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Novel small-molecule inhibitor shows promise for pigmented villonodular synovitis
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The novel oral tyrosine kinase inhibitor PLX3397 induced tumor shrinkage and stable disease in patients with recurrent pigmented villonodular synovitis, according to study results.
Pigmented villonodular synovitis (PVNS) is a rare proliferative neoplasm that causes tumors in joint cavities. PLX3397 inhibits colony-stimulating factor 1 (CSF1) receptor — which is overproduced in patients with PVNS — as well as Kit and Flt3 kinases, according to background information provided by the researchers.
William D. Tap
“The physiological implications of this include collagen scarring, bone destruction and repeat joint bleeding,” study researcher William D. Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center, said during a press conference. “This process has devastating clinical implications for patients, and these often include joint swelling, pain, decreased range of motion and stiffness. Clinically, these often result also in functional impairment, significant narcotic use and disability. Currently, there is no FDA treatment, and surgery is the standard of care with patients often undergoing joint replacements and amputations.”
The analysis included 23 patients with advanced PVNS. Patients had tumors in their knees, ankles, feet or elbows. Most patients had undergone previous surgery, radiation therapy and/or treatment with targeted therapy, such as imatinib (Gleevec, Novartis) or nilotinib (Tasigna, Novartis).
Patients received 1,000 mg daily PLX3397 in 28-day cycles until disease progression or intolerability.
Tap and colleagues used MRI to identify a tumor volume score in each patient every 2 months. They defined partial responses as at least a 50% reduction in tumor volume score and progressive disease as at least a 30% increase in tumor volume score.
Fourteen patients were evaluable at the time of the analysis. Eleven patients (79%) responded to treatment, and researchers reported a mean 61% reduction in tumor volume. The other three patients demonstrated stable disease.
Researchers said PLX3397 was associated with improved overall joint functionality, as well as decreased pain and stiffness.
Hair color changes, fatigue, nausea, swelling around the eyes, abnormal taste, diarrhea, vomiting and decreased appetite were the most common adverse events associated with PLX3397.
“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,” Tap 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.”
For more information:
Tap WD. Abstract #10503. Scheduled for presentation at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Disclosure: The study was funded by Plexxikon Inc. Researchers report research funding or honoraria from, advisory/consultant roles with, employment/leadership roles with and stock ownership in Bristol-Myers Squibb, CytRx Corporation, Daiichi Sankyo, Genentech, GlaxoSmithKline, Novartis, Plexxikon, Prometheus and Spire Sciences Inc.
Perspective
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Clifford A. Hudis, MD, FACP
This disease is driven by a unique genetic abnormality. This is a demonstration of our ability through understanding the genetic abnormality to provide this specifically targeted drug, predicted to be effective. It’s exciting that by targeting this abnormality, and specifically the CSF1 receptor, we’re able to demonstrate the promise of a novel therapeutic for a heretofore untreatable-with-drugs disease. 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 malignancy. While it’s still early, this study offers an exciting glimpse of the payoff of the precision medicine era, even for rare diseases like PVNS. The research shows what’s possible when we unravel the molecular drivers of a disease and identify a drug that directly targets these defects.
In some cases there will be, if you will, spill-over benefits. This may be one such example. The numbers are modest; 11 of the 14 evaluable patients appear to have a pretty marked response. We will have to see how durable this is, and how this fits into the overall management of these patients. This is a very rare illness, it’s not a cancer per se, although it is a neoplasm. The gradual joint destruction that these patients face is really debilitating. This may be an opportunity to truly transform this rare illness.
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