liver enzyme elevations. The pexidartinib prescribing information and the Risk Evaluation and Mitigation Strategy program provide guidance and support regarding the monitoring of liver enzymes and the management of any elevations during the first few months of pexidartinib treatment [8].

In this case study, all possible treatment options were discussed with the patient, and the MDTB determined that surgery would have negatively impacted the patient. If the patient had not been experiencing symptoms, active surveillance with a “watch and wait” approach and routine imaging could have been taken (Fig. 4). However, given the young age of the patient and the extent and severity of disease, treatment with pexidartinib was chosen as the first option in an attempt to avoid the morbidity of the joint, considering the high risk of relapse/progression after surgery. This treatment approach aligns with the current labeling recommendations for pexidartinib in patients with TGCT associated with severe morbidity or functional limitations and not amenable to surgery because the patient in this case report was not eligible for surgery [8]. Pexidartinib is currently the only approved systemic treatment for patients with TGCT; however, it is not available in all countries. In countries without approved systemic therapy, consensus guidelines recommend participation in a clinical trial or off-label CSF1 receptor inhibitors [12]. Standard treatment for symptomatic TGCT is surgery when it can be accomplished without significant morbidity. However, for patients with difficult to manage, symptomatic disease or with moderate/severe functional impairment for which surgery would be associated with significant morbidity, medical management with systemic treatments is considered. CSF1 receptor inhibitors are considered the standard systemic treatment for adult patients with TGCT. Currently, pexidartinib is the only approved CSF1 receptor inhibitor, in the USA, South Korea, and Taiwan, for adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery [8, 13, 14]. Other CSF1 receptor inhibitors are available for patients either as investigational agents in ongoing clinical trials for TGCT or by off-label treatment, when available [12].

Treatment paradigm for use of upfront pexidartinib in patients with TGCT. CR complete response, CSF1R colony-stimulating factor 1 receptor, PD progressive disease, PR partial response, TGCT tenosynovial giant cell tumor

Several other case reports of neoadjuvant use of pexidartinib have been reported in the literature. Bernthal et al. reported on three separate patients who were treated with pexidartinib prior to surgery, after surgery, or at both times to improve outcomes in patients with TGCT [15]. In one of these patients, neoadjuvant pexidartinib over 16 months reduced the tumor size and allowed for successful total hip arthroplasty. The second patient had d-TGCT of the foot and recurrence after surgery; pexidartinib treatment resulted in disease stabilization and symptom control. The third patient with d-TGCT of the knee was able to successfully eliminate disease with surgery plus pre- and postoperative pexidartinib [15]. In a separate report, neoadjuvant pexidartinib was used in a 32-year-old patient for recurrence of d-TGCT in the shoulder, neck, and chest that could not be cured with resection or amputation; pexidartinib therapy reduced tumor masses by approximately 80% and the patient underwent limb-salvage surgery, after which the patient resumed adjuvant pexidartinib [16]. Finally, pexidartinib was initiated in a 47-year-old woman with extensive d-TGCT of the right knee who was not a surgical candidate; pexidartinib treatment reduced tumor size, which allowed the patient to return to work and reduce the use of pain medications [17]. Taken together, these cases suggest that use of neoadjuvant targeted therapy that reduces tumor burden may allow for successful resection and reconstruction to restore joint functionality, redefining inoperable cases of TGCT [16].

Given the dramatic response in this patient with severe TGCT not amenable to surgery, future studies are warranted to investigate the benefits of CSF1 receptor inhibitors, such as pexidartinib, (1) to reduce TGCT burden of disease prior to surgery (neoadjuvant setting) or (2) as the sole treatment option to reduce tumor size, reduce symptoms, and improve function of the involved joint or joints (upfront therapy), followed by treatment dose reduction or delays (maintenance treatment) or treatment interruption (drug holidays) and rechallenge (Fig. 4).