Designer molecule targets key protein in tenosynovial giant-cell tumor

1. PLX3397 is a targeted inhibitor of the CSF1 receptor that produced a partial response in about half of study patients treated with it for tenosynovial giant-cell tumor.

2. The next steps would include formal testing of the agents against one another in a randomized trial.

Evidence Rating Level: 2 (Good)

Study Rundown: Tenosynovial giant-cell tumor is a rare tumor of joints and tendon sheaths. Colony-stimulating factor 1 (CSF1) is expressed at high levels in these tumors. PLX3397 is a molecule specifically designed to inhibit the colony-stimulating factor 1 receptor (CSF1R).

In the first phase of the study, the authors tested the drug for safety. They ultimately selected a dose of 1000 mg/day for the second phase of the study, in which they evaluated the effectiveness of the drug. Out of 23 patients, 12 had some decrease in tumor size and 7 had stable tumor size after an average of 8 months of treatment.

Larger and longer trials will be needed to determine whether PLX3397 is an effective and safe option for treatment of tenosynovial giant-cell tumors.

Click to read the study, published today in NEJM 

Relevant Reading: Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/ pigmented villonodular synovitis

In-Depth [prospective cohort]: In this combined phase 1 and 2 trial, PLX3397 was first tested with a dose-escalation protocol to evaluate its safety and pharmacokinetics. A dose of 1000 mg/day was chosen for the second phase of the trial, in which the drug was given to 23 patients with tenosynovial giant-cell tumors.

Response to treatment was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines, which focus on the change in the longest dimension of the tumor. According to these criteria, there was a partial response in 12 of 23 of the patients, and stable disease in 7 of 23. The overall response rate of participants to PLX3397 was significantly higher than the overall response rate reported with imatinib (52% versus 19%, chi-square test with first degree of freedom, 4.86; p = 0.03). The authors also used a new, unvalidated metric called the Tumor Volume Score to evaluate response. This score takes the entire tumor volume into account, and may reflect tumor response more accurately when considering irregularly shaped tumors.

In the treatment group of 23, 61% had a dose reduction, most commonly due to fatigue. The most common treatment-related adverse events were changes in hair color (74%), fatigue (65%), nausea (39%), dysgeusia (26%) and periorbital edema (26%). Treatment-related adverse events of grade 3 or higher included diarrhea, anemia, neutropenia, hyponatremia and elevated AST or ALT. There were no deaths.  Further testing of this agent against other competing agents is warranted to validate the information from this phase 1 study.

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