A Phase 3 Study of the Efficacy and Safety of Pexidartinib in East Asian Patients with Tenosynovial Giant Cell Tumor

Abstract

Introduction

The aim of this study was to assess the efficacy and safety of pexidartinib, an inhibitor of colony-stimulating factor 1 receptor, in East Asian patients with tenosynovial giant cell tumor (TGCT).

Methods

This multicenter, single-arm, phase 3 study (NCT04488822) enrolled patients with symptomatic TGCT to receive pexidartinib 400 mg twice daily. The primary efficacy endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) per central review at week 25. Secondary endpoints included ORR by tumor volume score (TVS), change in range of motion (ROM) of the affected joint, best overall response (BOR), and treatment-emergent adverse events (TEAEs).

Results

A total of 40 East Asian patients with TGCT received pexidartinib. RECIST v1.1 ORR was 22.5% (95% confidence interval [CI] 10.8–38.5), with no complete responses (CRs), 9 partial responses (PRs), 21 patients with stable disease (Sd), and 1 patient with progressive disease (PD). TVS ORR was 47.5% (95% CI 31.5–63.9), with no CRs, 19 PRs, 12 patients with Sd, and none with PD. At week 25, mean (standard error [SE]) change in ROM was 23.05 (3.207), with improvement noted at week 13 (15.64 [3.312]). RECIST v1.1 BOR was 30.0% (95% CI 16.6–46.5), and TVS BOR was 47.5% (95% CI 31.5–63.9). All patients had TEAEs, and grade ≥ 3 TEAEs were reported in 16 (40.0%) patients. The most common TEAEs were hair color changes (77.5%); increases in alanine aminotransferase (60.0%), aspartate aminotransferase (57.5%), and blood lactate dehydrogenase (47.5%); and pruritus (47.5%).

Conclusions

In East Asian patients with symptomatic TGCT, pexidartinib demonstrated clinical benefits, with a safety profile comparable to previous reports.

Trial Registration

ClinicalTrials.gov identifier NCT04488822.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40487-025-00365-z.

Key Summary Points

Why carry out this study?

Despite the high unmet need among patients with TGCT in China, limited data exist on the use of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in East Asian patients with TGCT.

In accordance with Chinese regulations, this phase 3 study was designed as a bridging study using the results of the phase 3 ENLIVEN study; it aimed to examine tumor response, joint function, and safety in East Asian patients with TGCT who were treated with pexidartinib.

What was learned from the study?

At week 25, pexidartinib demonstrated clinical benefits (22.5% ORR by RECIST v1.1 and 47.5% ORR per TVS) and improvements in range of motion. ORR by RECIST v1.1 in the phase 3 study was inferior to the ORR at week 25 in the phase 3 ENLIVEN study, but the ORR by RECIST v1.1 at week 37 in the phase 3 study increased to 35.0%, which is close to the ORR at week 37 in the phase 3 ENLIVEN study.

With continuous treatment, pexidartinib has clinically important effectiveness in controlling tumors. Because TGCT is a nonmalignant tumor that progresses continuously and slowly, the result of ORR at week 37 in this study is meaningful for relative long-term tumor control of East Asian patients with TGCT. The safety result was consistent with previous studies, and hepatotoxicity was managed through frequent liver function monitoring and dose-modification guidelines.

This study supports the use of pexidartinib in East Asian patients with TGCT from the Chinese mainland and Taiwan and informs the medical management of TGCT in this population.

Introduction

Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the joints, bursa, and tendon sheaths [1, 2]. Symptoms may appear gradually and are highly variable. As the disease expands into the intra- and extra-articular space, symptoms of pain, swelling, and reduced range of motion (ROM) can become severe and limit functional capabilities [1–3]. The mainstay of treatment for TGCT is surgery, but recurrence is frequent, particularly in patients with diffuse TGCT (d-TGCT). Although TGCT usually does not pose a serious threat to patients’ lives, it does seriously affect patients’ daily activities and has adverse effects on their quality of life due to joint damage and repeated surgical interventions [1, 3, 4].

TGCT overexpresses colony-stimulating factor 1 (CSF1), usually due to the chromosomal translocation t(1;2) (CSF1;COL6A3) [1, 3]. Pexidartinib is a small-molecule tyrosine kinase inhibitor with selective activity against the CSF1 receptor as well as inhibitory action against c-KIT receptor tyrosine kinase and FMS-like tyrosine kinase 3 internal tandem duplication [5, 6]. Pexidartinib was approved by the US Food and Drug Administration in 2019 and by Korean and Taiwanese authorities in 2021 and 2022, respectively, for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations that were not amenable to improvement with surgery (or other treatment [e.g., local radiotherapy] in Taiwan) on the basis of the results of the phase 3 ENLIVEN study [6–9]. The results showed that an overall response rate (ORR) of 39% (versus 0% in placebo) was achieved by pexidartinib at week 25. The ROM and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Scale scores were also significantly improved [6].

Limited data exist on the use of pexidartinib in East Asian patients with TGCT. In an open-label, phase 1 study including 11 patients from Taiwan with various solid tumors, 1 patient with TGCT showed an objective tumor response; time to response was 1.9 months [10]. In a retrospective cohort of Asian (China, Japan, Korea, and the Philippines) patients with d-TGCT, 44% of patients who completed surgical resection had a tumor recurrence, and 12% reported complications, such as joint stiffness, superficial wound infection, and neurovascular damage [11].

There is a high unmet medical need for patients with TGCT in China; given the lack of data on use of pexidartinib in East Asian patients with TGCT, this phase 3 study was conducted. This phase 3 study, PL3397-A-A303, is the first registry evaluating efficacy and safety of pexidartinib in patients with TGCT from the Chinese Mainland and Taiwan.

Methods

Study Design and Treatment

This multicenter, single-arm, open-label, phase 3 study (ClinicalTrials.gov identifier: NCT04488822) was conducted in nine hospitals from the Chinese Mainland and Taiwan. Patients received pexidartinib 400 mg (2 × 200 mg capsules) twice daily (every 12 h) for a total daily dose of 800 mg. Pexidartinib was taken on an empty stomach at approximately the same time each day. Patients continued to receive pexidartinib until disease progression, unacceptable toxicity, patient or investigator decision, surgery, or pregnancy.

All study documents were approved by the sites’ independent ethics committees or institutional review boards (provided in Supplementary File 1). The study was conducted in compliance with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and Good Clinical Practice guidelines. All patients provided written informed consent.

Eligibility

Eligible patients were ≥ 18 years of age (≥ 20 years of age in Taiwan) and had a diagnosis of TGCT that was histologically confirmed by a pathologist and associated with severe morbidity or functional limitation and not amenable to improvement with surgery, as determined by two or more surgeons or a multidisciplinary tumor board. Patients were required to have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, with a minimal size of 2 cm, as assessed by magnetic resonance imaging (MRI) and read by a central radiologist. The patient’s prescription analgesic regimen was required to be stable for 2 weeks prior to enrollment. Patients were excluded if they had metastatic TGCT, had used an investigational drug or device within 28 days of enrollment, or had previously received pexidartinib or any biologic treatment targeting CSF1 or the CSF1 receptor. Prior use of oral tyrosine kinase inhibitors (e.g., imatinib or nilotinib) was allowed.

Outcomes

The primary efficacy endpoint was ORR, defined as complete response (CR) or partial response (PR) by RECIST v1.1 (sum of diameters) at week 25, as determined by centrally read MRI scans, with readers blinded to patient information. Determination of ORR for each time point was based on the combination of responses for target lesions and the presence/absence of ≥ 1 new lesion. To be considered a response, tumors had to meet the criteria for response and have no documented progression at week 25. This study did not require confirmation of response.

Secondary endpoints included ORR by tumor volume score (TVS; based on 10% increments in estimated tumor volume), with CR indicating complete disappearance of lesions and PR indicating ≥ 50% decrease in volume score relative to baseline by centrally reviewed MRI at week 25; mean (standard error [SE]) change in ROM of the affected joint from baseline at week 25, measured in degrees using a goniometer by a qualified assessor (e.g., orthopedic surgeon or physical therapist); best overall response (BOR), defined as CR or PR by RECIST v1.1 and TVS recorded from the start of treatment until the last radiographic assessment; and duration of response (CR or PR) by RECIST v1.1 and TVS, defined as the time from the first recorded response to the first documented disease progression. The effect of pexidartinib on limb function was assessed as the mean change from baseline in the PROMIS Physical Function Scale score at week 25. ORR by RECIST v1.1 and TVS at week 37 were also assessed in an ad hoc analysis.

Safety assessments included vital signs, 12-lead electrocardiograms, laboratory tests, and treatment-emergent adverse events (TEAEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Liver function tests included alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, and gamma-glutamyl transpeptidase (GGT), which were assessed weekly for the first 8 weeks, then every 2 weeks for the next month and every month thereafter.

Statistical Analysis

The planned sample size was approximately 35 patients, which provided > 95% power to detect a significant difference against 5% ORR, with an expected ORR of 37.7%. The data cutoff for the primary analysis was 27 October 2021, after all patients completed week 25, and 21 December 2021, for an ad hoc analysis at week 37.

Efficacy analyses were conducted on the full analysis set (defined as all patients who received ≥ 1 dose of pexidartinib). Patients who were missing response data were considered nonresponders. The safety analysis set included all patients who received ≥ 1 dose of pexidartinib. The full analysis set and safety analysis set were identical in this study. The proportion of patients meeting the primary and secondary efficacy endpoints (except duration of response), point estimates, and accompanying 95% confidence intervals (CIs) were calculated on the basis of the Clopper–Pearson method. The duration of response was determined using the Kaplan–Meier product limit methodology with median and 25th and 75th percentiles. Change from baseline to posttreatment assessments was determined for patients with values at both time points. ROM and PROMIS Physical Function Scale scores were analyzed using a mixed model for repeated measurements with joint type and extremity type as factors, respectively, and reported as the least squares mean (LSM) with 95% CIs. All analyses were performed using SAS statistical software version 9.4.

Data Availability

Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be available upon request at https://vivli.org. In cases where clinical study data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of the company and the clinical study subjects. Details on data-sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo.

Results

Patients

A total of 40 patients received pexidartinib at nine study sites in mainland China (n = 31) and Taiwan (n = 9; Fig. 1). At the data cutoff for the primary analysis (27 October 2021), 2 patients had completed the study (i.e., 24 weeks of dosing), 29 patients were ongoing (having reached the 25-week assessment of the primary endpoint), and 9 patients had discontinued the study owing to a TEAE (n = 8) or withdrawal of consent (n = 1). Demographic and baseline characteristics are presented in Table 1. All patients were East Asian and had a median (range) age of 40.0 (18–68) years; 27 (67.5%) patients were female. Most patients had d-TGCT (82.5%), with the most common involving the knee (45.0%) and hip (20.0%). The mean treatment compliance (as a percentage of the scheduled dose) from week 1 to the end of treatment was 89.9%.

Fig. 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram

Table 1.

Demographic and baseline characteristics

Characteristic	Pexidartinib (N = 40)
Median (range) age, years	40.0 (18–68)
Sex, n (%)
Male	13 (32.5)
Female	27 (67.5)
Region, n (%)
Mainland China	31 (77.5)
Taiwan	9 (22.5)
Type of tumor, n (%)
Diffuse	33 (82.5)
Localized	7 (17.5)
Extremity involvement, n (%)
Upper	5 (12.5)
Shoulder	1 (2.5)
Elbow	3 (7.5)
Spine	1 (2.5)
Lower	35 (87.5)
Hip	8 (20.0)
Knee	18 (45.0)
Ankle	7 (17.5)
Foot	2 (5.0)
Prior surgeries for TGCT, n (%)
0	7 (17.5)
1	13 (32.5)
2	10 (25.0)
≥ 3	10 (25.0)
Prior systemic therapies, n (%)
None	36 (90.0)
Imatinib	2 (5.0)
Nilotinib	0
Other	2 (5.0)
Tumor sum of longest diameters, mean (SD), mm	72.36 (45.55)
TVS, mean (SD)	16.63 (20.70)
ROM in affected joints, mean (SD), % relative to reference standard	67.07 (31.32)
PROMIS Physical Function Scale score, mean (SD)	46.13 (8.58)

PROMIS, Patient-Reported Outcomes Measurement Information System; ROM, range of motion; SD, standard deviation; TGCT, tenosynovial giant cell tumor; TVS, tumor volume score

Primary Efficacy Endpoint

At week 25, ORR by RECIST v1.1 was 22.5% (95% CI 10.8–38.5), with nine (22.5%) patients achieving PR and no patient achieving CR (Table 2). Stable disease (Sd) was reported in 21 (52.5%) patients, and 1 (2.5%) patient had progressive disease (PD).

Table 2.

Primary and secondary efficacy endpoints at week 25

% (95% CI)	All pexidartinib-treated patients (N = 40)
	By RECIST v1.1	By TVS
ORR (CR or PR) at week 25 (primary endpoint)	22.5 (10.8–38.5)	47.5 (31.5–63.9)
CR	0 (0–8.8)	0 (0–8.8)
PR	22.5 (10.8–38.5)	47.5 (31.5–63.9)
Sd	52.5 (36.1–68.5)	30.0 (16.6–46.5)
PD	2.5 (0.1–13.2)	0 (0–8.8)
NE	22.5 (10.8–38.5)	22.5 (10.8–38.5)
Best ORR (CR or PR)a	30.0 (16.6–46.5)	47.5 (31.5–63.9)
CR	5.0 (0.6–16.9)	0 (0–8.8)
PR	25.0 (12.7–41.2)	47.5 (31.5–63.9)
Sd	50.0 (33.8–66.2)	32.5 (18.6–49.1)
PD	2.5 (0.1–13.2)	2.5 (0.1–13.2)
NE	17.5 (7.3–32.8)	17.5 (7.3–32.8)

CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; Sd, stable disease; TVS, tumor volume score

^aBest overall response was defined as the best response (in the order of CR, PR, Sd, PD, and NE) among all responses recorded from the start of treatment until the last radiographic tumor assessment

Secondary Endpoints

On the basis of TVS, ORR was 47.5% (95% CI 31.5–63.9), with 19 (47.5%) patients having PR and none having CR; 12 (30.0%) patients had Sd, and no patients had PD (Table 2). The change from baseline in ROM at week 25 (LSM [95% CI]) was 23.05° (95% CI 16.4–29.7), with improvement noted in the affected joint at week 13 (15.64° [95% CI 8.8–22.4]). BOR by RECIST v1.1 was observed in 12 (30.0%; 95% CI 16.6–46.5) patients, with 2 (5.0%) achieving CR and 10 (25.0%) achieving PR; 20 (50.0%) patients had a BOR of Sd, and there was 1 (2.5%) patient with PD. BOR by TVS was observed in 19 (47.5%; 95% CI 31.5–63.9) patients, all with PR and none achieving CR; 13 (32.5%) patients had a BOR of Sd, and there was 1 (2.5%) patient with PD.

On the basis of the cutoff date for the primary analysis, the median duration of response could not be calculated because too few patients had disease progression after being assessed as a responder. By RECIST v1.1, the proportion of responders maintaining a response at weeks 12 and 24 since their first recorded response was 100% and 87.5%, respectively. The range of response duration was 0.03–7.62 months. By TVS, 100% of patients maintained their responses at weeks 12 and 24 since their first recorded response, with a range of response duration of 0.03–9.46 months. The overall LSM change from baseline in PROMIS Physical Function Scale score at week 25 was 0.46 (95% CI −2.3–3.3), indicating no remarkable change.

Ad Hoc Analysis at Week 37

At week 37, ORR by RECIST v1.1 was 35.0% (95% CI 20.6–51.7), with 2 (5.0%) patients achieving CR and 12 (30.0%) patients achieving PR. ORR by TVS at week 37 was 45.0% (95% CI 29.3–61.5), with 18 (45.0%) patients achieving PR (Fig. 2 and Table 3).

Fig. 2.

Maximum change in tumor size according to (A) RECIST v1.1 and (B) TVS. RECIST, Response Evaluation Criteria in Solid Tumors; SD, standard deviation; TVS, tumor volume score

Table 3.

Efficacy endpoint (by RECIST v1.1) at week 37 (PL3397-A-A303 and phase 3 ENLIVEN studies)

	PL3397-A-A303	Phase 3 ENLIVEN study
% (95% CI)	Pexidartinib (N = 40)	Pexidartinib (part 1) (N = 61)
ORR (CR or PR)	35.0 (20.6–51.7)	42.6 (30.0–55.9)
CR	5.0 (0.6–16.9)	14.8 (7.0–26.2)
PR	30.0 (16.6–46.5)	27.9 (17.1–40.8)
Sd	27.5 (14.6–43.9)	32.8 (21.3–46.0)
PD	2.5 (0.1–13.2)	1.6 (0–8.8)
NE	35.0 (20.6–51.7)	23.0 (13.2–35.5)

CI, confidence interval; CR, complete response; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; Sd, stable disease

Safety

All patients had TEAEs (100%) and TEAEs related to pexidartinib (100%). Grade ≥ 3 TEAEs were reported in 16 (40.0%) patients, with 12 (30.0%) patients reporting treatment-related grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs were increased ALT (n = 8 [20.0%]), increased GGT (n = 7 [17.5%]), and increased AST (n = 5 [12.5%]). The most common TEAEs were hair color changes (n = 31 [77.5%]), increased ALT (n = 24 [60.0%]), increased AST (n = 23 [57.5%]), increased blood lactate dehydrogenase (n = 19 [47.5%]), pruritus (n = 19 [47.5%]), rash (n = 17 [42.5%]), and facial edema (n = 17 [42.5%]; Table 4).

Table 4.

TEAEs occurring in ≥ 10% of patients

	Pexidartinib (N = 40)
TEAE, n (%)	Any grade	Grade ≥ 3
Patients with any TEAE	40 (100)	16 (40.0)
Skin and subcutaneous tissue disorders
Hair color changes	31 (77.5)	0
Pruritus	19 (47.5)	0
Rash	17 (42.5)	1 (2.5)
Skin discoloration	7 (17.5)	0
Drug eruption	5 (12.5)	0
Abnormal hair texture	5 (12.5)	0
Investigations
ALT increased	24 (60.0)	8 (20.0)
AST increased	23 (57.5)	5 (12.5)
Blood lactate dehydrogenase increased	19 (47.5)	0
Gamma-glutamyl transferase increased	15 (37.5)	7 (17.5)
White blood cell count decreased	14 (35.0)	0
Blood ALP increased	12 (30.0)	0
Neutrophil count decreased	11 (27.5)	0
Blood creatine phosphokinase increased	8 (20.0)	1 (2.5)
Bilirubin conjugated increased	6 (15.0)	2 (5.0)
Blood bilirubin increased	6 (15.0)	2 (5.0)
Lymphocyte count decreased	5 (12.5)	1 (2.5)
General disorders and administration-site conditions
Facial edema	17 (42.5)	0
Fatigue	12 (30.0)	0
Peripheral edema	4 (10.0)	0
Swelling of the face	4 (10.0)	0
Gastrointestinal disorders
Nausea	6 (15.0)	0
Diarrhea	5 (12.5)	0
Dry mouth	5 (12.5)	0
Constipation	4 (10.0)	0
Nervous system disorders
Dizziness	4 (10.0)	0
Dysgeusia	4 (10.0)	0
Eye disorders
Periorbital edema	9 (22.5)	0
Metabolism and nutrition disorders
Decreased appetite	4 (10.0)	0
Hypokalemia	4 (10.0)	0
Blood and lymphatic system disorders
Anemia	8 (20.0)	0
Infections and infestations
Nasopharyngitis	5 (12.5)	0
Musculoskeletal and connective tissue disorders
Arthralgia	4 (10.0)	1 (2.5)
Vascular disorders
Hypertension	5 (12.5)	1 (2.5)

If a patient had both missing and nonmissing NCI-CTCAE grades for a TEAE, the missing NCI-CTCAE grade was treated as the lowest-severity grade. If a patient had > 1 event per SOC (or PT) level, the patient was counted once at each level of summation

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PT, preferred term; SOC, system organ class; TEAE, treatment-emergent adverse event

A total of six (15.0%) patients experienced at least one serious TEAE: abnormal hepatic function in three (7.5%) patients (all pexidartinib related) and inflamed fistula, osteonecrosis, epithelioid sarcoma, and pneumothorax in one patient each (none of which were considered related to pexidartinib). All three patients with abnormal hepatic function were hospitalized and treated; two patients recovered and one patient was still recovering at the data cutoff for the primary analysis. A total of 24 (60.0%) patients had a TEAE leading to pexidartinib dose interruption or reduction, and 11 (27.5%) patients had a TEAE leading to discontinuation of pexidartinib. The study drug–related TEAEs leading to pexidartinib dose interruption were increased ALT, AST, blood bilirubin, and conjugated bilirubin; adverse skin reaction; pruritus; facial edema; and rash. The study drug–related TEAEs leading to dose reduction included adverse skin reaction, facial edema, and rash. The most common TEAEs leading to discontinuation of pexidartinib were increased conjugated bilirubin, increased blood alkaline phosphatase, and increased GGT. Table 5 provides more information concerning elevated liver enzymes and total bilirubin found in patients receiving pexidartinib. Overall, 16 (40.0%) patients had increased AST ≥ 3 × the upper limit of normal (ULN) or ALT ≥ 3 × ULN, and 9 (22.5%) patients had AST ≥ 5 × ULN or ALT ≥ 5 × ULN. Most of the events occurred within the first two study treatment cycles. There were two (5.0%) patients who had AST or ALT ≥ 3 × ULN with total bilirubin ≥ 2 × ULN. No clinically relevant changes in mean values for vital signs or electrocardiograms were observed, although individual clinically significant vital sign abnormalities were reported as TEAEs, such as hypertension and pyrexia, at the investigator’s discretion.

Table 5.

Patients with elevated liver enzymes and TBL

Category, n (%)	Pexidartinib (N = 40)
Baseline AST ≥ ULN	0
Baseline ALT ≥ ULN	0
Baseline ALP ≥ ULN	0
Baseline TBL ≥ ULN	1 (2.5)
Postbaseline AST ≥ 3 × ULN	14 (35.0)
Postbaseline ALT ≥ 3 × ULN	15 (37.5)
Postbaseline AST ≥ 3 × ULN or ALT ≥ 3 × ULN	16 (40.0)
Postbaseline AST ≥ 5 × ULN	6 (15.0)
Postbaseline ALT ≥ 5 × ULN	8 (20.0)
Postbaseline AST ≥ 5 × ULN or ALT ≥ 5 × ULN	9 (22.5)
Postbaseline ALP ≥ 2.5 × ULN	3 (7.5)
Postbaseline TBL ≥ 2 × ULN	2 (5.0)
Concurrent TBL ≥ 2 × ULN with AST ≥ 3 × ULN	2 (5.0)
Concurrent TBL ≥ 2 × ULN with ALT ≥ 3 × ULN	2 (5.0)
Concurrent TBL ≥ 2 × ULN with AST ≥ 3 × ULN or ALT ≥ 3 × ULN	2 (5.0)

Baseline values were defined as the last nonmissing value before the first dose of the study drug. Concurrent was defined as ≥ 1 case of postdose TBL ≥ 2 × ULN that occurred between the first incidence date and 30 days after the last incidence date of the corresponding liver enzyme(s) ≥ 3 × ULN

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBL, total bilirubin; ULN, upper limit of normal

Discussion

This phase 3 study investigated the efficacy and safety of pexidartinib in East Asian patients with TGCT. The primary endpoint, ORR by RECIST v1.1 at week 25, was 22.5% (95% CI 10.8–38.5). The ORR by RECIST v1.1 at week 25 in the phase 3 study was lower than 27%; this value is derived from the lower limit of the 95% CI for the ORR (37.7%: 95% CI 26.6–50.3) at week 25 in the phase 3 ENLIVEN study [6]. Although it is difficult to discern definitive reasons for why the ORR at week 25 in the phase 3 study was lower than 27%, it could be affected by the following two facts. First, a high discontinuation rate due to adverse events (25.0%) was observed in the phase 3 study and was higher than the rate in the phase 3 ENLIVEN study (part 1 [randomized to pexidartinib]; 13.1%). The discontinued patients were regarded as nonresponders for ORR at week 25. To prevent severe hepatotoxicity, the dose modification guideline for the phase 3 study was stricter than that for the phase 3 ENLIVEN study; thus, the difference in dose modification guidelines may have contributed to the discontinuation rates. Second, the percentage of the patients who had prior surgical history was different between the phase 3 study (82.5%) and the phase 3 ENLIVEN study (part 1; 52.5%). It has been previously reported that the patients who have surgical history may be more progressive owing to the risk of recurrence compared with patients who had no surgical history [11, 12]. Therefore, the patients’ different surgical history might affect the primary outcome of the phase 3 study.

There is also a potential for racial differences in pexidartinib exposure and response, but more confirmatory data are needed to show this. A population pharmacokinetics analysis of pexidartinib found an approximately 21% lower exposure of the drug in eight Asian patients compared with non-Asian patients (n = 375), with wide 95% CIs [13].

Because the ORR by RECIST v1.1 is expected to increase over time on the basis of the updated long-term efficacy outcome in the ENLIVEN study, ORR at week 37 by RECIST v1.1, which was available at the data cutoff date (1 June 2021), was also assessed as an ad hoc analysis. The ORR by RECIST v1.1 at week 37 increased to 35.0% (95% CI 26.6–50.3) including two patients with CR, which is close to the ORR (42.6% [95% CI 30.0–55.9]) at week 37 in the ENLIVEN study (Table 3). Similar to the efficacy evaluation at week 25, the ORR by RECIST v1.1 at week 37 was assessed from the viewpoint of being higher than the lower limit of 95% CI for the ORR at week 37 in the ENLIVEN study. The ORR (35.0%) by RECIST v1.1 at week 37 was higher than the lower limit of 95% CI for the ORR (30.0%) in the ENLIVEN study.

In addition, placebo data in the ENLIVEN study showed that no tumor shrinkage or improvement were observed during the treatment period (ORR by RECIST v1.1 at week 25: 0%). Because TGCT does not regress without medical therapies, substantial efficacy of pexidartinib is suggested in comparison with placebo.

Moreover, significant improvement was observed in the secondary endpoints. The ORR by TVS in the PL3397-A-A303 study (47.5% [95% CI 31.5–63.9]) was comparable to the ORR in the PLX108-10 study (55.7% [95% CI 43.3–67.5]) at week 25 (Table 2).

TVS is a novel method developed specifically for TGCT that might provide an accurate measurement of disease response with less error and variability than RECIST v1.1 [14]. As several TGCT clinical studies reported that TVS was more sensitive than RECIST v1.1 in the past few years, TVS may be a potential alternative to RECIST v1.1 to measure the efficacy of pexidartinib in TGCT [5, 6]. The TVS result strongly supports that pexidartinib is effective for East Asian patients with TGCT.

The overall safety profile of pexidartinib was comparable with that of previous reports; no new safety signals emerged in this Asian population. Hair color changes were the most common TEAE, followed by increased liver enzymes. The frequency of increased liver enzymes tended to be higher in the current study as compared with the ENLIVEN study [6]; further analysis is required to confirm whether the higher frequency is due to differences in ethnicity. In any case, frequent monitoring of liver function is recommended, and if liver enzymes are elevated, the dose of pexidartinib should be held and then resumed at a reduced dose or permanently discontinued as directed [7]. The dose of pexidartinib used in this study (400 mg twice daily on an empty stomach) was consistent with that of the phase 3 ENLIVEN study after the 2-week loading dose. Pexidartinib exposure increases with food consumption, approximately doubling when administered with a high-fat meal and increasing by approximately 60% when administered with a low-fat meal [15]. The recommended dosing regimen in the US product label has been updated to 250 mg twice daily with a low-fat meal [7]. This dosing update has no impact on the efficacy and safety findings of studies using pexidartinib 400 mg twice daily on an empty stomach dosing regimen [7, 15].

Limitations of this study include the single-arm study design. The addition of a placebo-controlled comparator group would allow for confirmation of the effectiveness of pexidartinib in East Asian patients with TGCT. In addition, it is important to acknowledge that the limited sample size (N = 40) may not reflect the total real-world East Asian population with TGCT. Such limitations may also explain the lower ORR reported here compared with the phase 3 ENLIVEN study.

Conclusions

In East Asian patients with symptomatic TGCT not amenable to improvement with surgery, pexidartinib demonstrated clinical benefit in tumor response and improvement in joint function.

Pexidartinib was generally well tolerated, with a known risk of hepatotoxicity that was manageable with frequent liver function monitoring and dose-modification guidelines.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Hairong Xu: conceptualization, writing—original draft, reviewed the manuscript, and provided final approval of the version to be submitted. Po-Kuei Wu: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Zhaoming Ye: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Zhengfu Fan: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Tao Li: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Tom Wei-Wu Chen: conceptualization, data curation, investigation, project administration, supervision, validation, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Jingnan Shen: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Wangjun Yan: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Issei Achiwa: conceptualization, project administration, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Kazukoh Yoh: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Kunika Kikumori: conceptualization, formal analysis, methodology, reviewed the manuscript, and provided final approval of the version to be submitted. Yoshiharu Hiruma: conceptualization, reviewed the manuscript, and provided final approval of the version to be submitted. Jonathan Greenberg: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted. Xiaohui Niu: conceptualization, writing—review and editing, reviewed the manuscript, and provided final approval of the version to be submitted.

Funding

This study was funded by Daiichi Sankyo. ClinicalTrials.gov identifier: NCT04488822. The journal’s Rapid Service Fee was funded by Daiichi Sankyo, Inc.

Data Availability

Anonymized individual participant data on completed studies and applicable supporting clinical study documents may be available upon request at https://vivli.org. In cases where clinical study data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of the company and the clinical study subjects. Details on data-sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo.

Declarations

Conflicts of Interest

Hairong Xu: no conflicts to disclose. Po-Kuei Wu: no conflicts to disclose. Zhaoming Ye: no conflicts to disclose. Zhengfu Fan: no conflicts to disclose. Tao Li: no conflicts to disclose. Tom Wei-Wu Chen: no conflicts to disclose. Jingnan Shen: no conflicts to disclose. Wangjun Yan: no conflicts to disclose. Issei Achiwa: employee of Daiichi Sankyo Co., LTD. Kazukoh Yoh: employee of Daiichi Sankyo Co., LTD. Kunika Kikumori: employee of Daiichi Sankyo Co., LTD. Yoshiharu Hiruma: employee of Daiichi Sankyo Co., LTD. Jonathan Greenberg: employee of Daiichi Sankyo Inc. Xiaohui Niu: no conflicts to disclose.

Ethical Approval

All study documents were approved by the sites’ independent ethics committees or institutional review boards. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and Good Clinical Practice guidelines. All patients provided written informed consent.