Pexidartinib Demonstrates Long-Term Efficacy, Safety in Tenosynovial Giant Cell Tumors

November 24, 2020 - Pexidartinib was found to result in prolonged efficacy with favorable safety in patients with tenosynovial giant cell tumors, according to long-term data from a pooled analysis of 3 cohorts of patients who received the agent.

Pexidartinib (Turalio) was found to result in prolonged efficacy with favorable safety in patients with tenosynovial giant cell tumors (TGCT), according to long-term data from a pooled analysis of 3 cohorts of patients who received the agent.1

Results showed that pexidartinib elicited an overall response rate (ORR) of 60% per RECIST criteria, with a tumor volume score (TVS) ORR of 65%. The median times to response were 3.4 months per RECIST criteria and 2.8 months via TVS. Moreover, 62% (n = 48) of patients experienced a partial response (PR) per RECIST criteria at 6 months; 92% (n = 72) achieved a PR by 18 months.

“With prolonged follow-up with a median of 39 months, pexidartinib was confirmed to be an effective long-term treatment in adult patients with locally advanced TGCT with an overall tumor response rate of 60% and a prolonged duration of response [DOR],” first author of the study Hans Gelderblom, MD, of Leiden University Medical Centre, and colleagues, wrote in the paper published in Cancer.

Pexidartinib, an orally administered small molecule TKI, was designed to act as a selective, potent inhibitor of CSF1R, KIT, and FLT3-ITD. The agent showcased encouraging preliminary results in the phase 1 extension trial PLX108-01 (NCT01004861), which examined the safety and pharmacokinetics of the agent in patients with advanced, incurable, solid tumors.2 Here, the agent was given at a daily dose of 1000 mg; 12 patients achieved a PR, while 7 had stable disease.3 Responses were experienced within the first 4 months of treatment and the median DOR surpassed 8 months.

The agent was then examined in the phase 3 ENLIVEN trial (NCT02371369) in patients with pigmented villondular synovitis or giant cell tumor of the tendon sheath.4 Again, more patients who received pexidartinib achieved a higher overall response versus placebo at week 25 per RECIST criteria, at 39% versus 0% (absolute difference, 39%; 95% CI, 27-53; P <.0001).5 The results from the study further established the safety profile of the drug.

In the pooled analysis, investigators set out to evaluate the long-term safety and efficacy of pexidartinib across the phase 3 ENLIVEN trial and the subset of patient with TGCT from the phase 1 PLX108-01 trial. To be eligible for participation on both trials, patients had to be at least 18 years of age and have histologically confirmed disease that was unresectable and symptomatic.

The analysis comprised 3 cohorts of patients with TGCT who received pexidartinib. The first cohort contained patients from the phase 1 extension study. The second cohort included those from the ENLIVEN trial who received pexidartinib at a dose of 1000 mg daily for 2 weeks and then 80 mg daily. The third cohort was comprised of patients who crossed over in ENLIVEN and received 800 mg daily.

The first-in-human phase 1 trial had a dose-escalation phase with an expansion cohort, which was comprised of 39 patients with TGCT. Pexidartinib was given at a dose of 1000 mg, which was split into 2 doses daily; treatment was given until either disease progression or intolerable toxicity.

ENLIVEN enrolled a total of 120 patients with TGCT for whom surgical resection would be linked with a potentially worse functional limitation or severe morbidity. In part 1 of the trial, investigators were given either a 1000-mg daily dose of pexidartinib (n = 61) or matching placebo (n = 59) for 2 weeks; this was followed by pexidartinib at a daily dose of 800 mg or matching placebo for the duration of 22 weeks. In part 2 of the trial, patients continued treatment with pexidartinib. Thirty patients comprised the crossover population, which were given open-label pexidartinib following placebo in part 1.

The data cutoff for the safety and efficacy analyses was May 31, 2019, which translated to a median follow-up duration of 39 months. A total of 130 patients who received pexidartinib across the studies were included in the efficacy analysis.

The median age of these patients was 45 years; 59% (n = 77) had undergone at least 1 prior surgical procedure, while 12% (n = 16) had previous systemic treatment. Moreover, 6% (n = 8) of these patients had previously received radiation treatment. Patients had received a median duration of treatment of 19 months and 42% of patients (n = 54) were still receiving treatment at the time of data cutoff.

Results indicated high overall tumor response rates with pexidartinib, which were consistent across the 3 cohorts; these responses were also determined to be durable. The best response per RECIST criteria was complete response (CR) or partial response (PR) in a total of 78 patients, with an ORR of 60% (95% CI, 51.4%-68.0%). Twenty percent of patients (n = 26) achieved stable disease and 1% (n = 1) experienced disease progression. Sixty-five percent (n = 84) had a complete TVS or partial TVS response.

The median time to an initial response was 3.4 months per RECIST criteria and 2.8 months per TVS. The majority of responses, or 77%, were reported within the first 6 months following the initiation of pexidartinib treatment. Twenty-three percent of patients experienced responses after 6 months of treatment.

Among 78 patients who responded to treatment per RECIST criteria, 41% (n = 32) experienced a response by 3 months, 62% (n = 48) responded by 6 months, and 92% (n = 72) responded by 18 months. Among 84 patients who responded to treatment per TVS, 60% (n = 50) responded by 3 months, 77% (n = 65) responded by 6 months, and 98% (n = 82) by 12 months. Between 12 months and 34 months following the initiation of pexidartinib, 2 more patients achieved a TVS response.

Of the 130 patients included in the analysis, 26% (n = 34) experienced a CR per RECIST criteria. Of the 34 responders, 44% (n = 15) achieved their response by 8 months following pexidartinib initiation. Seventy-six percent (n = 26) experienced a CR by 20 months. The final patient to achieve a CR per RECIST criteria did so at about 42 months following pexidartinib initiation.

Additionally, 1 patient experienced disease progression per RECIST criteria as the best overall response, with no progression per TVS. Twelve percent (n = 16) of patients experienced disease progression per RECIST criteria; 11% (n = 14) progressed while on treatment, while 2% (n = 2) progressed following treatment. After responding to pexidartinib, 1 patient (1%) went to surgery for residual disease.

Regarding safety, pexidartinib was found to be safe, with most treatment-emergent adverse effects (TEAEs) determined to be low grade. All 130 patients analyzed reported 1 or more TEAEs; 98% (n = 127) experienced at least 1 treatment-related toxicity. The most commonly experienced TEAEs included hair color change (75%), fatigue (61%), nausea (47%), and arthralgia (39%). All of these toxicities were found to be reversible.

Fifty-two percent (n = 67) of patients experienced TEAEs that were determined to be grade 3 or greater in severity; 85% (n = 57) of these patients reported toxicities that were determined to be associated with study treatment. Eighteen percent (n = 23) of patients reported 32 serious toxicities; 61% (n = 14) were determined to be related to treatment. One participant (1%) from the crossover group experienced a grade 5 toxicity in the form of aortic dissection, although it was not determined to be related to pexidartinib.

Sixty-eight percent (n = 89) had TEAEs that required either a dose reduction or interruption. Fifty-three percent (n = 69) of patients discontinued treatment. The most common reason given for treatment discontinuation was because of a toxicity; this was the case for 24% (n = 31) of patients. Such toxicities included abnormal laboratory investigations (7%), nervous system disorders (5%), and musculoskeletal/connective tissue disorders (5%).

In August 2019, pexidartinib was approved by the FDA for use in adult patients with symptomatic TGCT that is associated with severe morbidity or functional limitations and not responsive to improvement with surgery based on data from ENLIVEN, which showed a 38% ORR (95% CI, 28%-52%) with the agent.5

“Because the risk of hepatotoxicity, pexidartinib is available only through the Risk Evaluation Management System program in the United States,” the authors wrote. “Frequent monitoring of liver function, early intervention with dose modification, and education on symptoms of emerging hepatotoxicity and the approved indication of pexidartinib are critical for a robust benefit-to-risk assessment on an individual patient basis.”

The additional safety data from the analysis did not expose any late-emerging or cumulative toxicities that would necessitate revised risk management procedures beyond those proposed for patients within the first 2 months of treatment with pexidartinib.


  1. Gelderblom H, Wagner AJ, Tap WD, et al. Long-term outcomes of pexidartinib in tenosynovial giant cell tumors. Cancer. Published online November 16, 2020. doi:10.1002/cncr.33312
  2. Safety study of PLX108-01 in patients with solid tumors. Updated April 22, 2020. Accessed November 22, 2020.
  3. Tap WD, Wainberg ZA, Anthony SP, et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N Engl J Med. 2015;373(5):428-437. doi:10.1056/NEJMoa1411366
  4. Phase 3 study of pexidartinib for pigmented villondular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS) (ENLIVEN). Updated January 10, 2020. Accessed November 22, 2020.
  5. 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. doi:10.1016/S0140-6736(19)30764-0