NCHR Testimony at FDA at the Onolcogy Drugs Advisory Committee Meeting on Pexidartinib

Varuna Srinivasan, MBBS, MPH, National Center for Heath Research; May 14, 2019

Thank you for the opportunity to speak today. My name is Dr. Varuna Srinivasan. I am a physician with a Master’s in Public Health from Johns Hopkins University. I am speaking today as a Senior Fellow at the National Center for Health Research, which analyzes scientific and medical data to provide objective health information to patients, health professionals, and policymakers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.

We have several strong concerns about the drug, Pexidartinib.
About 1.8 per 1 million persons will develop GCT- ts and 9.2 per 1 million persons will develop PVNS. These are forms of cancer are benign and with a very low chance of becoming malignant.  However, patients often experience a debilitating quality of life with reduced range of motion. Currently, radiation therapy has been shown to be beneficial in preventing tumor recurrence in infiltrative cases when surgery is not possible.
When looking at the drug in question today, it is more important to focus on functional outcomes and what it means for patients rather than overall response rate or decrease in tumor volume. It appears that while this drug offers a modest functional improvement on average, there are major risks.  Almost half of the patients dropped out, mostly due to liver injury and liver failure. We agree with the FDA that there is a lack of understanding of the long-term effect of this drug on those injuries.
The big picture is important. These cancers typically affect people between ages 20-40. Should such young patients be exposed to the risk of liver failure in order to possibly have a small short-term decrease in tumor size or a 10-degree allowance in range of motion?
In the pivotal clinical trial conducted on this drug, 39% of patients showed an overall response rate after six months but close to 94% had elevated liver enzymes within the first two months of treatment. Further scrutiny reveals that recurrence rates were not studied and while patients’ liver enzymes were monitored regularly, the sponsor’s failure to adequately characterize which patients would be more at risk for liver injury or failure. The sponsor also did not determine for which patients this side effect of liver injury would be irreversible.
As we all know, there is more monitoring in a clinical trial than in the real world of medicine, where the expertise of physicians and the understanding of patients varies widely.  And yet, the sponsor is proposing the same monitoring strategy as part of their REMS. If monitoring is less stringent than in the clinical trials, the incidence of liver failures cases could be far worse in a real-world setting.
Furthermore, this tumor has highly heterogeneous histology and some of the patients in the pivotal trial had previous systemic therapy.  As a result, the target population for whom this drug would be most beneficial has not been established. This tumor is nonlethal and the persistence of this tumor does not lead to malignancy so we ask again that you consider whether the higher rates of liver injury are really worth the risk.
The bottom line is that it is not known how many patients would develop irreversible liver injury from this medication. Merely establishing a basic patient indication profile with moderate REMS strategy does not guarantee a positive risk-benefit profile.
I hope that you will agree that better clinical studies that accurately evaluate the functional efficacy outcomes as well the safety profile of this drug are needed before approval should even be considered. We urge the committee today to consider these important points while discussing and voting today.