A phase 4, multicenter, global clinical study to evaluate discontinuation and rechallenge of pexidartinib in patients with tenosynovial giant cell tumor previously treated with pexidartinib

Abstract

Background: Pexidartinib is effective in patients with tenosynovial giant cell tumor(TGCT) for whom surgery is not feasible. Durability of response after discontinua-tion of pexidartinib and the safety and efficacy of restarting pexidartinib have notbeen previously recorded. This phase 4 study was designed to mimic the real‐worldexperience with pexidartinib to evaluate the effects of discontinuation of andretreatment with pexidartinib in patients with TGCT who previously benefited fromthe drug.Methods: This was a global, multicenter, phase 4 study that enrolled patients withTGCT who were experiencing clinical benefit from pexidartinib in one of four priorphase 1 or phase 3 studies investigating pexidartinib in the disease. Patients couldchoose to continue pexidartinib at the same dose (the treatment‐continuation cohort)or discontinue treatment with the option to restart pexidartinib (the treatment‐free/retreatment cohort). Tumor progression determined by Response EvaluationCriteria in Solid Tumors (RECIST) version 1.1, patient‐reported outcomes (thePatient‐Reported Outcomes Measurement Information System–Physical Function[PROMIS‐PF] questionnaire and the EuroQol 5‐dimension, 5‐level [EQ‐5D‐5L] vi-sual analog scale), and safety were assessed every 3 months. The primary end pointwas the proportion of patients in the treatment‐free/retreatment cohort who remained treatment‐free at month 12 and 24; this did not depend on diseaseprogression.Results: Thirty‐two patients were enrolled: 21 chose to enter the treatment‐continuation cohort, and 11 entered the treatment‐free/retreatment cohort. Duringthe treatment‐free period, six of 11 (54.5%) patients in the treatment‐free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1,whereas no patient in the treatment‐continuation cohort had disease progression.Over the 24‐month study, three of 11 (27.3%) patients in the treatment‐free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symp-tomatic progression, or both (n = 1 each). The probability of remaining treatment‐free in the treatment‐free/retreatment cohort was 73% (95% confidence interval,37%–90%). In the treatment‐free/retreatment cohort, the median progression‐freesurvival of the treatment‐free period was 22.8 months (95% confidence interval, 1.6months to not estimable). By 6 months of retreatment, all retreated patients ach-ieved new disease stabilization with no new safety concerns; two patients hadclinically significant improvements in PROMIS‐PF and EQ‐5D‐5L visual analog scalescores. The mean PROMIS‐PF and EQ‐5D‐5L scores remained stable throughoutthe study. There was no hepatotoxicity and no new safety signal in either cohort.Conclusions: In this small phase 4 study designed to evaluate outcomes in patientswho stopped and restarted pexidartinib, 54.5% of patients who discontinued pex-idartinib showed PD, with a median progression‐free survival of 22.8 months. Eachof the three patients who restarted pexidartinib stopped progressing, and somereported a new gain in physical function. No PD was detected in patients whoremained on treatment, and the safety profile did not indicate long‐term hepato-toxicity or any new safety concerns.