Pexidartinib for advanced tenosynovial giant cell tumor (TGCT): Long-term efficacy and safety from the phase 3 ENLIVEN and phase 1 PLX108-01 (TGCT cohort) studies.

person Hans Gelderblom Leiden University Medical Center, Leiden, Netherlands info_outline Hans Gelderblom, William D. Tap, Emanuela Palmerini, Silvia Stacchiotti, Zev A. Wainberg, Jayesh Desai, John H. Healey, Michiel van de Sande, Nicholas M. Bernthal, Charles Peterfy, Dale Edward Shuster, Qiang Wang, Henry Hsu, Andrew J. Wagner

Authors person Hans Gelderblom Leiden University Medical Center, Leiden, Netherlands info_outline Hans Gelderblom, William D. Tap, Emanuela Palmerini, Silvia Stacchiotti, Zev A. Wainberg, Jayesh Desai, John H. Healey, Michiel van de Sande, Nicholas M. Bernthal, Charles Peterfy, Dale Edward Shuster, Qiang Wang, Henry Hsu, Andrew J. Wagner Organizations Leiden University Medical Center, Leiden, Netherlands, Memorial Sloan Kettering Cancer Center, New York, NY, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, David Geffen School of Medicine at UCLA, Santa Monica, CA, Peter MacCallum Cancer Centre, Melbourne, Australia, Spire Sciences, Inc., Boca Raton, FL, Daiichi Sankyo, Inc., Basking Ridge, NJ, Plexxikon, Berkeley, CA, Dana-Farber Cancer Institute, Boston, MA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: TGCT is a rare, locally aggressive neoplasm of the joint/tendon sheath linked to colony-stimulating factor 1 (CSF1) overexpression. Pexidartinib (pex), a selective inhibitor of CSF1 receptor, KIT, and FLT3-ITD, had a compelling tumor response rate in the TGCT cohort of a phase 1 study (NCT01004861) and significant tumor response vs placebo by RECIST v1.1 (39% vs 0%, P < 0.0001) and tumor volume score (TVS) (56% vs 0%, P < 0.0001) in the randomized, 2-part, crossover phase 3 ENLIVEN study (NCT02371369). Updated efficacy and safety with longer treatment are reported. Methods: Patients (pts) were ≥18 y with TGCT that was inoperable or for which surgery would likely be associated with worsening functional limitation or severe morbidity. Best overall response (complete or partial [CR/PR]) and duration of response (DOR) by RECIST and TVS were assessed by independent central review. Data cutoff was Jan 31, 2018, 16-67 mo after pts’ first dose. Results: In both studies 130 pts received pex, 61 ongoing at data cutoff. Median treatment duration was 17 mo (1, 60+). CR/PR rates were high and consistent and, together with DOR, improved with prolongation of treatment (Table). Most frequent adverse events were hair color change (75%), fatigue (60%), nausea (45%), arthralgia (38%), AST increase (30%), and diarrhea (30%). In ENLIVEN part 1, 3 of 61 (5%) pts had reversible ALT and AST ≥3 × ULN with TBil and ALP ≥2 × ULN; all started in the first 8 weeks of treatment, and no new cases emerged with continuation of treatment. Conclusions: Tumor response rate increased with continuation of pex treatment. The safety profile remained similar, with no new mixed or cholestatic hepatotoxicity. Clinical trial information: NCT01004861 and NCT02371369 Endpoint ENLIVEN Randomized (1000 mg/d)* n = 61 ENLIVEN Crossover (800 mg/d)* n = 30 PLX108-01 TGCT Cohort (1000 mg/d)* n = 39 Pooled TGCT Pts N = 130 RECIST CR/PR, n (%) 32 (53) 16 (53) 22 (56) 70 (54) Median (range) DOR, mo NR NR 33.6 NR (2.8+, 24.9+) (3.1+, 23.1+) (1.7, 53.2+) (1.7, 53.2+) TVS CR/PR, n (%) 39 (64) 20 (67) 24 (62) 83 (64) Median (range) DOR, mo NR NR 37.1 NR (0.0+, 27.6+) (6.0+, 23.1+) (1.7, 53.2+) (0.0+, 53.2+) *Starting dose of pex. NR = not reached.