Long‐term outcomes of pexidartinib in tenosynovial giant cell tumors

Abstract

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. Results: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). Conclusions: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT. Cancer 2020;0:1-10.

The challenge of drug approval in rare cancers

“…Interestingly, even more patients could achieve a response with long‐term pexidartinib treatment, and this supports the finding that targeting the CSF1 receptor pathway is an effective therapeutic strategy in this disease and that pexidartinib is able to provide encouraging long‐term control in patients with advanced TGCTs. No new or different safety signals in comparison with the previously published studies and analyses were detected 6 …”

“…Altogether, Gelderblom et al 6 could demonstrate an overall long‐term benefit of continued treatment with pexidartinib in patients with advanced TGCTs. Besides the obvious clinical benefit for this distinct patient population, I would like to focus in this editorial on the topic of the complex and somehow unfortunate registration status of the compound pexidartinib in Europe in comparison with the United States.…”

“…With this background in mind, the article in this issue of Cancer titled “Long‐Term Outcomes of Pexidartinib in Tenosynovial Giant Cell Tumors” by Hans Gelderblom et al is of special interest 6 . The authors investigated the overall long‐term benefit of continued treatment with pexidartinib in 130 patients with TGCTs receiving pexidartinib for a median treatment duration of 19 months and for an overall duration of up to 76 months of therapy.…”

“…There was also serious concern about unpredictable, potentially life‐threatening effects of Turalio on the liver. Therefore, the Agency's opinion was that the benefits of Turalio did not outweigh its risks and it recommended refusing marketing authorisation.” 9 With the current article kept in mind, the doubts raised about the long‐term benefits for patients with TGCTs can be clearly overruled by the current long‐term analysis of pexidartinib in patients with TGCTs 6 . Because of the possible risk of hepatotoxicity, pexidartinib is available only through the Risk Evaluation Management System program in the United States; however, a similar program for Europe has not even been taken into consideration.…”

Translating Molecular Profiling of Soft Tissue Sarcomas into Daily Clinical Practice

“…Sixty percent achieved an OR (CR or PR) by RECIST, and 26% achieved a CR, with a median time to response of 3.4 months and a median duration of treatment of 19 months. We remark that 92% showed a response by 18 months [ 59 ].…”