Sarcomas Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors JAMES H. LEWIS ,a HANS GELDERBLOM ,b MICHIEL VAN DE SANDE,b SILVIA STACCHIOTTI,c JOHN H. HEALEY,d WILLIAM D. TAP,d ANDREW J. WAGNER,e ANTONIO LOPEZ POUSA,f MIHAELA DRUTA,g CHIA-CHI LIN,h HIDEO A. BABA,i YOUNGSOOK CHOI,j QIANG WANG,j DALE E. SHUSTER,j SEBASTIAN BAUERi a Georgetown University Hospital, Washington, District of Columbia, USA; bLeiden University Medical Center, Leiden, The Netherlands; c Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; dMemorial Sloan Kettering Cancer Center and Weill Cornell Medical Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 College, New York, New York, USA; eDana-Farber Cancer Institute, Boston, Massachusetts, USA; fHospital de la Santa Creu I Sant Pau, Barcelona, Spain; gMoffitt Cancer Center, Tampa, Florida, USA; hNational Taiwan University Hospital, Taipei, Taiwan; iUniversity Hospital Essen, University of Duisburg-Essen, Germany; jDaiichi Sankyo, Inc, Basking Ridge, New Jersey, USA Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Hepatic safety • Adverse reactions • Long-term • Pexidartinib • Tenosynovial giant cell tumor ABSTRACT Background. Pexidartinib is approved in the U.S. for ten- 19 months [range, 1–76]), experienced a hepatic AR. A total osynovial giant cell tumors (TGCTs). Herein, we assessed of 128 patients (91%) had reversible, low-grade dose- the hepatic safety profile of pexidartinib across patients dependent isolated AST/ALT elevations without significant with TGCTs receiving pexidartinib. ALP elevations. Five patients (4%) experienced serious mixed Materials, and Methods. Hepatic adverse reactions (ARs) or cholestatic injury. No case met Hy’s law criteria. Onset of were assessed by type and magnitude of liver test abnor- hepatic ARs was predominantly in the first 2 months. All five malities, classified as (a) isolated aminotransferase eleva- serious hepatic AR cases recovered 1–7 months following tions (alanine [ALT] or aspartate [AST], without significant pexidartinib discontinuation. Five patients from the non- alkaline phosphatase [ALP] or bilirubin elevations), or (b) TGCT population (N = 658) experienced serious hepatic mixed or cholestatic hepatotoxicity (increase in ALP with or ARs, two irreversible cases. without ALT/AST and bilirubin elevations, based on adjudi- Conclusion. This pooled analysis provides information to help cation). Median follow-up from initial pexidartinib treat- form the basis for the treating physician’s risk assessment for ment was 39 months (range, 32–82) in 140 patients with patients with TCGTs, a locally aggressive but typically non- TGCTs across clinical studies NCT01004861, NCT02371369, metastatic tumor. In particular, long-term treatment with NCT02734433, and NCT03291288. pexidartinib has a predictable effect on hepatic aminotrans- Results. In total, 95% of patients with TGCTs (133/140) ferases and unpredictable risk of serious cholestatic or mixed treated with pexidartinib (median duration of exposure, liver injury. The Oncologist 2021;26:e863–e873 Implications for Practice: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program. Correspondence: James H. Lewis, M.D., Department of Gastroenterology, MedStar Georgetown University Hospital, Second Floor, Main Hospital, M2408, Washington, District of Columbia 20007, USA. Telephone: (202) 444-1671; e-mail: lewisjh@gunet.georgetown. edu Received August 28, 2020; accepted for publication November 25, 2020; published Online First on December 24, 2020. http://dx.doi. org/10.1002/onco.13629 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adapta- tions are made. The Oncologist 2021;26:e863–e873 www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. e864 Pexidartinib Hepatic Safety INTRODUCTION elevations (in the absence of significant alkaline phosphatase [ALP] or bilirubin elevations) or (b) mixed or cholestatic hep- Tenosynovial giant cell tumor (TGCT), also known as atotoxicity (increase in ALP with or without aminotransferase pigmented villonodular synovitis (PVNS)/diffuse type TGCT or elevations) [23]. Hepatic ARs were examined by three hepa- giant cell tumor of tendon sheath/localized-TGCT, is a rare totoxicity experts with extensive experience evaluating drug- monoarticular disease primarily affecting the synovial lining induced liver injury who composed the pexidartinib Hepatic of joints, bursae, or tendon sheaths [1–3]. It is characterized Event Adjudication Committee (HEAC) that supported the by overexpression of the colony-stimulating factor 1 (CSF1) comprehensive evaluation of hepatic safety data across the protein [1, 4–6]. Systemic therapies, particularly tyrosine pexidartinib clinical program. The HEAC assessed severe kinase inhibitors (TKIs) targeting CSF1/CSF1 receptor (CSF1R) hepatic events for type of liver injury and potential related- signaling pathways, have shown promising results as novel ness to pexidartinib treatment. The HEAC provided advice on treatment options in patients with TGCTs [3, 6–16]. identification, management, and risk mitigation of drug- Pexidartinib was developed as a novel orally administered induced hepatic events. As a postapproval recommendation small-molecule TKI with selective activity against the CSF1R. to manage hepatic ARs and the risk of mixed or cholestatic Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 It is the first U.S. Food and Drug Administration (FDA)– hepatotoxicity, pexidartinib dose modification criteria have approved systemic therapy for TGCT, recently added by the been carefully defined according to the type and magnitude National Comprehensive Cancer Network as a category 1 rec- of liver test abnormality [17]. ommendation for the treatment of adult patients with Dose reductions and modifications were based on pre- symptomatic TGCT/PVNS associated with severe morbidity or scribing information recommendations [17]. A Hy’s law case functional limitations not amenable to improvement with was defined as any patient presenting with ALT or AST ≥3× surgery [17, 18]. Treatment with TKIs has been associated ULN with TBIL ≥2× ULN, and ALP ≤2× ULN [24]. The data with the risk of serious adverse events, including hepatotox- cutoff for the hepatic ARs analysis was May 31, 2019. icity [6, 9, 10, 16, 19–21]. Two clinically distinct types of Descriptive statistics were calculated including median hepatic adverse reactions (ARs) were observed with (range), and Kaplan-Meier curves were plotted for the time pexidartinib: (a) reversible aminotransferase elevations that from the start of pexidartinib treatment to first occurrence are frequently seen and attributed to CSF1R inhibition and, of hepatic ARs based on lab values criteria. less frequently, (b) mixed or cholestatic hepatotoxicity that is unpredictable and may lead to irreversible liver injury, includ- ing vanishing bile duct syndrome (VBDS) [6, 14]. The exact RESULTS mechanism of these liver abnormalities and impact of devel- oping liver injury on clinical outcomes remain unknown. Patient Characteristics The aim was to assess the hepatic safety profile of In all, 140 patients with TGCTs who received pexidartinib pexidartinib in TGCT cases and describe the risk mitigation (starting dose of 600–1,000 mg per day) were included, with procedures designed to identify any instances of serious demographics and baseline disease characteristics summa- liver injury as early as possible, to better inform prescribers rized in Table 2. The median age was 44 years (range, and patients about this drug. 18–80). Median duration of exposure to pexidartinib was 19 months (range, 1–76), with a median follow-up from ini- tial pexidartinib treatment of 39 months (range, 32–82). MATERIALS AND METHODS Treatment was ongoing in 60 patients (43%) as of the May Study Design and Participants 2019 cutoff. This retrospective pooled analysis evaluated hepatic ARs that developed in pexidartinib-treated patients with TGCTs. Key Characterization of Liver Test Abnormalities eligibility criteria and study designs for the PLX108-01 exten- Nearly all patients (n = 133, 95%) experienced liver test abnor- sion (NCT01004861) [6] and ENLIVEN (NCT02371369) [14] malities, of whom 128 experienced aminotransferase eleva- study have been reported and are summarized in Table 1. Fur- tions. Most (66%) experienced an isolated ALT or AST increase thermore, patients with TGCTs from two additional studies of ≥1 to <3× ULN, with 11% experiencing increases ≥3 to <5× (NCT02734433 [22] and NCT03291288 [23]) were included ULN in the absence of TBIL ≥2 ULN (Table 3). Aminotransfer- (Table 1). Briefly, patients were > 18 years, with histologically ase elevations were dose-dependent and responsive to dose confirmed TGCT that was symptomatic, and for which surgery reductions, usually persisted at low-grade levels with contin- was not recommended or potentially associated with worse ued treatment, and resolved upon treatment interruption. function or severe morbidity. Patients enrolled had aspartate Individual laboratory abnormalities were assessed aminotransferase (AST) and alanine aminotransferase (ALT) across the pooled studies. AST increase was the most com- levels ≤1.5× upper limit of normal (ULN) and total bilirubin mon hepatic laboratory abnormality, occurring in 126 patients (TBIL) was ≤1.5× ULN. Select previously reported serious (90%), with mostly grade 1. ALT was increased in 86 patients hepatic AR cases are described in pexidartinib-treated (61%), and ALP was increased in 45 patients (32%). Most ALT patients without TGCTs in supplemental online Table 1 [23]. and ALP elevations were also low grade. Increased direct bili- rubin (DBIL) and TBIL occurred in 19 patients (15%) and Assessments and Statistical Analysis 14 patients (10%), respectively (Table 3). Regarding gender- Hepatic ARs were assessed by type and magnitude of based differences and specifically grade ≥ 3 laboratory liver test abnormalities, classified as (a) aminotransferase abnormalities, women compared with men experienced a © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. Lewis, Gelderblom, van de Sande et al. e865 Table 1. Summary of pooled studies (TGCT population) Dosing regimen for patients with Study ID (NCT no.) Study title Study design TGCTs PLX108-01 A phase 1 study to assess Phase I, first in-human study Part 2: pexidartinib (n = 39), 1,000 (NCT01004861) [6] safety, pharmacokinetics, with a dose escalation (part 1) mg/d (split dose) and pharmacodynamics and extension (part 2); 16 of PLX3397 in patients additional patients were added with advanced, incurable, after the interim cutoff date: solid tumors in which the April 14, 2014 target kinases are linked to disease pathophysiology ENLIVEN Pexidartinib versus Phase III, multicenter study with Part 1 (n = 61):pexidartinib: 1,000 (NCT02371369) placebo for advanced 2 parts: randomized, double- mg/d (split dose) for 2 weeks, then [14] tenosynovial giant cell blind, placebo-controlled part pexidartinib: 800 mg/d (split dose) tumor (ENLIVEN): a and open-label, long-term part or matching placebo for 22 weeks. Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 randomized phase 3 trial Part 2 (n = 30): pexidartinib: 800 mg/d (400 mg BID) PL3397-A-A103 A phase 1 study of single Phase I, nonrandomized, open- n = 1 (part of cohort 1). Cohort 1: (NCT02734433) agent pexidartinib in label, multiple-dose study of 600 mg/d (200 mg in the morning [22] asian subjects with pexidartinib in Asian patients and 400 mg in the evening) advanced solid tumors with advanced solid tumors. Dose-escalation 3 + 3 design. 2 dose levels (cohort 1, 600 mg/d [n = 3] and cohort 2, 1000 mg/d [n = 8]) to assess the safety and tolerability, RP2D, PK and PD, and preliminary antitumor activity of pexidartinib PL3397-A-U126 An open-label, single Single-sequence, crossover study Pexidartinib: 400 mg BID from (NCT03291288) sequence, crossover study will comprise 2 parts: part 1: an day 5; midazolam: 2 mg on days 1, [23] assessing the effect of initial single-sequence crossover 5, and 15; S-warfarin: 10 mg on pexidartinib on the part to evaluate the effect of days 1, 5, and 15 pharmacokinetics of pexidartinib on the PK of midazolam and S-warfarin midazolam and S-warfarin (DDI in patients phase); part 2: an evaluation of efficacy and safety of pexidartinib treatment in various tumors Abbreviations: BID, twice daily; d, day; DDI, drug-drug interaction; ID, identifier; PD, pharmacodynamics; PK, pharmacokinetics; RP2D, rec- ommended phase 2 dose; TGCT, tenosynovial giant cell tumor. higher percentage of ALT elevations (17% vs. 3%), AST eleva- 1 and 2× ULN. Four of these patients started pexidartinib at tions (20% vs. 10%), ALP elevations (6 vs. 0%), TBIL elevations a dose of 1,000 mg per day (all in ENLIVEN), and the other (5% vs. 2%), and DBIL elevations (8% vs. 4%) (Table 3). started pexidartinib at a dose of 800 mg per day (Study Increased partial thromboplastin time and international nor- PL3397-A-U126). Mixed or cholestatic liver injury was diag- malized ratio occurred in 13% and 11% of patients with nosed by determining ratio (R) values, calculated by dividing TGCTs, respectively, with all cases being grade 1 (supplemen- peak ALT/ULN by peak ALP/ULN. R values of 2 to 5 are con- tal online Table 2). The time to first occurrence of any of sidered mixed, R values <2 are considered cholestatic, and these laboratory criteria was predominantly in the first R values >5 are considered hepatocellular [25]. Serum bili- 2 months of treatment (Fig. 1). rubin does not define any of the injury patterns, but accom- panying hyperbilirubinemia is a sign of more serious Mixed or Cholestatic Hepatotoxicity hepatotoxicity and may indicate impaired hepatic function. Of the 140 patients with TCGTs treated with pexidartinib, The first and most prolonged case occurred in a 5 (4%) were adjudicated as experiencing drug-related mixed 75-year-old White woman (case 1). The total duration of or cholestatic hepatotoxicity and are described individually treatment was 31 days, and starting on day 22, the patient below (Table 4). None of these patients met strict Hy’s law experienced fatigue, diarrhea, and nausea. Lab tests rev- criteria (ALT or AST ≥3×, TBIL ≥2×, and ALP ≤2× ULN) [24]. ealed cholestatic jaundice with TBIL 15× ULN (Fig. 2A) and The onset of these serious hepatic ARs occurred only within DBIL 84× ULN. At the time of admission (day 31), laboratory the first 2 months of pexidartinib treatment. Four of the values were AST (281 U/L, 7.5× ULN), ALT (376 U/L, 9.3× five cases were experienced in female patients. ULN), and ALP (231 U/L, 2.3× ULN), R value 4.0: mixed. This Each of these patients eventually discontinued case was initially classified as acute hepatocellular and pexidartinib treatment permanently. Four of these cases evolved into mixed and cholestatic injury. She underwent had ALT or AST ≥3× ULN, TBIL ≥2× ULN, and ALP >2× ULN bilirubin dialysis and a liver biopsy that showed severe cho- (Fig. 2; Table 3), and the remaining case had TBIL between lestasis, mild fatty transformation, and changes suggestive www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. e866 Pexidartinib Hepatic Safety Table 2. Patient demographics and baseline disease characteristics ENLIVEN PLX108-01 randomized ENLIVEN TGCT cohort Other phase 1 (1,000 crossover (800 (1,000 mg/ (600 or 800 Pooled, Characteristic mg/d), n = 61 mg/d),a n = 30 d),a n = 39 mg/d),a n = 10b N = 140c Median age (range), yr 44 (22–75) 47 (20–79) 42 (22–80) 25 (18–57) 44 (18–80) Sex, n (%) Male 26 (43) 14 (47) 17 (44) 3 (30) 60 (43) Female 35 (57) 16 (53) 22 (56) 7 (70) 80 (57) Race, n (%) White 52 (85) 30 (100) 33 (85) 6 (60) 121 (86) Black 3 (5) 0 3 (8) 0 6 (4) Asian 1 (2) 0 3 (8) 4 (40) 8 (6) Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 Native American 2 (3) 0 0 0 2 (1) Hawaiian/Pacific Islander 2 (3) 0 0 0 2 (1) Multiracial 1 (2) 0 0 0 1 (1) Geographic region, n (%) U.S. region 23 (38) 13 (43) 39 (100) 6 (60) 81 (58) Non-U.S. region 38 (62) 17 (57) 0 4 (40) 59 (42) Disease location, n (%)d Knee 34 (56) 19 (63) 21 (54) 0 74 (56) e Ankle 14 (23) 3 (10) 7 (18) 0 24 (18) Hip 6 (10) 3 (10) 7 (18)f 0 16 (12) Otherg 7 (11) 5 (17) 4 (10) 1 (100) 16 (12) Prior surgeries for TGCT, n (%) Yes 32 (52) 14 (47) 31 (79) 7 (70) 84 (60) No 29 (48) 16 (53) 8 (21) 3 (30) 56 (40) Prior systemic therapy, n (%)d Yesh 8 (13) 2 (7) 6 (15) 0 16 (12) No 53 (87) 28 (93) 33 (85) 1 (100) 115 (88) a Starting dose. b For disease location and prior systemic therapy, patient information only available for one patient from A-103 study. Not collected from nine patients with TGCTs in PL3397-A-U126. c For disease location and prior systemic therapy, patient information not collected from nine patients with TGCTs in PL3397-A-U126 study. Total patients for those characteristics = 131. d Not collected in study PL3397-A-U126. e Included foot/ankle. f Included hip/thigh. g Included wrist, shoulder, spine, finger, and elbow. h 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. Abbreviation: d, day; TGCT, tenosynovial giant cell tumor. of significant VBDS, implicating specific damage of gamma-glutamyl transferase (GGT) 17.9× ULN, ALP 2.1× ULN, cholangioepithelium (Fig. 2B, C). After 7 months, the patient ALT 7.9× ULN, and AST 4.7× ULN (R value 3.8: mixed). The recovered, with all liver biochemical tests (ALT, AST, ALP, patient also developed clinical symptoms of acute cholangitis TBIL) returning to within the normal ranges (Fig. 2A). that resulted in hospitalization with peak levels of TBIL 2.5× The second patient (case 2) was a 52-year-old White man ULN and DBIL 7.2× ULN but recovered after 1 month (Fig. 2E). who discontinued pexidartinib on day 36 of treatment The fourth patient (case 4) was a 39-year old White because of elevated liver tests and symptoms of jaundice, woman in whom pexidartinib was interrupted on day pruritus, and nausea. Laboratory values revealed peak eleva- 15 because of elevated liver test values of ALT 8.3× ULN, AST tions of ALT 9.3× ULN, AST 4.8× ULN, ALP 2.2× ULN, TBIL 7.6× ULN, and ALP 1.9× ULN (R value 4.4: mixed). Two weeks 6.5× ULN, and DBIL 18.8× ULN (R value 4.2: mixed) at later, after the liver tests were back within normal range, 7 weeks after the start of pexidartinib treatment. Following pexidartinib was restarted at a lower dose of 800 mg per day the discontinuation of pexidartinib, he recovered fully within (day 29), with subsequent liver tests rebounding to AST 3.3× 2 months (Fig. 2D). ULN, ALT 8.6× ULN, and ALP 6.2× ULN on day 50 (R value The third patient (case 3) was a 67-year-old White woman 1.4: cholestatic), and treatment was interrupted for a second who discontinued treatment 8 weeks after the start of time. Pexidartinib was restarted again on day 68 at 400 mg pexidartinib because of laboratory results that showed per day but was permanently discontinued 1 day later © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. Table 3. Frequency of liver test abnormalities ENLIVEN randomized ENLIVEN crossover PLX108-01 TGCT cohort Other phase I Clinical parametera (1,000 mg/d),b n = 61 (800 mg/d),b n = 30 (1,000 mg/d),b n = 39 (600 or 800 mg/d),b n = 10 Total,c N = 140d Aminotransferase evaluations, n (%)a ALT or AST ≥ 1 to <3× ULN 39 (64) 21 (70) 26 (67) 7 (70) 93 (66) ≥ 3 to <5× ULN 7 (12) 4 (13) 4 (10) 1 (10) 16 (11) ≥ 5 to <10× ULN 6 (10) 2 (7) 2 (5) 1 (10) 11 (8) www.TheOncologist.com ≥ 10 to <20× ULN 3 (5) 1 (3) 2 (5) 0 6 (4)e ≥ 20× ULN 2 (3) 0 0 0 2 (1)f Mixed or cholestatic hepatotoxicity, n (%) Lewis, Gelderblom, van de Sande et al. ALT or AST ≥3×, TBIL 0 0 0 0 0 ≥2×, and ALP ≤2× ULN (true Hy’s law) ALT or AST ≥3×, TBIL 3 (5) 0 1 (3) 1 (10) 5 (4)g ≥2×, and ALP >2× ULN TBIL ≥2× ULN (in 0 0 1 (3) 0 1 (1) absence of ALT ≥3× or ALP >2× ULN) Hepatic Grade 1 or 2 Grade ≥ 3 Grade 1 or 2 Grade ≥ 3 Grade 1 or 2 Grade ≥ 3 Grade 1 or 2 Grade ≥ 3 Grade 1 or 2 Grade ≥ 3 abnormalities, n (%)h AST 48 (79) 8 (13) 25 (83) 2 (7) 30 (77) 4 (10) 8 (80) 1 (10) 111 (79) 15 (11)i ALT 28 (46) 14 (23) 18 (60) 3 (10) 16 (41) 3 (8) 2 (20) 2 (20) 64 (46) 22 (16)j ALP 21 (34) 3 (5) 9 (30) 0 9 (23) 1 (3) 1 (10) 1 (10) 40 (29) 5 (4)k TBIL 5 (8) 2 (3) 1 (3) 0 3 (8) 2 (5) 0 1 (10) 9 (6) 5 (4)l DBILm 6 (10) 4 (7) 2 (7) 0 3 (8) 4 (10) 0 0 11 (8) 8(6)n a Patients who had isolated aminotransferase elevations were separate from those who had mixed or cholestatic hepatotoxicity. b Pexidartinib starting dose. c Includes one patient with a single time point elevation of TBIL considered unrelated to treatment. d Women (n = 80); men (n = 60). e 5 women (6%) and 1 man (2%) experienced ALT or AST elevations of ≥10 to <20× ULN. f Both patients were female. g 4 women (5%) and 1 man (2%) experienced mixed or cholestatic hepatotoxicity h Graded per NCI CTCAE v. 4.03. i 13 women (17%) and 2 men (3%) experienced grade ≥ 3 AST elevations. j 16 women (20%) and 6 men (10%) experienced grade ≥ 3 ALT elevations. k 5 women (6%) and no men experienced grade ≥ 3 ALP elevations. l 4 women (5%) and 1 man (2%) experienced grade ≥ 3 TBIL elevations. m Direct bilirubin is not collected in study PL3397-A-U126. The number of patients who have at least one baseline and postbaseline value = 130. n 6 women (8%) and 2 men (4%) experienced grade ≥ 3 DBIL elevations. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; d, day; DBIL, direct bilirubin; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; TBIL, total bilirubin; TGCT, tenosynovial giant cell tumor; ULN, upper limit of normal. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. © 2020 The Authors. e867 Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 e868 Pexidartinib Hepatic Safety 1.0 + Censored All Pexidartinib Treated TGCT Subjects (n = 140) Probability of Subjects Meeting 0.8 Hepatic Lab Criteria 0.6 0.4 0.2 0.0 Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 0 2 6 12 18 24 30 36 42 48 54 60 Time since start of pexidartinib treatment, months # at Risk 140 103 90 67 51 47 44 21 8 7 3 1 # of Events 0 35 41 45 47 49 49 49 49 49 49 49 Figure 1. Kaplan-Meier curve of time to first occurrence of hepatic adverse reactions. Hepatic Laboratory Criteria: alanine amino- transferase >3× upper limit of normal (ULN), or aspartate aminotransferase >3× ULN, or alkaline phosphatase (ALP) >2× ULN, or total bilirubin > ULN, or direct bilirubin > ULN. If ALP >2× ULN and gamma-glutamyl transferase (GGT) is measured on the same date, GGT must also be >2× ULN. Abbreviation: TGCT, tenosynovial giant cell tumor. Table 4. Patients with TGCTs with serious hepatic adverse reactions Pexidartinib Starting TGCT Cases Dose (Onset) Type of Hepatic Injury, R valuea Outcome ENLIVEN No. 1. 75-yr-old woman 1,000 mg/d (d 22) Cholestatic hepatotoxicity (biopsy: Recovered 7 mo ductopenia, severe cholestasis), Hyperbilirubinemia, R value 5.9 = hepatocellular No. 2. 52-yr-old man 1,000 mg/d (d 36) Mixed hepatotoxicity, Hyperbilirubinemia, Recovered 2 mo R value 4.2 = mixed No. 3. 67-yr-old woman 1,000 mg/d (d 43) Mixed hepatotoxicity, Hyperbilirubinemia, Recovered 1 mo R value 3.8 = mixed No. 4. 39-yr-old woman 1,000 mg/d (d 28) Cholestatic hepatotoxicity, Intermittent Recovered 2 mo ALP increases due to 2 rechallenges, R value 4.4 = mixed PL3397-A-U126 (NCT03291288) No. 5. 43-year-old woman 800 mg/d (d 21) Mixed hepatotoxicity, Hyperbilirubinemia, Recovered 2 mo R value <2 = cholestatic a R value is at the time of initial event. Abbreviations: ALP, alkaline phosphatase; d, day; mo, month(s); R, ratio; TGCT, tenosynovial giant cell tumor. because of further liver test elevations (ALP 2.9× ULN, ALT investigator-initiated studies for the treatment of various 7.9× ULN, AST 6.7× ULN, TBIL 1.4× ULN, and GGT 6.4× ULN; malignancies (supplemental online Table 1). Among these R value 2.7: mixed). She recovered 1 month later (Fig. 2F). patients, there were five instances (0.76%) of serious mixed The fifth patient (case 5) was a 43-year-old Asian woman or cholestatic hepatotoxicity that were judged as probably who was treated with pexidartinib 800 mg per day in the related to pexidartinib treatment by the HEAC. All five serious PL3397-A-U126 study. By day 21, hepatic evaluation showed hepatic AR cases occurred in female patients (supplemental ALT 8.7× ULN, AST 8.8× ULN, ALP 5.3× ULN, and GGT 3.9× online Table 3). ULN (R value <2: cholestatic), resulting in pexidartinib discon- Two of these cases were not reversible. The first irre- tinuation. Four days later (25 days after starting versible case was a 66-year-old woman with melanoma pexidartinib), TBIL peaked at 3× ULN and DBIL at 2.3× ULN, (PLX108-13 study; supplemental online Table 3) who started but the patient recovered after 2 months (Fig. 2G). on pexidartinib 1,000 mg per day, and liver tests were mon- itored weekly from the start of treatment. By day 21, grade Serious Hepatic Adverse Reactions in Patients 3 elevations in aminotransferases were observed with dou- Without TGCTs bling of TBIL from baseline, which was considered a dose- The pexidartinib clinical program also included a non-TGCT limiting toxicity (R value >5: hepatocellular). Four days later, population (N = 658) in which patients were enrolled in mon- TBIL increased to 3× ULN with decreasing aminotransferase otherapy or combination therapy studies as well as eight values (supplemental online Fig. 1A). She was diagnosed © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. Lewis, Gelderblom, van de Sande et al. e869 A 18 Hospitalized/ Liver biopsy/ ALT Bilirubin dialysis AST 16 Pexidartinib Hospitalized/ permanently ALP 14 Bilirubin dialysis discontinued Total bilirubin LFT values in ULN 12 10 Pexidartinib started at 8 1000 mg/d Pexidartinib 6 800 mg/d per protocol 4 2 0 BL 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 Time, weeks B C D 20 ALT Abdominal AST Ultrasound 18 ALP 16 Direct bilirubin Total bilirubin 14 LFT values in ULN 12 10 Pexidartinib 8 discontinued 6 Pexidartinib Pexidartinib 800 mg/d started at 4 per protocol 1000 mg/d 2 0 BL 2 3 4 5 7 9 Week Figure 2 (Continued on next page). with drug-induced hepatitis and remained jaundiced until (ALT/AST 150 to 200 U/L; ALP 350 to 400 U/L; TBIL 20 to her death on day 124 (R value <2: cholestatic); cause of 25 mg/dL; R value <2: cholestatic), and she eventually death was listed as melanoma and cachexia. required liver transplantation. Following successful trans- The second irreversible case was a 60-year-old woman plant, her liver tests normalized and her performance status with metastatic breast cancer (I-SPY2 study; supplemental vastly improved [26]. online Table 3) who received pexidartinib 1,200 mg per day in combination with weekly paclitaxel. On day 18, amino- transferases were noted to be increasing accompanied by a DISCUSSION fever. Although the study treatment was withheld, liver tests TKIs are well-recognized to cause abnormal liver tests continued to rise (supplemental online Fig. 1B). Over the [6, 9, 14, 16, 19–21]. Understanding, monitoring, and man- ensuing 13 months, her liver enzymes remained abnormal aging possible hepatotoxicity is important to optimize www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. e870 Pexidartinib Hepatic Safety E 9 Pexidartinib permanently discontinued 8 ALT 7 AST LFT values in ULN 6 ALP Pexidartinib Direct bilirubin 5 started at Total bilirubin 1000 mg/d 4 Pexidartinib 3 reduced to 800 mg/d 2 1 0 Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time, weeks F 10 Pexidartinib ALT Pexidartinib Pexidartinib interrupted interrupted 9 permanently AST discontinued ALP 8 Direct bilirubin LFT values in ULN 7 Pexidartinib Total bilirubin restarted 6 400 mg/d Pexidartinib 5 restarted Pexidartinib Pexidartinib 600 mg/d started at restarted Pexidartinib 4 interrupted 1000 mg/d 800 mg/d 3 2 1 0 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time, weeks G 12 Pexidartinib discontinued ALT AST 10 ALP LFT values in ULN Total bilirubin 8 6 4 Pexidartinib started at 800 mg/d 2 0 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 Time, weeks Figure 2. Clinical laboratory results of patients with tenosynovial giant cell tumors (TGCTs) experiencing serious hepatic adverse reactions. (A): Case no. 1. (B): Case no. 1: H&E: portal tract (black circle) without a bile duct or ductular proliferation but with few inflammatory cells. 400× magnification. (C): Case no. 1: immunohistochemical staining against CK7. Portal tract shows loss of bile duct but CK7-positive adjacent hepatocytes indicating chronic cholestasis (arrows). 400× magnification. (D): Case no. 2. (E): Case no. 3. (F): Case no. 4. (G): Case no. 5. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; CK7, cytokeratin 7; d, day; H&E, hematoxylin and eosin; LFT, liver function test; ULN, upper limit of normal. systemic therapy for patients with TGCTs, particularly 133 patients (95%) experienced a hepatic AR. However, in because, although this condition can cause significant mor- most cases hepatic toxicity was mild and manageable, and bidity, it is not life-threatening, unlike malignancies. Of the only five patients (4%) experienced serious mixed or chole- 140 patients with TGCTs exposed to pexidartinib for a static injury. All cases of serious liver toxicity observed pres- median treatment duration of 19 months (range, 1–76), ented in the first 8 weeks of treatment and all resolved. © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. Lewis, Gelderblom, van de Sande et al. e871 However, there is still an unpredictable risk of serious chole- Although it is generally known that women appear to be static or mixed liver injury, as shown by two irreversible at higher risk based on the demographics of various DILI reg- cases in the non-TGCT population. istries, possibly due to being prescribed a greater number of Based on the clinical laboratory findings, pexidartinib potentially hepatotoxic medications (e.g., minocycline, meth- appears to be associated with two types of hepatotoxicity. yldopa, diclofenac, and nitrofurantoin drug classes) [32, 33], The most common form was aminotransferase elevations other factors may be at play. An analysis of the FDA Adverse that were frequent, dose-dependent, and generally low- Event Reporting System database found that women were at grade and occurred in the absence of significant TBIL and higher risk of developing adverse events from TKIs [34] and ALP elevations. We postulate that these ALT/AST elevations women composed 69% of the DILI cases due to antineoplas- are a pharmacologic effect of CSF1R inhibition, possibly tic drugs in the U.S. DILI Network registry [35], and several related to reduced clearance from the circulation and asso- case series of DILI related to other TKIs appear to confirm an ciated with a reduced number of Kupffer cells in the liver [6, increased female risk as illustrated in the LiverTox Web site 27, 28]. In support of this theory, similar aminotransferase [36]. However, men outnumbered women in DILI cases asso- increases have also been observed with other CSF1R inhibi- ciated with erlotinib [37], suggesting that gender differences Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 tors, including monoclonal antibodies [27, 28]. regarding DILI risk may be drug-specific. The risk to women In contrast, mixed or cholestatic hepatotoxicity associ- receiving pexidartinib deserves further study. ated with pexidartinib, which can be nonreversible, is con- All patients with TGCTs had reversible injury following sidered idiosyncratic and relatively infrequent. In some discontinuation of therapy, with four of five recovering cases, as indicated by the R values, the initial injury pattern within 2 months of injury, and one patient recovering after suggested hepatocellular injury but evolved into mixed and 7 months, due to VBDS (Fig. 2A–C). It is well known that cholestatic injury, including VBDS. In the current analysis, the resolution of cholestatic and mixed injury (as was seen both forms of hepatotoxicity occurred only within the first with this case) is often prolonged over weeks to months. In 2 months of treatment. patients who do not appear to recover within that time The approved dose regimen for pexidartinib of 800 mg frame, chronic cholestatic injury is a possible consequence. per day (as 400 mg twice daily) was revised downward from VBDS is a rare form of chronic cholestasis with no specific the original dose regimen of 1,000 mg per day for 2 weeks or proven treatment, and it has eventually resulted in the followed by 800 mg per day (400 mg twice daily) used in need for liver transplant, as was the case with the one the open-label phase I study and the randomized phase of patient without TGCTs [26]. However, VBDS is not specific the ENLIVEN study. Four of the five patients with TGCTs to pexidartinib, having been associated with a long list of who experienced mixed or cholestatic hepatotoxicity had a agents from numerous drug classes [38–40]. starting dose of 1,000 mg per day, although it is not known with any certainty if this was a significant factor in the development of their idiosyncratic drug-induced liver injury Recommended Dose Modifications and the (DILI), given that a 50- to 100-mg dose threshold for trigger- Pexidartinib Risk Evaluation and Mitigation Strategy ing DILI has been widely accepted [29–31]. Program Nevertheless, the risk-benefit consideration of starting Careful monitoring of liver enzymes following the start of with 800 mg per day relates to the significant reduction in pexidartinib treatment is critical, and the intensity of monitor- the frequency of reversible, dose-dependent aminotransfer- ing depends upon the occurrence of hepatic ARs. Across the ase elevations observed at this dose level. In most patients pooled studies, the most frequent elevations in hepatic labora- receiving pexidartinib, serum aminotransferases normalized tory values requiring dose modifications were ALT or AST rapidly when the drug was withheld. In patients with serum increases to >3 to 5× ULN and TBIL ≥2× ULN, or DBIL >1.5× aminotransaminase elevations, in whom pexidartinib was ULN, followed by ALT or AST increases to >5 to 10× ULN and resumed at a lower dose, no additional or only mild, clini- ALP >2× ULN (supplemental online Table 4). With the approval cally insignificant aminotransferase elevations were seen. of pexidartinib as the first systemic therapy for the treatment A gender imbalance was noted with respect to DILI risk of adult patients with symptomatic TGCT/PVNS associated in the TGCT program; four of the five patients with TGCTs with severe morbidity or functional limitations and not amena- and all five of the patients without TCGTs (9 of 10 total) ble to improvement with surgery [17, 18] came the need for who developed the mixed/cholestatic form of liver injury liver test monitoring and other measures stipulated in the were female (Tables 3, 4; supplemental online Table 3), Pexidartinib Risk Evaluation and Mitigation Strategy (REMS) although the reason is not clear. Although women out- for the drug in the U.S. (supplemental online Table 5) [17]. numbered men in the ENLIVEN and crossover studies as Because of the unpredictable risk of the more serious mixed well as in the pooled TGCT data set (n = 80, 57% vs. n = 60, or cholestatic hepatic injury (including the VBDS) seen in the 43%; Table 2), this modest difference is unlikely to explain clinical trials [6, 14], monitoring of liver tests is recommended why women developed more severe DILI associated with every week for the first 2 months and then biweekly for the pexidartinib compared with men. When we analyzed the third month, which is believed to cover the period of maximal isolated laboratory abnormalities/elevations (ALT, AST, ALP, risk (i.e., the first 8 weeks). Based on the label, dose modifica- TBIL, DBIL) by grade and gender across the TGCT program, tions for pexidartinib (including early withholding treatment women also appeared to have a higher incidence of for liver test monitoring, dose reduction in 200-mg increments, reaching grade 3 elevations compared with men in those and/or permanent discontinuation) have been established randomized to receive pexidartinib (Table 3). (supplemental online Table 5) [17]. www.TheOncologist.com © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. e872 Pexidartinib Hepatic Safety It was observed that reducing the pexidartinib dose Presented previously in part at American Society of Clini- allowed some patients who developed transiently elevated cal Oncology Annual Meeting, May 31–June 4, 2019, Chicago, ALT to resume therapy without developing a second rise in IL; and European Society for Medical Oncology Congress, ALT values. The approved pexidartinib starting dose is September 27–October 1, 2019, Barcelona, Spain. 800 mg per day for men and women (which is lower than the 1,000-mg starting dose given in part 1 of the ENLIVEN study). In conjunction with the frequent liver test monitor- AUTHOR CONTRIBUTIONS ing that is required and adhering to the conservative stop- Conception/design: Silvia Stacchiotti, William D. Tap, Dale E. Shuster. Collection/assembly of data: Hans Gelderblom, William D. Tap, Andrew ping rules (supplemental online Table 5) [17], it is J. Wagner, Antonio Lopez Pousa, Chia-Chi Lin, Hideo A. Baba, Youngsook anticipated that any potential hepatotoxicity will be identi- Choi, Dale E. Shuster. fied early and immediate treatment interruption will reduce Data analysis/interpretation: James H. Lewis, Hans Gelderblom, Michiel van de Sande, Silvia Stacchiotti, John H. Healey, William D. Tap, Andrew the risk of progressing further for both men and women. J. Wagner, Antonio Lopez Pousa, Mihaela Druta, Youngsook Choi, Qiang We recognize the limitations of this pooled analysis, Wang, Dale E. Shuster, Sebastian Bauer. Manuscript writing: James H. Lewis, Hans Gelderblom, Michiel van de including the lack of a control group for comparison of the Downloaded from https://academic.oup.com/oncolo/article/26/5/e863/6445662 by guest on 08 March 2023 Sande, Silvia Stacchiotti, John H. Healey, William D. Tap, Andrew hepatic safety profile following long-term pexidartinib treat- J. Wagner, Antonio Lopez Pousa, Mihaela Druta, Chia-Chi Lin, Hideo ment. In addition, the different study designs among the four A. Baba, Youngsook Choi, Qiang Wang, Dale E. Shuster, Sebastian Bauer. Final approval of manuscript: James H. Lewis, Hans Gelderblom, Michiel patient cohorts included varying administered daily doses of van de Sande, Silvia Stacchiotti, John H. Healey, William D. Tap, Andrew pexidartinib ranging from 600 to 1,000 mg per day. Nonethe- J. Wagner, Antonio Lopez Pousa, Mihaela Druta, Chia-Chi Lin, Hideo less, the long-term hepatic safety profile of pexidartinib as A. Baba, Youngsook Choi, Qiang Wang, Dale E. Shuster, Sebastian Bauer. demonstrated in this pooled analysis provides guidance for its proper use for appropriate patients within risk mitigation programs such as the Pexidartinib REMS program. DISCLOSURES James H. Lewis: Daiichi Sankyo, Otsuka, Reata, Allergan, B-I, Pfizer, Zydus, Chimerix, Akebia, CiVi, Sanofi, Intercept, Madrigal, Palladio, Biohaven, Orphazyme (C/A), AbbVie, GlaxoSmithKline, Gilead, CONCLUSION Pfizer (OI), Gilead (Other-speaker’s bureau); Hans Gelderblom: Long-term treatment with pexidartinib has demonstrated Amgen, Boehringer Ingelheim, Daiichi Sankyo, Five Prime Therapeutics, Novartis, Pfizer, PharmaMar (RF-institutional); both a predictable and an unpredictable effect on hepatic Michiel van de Sande: Daiichi Sankyo (C/A), CarboFix, Daiichi enzymes. This knowledge can help form the basis for the Sankyo, and Implantcast (RF-institutional); Silvia Stacchiotti: prescribing physician’s risk/benefit assessment for their Bavarian Nordic, Bayer, Deciphera, Daiichi Sankyo, Eli Lilly & Co, Epizyme, Glaxo, Karyopharm Therapeutics, Maxivax, Novartis, and patients with TGCTs. Results from our analysis support the PharmaMar (C/A), Advenchen, Bayer, Blueprint Medicines, current risk mitigation strategies, adherence to which can Deciphera, Eli Lilly & Co, Epizyme, Daiichi Sankyo, Glaxo, lead to optimized patient outcomes, foremost of which is Karyopharm Therapeutics, Novartis, PharmaMar, and Springworks (RF-institutional), Eli Lilly & Co, PharmaMar, and Takeda (H), safety. PharmaMar (Other travel support); John H. Healey: Daiichi Sankyo (C/A); William D. Tap: Agios Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, Eisai, Eli Lilly & Co, EMD Serono, GlaxoSmithKline, Immune Design, Janssen, Loxo Oncology (C/A), Atropos ACKNOWLEDGMENTS Therapeutics, Certis Oncology Solutions (OI), Companion We thank the patients who participated in this analysis, Diagnostic for CDK4 inhibitors - 14/854,329 pending to Memorial their family members and caregivers, the study staff mem- Sloan Kettering Cancer Center/Sloan Kettering Institute (IP), Agios Pharmaceuticals, Atropos Therapeutics, Blueprint Medicines, Certis bers at each site who cared for the patients, the sponsor Oncology Solutions, Daiichi Sankyo, Eisai, Eli Lilly & Co, EMD staff involved in data collection and analyses, and Phillip Serono, GlaxoSmithKline, Immune Design, Janssen, Loxo Oncology, Giannopoulos, Ph.D. (SciStrategy Communications) for med- NanoCarrier, and Deciphera (SAB), Eisai, Eli Lilly & Co, EMD Serono, Immune Design, Janssen (Other-travel support); Andrew ical writing assistance in the development of the manu- J. Wagner: Daiichi-Sankyo, Deciphera, Eli Lilly & Co, Five Prime script. Research and manuscript support were provided by Therapeutics, NanoCarrier, Novartis (C/A), Aadi Bioscience, Daiichi Daiichi Sankyo, Co., Ltd., Tokyo, Japan. All research funding Sankyo, Eli Lilly & Co, Five Prime Therapeutics, Karyopharm Therapeutics, Plexxikon (RF-institutional), Novartis (H); Mihaela for Memorial Sloan Kettering is supported in part by a grant Druta: Adaptimmune, Blueprint, Daiichi Sankyo, Deciphera, from the National Institutes of Health/National Cancer Insti- Epizyme (C/A), Adaptimmune, Blueprint, Daiichi Sankyo, Deciphera, Epizyme (H), Blueprint, Deciphera (Other-speaker’s tute (no. P30 CA008748). bureau), Adaptimmune, Daiichi Sankyo, and Epizyme (Other-travel Sponsored by Daiichi Sankyo, Co., Ltd; ClinicalTrials.gov support); Chia-Chi Lin: Blueprint Medicines, Boehringer-Ingelheim, numbers: NCT01004861, NCT02371369, NCT02734433, and Bristol-Myers Squibb, Daiichi Sankyo, and Novartis (C/A), Eli Lilly & Co, Novartis, Roche (H), BeiGene, Eli Lilly & Co(Other-travel NCT03291288. support); Hideo A. Baba: Alexion and Intercept (H), Intercept (OI), Deidentified individual participant data and applicable Alexion (Other-travel support); Youngsook Choi: Daiichi Sankyo (E), supporting clinical study documents may be available upon Daiichi Sankyo (OI); Qiang Wang: Daiichi Sankyo (E), Daiichi Sankyo (OI); Dale E. Shuster: Daiichi Sankyo (E); Amgen, Bristol-Myers request at https://www.clinicalstudydatarequest.com//. In Squibb, Daiichi Sankyo, Exelixis, Merck, Regeneron (OI); Sebastian cases where clinical study data and supporting documents Bauer: Blueprint Medicines, Incyte, and Novartis (RF-institutional), are provided pursuant to the sponsor’s policies and proce- PharmaMar, Eli Lilly & Co, Novartis (H), ADC Therapeutics, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eli Lilly & Co, dures, the sponsor will continue to protect the privacy of the Exelixis, Nanobiotix, Novartis, Roche (SAB), PharmaMar (Other- clinical study participants. Details on data sharing criteria and travel support). The other author indicated no financial the procedure for requesting access can be found at this relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert web address: https://www.clinicalstudydatarequest.com/ testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ Study-Sponsors/Study-Sponsors-DS.aspx. inventor/patent holder; (SAB) Scientific advisory board © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. Lewis, Gelderblom, van de Sande et al. e873 REFERENCES 1. Mastboom MJL, Palmerini E, Verspoor FGM 13. Rebuzzi SE, Grassi M, Catalano F et al. Mul- 27. Genovese MC, Hsia E, Belkowski SM et al. et al. Surgical outcomes of patients with diffuse- tiple systemic treatment options in a patient Results from a phase IIA parallel group study of type tenosynovial giant-cell tumours: An interna- with malignant tenosynovial giant cell tumour. JNJ-40346527, an oral CSF-1R inhibitor, in tional, retrospective, cohort study. 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