BY MARK FUERST
A novel, oral tyrosine kinase inhibitor (TKI) may provide a new treatment option for patients with the rare neoplastic joint disorder of pigmented villonodular synovitis (PVNS), according to data set to be reported at the ASCO Annual Meeting on June 1.
The Phase I study, one of five reports selected to be discussed in a pre-meeting conference call briefing for the media last week, evaluated 23 patients whose disease had progressed despite all other available therapies (Abstract 10503^). Approximately three-quarters of the evaluable patients responded to the new treatment, PLX3397, with a mean reduction in tumor volume of 61 percent and rapid and substantial 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,” said
William D. Tap, MD, Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center. “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.”
About 600 Americans are affected by PVNS each year. In these patients, tumors form in the joint cavity, leading to gradual destruction of the joint and debilitating symptoms. Tap explained that although this is characterized by an overgrowth of abnormal cells, PVNS is not considered a cancer per se because it usually does not spread to other parts of the body.
The clonal neoplastic process is due to a genetic translocation. There is overexpression of colony stimulating factor 1 (CSF1) in the synovium and reactive inflammatory proliferation of CSF1 receptor expressing cells. CSF1 receptor and Kit regulate key components of both the tumor and its microenvironment, including monocytes, macrophages, and osteoclasts. The physiological implications include collagen scarring, bone destruction, and repeat joint bleeds. The clinical implications include joint swelling, pain, decreased range of motion, stiffness, and functional impairment, as well as narcotic use and disability.
“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,” he said.
PVNS typically affects the hip or knee, and occurs most often in younger people in their 20s and 30s, although “we see it in patients of all ages. It’s probably more prevalent than we know since it is often misdiagnosed as rheumatoid arthritis or other arthritis.”
While most patients are well managed with surgery, in some patients the disease comes back, necessitating additional surgery, often requiring a joint replacement, and eventually advances to the point where it is no longer operable.
“If it becomes progressive, using medications, we have a chance to affect the course of these patients’ lives,” he said. “In 2006, we began to understand the genetic abnormalities, which allowed us to look for therapeutic drugs. This may be a springboard for research in other diseases, not just rare diseases.”
PLX3397, an oral small molecule, potently and selectively inhibits the CSF1R, Kit, and Flt3 kinases, thereby blocking the molecular pathways of the genetic abnormality that drives PVNS. This may slow the destruction of the joint and reduce the accompanying inflammation.
The patients in the trial, who had a median age of 46, all had advanced PVNS with tumors in the knees, ankles, feet, or elbows. Most of the patients had undergone multiple surgeries, and some had received prior treatment with radiation and/or with other systemic targeted treatments, such as imatinib or nilotinib.
PLX3397 at 1,000 mg daily was administered in 600-mg doses in the morning and 400-mg doses in the evening on 28-day cycles. Evaluable patients in the study were exposed to the drug for an average of 244 days. The patients remained on the study until disease progression or inability to tolerate the drug.
Patients were assessed by magnetic resonance imaging every two months for response. Tap noted that 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 was defined as at least 50 percent reduction in TVS, and progressive disease was defined as at least 30 percent increase in TVS relative to the lowest score. Eleven of 14 (79%) evaluable patients had tumor shrinkage sufficient to qualify as responders. The disease was stable in the other three patients. Patients had substantial improvements in overall joint functionality, as well as decreased pain and stiffness.
The drug was well tolerated, Tap said. The most common treatment-related side effects were hair color changes, fatigue, nausea, swelling around the eyes, abnormal taste, diarrhea, vomiting, and decreased appetite. Treatment-related adverse events of at least Grade 3 included anemia (in one patient), hyponatremia (two patients), elevated liver enzymes (two patients), and fatigue, diarrhea, and neutropenia (one patient each).
Tap described one patient who, before the trial, was walking with a cane, was unable to straighten her knee, took narcotics for pain, and was unable to work. The situation was so severe that she was considering amputation. “After four months on PLX3397,” Tap reported, “she was walking unassisted, had increased range of motion, was off narcotics, and was back to work.”
In conclusion, Tap said, “The PVNS expansion cohort of this Phase I trial demonstrated encouraging activity of PLX3397 in patients with advanced, diffuse PVNS. The overall response rate as assessed by TVS was 79 percent. There was early, dramatic, and sustained reduction in tumor mass. This was associated with substantial clinical benefit, per physician assessment.
“Patients can benefit significantly when a clonal neoplastic process that is driven by a single genetic event is blocked. PLX3397 is well tolerated, with manageable side effects, and is a very promising novel treatment for patients with advanced PVNS.”
A Phase III study of the drug is now being planned, he said.
Commenting during the presscast, ASCO President Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service, also at Memorial Sloan-Kettering Cancer Center, said, “While it is 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.
“This disease is driven by a unique genetic abnormality. Dr. Tap has demonstrated the ability to understand the genetic abnormality and provide a targeted drug. The CSF1 receptor kinase inhibitor is a novel therapeutic for an untreatable disease. It shows that tremendous progress can be achieved in the effort of the how and why of a malignancy.”
He noted that the study numbers are “modest,” with only 11 evaluable patients showing a marked response. “We have to see how durable this response is and the overall management of patients. The gradual joint destruction is debilitating. This therapy may truly transform this illness.”