Overcoming concerns of hepatotoxicity and missing data, an FDA advisory panel voted to recommend approval of pexidartinib for the treatment of adults with inoperable tenosynovial giant cell tumors (TGCTs) on Wednesday, but with restrictions.
On whether benefits of the treatment outweighed the risks, the Oncology Drug Advisory Committee (ODAC) voted 12-3 in favor of pexidartinib for symptomatic unresectable TGCT, and agreed that a Risk Evaluation and Mitigation Strategy (REMS) program proposed by the FDA and drug sponsor Daiichi-Sankyo would be necessary to monitor for drug-associated liver damage.
"This is an ultra-rare disease, with no good therapies available to patients with it, that can be highly morbid," said Victor Villalobos, MD, PhD, of the University of Colorado Denver, who voted in favor of approval. "I feel that getting more real-world data on how we can use this drug in a safe and effective manner will be real important for the academic community."
TGCTs, also called tendon sheath or pigmented villonodular synovitis (PVNS), are rare non-malignant tumors that can lead to swelling, pain, and stiffness in patients' joints, and require multiple surgeries or joint replacements. Serious cases can render patients permanently disabled or necessitate limb amputation.
Roughly 15,000 cases of localized TGCT are diagnosed each year, most of which are resectable, but an additional 1,500 cases occur and are diffuse in nature. Some of these diffuse tumors cannot be treated with surgery due to their pattern of spread, and for these patients, pexidartinib could become an option -- the proposed dosing regimen is 400 mg (200 mg taken orally twice daily on an empty stomach). Currently, no systemic therapies are approved for TGCT.
Pexidartinib which is thought to promote abnormal cell proliferation in the synovium.
"This is a drug for the minority of the minority of patients," said Valerae Lewis, MD, of MD Anderson Cancer Center in Houston, who also backed approval. "While I'm quite concerned about the ramifications of the drug on the liver, this drug does have the potential really to be life-changing for those individuals who have the diffuse PVNS."
But "no" voter Massimo Cristofanilli, MD, of Robert H. Lurie Comprehensive Cancer Center in Chicago, cautioned that the use of the drug might become more widespread in clinical practice.
"If this drug goes out in the community, it would be used in place of surgery for patients that are simply symptomatic," he said. "Being inoperable is a very subjective criteria."
Data supporting the drug's efficacy came in large part from the randomized ENLIVEN trial, which showed an improved rate of tumor shrinkage at week 25 among 61 patients treated with pexidartinib compared to 59 who received placebo (39% vs 0%, P<0.0001) -- a majority of participants had at least one prior surgery for their tumors.
In all, 15% of pexidartinib-treated patients had a complete response. At 6 and 12 months, respectively, 97% and 57% of responding patients continued to respond to treatment (median duration not reached).
"The activity data was quite compelling and really the hard part in a study like this is showing the clinical benefit," said Thomas Uldrick, MD, of Fred Hutchinson Cancer Research Center in Seattle, discussing his yes vote. "The totality of the data that was shown suggests that there probably is clinical benefit."
Secondary endpoints favored pexidartinib over placebo, including significant improvements in range of motion (ROM), reductions in tumor volume, reductions in joint stiffness and pain, and improved patient-reported outcome (PRO) data on PROMIS physical function scores. But missing data at week 25 in the pexidartinib arm -- mostly due to patient adverse events (AEs) -- raised concerns about these secondary endpoints. There was missing data for physical function and stiffness in 43% of patients each, and on ROM in 27%. Also, possible unblinding in the treatment arm was an issue in the trial, as 61% of pexidartinib-treated patients had their hair turn white.
For those with ROM data at 25 weeks, the drug outperformed placebo (15.1% vs 6.2% improvement, P=0.0043). Tipping point analyses conducted by FDA staff estimated that all patients with missing data on pexidartinib would have to have had a 12% decline in ROM for the results to no longer be significant.
Liver Toxicity
In the pexidartinib arm of ENLIVEN, increased alanine aminotransferase occurred in 67% of patients (34% with increases ≥3 times normal level), increased aspartate aminotransferase occurred in 90% (30% with increases ≥3 times normal level), and elevated total bilirubin occurred in 12% (5% with increases ≥2 times normal level). Twice the trial was put on partial clinical hold, first due to hyperbilirubinemia and then for severe liver injury cases.
The FDA estimated that 4.9% of patients experienced serious but reversible liver injury during the trial. In a larger safety cohort of over 700 patients treated with the agent, the agency estimated that 0.3% experienced irreversible liver injury (one patient required a liver transplant and one patient died).
Uldrick said that with a range of correlatives that suggest clinical benefit, this overall risk of irreversible liver injury is acceptable if and when a REMS program is in place.
Overall, grade 3 or higher AEs were more than three times as common in the treatment arm (44% vs 12%, respectively), and serious AEs were more frequent with pexidartinib (13% vs 2%). More than one-third (38%) of the pexidartinib group needed dose reductions or interruptions compared with 10% of the placebo group, and 13% versus 0% discontinued treatment, respectively.
REMS Program
The proposed REMS for pexidartinib would aim to "mitigate and further characterize the risk of serious and potentially fatal hepatotoxicity," according to a presentation from Daiichi Sankyo during the meeting. The drug would be made available only to trained and certified prescribers, and a patient registry would collect data to track the hepatic safety profile.
Blood tests performed at baseline and throughout treatment would be required as part of the REMS, and it would provide clear directions on when to withhold or permanently cease treatment with the agent based on liver function blood tests. Unclear was how long patients in the registry would be followed -- the assumption was that responders may take the drug for their entire lives -- but FDA staff said they believed it would be at least 5 years.
"I think the REMS program will be really important and that's our best way to get safety data and understand the long-term effect," said Sally Hunsberger, PhD, of the National Institutes of Health in Bethesda, Maryland, who recommend approval of the drug.
"Also, what's going to happen in practice is what happened in the study," she said, pointing out that in ENLIVEN, patients with progression or severe AEs discontinued treatment. "It's not like they're going to go on it and stay on it even if there's no benefit."
Although the FDA is not required to follow its advisory committees' recommendations, it typically does.