Tap, Lancet 2019 - Pexidartinib versus Placebo for Advanced Tenosynovial Giant Cell Tumour (ENLIVEN): A Randomised Phase 3 Trial

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Pexidartinib versus Placebo for Advanced Tenosynovial Giant Cell Tumour (ENLIVEN): A Randomised Phase 3 Trial

Tap, ENLIVEN investigators, et al.·Lancet·2019·480 citations·RCT

Free Full Text·DOI·PubMed

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Background

Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. This phase 3 randomized, double-blind study evaluated pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT.

Methods

In part 1 of this two-part study, 120 patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomized (1:1) to pexidartinib (n=61) or placebo (n=59).
Part 2 was open-label pexidartinib for all patients.
Primary endpoint was centrally reviewed overall response rate (week 25) by RECIST, version 1.1.
Secondary endpoints included range of motion, response rate by tumor volume score (TVS), patient-reported outcomes (PROs), and response duration.
Emergence of mixed and cholestatic hepatotoxicity caused the Data Monitoring Committee to stop enrollment six patients short of target.

Results

The overall response rate was higher for pexidartinib versus placebo at week 25 by RECIST (39 vs 0%; p<0·0001).
At 22 months median follow-up, the best overall response with pexidartinib had increased to 53% by RECIST.
Hair color changes, liver enzyme increase, fatigue, and dysgeusia were the most frequent pexidartinib-associated adverse events.
Three patients had transaminases ≥3×ULN with total bilirubin and alkaline phosphatase ≥2×ULN indicative of mixed and cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.

Conclusions

Pexidartinib is the first systemic therapy to demonstrate a robust tumor response in TGCT with improved patient symptoms and functional outcomes; mixed and cholestatic hepatotoxicity is an identified risk.

Copyright remains with the authors and publisher.

Pexidartinib versus Placebo for Advanced Tenosynovial Giant Cell Tumour (ENLIVEN): A Randomised Phase 3 Trial

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|

Pexidartinib versus Placebo for Advanced Tenosynovial Giant Cell Tumour (ENLIVEN): A Randomised Phase 3 Trial

Tap, ENLIVEN investigators, et al.·Lancet·2019·480 citations·RCT

Free Full Text·DOI·PubMed

|

Background

Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. This phase 3 randomized, double-blind study evaluated pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT.

Methods

In part 1 of this two-part study, 120 patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomized (1:1) to pexidartinib (n=61) or placebo (n=59).
Part 2 was open-label pexidartinib for all patients.
Primary endpoint was centrally reviewed overall response rate (week 25) by RECIST, version 1.1.
Secondary endpoints included range of motion, response rate by tumor volume score (TVS), patient-reported outcomes (PROs), and response duration.
Emergence of mixed and cholestatic hepatotoxicity caused the Data Monitoring Committee to stop enrollment six patients short of target.

Results

The overall response rate was higher for pexidartinib versus placebo at week 25 by RECIST (39 vs 0%; p<0·0001).
At 22 months median follow-up, the best overall response with pexidartinib had increased to 53% by RECIST.
Hair color changes, liver enzyme increase, fatigue, and dysgeusia were the most frequent pexidartinib-associated adverse events.
Three patients had transaminases ≥3×ULN with total bilirubin and alkaline phosphatase ≥2×ULN indicative of mixed and cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.

Conclusions

Pexidartinib is the first systemic therapy to demonstrate a robust tumor response in TGCT with improved patient symptoms and functional outcomes; mixed and cholestatic hepatotoxicity is an identified risk.

Copyright remains with the authors and publisher.

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