(P 44) TUMOR RESPONSE AND REGROWTH IN RELATION TO CLINICAL EVENTS AMONG PEXIDARTINIB-TREATED SUBJECTS IN THE PHASE 3 ENLIVEN TRIAL

Objective: Based on results from the pivotal ENLIVEN trial, pexidartinib became the first systemic therapy to receive U.S. FDA approval (2019) to treat symptomatic tenosynovial giant cell tumor (TGCT) not amenable to surgical improvement. Since then, interest emerged regarding long-term dosing strategies of pexidartinib. This exploratory analysis examined the clinical course of pexidartinib-treated participants in the trial, identifying dose at time of objective response (OR) and first timepoint response of progressive disease (PD) in relation to adverse events.

Methods: The ENLIVEN trial randomized adults with symptomatic TGCT not recommended for surgery 1:1 in blinded fashion to pexidartinib or placebo for 25 weeks (Part 1). Pexidartinib was administered orally with a loading dose of 1000 mg pexidartinib per day (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Afterwards, patients from either group could take open-label pexidartinib (800 mg per day) until progression or toxicity (Part 2). In either part, the pexidartinib dose could be reduced, interrupted, or discontinued due to treatment-related toxicity. The primary endpoint was centrally assessed OR rate by RECIST v1.1. Secondary endpoints included OR rate by tumor volume score (TVS) and safety. Progressive disease was defined as ≥ 20% increase in the sum of diameters of target tumors, using the smallest sum on study as the reference. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new tumors was also considered progression. An additional definition of progressive disease by TVS was defined as ≥ 30% increase in volume relative to the lowest score during the study whether at Baseline or some other visit. Herein we present rates of OR by dose, treatment-emergent adverse events requiring dose reduction, and progressive disease, based on a data cutoff of APR2021 (240 weeks of study).

Results: Of 120 patients, 61 were randomly assigned to pexidartinib and 59 to placebo in Part 1. Thirty of the placebo recipients crossed over to open-label pexidartinib in Part 2, yielding a total of 91 pexidartinib-treated patients in this trial. Considering the extended follow-up period, a total of 55 (60.44%) pexidartinib-treated subjects achieved an OR per RECIST. Response rates were similar, regardless of Part 1 assignment (Table 1). Of the responders, 9 (16.36%) achieved their OR at a daily dose < 800 mg. Similarly, there were 62 (68.13%) responders per TVS and 10 (16.13%) of them achieved their OR at a daily dose < 800 mg. Overall, there were 23 (25.3%) patients who had a TEAE leading to dose reduction, with the most common (10/23) being a laboratory investigation followed by general disorders and administration site conditions (5/23) and nervous system disorders (5/23). Of these patients who had a TEAE requiring dose reduction, 65% (15/23) achieved or maintained an OR post-reduction (4/23 had SD, 4 were missing response results post-reduction). At study week 240 (60 months), the median duration of response had not been reached (per RECIST or TVS). In total, there were 14 (15.38%) instances of PD per RECIST and 12 (13.19%) per TVS, with nearly all (13/14, 11/12) instances of PD occurring after an OR (i.e., tumor regrowth; Table 2). Neither of the primary progression cases had a TEAE requiring dose reduction or interruption prior to progression. Two of the secondary progression cases occurred while off-treatment due to family planning (Table 3).

Conclusion: Pexidartinib demonstrated robust durable tumor responses in TGCT, with most pexidartinib-treated patients achieving OR. Most patients who had a TEAE requiring dose reduction achieved or maintained an OR post-reduction, indicating a continued benefit of pexidartinib, even if dose modification is required. Tumor regrowth occurred in less than 25% of responders, some of whom were not on active treatment.