798 - Pexidartinib (Pex) for locally advanced tenosynovial giant cell tumor (TGCT): characterization of hepatic adverse reactions (ARs)

Background

TGCT is a rare, locally aggressive neoplasm of the joint/tendon sheath associated with colony-stimulating factor 1 (CSF1) overexpression. No systemic therapy is approved. Pex, a selective inhibitor of CSF1 receptor, KIT, and FLT3-ITD, showed tumor responses in TGCT in 3 phase I studies, and significant response by Response Evaluation Criteria in Solid Tumors v1.1 (39% vs 0%; P < 0.0001) and improved functional outcomes vs placebo in a phase III study (ENLIVEN, NCT02371369). Here we report treatment-emergent hepatic ARs across TGCT studies.

Methods

Patients (pts) ≥18 y had symptomatic, unresectable TGCT; surgery was not recommended and/or was associated with potentially worse function or severe morbidity. Hepatic ARs were assessed by type and magnitude of liver test abnormalities.

Results

In 130 pts assessed for hepatic ARs from the ENLIVEN and phase I extension (PLX108-01, NCT01004861) studies, mean Pex duration was 75 wk (range, 2.14-259.14); 10 additional Pex-treated pts from 2 other phase I studies are included in the table (N = 140). Hepatic ARs were of 2 types: (1) aminotransferase elevations, which were frequent, dose-dependent, and related to CSF1 receptor inhibition, and (2) mixed or cholestatic hepatotoxicity, which was uncommon, idiosyncratic, and rarely serious (Table). All serious hepatic ARs developed in the first 8 wk of treatment. Four serious but nonfatal mixed and cholestatic cases with increased bilirubin (1 ductopenia) resolved after 1-7 mo. In non-TGCT pts (N = 658), 2 severe cases of liver toxicity (1 leading to liver transplant, 1 death with ongoing cholestasis and tumor progression) were observed with Pex.Table:

1696P

Pex starting dose.

Includes 1 TGCT pt receiving 600 mg/d in NCT02734433 and 9 TGCT pts receiving 800 mg/d in NCT03291288. ^‡Mean Pex duration of all studies was 71 wk (range, 2.14-259.14).

Includes 1 TGCT pt with a single time-point elevation of TBIL considered unrelated to treatment. ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBIL = total bilirubin; ULN = upper limit of normal.

Conclusions

Pex is the first systemic therapy assessed in a randomized placebo-controlled study showing significantly improved tumor response and clinical benefit in locally advanced TGCT. With liver test monitoring, Pex may offer a relevant treatment option for select pts with symptomatic TGCT.

Clinical trial identification

NCT02371369, NCT02734433, NCT03291288, NCT01004861.

Editorial acknowledgement

Phillip Giannopoulos, PhD, SciStrategy Communications.

Legal entity responsible for the study

Overall abstract: Daiichi Sankyo, Inc. Individual studies: NCT02371369 – Daiichi Sankyo, Inc., NCT01004861 – Plexxikon Inc., NCT02734433 – Daiichi Sankyo Co., Ltd., NCT03291288 – Daiichi Sankyo, Inc.

Funding

Overall abstract funded by Daiichi Sankyo, Inc. Individual studies: NCT02371369 – Daiichi Sankyo, Inc., NCT01004861 – Plexxikon Inc., NCT02734433 – Daiichi Sankyo Co., Ltd., NCT03291288 – Daiichi Sankyo, Inc.

Disclosure

S. Bauer: Advisory / Consultancy, Research grant / Funding (self): Blueprint Medicines; Advisory / Consultancy: Deciphera; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self): PharmaMar; Advisory / Consultancy: ADC Therapeutics; Advisory / Consultancy, CME-educational presentations: Lilly; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: Bayer; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Nanobiotix; Research grant / Funding (self), Investigator-initiated trial: Incyte; Officer / Board of Directors, Member of External Advisory Board for "Off-label use in oncology": Federal Ministry of Health. J.H. Lewis: Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Gilead. H. Gelderblom: Research grant / Funding (institution), Licensing / Royalties: Daiichi Sankyo; Licensing / Royalties: Boehringer Ingelheim; Licensing / Royalties: Pfizer; Licensing / Royalties: Novartis; Licensing / Royalties: PharmaMar; Licensing / Royalties: Five Prime; Licensing / Royalties: Amgen. M. van de Sande: Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo. S. Stacchiotti: Honoraria (self): Takeda; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): PharmaMar; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Epizyme; Advisory / Consultancy: Immunedesign; Advisory / Consultancy: Maxivax; Advisory / Consultancy, Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Advenchen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer. J.H. Healey: Advisory / Consultancy: Stryker; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Agios; Research grant / Funding (self): Illuminoss. W.D. Tap: Shareholder / Stockholder / Stock options: Certis Oncology Solutions; Shareholder / Stockholder / Stock options: Atropos Therapeutics; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Immune Design; Honoraria (self), Advisory / Consultancy: Adaptimmune; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Blueprint; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Agios Pharmaceuticals; Honoraria (self), Advisory / Consultancy: NannoCarrier; Advisory / Consultancy: Plexxikon Pharmaceuticals; Licensing / Royalties, Companion Diagnostic for CDK4 inhibitors: Companion Diagnostic for CDK4 inhibitors. A.J. Wagner: Honoraria (self): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy: Nanosphere; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Aadi Bioscience. A. Lopez Pousa: Research grant / Funding (self): CEBIOTEX. M. Druta: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai. C. Lin: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Travel / Accommodation / Expenses: BeiGene; Research grant / Funding (institution): Daiichi Sankyo. A. Yver: Shareholder / Stockholder / Stock options, Full / Part-time employment: Daiichi Sankyo. D.E. Shuster: Shareholder / Stockholder / Stock options, Full / Part-time employment: Daiichi Sankyo; Shareholder / Stockholder / Stock options: Pfizer; Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Shareholder / Stockholder / Stock options: Merck; Shareholder / Stockholder / Stock options: Regeneron; Shareholder / Stockholder / Stock options: Exelixis. J. McGill: Advisory / Consultancy, Full / Part-time employment: Daiichi Sankyo. X. Gu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Daiichi Sankyo; Shareholder / Stockholder / Stock options, Full / Part-time employment, Immediate family member: PTC Therapeutics. L.D. DeLeve: Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: AbbVie; Advisory / Consultancy: SeaGen; Licensing / Royalties, Univ and I have filed provisional patent: University of Southern California. All other authors have declared no conflicts of interest.