CORR Insights®: Pexidartinib Provides Modest Pain Relief in Patients With Tenosynovial Giant Cell Tumor: Results From ENLIVEN

Where Are We Now?

Tenosynovial giant cell tumor (TGCT) includes giant cell tumor of the tendon sheath and pigmented villonodular synovitis. Although giant cell tumors of the tendon sheath occur in juxta-articular locations, pigmented villonodular synovitis is an intra-articular neoplasm that may occur in either localized or diffuse forms; it most commonly affects the knee and may cause a mass effect, pain, stiffness, functional limitations, and arthritis. The resulting functional disability in patients with recalcitrant tumors may be severe. Surgical removal is used for all forms of TGCT. Radiotherapy is less commonly used [6]. The success of surgery alone for giant cell tumor of the tendon sheath and localized pigmented villonodular synovitis is high. The success of surgery alone for diffuse pigmented villonodular synovitis, however, is not [4, 6].

Pexidartinib, a colony-stimulating factor-1 receptor (CSF1R) inhibitor, is a newer treatment option that provides targeted therapy for diffuse pigmented villonodular synovitis [1]. In 2019, the FDA approved pexidartinib for adult patients with symptomatic TGCT associated with severe morbidity or functional limitations who did not improve with surgery. The ENLIVEN industry-sponsored randomized, international, multicenter trial showed improvements in disease control compared with placebo, as measured by the Response Evaluation Criteria in Solid Tumors and tumor volume score [8]. The positive response proportions remained durable through longer-term follow-up among three cohorts [3]. In addition to disease control, secondary outcomes have also been reported. Physical functioning and stiffness both improved by clinically relevant amounts, as measured by the Patient-Reported Outcomes Measurement Information System [9].

In a paper by Healey et al. [5] in this month’s Clinical Orthopaedics and Related Research®, ENLIVEN data were analyzed with respect to another secondary endpoint—pain relief—because the benefit of pexidartinib for relieving pain has been less clear. The primary pain response assessment showed no difference, although additional exploratory analyses showed modest improvements in pain that correlated with the MRI-based disease response but were just above the minimum clinically important difference. Based on these findings, surgeons should be circumspect regarding patient expectations of pain relief using pexidartinib, despite demonstrated positive tumor responses and improvements in physical functioning and stiffness.

Where Do We Need To Go?

Is pexidartinib better than surgery? The FDA-approved indication for pexidartinib is narrow and based largely on the ENLIVEN study results. In the ENLIVEN study, eligible patients were those 18 years and older with histologically confirmed TGCT and “advanced disease for which surgical resection would be associated with potentially worsening functional limitation or severe morbidity” [1]. Naturally, when a new treatment shows success for a specific indication, the tendency is to broaden the indications. In the setting of pexidartinib treatment for TGCT, diffuse pigmented villonodular synovitis of the knee is a common scenario in which patients may benefit from off-label use. In these patients, the potential morbidity of primary open anterior and posterior synovectomy is substantial and potentially severe. However, we cannot expand this indication without additional evidence.

Is pexidartinib worth the risk? Pexidartinib has its own morbidity. Although the most common adverse events are mild (hair color changes and fatigue), liver enzyme abnormalities and hepatotoxicity are concerning enough to the FDA to mandate Risk Evaluation and Mitigation Strategies monitoring [4]. Observation without treatment, by contrast, completely eliminates those risks. If there was certainty that TGCT would progress, the risk-benefit ratio favoring pexidartinib would be even more favorable. However, we don’t know the natural history of TGCT. Only one patient (2%) in the ENLIVEN placebo group had a progressive tumor; the remainder of patients given a placebo with evaluable results showed stable disease [8]. On the other hand, the prospective multi-institutional TGCT Observational Platform Project documented the impact this disease can have on all patients, including those who were observed [2]. Depending on disease extent, age, functional activity level, comorbidities, and goals, and given the alternatives, patients’ choices will differ.

Is there something better out there? Other drugs have shown a response in TGCT [4, 7]. Imatinib is another CSF1R blocker with demonstrated efficacy in a retrospective study [7]. Other agents being studied include multi-target tyrosine kinase inhibitor, anti-CSF1R antibodies, anti-cytokine systemic and injectable biologics targeting the proinflammatory cytokines, and agents targeting local synoviocytes such as intra-articular cadmium injection and PUMA gene delivery, which was developed for rheumatoid arthritis but has theoretical applications in TGCT.

How Do We Get There?

Let’s compare pexidartinib with surgery. Before we broaden our clinical indications for pexidartinib, we need information from a prospective randomized study comparing the drug to surgery for a single indication. The obvious choice would be untreated diffuse pigmented villonodular synovitis of the knee, because it is the most difficult to treat and results in the highest recurrence rates, and the knee is the most common site. As orthopaedic surgeons, we should implore industry to sponsor this natural next step.

Let’s find out what the patients want. We report what happens when we treat, but we don’t write much about observation. The TGCT Observational Platform Project reports documented outcomes at a median of 34.3 months for 81 patients with TGCT treated with watchful waiting [2], but similar studies with more-detailed patient satisfaction and quality of life measures might better inform patient decision-making when choosing among observation, surgery, and medical management.

Let’s keep the pipeline open. Drug development is ongoing and should continue to evaluate the safety and efficacy of less-studied drugs. Currently, there are numerous active studies evaluating agents other than pexidartinib, including two Phase III studies of emactuzumab CSF1R antibody (NCT05417789 TANGENT) and vimseltinib CSF1R inhibitor (NCT05059262 MOTION study); four Phase I/II or Phase II studies of intra-articular monoclonal antibody AMB-05X (NCT04731675 [Phase I], INCT05349643 [Phase II]), intravenous AMB-05X (NCT04938180 [Phase II]), intravenous cabiralizumab FPA008 CSF1R antibody (NCT02471716 [Phase I/II]), and axatilimab CSF1R antibody (NCT03069469 [Phase I/II]); and three Phase I studies of the ABSK-021 CSF1R inhibitor (NCT04192344), HMPL-653 CSF1R inhibitor (NCT05277454), and BC006 CSF1R antibody (NCT05212896). One or more of these may provide improved efficacy and a more favorable toxicity profile than pexidartinib. As orthopaedic oncologists, we should be aware of these studies to educate and advocate for our patients and encourage their participation in these and future trials.