Targeted Agent Brings Hope For Tenosynovial Giant-Cell Tumour Patients

In a phase I trial, novel targeted agent shows efficacy in patients with advanced tenosynovial giant-cell tumours

medwireNews: Promising phase I results for a drug targeting the underlying molecular cause of locally aggressive tumours of the joint or tendon sheath have been published in The New England Journal of Medicine.

Neoplastic clones present in tenosynovial giant-cell tumours, also known as pigmented villonodular synovitis, often have a chromosomal translocation between colony-stimulating factor 1 (CSF1) and a gene encoding type IV collagen. Until recently there have not been any systemic treatment options for patients.

The oral, conformation-specific inhibitor of CSF1, PLX3397, was designed using X-ray crystallography to disrupt binding to the CSF1 receptor, explain William Tap, from Memorial Sloan-Kettering Cancer Center in New York, USA, and co-authors.

The study initially included 41 patients given one of seven doses of PLX3397 over a median of 70.7 days. There were no deaths in the study and 23% of the 35 patients who completed at least one treatment cycle achieved stable disease, while one patient given the highest dose in the escalation study experienced a partial response.

An extension study was therefore conducted in 23 patients with advanced disease, mostly affecting the knee. Patients received the maximum tolerated dose of 500 mg twice daily for a median of 8 months, during which time 61% required a dose reduction and 30% a temporary break in treatment, mostly attributed to fatigue.

Patients reported changes in hair colour (74%), fatigue (65%), nausea (39%), dysgeusia (26%) and periorbital oedema (26%); grade 3 and more serious events were rare, with fatigue, diarrhoea anaemia and neutropenia affecting one patient each, and hyponatremia and elevated liver enzymes two patients each.

Intention-to-treat analysis revealed a partial RECIST response in 12 of the 23 patients and stable disease in seven, giving an overall disease control rate of 83%.

And magnetic resonance imaging in 14 patients showed a partial response based on tumour volume score in 11 patients and stable disease in three.

Indeed, one patient had an 85% decrease in tumour volume over 4 months and a significant decrease in contrast media uptake, “which shows that PLX3397 can very rapidly affect the reactive inflammatory process that is a hallmark of tenosynovial giant-cell tumors”, the authors say. They note that this was accompanied by a “marked improvement” in clinical findings, symptoms and activities of daily living.

At time of data cutoff, 17 patients remained in the trial and seven continued to use PLX3397 – thus, median progression-free survival had not been reached at this point.

“There is a growing list of oncogene-driven neoplasms that respond to drugs targeting the oncogenic driver”, William Tap et al write.

“It appears that tenosynovial giant-cell tumor can be added to this list, given our results and the results from a recent trial  that reported similar effects from the use of an anti-CSF1R antibody.”

Nevertheless, they conclude: “Although tenosynovial giant-cell tumors appear to be stable with respect to mutation and genetically homogeneous relative to other oncogene-driven tumors, it will be important to determine whether resistance to CSF1R inhibition will occur and, if so, by what mechanism.”


Tap WD, Wainberg ZA, Anthony SP,et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor.N Engl J Med2015; 373: 428–437. DOI: 10.1056/NEJMoa1411366  

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