Research in context
Evidence before this study
No approved systemic therapies are currently available for patients with tenosynovial giant cell tumour (TGCT). A PubMed search was done using the search terms “tenosynovial giant cell tumor” and the commonly used alternatives “giant cell tumor of the tendon sheath” and “pigmented villonodular synovitis,” to identify clinical studies of investigational systemic agents in this disease. Studies were included from database inception until Nov 14, 2018. There were no language restrictions. All potentially relevant articles were assessed for quality and relevance. A small number of clinical studies, case studies, and retrospective analyses were identified, and none were randomised phase 3 studies.
Added value of this study
To the best of our knowledge, ENLIVEN is the first randomised, placebo-controlled phase 3 study in patients with TGCT. The study was designed not only to evaluate the risk and benefit profile for pexidartinib as the first systemic therapy in TGCT but also to increase knowledge of the disease and how to evaluate the effectiveness of new therapies in this rare, non-malignant tumour. In addition to evaluating the proportion of patients who had a tumour response, ENLIVEN assessed patient symptoms and physical functional outcomes of key importance to patients by using a novel TGCT-specific MRI-based tumour response evaluation method and a unique TGCT-specific patient-reported outcomes score. The results of the study were very positive in favour of pexidartinib; mixed or cholestatic hepatotoxicity was an identified risk.
Implications of all the available evidence
As the first randomised, placebo-controlled phase 3 study in TGCT, ENLIVEN is a landmark study that sets the standard for drug development in this rare disease. The results are potentially practice-changing for TGCT. The use of TGCT-specific patient-reported outcomes allows the results to inform clinical practice. Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT while improving patient symptoms and functional outcomes. Mixed or cholestatic hepatotoxicity is an identified risk and should be highlighted in informed discussions between patients and their health-care team. Pexidartinib might be a relevant treatment option for TGCT, which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery.