Abstract
Background:
To report on long-term effects of pexidartinib in tenosynovial giant cell tumor (TGCT).
Methods:
Pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) phase 1 extension study (NCT01004861, 1000 mg/d, n = 39); 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks then 800 mg/d, n = 61); and 3) ENLIVEN crossover patients (NCT02371369, 800 mg/d, n = 30). Eligible patients: ≥18 years histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included best overall response (complete or partial response [CR/PR]) and duration of response (DOR) by RECIST and tumor volume score (TVS). Safety assessed frequency of treatment-emergent adverse events (TEAEs) and hepatic lab abnormalities (aminotransferase elevations; mixed/cholestatic hepatotoxicity). Data cutoff was May 31, 2019.
Results:
130 TGCT patients received pexidartinib (median treatment duration, 19 months [range >1–76 months]); 54 (42%) remained on treatment at the analysis end (32 months after enrollment completion). RECIST overall response (ORR) was 60%; TVS ORR, 65%. Median time to response was 3.4 months (RECIST), and 2.8 months (TVS), with 48 (62%) of responding patients achieving a RECIST PR by 6 months, and 72 (92%) by 18 months. Median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low grade, most frequent being hair color change (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), reversible in all cases (recovery spanning 1–7 months).
Conclusion:
This study demonstrates prolonged efficacy and tolerability of long-term pexidartinib treatment in TGCT.
Keywords: efficacy, long-term, pexidartinib, pooled analysis, safety, TGCT, tumor response
Condensed Abstract
This analysis further illustrates that systemic therapy targeting the CSF1/CSF1R pathway is an effective therapeutic strategy in patients with TGCT.
Given the limited availability of long-term prospective data in TGCT, these findings are encouraging and demonstrate the overall long-term benefit of continued treatment with pexidartinib.
Introduction
Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm associated with colony-stimulating factor 1 (CSF1) overexpression,1–5 affecting primarily the synovium of joints, bursae, or tendon sheaths.2, 3 Localized-type TGCT is a locally aggressive disease, accounting for 80% to 90% of TGCT cases and most commonly occurring in the digits. Diffuse-type TGCT, formerly called pigmented villonodular synovitis (PVNS), constitutes 10% to 20% of cases, usually occurring in large joints (e.g., knee, ankle, and hip) and showing a higher tendency toward recurrence.6, 7 The diffuse variant often causes debilitating symptoms, including pain, swelling, limited range of motion, and stiffness.1, 3 While surgery cures the vast majority of localized TGCT cases, the diffuse-type disease shows a high tendency toward local recurrence, occurring in approximately 50% of resected cases, therefore limiting the value of surgery in this subtype.8, 9
Pexidartinib is an orally administered small-molecule tyrosine kinase inhibitor10 that acts as a selective, potent inhibitor of CSF1R, c-kit receptor tyrosine kinase (KIT), and fms-like tyrosine kinase 3 internal tandem duplication (FLT3- ITD).11 Following preliminary positive results from the phase 1 extension study (NCT01004861, PLX108–01),10 compelling efficacy in TGCT patients was demonstrated in the phase 3 ENLIVEN study (NCT02371369), which utilized blinded, independent central review RECIST response as the primary endpoint comparing pexidartinib versus placebo at week 25.4 The safety profile of pexidartinib was well established in the ENLIVEN study4 and supported by data from other studies in the clinical program. Pexidartinib can cause serious and potentially fatal mixed or cholestatic hepatotoxicity. In July 2019, the US FDA Multidisciplinary Review team determined that the benefit/risk assessment was favorable for a patient population with no treatments (ie, surgical interventions) available or for whom treatment with surgery would not be possible due to predicted morbidity. Subsequently, pexidartinib became the first approved systemic therapy for TGCT in the United States, and it was added by the National Comprehensive Cancer Network as a category 1 recommendation for the treatment of adult patients with symptomatic TGCT/PVNS associated with severe morbidity or functional limitations and not amenable to improvement with surgery.12, 13 By contrast, the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) considered that the safety and efficacy balance of pexidartinib was not sufficiently demonstrated. This was essentially based on a negative assessment of the balance between the potential risk of life-threatening liver toxicity and the non-metastatic nature of the disease. On this basis pexidartinib is currently not available to advanced TGCT patients in the EU.
The aim of this pooled analysis is to report on the long-term efficacy and safety of pexidartinib across the phase 3 ENLIVEN study and the TGCT cohort of the PLX108–01 study, extending beyond what has been previously published, with insights from prolonged follow-up for a median of 39 months (range, 32–82).
Methods
Study design and participants
Key eligibility criteria and study designs for the ENLIVEN study (NCT02371369)4 and PLX108–01 extension (NCT01004861)10 have been described elsewhere and are summarized in Table 1. In brief, patients were required to be >18 years old and have histologically confirmed TGCT that was both unresectable and symptomatic; ENLIVEN eligibility specifically required symptoms of pain (a worst pain score of ≥ 4 on a scale of 0 to 10, with 10 representing pain as bad as can be imagined) or stiffness (≥ 4 on a scale of 0 to 10).
Table 1.
Summary of PLX108–01 and ENLIVEN studies
| Study ID (NCT#) | Study Title | Study Design | Dosing Regimen for TGCT Patients |
|---|---|---|---|
| PLX108–01 (NCT01004861)10 |
A Phase 1 Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of pexidartinib in Patients with Advanced, Incurable, Solid Tumors in which the Target Kinases Are Linked to Disease Pathophysiology | Phase 1, first in-human study with a dose escalation (Part 1) and extension (Part 2) | TGCT Cohort of Part 2: pexidartinib (n = 39), 1000 mg/d (split dose) |
| ENLIVEN (NCT02371369)4 |
A Double-blind, Randomized, Placebo-controlled Phase 3 Study of Orally Administered PLX3397 in Subjects with Pigmented Villonodular Synovitis or Giant Cell Tumor of the Tendon Sheath (ENLIVEN) | Phase 3, multicenter study with 2 parts: randomized, double-blind, placebo-controlled part and open-label, long-term part | Randomized cohort (n = 61): pexidartinib: 1000 mg/d (split dose) for 2 weeks, then pexidartinib: 800 mg/d (split dose) Cross-over cohort (n = 30): pexidartinib: 800 mg/d (split dose) |
Abbreviation: TGCT, tenosynovial giant cell tumor
The pooled analysis encompassed 3 groups of pexidartinib-treated TGCT patients from: a) phase 1 extension study, b) ENLIVEN (patients randomized to pexidartinib 1000 mg/d x 2 weeks then 800 mg/d), and c) ENLIVEN (crossover patients, 800 mg/d). The phase 1 PLX108–01 study was the first-in-human study with a dose-escalation phase with an expansion cohort phase (n = 39 TGCT patients) conducted in patients with solid tumors. Pexidartinib 1000 mg/d (split in twice-daily dosing) was taken until tumor progression or the development of unacceptable toxicities.
ENLIVEN, which included 120 TGCT patients, was a phase 3, randomized, placebo-controlled, two-part, multicenter study conducted in patients with symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity.4 In Part 1, a double-blind, randomized, placebo-controlled 24-week treatment, patients received either pexidartinib 1000 mg/d (n = 61) or matching placebo (n = 59) for the first 2 weeks followed by 800 mg/d pexidartinib or matching placebo for 22 weeks (both twice-daily dosing). In Part 2, patients were allowed to continue treatment with open-label pexidartinib for long-term evaluation of safety and efficacy. The crossover population (n = 30) received open-label pexidartinib after receiving placebo in Part 1.
Assessments and analysis
Efficacy (tumor response) was determined by best overall response (complete or partial response [CR/PR]) and duration of response (DOR) by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 and tumor volume score (TVS), with tumor assessments by independent central review. Frequency of imaging was every 8 weeks for the phase 1 extension cohort and every 12 weeks for patients from ENLIVEN.4, 10 DOR was defined as the time from first recorded response by RECIST to first documentation of subsequent disease progression. In the ENLIVEN study, overall response rate at week 25, per RECIST v 1.1, was the primary endpoint and overall response measured by TVS was a secondary endpoint. RECIST v 1.1 and TVS by independent central review was also used in the PLX108–01 study in measuring tumor response. TVS is a magnetic resonance imaging (MRI) scoring system describing tumor volume as a proportion of estimated volume of the maximally distended synovial cavity or tendon sheath involved. A TVS response was defined as ≥50% reduction in tumor size, and progressive disease was defined as a ≥30% increase in tumor size from baseline. Of note, the ENLIVEN study required central review confirmation of evaluable disease prior to enrollment, whereas the PLX108–01 study did not, and 5 of 39 patients total were not evaluable due to joint replacement hardware (n = 4) or myositis (n = 1). These 5 patients were non-responders and were included in the denominator for response rate calculations. Tumor response for this analysis followed the definition used in ENLIVEN, which did not require response confirmation.
For safety, the frequency of treatment-emergent adverse events (TEAEs) was tabulated according to Common Terminology Criteria for Adverse Events (CTCAE) by system organ class (SOC) and preferred term. Hepatic tests were also evaluated, and hepatic abnormalities were classified into 1 of 2 types — aminotransferase elevations, or mixed or cholestatic hepatotoxicity — based upon liver test results.
The data cutoff for the efficacy and safety analyses reported here was May 31, 2019, representing a median follow-up duration of 39 months (range, 32–82 months after patients’ first dose) and providing a long-term efficacy and safety evaluation of pexidartinib-treated TGCT patients.
Results
The 130 TGCT patients across both studies who received pexidartinib were included in the efficacy analysis, with patient demographics and baseline disease characteristics summarized in Table 2. The median age in the population was 45 years (range, 20–80) and the knee was the most common location of the disease (57%). Seventy-seven patients (59%) had at least 1 prior surgery, and 16 patients (12%) had received prior systemic therapy. Eight of 130 patients (6%) received prior radiation therapy.
Table 2.
Patient demographics and baseline disease characteristics
| Characteristic | ENLIVEN Randomized (1000 mg/d x 2 weeks then 800 mg/d) n = 61 |
ENLIVEN Crossover (800 mg/d)a n = 30 |
PLX108–01 TGCT Cohort (1000 mg/d)a n = 39 |
Pooled N = 130 |
|---|---|---|---|---|
| Median age, y (range) | 44 (22–75) | 47 (20–79) | 42 (22–80) | 45 (20–80) |
| Sex, n (%) | ||||
| Male | 26 (43) | 14 (47) | 17 (44) | 57 (44) |
| Female | 35 (57) | 16 (53) | 22 (56) | 73 (56) |
| Race, n (%) | ||||
| White | 52 (85) | 30 (100) | 33 (85) | 115 (88) |
| Asian | 3 (5) | 0 | 3 (8) | 6 (5) |
| Black | 1 (2) | 0 | 3 (8) | 4 (3) |
| Native American | 2 (3) | 0 | 0 | 2 (2) |
| Hawaiian/Pacific Islander | 2 (3) | 0 | 0 | 2 (2) |
| Other (multiracial) | 1 (2) | 0 | 0 | 1 (1) |
| Disease location, n (%) | ||||
| Knee | 34 (56) | 19 (63) | 21 (54) | 74 (57) |
| Ankle | 14 (23) | 3 (10) | 7 (18)c | 24 (18) |
| Hip | 6 (10) | 3 (10) | 7 (18)d | 16 (12) |
| Otherb | 7 (11) | 5 (17) | 4 (10) | 16 (12) |
| Prior surgeries for TGCT, n (%) | ||||
| 0 | 29 (48) | 16 (53) | 8 (21) | 53 (41) |
| 1 | 13 (21) | 5 (17) | 5 (13) | 23 (18) |
| 2 | 7 (12) | 6 (20) | 10 (26) | 23 (18) |
| 3 | 12 (20) | 3 (10) | 16 (41) | 31 (24) |
| Prior systemic therapy,e n (%) | ||||
| 0 | 53 (87) | 28 (93) | 33 (85) | 114 (88) |
| ≥1 | 8 (13) | 2 (7) | 6 (15) | 16 (12) |
| Prior radiation therapy,e n (%) | ||||
| 0 | 57 (93) | 29 (97) | 36 (92) | 122 (94) |
| 1 | 3 (5) | 1 (3) | 3 (8) | 7 (5) |
| ≥2 | 1 (2) | 0 | 0 | 1 (1) |
| Median (range) duration of exposure, mo. | 16.7 (1.0–46.1) | 31.7 (2.0–43.1) | 16.8 (0.5–75.5+) | 18.7 (0.5–75.5+) |
Abbreviation: TGCT, tenosynovial giant cell tumor
Starting dose.
Included wrist, foot, shoulder, spine, finger, and elbow.
Included foot/ankle.
Included hip/thigh.
Included nilotinib (n = 1) or imatinib (n = 7) in ENLIVEN and imatinib or nilotinib (n = 4) or denosumab or sirolimus (n = 2) in PLX108–01.
The pooled population had a median duration of treatment of 19 months, with treatment ongoing in 54 (42%) patients at the May 31, 2019, cutoff. Overall tumor response rates (best response of CR or PR) were high, consistent across the three cohorts, and durable (Table 3, Fig. 1). Best response according to RECIST was CR or PR in 78 patients (ORR = 60%, 95% CI, 51.4–68.0), stable disease (SD) in 26 patients (20%), and progressive disease (PD) in one patient (1%) (Fig. 1A; Table 3). Eighty-four patients (65%) achieved complete or partial TVS response (Fig. 1B; Table 3). The median time to initial response was 3.4 months (range, 1.6–38.3) via RECIST and 2.8 months (range, 1.6–33.6) via TVS, with most responses (65/84, 77%) occurring within the first 6 months after start of pexidartinib treatment (first 2 scans) and others (19/84, 23%) developing only after > 6 months of pexidartinib treatment. Regarding RECIST, of the 78 patients who achieved a response, 32 patients (41%) achieved a response by 3 months, 48 patients (62%) had shown a response by 6 months, and 72 patients (92%) by 18 months (Fig. 1C). Regarding TVS, of the 84 patients who reached a response, 50 patients (60%) had achieved a response by 3 months, 65 patients (77%) had shown a response by 6 months, and by 12 months, 82 patients (98%) did. Two additional patients reached a TVS response between 12 and 34 months after initiation of pexidartinib (Fig. 1D). Of the 130 patients in the pooled analysis, 34 (26%) achieved a RECIST CR. Fifteen of the 34 patients (44%) who had CR did so by 8 months after start of pexidartinib treatment. By 20 months, 26 (76%) patients reached CR, whereas the last patient to do so was at ~42 months following initiation of pexidartinib (Fig. 1E). One patient had RECIST PD as best overall response, with no progression per TVS (Table 3). Ultimately, according to RECIST, a total of 16 patients (12%) progressed on treatment or after treatment discontinuation, 14 (11%) progressed on treatment and 2 (2%) progressed after treatment. One patient (1%) underwent surgery of residual TGCT after response to pexidartinib therapy.
Table 3.
Summary of efficacy
| Endpoint | ENLIVEN Randomized (1000 mg/d x 2 weeks then 800 mg/d) n = 61 |
ENLIVEN Crossover (800 mg/d)a n = 30 |
PLX108–01 TGCT Cohort (1000 mg/d)a n = 39 |
Pooled N = 130 |
|---|---|---|---|---|
| RECIST, n (%) (95% CI) | ||||
| Complete response | 18 (30) (19.6, 41.9) |
8 (27) (14.2, 44.4) |
8 (21) (10.6, 35.5) |
34 (26) (19.4, 34.3) |
| Partial response | 20 (33) (22.3, 45.3) |
10 (33) (19.2, 51.2) |
14 (36) (22.7, 51.6) |
44 (34) (26.3, 42.3) |
| Stable disease | 13 (21) (12.9, 33.1) |
8 (27) (14.2, 44.4) |
5 (13) (5.6, 26.7) |
26 (20) (14.0, 27.7) |
| Progressive disease | 1 (2) (0.3, 8.7) |
0 (0.0, 11.4) |
0 (0.0, 9.0) |
1 (1) (0.1, 4.2) |
| Not evaluable | 9 (15) (8.0, 25.7) |
4 (13) (5.3, 29.7) |
12 (31) (16.3, 46.4) |
25 (19) (13.4, 26.8) |
|
Overall response rate
(complete or partial) n (%) 95% CI |
38 (62) (49.7, 73.4) |
18 (60) (42.3, 75.4) |
22 (56) (41.0, 70.7) |
78 (60) (51.4, 68.0) |
| Median (range) DOR, mo. |
NR
(0.0+− 41.4+) |
NR (6.1+−3.2+) |
NR
(1.7–70.0+) |
NR
(0.0+−70.0+) |
| TVS, n (%) (95% CI) | ||||
| Complete response | 5 (8) (3.6, 17.8) |
1 (3) (0.6, 16.7) |
8 (21) (10.8, 35.5) |
14 (11) (6.5, 17.3) |
| Partial response | 35 (57) (44.9, 69.0) |
19 (63) (45.5, 78.1) |
16 (41) (27.1, 56.6) |
70 (54) (45.3, 62.2) |
| Stable disease | 13 (21) (12.9, 33.1) |
6 (20) (9.5, 37.3) |
3 (8) (2.7, 30.3) |
22 (17) (11.4, 24.3) |
| Progressive disease | 0 (0.0, 5.9) |
0 (0.0, 11.4) |
0 (0.0, 9.0) |
0 (0.0, 2.9) |
| Not evaluable | 8 (13) (6.8, 23.8) |
4 (13) (5.3, 29.7) |
12 (31) (18.6, 46.4) |
24 (18) (12.7, 26.0) |
|
Overall response
(complete or partial) n (%) 95% CI |
40 (66) (53.0, 76.3) |
20 (67) (48.8, 80.8) |
24 (62) (45.9, 75.1) |
84 (65) (56.1, 72.3) |
| Median (range) DOR, mo. | NR (0.0+−41.4+) | NR (8.0+−39.2+) | 41.9 (1.7–70.0+) | 46.8 (0.0+−70.0+) |
Abbreviations: CI, confidence interval; DOR, duration of response; NR, not reached; RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; TGCT, tenosynovial giant cell tumor; TVS, tumor volume score
Starting dose of pexidartinib.
Figure 1. Tumor assessments by independent central in pexidartinib-treated TGCT patients.
A. Waterfall plot of best tumor size change by RECIST
B. Waterfall plot of best tumor size change by TVS
C. RECIST time to initial response
D. TVS time to initial response
E. RECIST time to complete response
Abbreviations: ITT, intention-to-treat; ORR, overall response rate; RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; TVS, tumor volume score
ORR is calculated using the pooled population as the denominator.
Evaluable patients (RECIST and TVS) were those who had a baseline and at least 1 postbaseline tumor assessment.
*For RECIST: 110 patients evaluable, 78 with ≥30% reduction. †For TVS: 111 patients evaluable, 84 with ≥50% reduction, 5 with no change.
Pexidartinib was generally well tolerated, with most TEAEs being low grade (1 or 2) even with long-term treatment (Table 4). All 130 patients experienced ≥1 TEAE, of which 127 (98%) patients experienced at least 1 treatment-related TEAE (Supplemental Table 2). The most frequently reported TEAEs by SOC (all reversible) were hair color change (75%), followed by fatigue (61%), nausea (47%), and arthralgia (39%) (Table 4). Sixty-seven patients (52%) had TEAEs of CTCAE grade 3 or higher, of which 57 patients (44%) had events that were treatment-related. There were 23 patients (18%) who experienced a total of 32 serious adverse events (SAEs). Of these 23 patients, 14 patients (11%) had treatment-related SAEs. One patient (1%) had a grade 5 event (cause of death: aortic dissection, after a long history of cardiac events; reported as unrelated to pexidartinib) in the crossover group of ENLIVEN (Table 4 and Supplemental Table 2).
Table 4.
Overall safety: Frequency of treatment-emergent adverse events by cohort reported in ≥10% of patients
| ENLIVEN Randomized (1000 mg/d x 2 weeks then 800 mg/d) (n = 61) |
ENLIVEN Crossover (800 mg/d)a (n = 30) |
PLX108–01 TGCT Cohort (1000 mg/d)a (n = 39) |
Total N = 130 |
|||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event | All Grades (%) |
Grade ≥3 (%) |
All Grades (%) |
Grade ≥3 (%) |
All Grades (%) |
Grade ≥3 (%) |
All Grades (%) |
Grade ≥3 (%) |
| Skin and subcutaneous tissue disorders | ||||||||
| Hair color change | 74 | NA | 83 | NA | 72 | NA | 75 | NA |
| Rash | 28 | 2 | 27 | 0 | 31 | 0 | 28 | 1 |
| Pruritus | 16 | 2 | 20 | 0 | 36 | 0 | 23 | 1 |
| Rash maculopapular | 16 | 2 | 10 | 0 | 21 | 0 | 16 | 1 |
| Erythema | 3 | 2 | 20 | 0 | 21 | 0 | 12 | 1 |
| Skin hypopigmentation | 8 | NA | 3 | NA | 18 | NA | 10 | NA |
| Gastrointestinal disorders | ||||||||
| Nausea | 46 | 0 | 23 | 0 | 67 | 0 | 47 | 0 |
| Diarrhea | 30 | 0 | 30 | 0 | 38 | 8 | 32 | 2 |
| Vomiting | 23 | 2 | 7 | 0 | 33 | 3 | 22 | 2 |
| Constipation | 16 | 0 | 10 | 0 | 28 | 0 | 18 | 0 |
| Abdominal pain | 25 | 0 | 10 | 0 | 5 | 0 | 15 | 0 |
| Dry mouth | 13 | 0 | 13 | 0 | 10 | 0 | 12 | 0 |
| General disorders and administration site conditions | ||||||||
| Fatigue | 57 | 0 | 27 | 0 | 92 | 3 | 61 | 1 |
| Edema peripheral | 21 | 0 | 20 | 0 | 28 | 0 | 23 | 0 |
| Face edema | 15 | 2 | 20 | 3 | 15 | 0 | 16 | 2 |
| Asthenia | 15 | 0 | 23 | 0 | 0 | 0 | 12 | 0 |
| Investigations | ||||||||
| Aspartate amino-transferase increased | 44 | 10 | 20 | 7 | 18 | 8 | 31 | 8 |
| Alanine amino-transferase increased | 31 | 10 | 23 | 10 | 18 | 10 | 25 | 10 |
| Blood alkaline phosphatase increased | 15 | 7 | 3 | 0 | 10 | 0 | 11 | 3 |
| Nervous disorders | ||||||||
| Dysgeusia | 28 | NA | 23 | NA | 38 | NA | 30 | NA |
| Headache | 23 | 2 | 20 | 0 | 33 | 0 | 25 | 1 |
| Dizziness | 15 | 2 | 13 | 0 | 28 | 0 | 18 | 1 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 28 | 3 | 33 | 0 | 62 | 3 | 39 | 2 |
| Pain in extremity | 11 | 0 | 13 | 0 | 26 | 0 | 16 | 0 |
| Eye Disorders | ||||||||
| Periorbital edema | 28 | 2 | 17 | 0 | 38 | 0 | 29 | 1 |
| Metabolic and nutrition disorders | ||||||||
| Decreased appetite | 18 | 0 | 10 | 0 | 23 | 0 | 18 | 0 |
| Hypophosphatemia | 5 | 3 | 7 | 3 | 28 | 13 | 12 | 6 |
| Vascular disorders | ||||||||
| Hypertension | 23 | 7 | 33 | 7 | 21 | 0 | 25 | 5 |
| Blood and lymphatic system disorders | ||||||||
| Anemia | 10 | 2 | 3 | 0 | 23 | 3 | 12 | 2 |
| Respiratory, thoracic, and mediastinal disorders | ||||||||
| Cough | 7 | 0 | 13 | 0 | 21 | 0 | 12 | 0 |
| Infections and infestations | ||||||||
| Upper respiratory tract infection | 11 | 0 | 3 | 0 | 15 | 0 | 11 | 0 |
| Psychiatric disorders | ||||||||
| Insomnia | 5 | 0 | 10 | 0 | 18 | 0 | 10 | 0 |
Abbreviations: NA, not applicable; TGCT, tenosynovial giant cell tumor
Starting dose of pexidartinib.
There were 89 patients (69%) who experienced TEAEs resulting in dose reduction/interruption. Treatment discontinuation occurred in 69 (53%) of the patients in the pooled analysis (Supplemental Table 1). The most common reason for discontinuation of pexidartinib was adverse event (AE), which was the case in 31 patients (24%) (Supplemental Table 1). These AEs leading to discontinuation included abnormal laboratory investigations (n = 9, 7%), nervous system disorders (n = 8, 6%), and musculoskeletal/connective tissue disorders (n = 6, 5%). Twenty patients (15%) discontinued due to withdrawal of consent, and 5 (4%) were non-compliant, all from the phase 1 extension study. Five patients (4%) discontinued pexidartinib due to disease progression, 2 (2%) of whom were phase 1 patients with malignant/metastatic disease. Investigator decision resulted in 3 patients (2%) discontinuing pexidartinib treatment (Supplemental Table 1).
Pexidartinib was associated with hepatic laboratory abnormalities, which included hepatic adverse reactions (ARs) (Table 5). Hepatic ARs were experienced by 95% of patients (123/130), and were of 2 clinically distinct types. The first type was isolated aminotransferase elevations, which were frequent, reversible with dose-interruption, and dose-dependent. The second type of hepatic AR was mixed or cholestatic hepatotoxicity, which in clinically significant cases presented as an increase in alkaline phosphatase and total bilirubin with aminotransferase elevations. These events were less frequent, idiosyncratic, and sometimes prolonged. The onset was within first 8 weeks of treatment, and all resulted in permanent treatment discontinuation.
Table 5.
Hepatic laboratory abnormalities
| Endpoint | ENLIVEN Randomized (1000 mg/d x 2 weeks then 800 mg/d) n = 61 |
ENLIVEN Crossover (800 mg/d)a n = 30 |
PLX108–01 TGCT Cohort (1000 mg/d)a n = 39 |
Pooled N = 130 |
|---|---|---|---|---|
| Aminotransferase elevations, n (%): 119 (92%) | ||||
| ALT or AST | ||||
| ≥1 to <3 × ULN | 39 (64) | 21 (70) | 26 (67) | 86 (66) |
| ≥3 to <5 × ULN | 7 (12) | 4 (13) | 4 (10) | 15 (12) |
| ≥5 to <10 × ULN | 6 (10) | 2 (7) | 2 (5) | 10 (8) |
| ≥10 to <20 × ULN | 3 (5) | 1 (3) | 2 (5) | 6 (5) |
| ≥20 × ULN | 2 (3) | 0 | 0 | 2 (2) |
| Mixed or cholestatic hepatotoxicity, n (%): 4 (3%) | ||||
| ALT or AST ≥3, TBIL ≥2, and ALP ≤2 × ULN (true Hy’s law) | 0 | 0 | 0 | 0 |
| ALT/AST ≥3, TBIL ≥2, and ALP >2 × ULN | 3 (5) | 0 | 1 (3) | 4 (3) b |
| TBIL ≥2 × ULN (in absence of ALT ≥3 or ALP >2 × ULN) | 0 | 0 | 1 (3) | 1 (1) |
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; ULN, upper limit of normal
Pexidartinib starting dose.
Includes 1 patient with a single timepoint elevation of TBIL considered unrelated to treatment.
In the pooled analyses, most patients (n = 119, 92%) treated with pexidartinib experienced aminotransferase elevations, most commonly alanine aminotransferase (ALT) and AST increases of ≥1 to <3 × upper limit of normal (ULN) (66%).
Of the 130 TGCT patients, 4 (3%) experienced mixed or cholestatic hepatotoxicity (Table 5). All cases started within the first 8 weeks of treatment and were reversible, but duration was prolonged in some cases with recovery spanning 1 to 7 months. Across all 768 patients who received pexidartinib in clinical trials, there were 2 (0.3%) irreversible cases of cholestatic liver injury. One patient died with advanced cancer and ongoing liver toxicity, and 1 patient required a liver transplant.
Time to first occurrence of lab values meeting hepatic lab criteria corresponding to dose reduction/interruption/withdrawal based on the United States Prescribing Information (USPI): ALT >3 × ULN, or AST >3 × ULN, alkaline phosphatase (ALP) >2 × ULN with gamma-glutamyl transferase (GGT) >2 × ULN if measured on the same date, total bilirubin (TBIL) > ULN, or direct bilirubin (DBIL) > ULN was analyzed and evaluated, and results were previously presented.14 Most events occurred in the first 2 months, and no additional events occurred later than 24 months after the start of pexidartinib treatment.14 In the long-term follow-up (median of 39 months from initial dosing, May 2019), no new cases of mixed or cholestatic hepatotoxicity were observed in patients continuing long-term pexidartinib treatment. A more comprehensive analysis of hepatic safety events will be reported elsewhere.
Discussion
With prolonged follow-up with a median of 39 months (range, 32–82), 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 DOR. Notably, there was 1 patient who had a RECIST-based best overall response of PD with continued pexidartinib use. A high and comparable best ORR was achieved across all pexidartinib-treated cohorts and evaluation methods. Tumor response rates from pooled ENLIVEN and PLX108–01 studies increased with long-term pexidartinib treatment. Median treatment duration was 19 months (range, 1–76+), resulting in compelling response rates: RECIST 1.1 ORR of 60% and TVS ORR rates of 65%. Many patients achieved a tumor response by RECIST and TVS within the first 6 months (first 2 scans) following the start of pexidartinib treatment, but even more patients achieved a response with long-term pexidartinib treatment. Previously, in the published phase 3 study, the RECIST response rate following 24 weeks of pexidartinib treatment was 39% (vs 0% with placebo; P <0.0001) and 4 of 5 comparative secondary endpoints were met, including TVS (56% vs 0%; P <0.0001).4
To date, there has been limited availability of long-term prospective data in TGCT. A retrospective study of patients treated across 12 centers in Europe, the United States, and Australia found that long-term imatinib treatment in TGCT patients resulted in a 31% RECIST-based response among 55 assessable patients with locally advanced or recurrent disease, with a median treatment duration of 9 months (range, 1–80). At the last follow-up, most patients (66%) had discontinued imatinib treatment.15 Of the 130 TGCT patients treated with pexidartinib 54 (42%) remained on treatment, with only 5 patients (4%) discontinuing due to disease progression, 2 of whom had malignant/metastatic disease. These data further support that pexidartinib provides long-term control of TGCT.
The main reasons for treatment discontinuation were AEs (24%) and patient withdrawal of consent (15). Treatment with novel drugs in this disease is discontinued for various reasons. In a prospective study evaluating nilotinib in PVNS patients (N = 56) with a median duration of treatment of 11.0 months (IQR 7.0–12.0), 25 patients (45%) discontinued nilotinib before 12 months due to progressive disease (n = 6), tumor resection (n = 4), toxicity (n = 5), patient’s refusal (n = 8), investigator decision (n = 1), or were lost to follow-up (n = 1).16
Long-term treatment with pexidartinib has demonstrated a tolerable safety profile, with no late-emerging toxicity. At the original data cutoff (March 2017), the most common were hair color change (73%), fatigue (42%), and nausea (32%).4 In the current pooled analysis, where patients in ENLIVEN were followed for an additional 26 months of pexidartinib treatment, the most common AEs were similar (Table 4). Of the 130 TGCT patients exposed to pexidartinib for a median treatment duration of 19 months, 4 patients had serious hepatic ARs, and all started within the first 8 weeks of treatment. Although all of these events were reversible in the TGCT population the duration of liver injury was prolonged in some cases, and in the overall clinical program there were 2 irreversible cases of cholestatic liver injury. One patient died with advanced cancer and ongoing liver toxicity, and 1 patient required a liver transplant. The present analysis showed no new mixed or cholestatic hepatotoxicity was reported beyond the first 8 weeks of treatment.
Due to risk of hepatotoxicity, pexidartinib is available only through the Risk Evaluation Management System (REMS) program in the United States. Frequent monitoring of liver function, early intervention with dose modification, and education on symptoms of emerging hepatoxicity and the approved indication of pexidartinib are critical for a robust benefit-to-risk assessment on an individual patient basis. The additional long-term safety data did not reveal late-emerging or cumulative toxicities of clinical significance that would require revised risk management procedures beyond those proposed for patients in the first 2 months of pexidartinib treatment. Overall, these findings are encouraging for this rare tumor population with a highly unmet need for effective systemic therapy.
A limitation of the present pooled analysis is the lack of a control group for comparison of symptomatic and functional improvement and safety with long-term treatment.17 In addition, it cannot provide data on the time to disease progression in those patients who stopped pexidartinib while on response or stable. Nonetheless, this analysis adds to previous findings showing that systemic therapy targeting the CSF1/CSF1R pathway is an effective therapeutic strategy in patients with TGCT, and demonstrates the overall long-term benefit of continued treatment with pexidartinib.
Supplementary Material
Acknowledgements
We thank the patients who participated in this analysis; their family members and caregivers; the study staff members at each site who cared for the patients; the sponsor staff involved in data collection and analyses; and Phillip Giannopoulos, PhD (SciStrategy Communications) for medical writing assistance in the development of the manuscript. Research and manuscript support were provided by Daiichi Sankyo, Co., Ltd., Tokyo, Japan. All research at Memorial Sloan Kettering is supported in part by a grant from the National Institutes of Health/National Cancer Institute (#P30 CA008748).
Footnotes
Conflict of Interest Disclosures
Hans Gelderblom reports research compensation to his institution from Daiichi Sankyo. Andrew J. Wagner reports personal fees for consulting from Eli Lilly, Novartis, Loxo, Five Prime Therapeutics, and Daiichi Sankyo outside the submitted work. William D. Tap reports a standard budget for site participation in the clinical trial from Daiichi Sankyo, during the conduct of the study; personal fees for advisory board and consulting from Eli Lilly, EMD Serono, Eisai, Janssen, Immune Design, Daiichi Sankyo, Blueprint, Loxo, GlaxoSmithKline, and Agios Pharmaceuticals, outside the submitted work; personal fees for advisory board from NanoCarrier and Deciphera, outside the submitted work; a patent Companion Diagnostic for CDK4 inhibitors - 14/854,329 pending to MSKCC/SKI; and participation on the Scientific Advisory Board for Certis Oncology Solutions and Atropos Therapeutics; stock ownership with Certis Oncology Solutions and Atropos Therapeutics; and served as a consultant for Daiichi Sanyko for FDA ODAC Meeting Pexidartinib. Emanuela Palmerini reports personal fees for advisory board from Amgen, Daiichi Sankyo, Lilly, Eusa Pharma, and Deciphera, outside the submitted work; received research support from Bristol-Myers Squibb, Pfizer, and PharmaMar, outside the submitted work; and travel support from Lilly, PharmaMar, and Takeda, outside the submitted work. Zev A. Wainberg reports personal fees for consulting from Merck, Lilly, AstraZeneca, Daiichi Sankyo, outside the submitted work, and grants to his institution from Plexxikon and Novartis, outside the submitted work. Jayesh Desai reports personal fees for consulting from BeiGene, Lilly, Amgen, Eisai, Biocon, outside the submitted work; and research funding to his institution from Roche, Lilly, AstraZeneca/MedImmune, BeiGene, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, and Bionomics, outside the submitted work. John H. Healey reports personal fees for consulting from Daiichi Sankyo, outside the submitted work. Michiel van de Sande reports grants to his institution from Daiichi Sankyo, during the conduct of the study. Nicholas M. Bernthal reports personal fees from Zimmer Biomet, Daiichi Sankyo, and Onkos Surgical, outside the submitted work. Eric Staals reports participation on the Steering Committee for Daiichi Sankyo Europe GmbH, during the conduct of the study, and the Advisory Board Pexidartinib/Enliven Study for Daiichi Sankyo, outside the submitted work. Charles Peterfy reports ownership of Spire Sciences, which provides central imaging analysis for TGCT or other neoplasms for Plexxikon, Daiichi Sankyo, Deciphera, and Five Prime Therapeutics. Anna Maria Frezza reports research funding to her institution from Daiichi Sankyo, during the conduct of the study, and research funding to her institution from Daiichi Sankyo, outside the submitted work. Henry H. Hsu reports employment with Allysta Pharmaceuticals and Plexxikon; stock ownership in Allysta Pharmaceuticals; personal fees for consulting from Plexxikon; and patent with Allysta Pharmaceuticals. Qiang Wang reports employment with Daiichi Sankyo. Dale E. Shuster reports employment with and stock ownership in Daiichi Sankyo. Silvia Stacchiotti reports personal fees for consulting from Bayer, Bavarian Nordic, Deciphera, Eli Lilly, Epizyme Inc, Daiichi Sankyo, Karyopharm, Immune Design, Intellisphere, Maxivax, PharmaMar, and Takeda, outside the submitted work; research funding to her institution from Amgen Dompé, Advenchen, Bayer, Bavarian Nordic, Blueprint, Deciphera, Eli Lilly, Epizyme Inc, Daiichi Sankyo, Karyopharm, Novartis, Pfizer, and PharmaMar, outside the submitted work; travel coverage from PharmaMar, outside the submitted work; and honoraria from Eli Lilly and PharmaMar, outside the submitted work. No other conflicts of interest were reported.
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