New Treatment on Horizon for Rare Joint Disorder


The new targeted drug, PLX3397, has demonstrated responses in patients with pigmented villonodular synovitis (PVNS), a rare joint disorder.

William D. Tap, MD

The new targeted drug, PLX3397, has demonstrated responses in patients with pigmented villonodular synovitis (PVNS), a rare joint disorder. The phase I, single-arm study included 23 patients, whose disease had progressed despite all other available therapies.

Results showed that more than 79% of evaluable patients responded to treatment demonstrating a mean 61% reduction in tumor volume as well as rapid and sustainable improvements in symptoms.

“These results are a shining example of how patients can experience a meaningful clinical benefit when we are able to match the right treatment with the right target,” lead author William D. Tap, MD, chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center said in a press release. “PLX3397 seemed to have a tremendous impact on the joint-destructive disease process as patients often reported a marked decrease in swelling and pain, even very early in their treatment course.”

Approximately 600 people in the United States are affected by PVNS, a neoplastic joint disorder. In patients with PVNS, tumors form in the joint cavity, leading to gradual destruction of the joint and debilitating symptoms. There are no treatments approved by the US Food and Drug Administration for PVNS. Surgery is the standard of care (eg, joint replacement or amputation).

PVNS is not classified as a cancer, because it does not typically spread to other parts of the body.

PLX3397 is a novel, oral tyrosine kinase inhibitor (TKI) that blocks several molecular targets including the colony stimulating factor 1 (CSF1) receptor, which becomes overexpressed within the synovium of patients with PVNS. PLX3397 blocks the molecular pathways of the genetic abnormality in PVNS, potentially slowing down the destruction of the joint and reducing inflammation associated with the disease.

“With our understanding of the disease process, and the mechanism of action of PLX3397, we questioned if we could truly help patients by blocking a clonal neoplastic process driven by a single genetic event using a highly targeted therapy,” Tap said during the press cast held in advance of the ASCO Annual Meeting.

For this study, patients with advanced PVNS with tumors in the knees, ankles, feet, or elbows were enrolled in an expansion cohort of an ongoing single-arm, multicenter, clinical study. The patients were given 1000 mg daily, with 600 mg administered in the morning and 400 mg administered in the evening on 28-day cycles. Evaluable patients in the study were exposed to PLX3397 for an average of 244 days (range 15-585).

Patients were given MRIs every 2 months to access response, according to Tap. Since linear measurements are not able to accurately assess the extent of PVNS, a novel tumor volume score (TVS) was utilized. TVS, a modification of the whole-organ MRI score that is commonly used in arthritis, calculates tumor volume as a percentage of the entire synovium.

Partial response (PR) was defined as ≥50% decrease in TVS compared to screening, while progressive disease was defined as ≥30% increase relative to lowest score. Patients remained on the treatment until disease progression or intolerability occurred.

Eleven out of 14 (79%) evaluable patients had tumor shrinkage sufficient to qualify as responders, and the disease was stable in the other 3 patients. Patients also experienced substantial improvements in joint function and decreased pain and stiffness.

“Patients on PLX3397 also demonstrated marked clinical improvement as assessed by the treating physicians,” Tap said. “The majority of patients had improvements in pain, stiffness, and their ability to perform their activities of daily living.”

The most common treatment-related side effects (>20%) were hair color changes, fatigue, nausea, swelling around the eyes, abnormal taste, diarrhea, vomiting, and decreased appetite.

Treatment-related side effects that were greater than or equal to grade 3 included anemia (1), hyponatremia (2), elevated liver enzymes (2), fatigue (1), diarrhea (1) and neutropenia (1).

“This is an example of the tremendous progress that can be achieved when we really pour our efforts into understanding the how and why of a malignancy,” Cliff Hudis, MD, FACP, ASCO President, said during the press cast. “We will have to see how durable this is and how this fits into the overall management of these patients.”

According to Tap, a phase III trial to further evaluate PLX3397 in patients with PVNS has been planned.


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