Elsevier

The Lancet

Volume 394, Issue 10197, 10–16 August 2019, Pages 478-487
The Lancet

Articles
Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial

https://doi.org/10.1016/S0140-6736(19)30764-0Get rights and content

Summary

Background

Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection.

Methods

This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369.

Findings

Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27–53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.

Interpretation

Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery.

Funding

Daiichi Sankyo.

Introduction

Tenosynovial giant cell tumour (TGCT), also known as giant cell tumour of the tendon sheath or pigmented villonodular synovitis, is a rare, locally aggressive, mesenchymal neoplasm that most often arises in the synovium of joints, bursae, or tendon sheaths.1, 2 A minority of cells within TGCT are neoplastic, aberrantly expressing colony-stimulating factor 1 (CSF1) as a result of genomic alterations at the CSF1 gene locus on chromosome 1p13.3, 4 Dysregulated CSF1 attracts histiocytoid and inflammatory cells, which compose the bulk of the tumour.3, 4 Annual TGCT incidence is estimated to be 43 cases per 1 million individuals, of which approximately 10% are of the diffuse subtype.5

Surgical resection, when feasible, is the standard treatment for TGCT; however, recurrence of the diffuse subtype is particularly common.1, 6, 7 Repeated surgeries often result in increasing morbidity and reduced function of affected joints.1 Persistent disease can cause cartilage destruction and bone erosion, in addition to functional limitations from tumour mass and associated effusions, resulting in long-term pain or joint dysfunction. Joint replacement or even amputation might be necessary.1 No approved systemic therapies currently exist.6

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.

Pexidartinib is a novel, orally administered small molecule tyrosine-kinase inhibitor with strong selective activity against CSF1 receptor (CSF1R); it also inhibits KIT and FLT3-internal tandem duplication.8 In a phase 1 study of patients with recurrent or inoperable TGCT (n=23), pexidartinib treatment resulted in 52% of patients achieving an overall response, assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST).8 To further evaluate pexidartinib in TGCT, a phase 3, randomised, multinational study (ENLIVEN) was done. We aimed to compare efficacy and safety of pexidartinib versus placebo in patients with symptomatic, advanced TGCT for whom surgery was not recommended.

Section snippets

Study design and participants

This phase 3, randomised, double-blind (part one) then open-label (part two), multinational trial was done in 39 hospitals and cancer centres: Australia (three sites), Canada (two sites), Denmark (one site), France (two sites), Germany (two sites), Hungary (one site), Italy (two sites), Netherlands (two sites), Poland (one site), Spain (two sites), UK (two sites), and USA (19 sites). Eligible patients were aged 18 years or older, had a histologically confirmed TGCT diagnosis, and had advanced

Results

In part one, from May 11, 2015, to Sept 30, 2016, 174 patients were assessed for eligibility and 120 patients from 12 countries were randomly assigned and received at least one dose of pexidartinib (n=61) or placebo (n=59) (Figure 1, Figure 2). Baseline characteristics were balanced between treatment groups (table 1). The most common disease site was the knee, present in 73 (61%) of 120 patients; 63 (53%) had at least one previous surgery for TGCT, and 11 (9%) had previous tyrosine-kinase

Discussion

In this first randomised, placebo-controlled phase 3 study in TGCT (ENLIVEN), pexidartinib significantly improved the overall proportion of patients who had a tumour response when compared with placebo in patients with symptomatic, advanced TGCT for whom surgery would be associated with potentially worsening functional limitation or severe morbidity. In addition, secondary endpoints favoured pexidartinib over placebo at week 25, including tumour volume score, a TGCT-specific imaging method to

Data sharing

De-identified individual participant data and applicable supporting clinical study documents are available on request, depending on circumstances, at https://vivli.org. In cases in which clinical study data and supporting documents are provided pursuant to the sponsor's policies and procedures, the sponsor will continue to protect the privacy of the clinical study participants. Details on data sharing criteria and the procedure for requesting access can be found at //vivli.org/ourmember/daiichi-sankyo/

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Contributed equally

A complete list of investigators is provided in the appendix

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