William D. Tap, MD, lead investigator of the ENLIVEN study provides latest update on pexidartinib as an effective treatment for patients with tenosynovial giant cell tumor (TGCT), especially the diffuse form.
In a recent interview, Rare Disease Report® spoke with William D. Tap, MD, lead investigator of the ENLIVEN study and chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City, New York, to discuss pexidartinib as a potential treatment option for patients with tenosynovial giant cell tumors (TGCT).
Rare Disease Report® (RDR®): Could you provide a brief overview of TGCT and explain why treatments have been so limited?
Tap: TGCT, also known as tenosynovial giant cell tumor, is a rare inflammatory neoplasm that often affects younger people. The median age is often around 40 with a slightly higher incidence in females. TGCT tends to affect a single joint in an individual, and it can be a very destructive process in that joint when patients have what we refer to as a diffuse type of TGCT.
That also means there are less aggressive variants. There is nodular TGCT, which is often cured by surgery alone, but the diffuse type can really encompass an entire joint. It can be a very difficult disease to manage surgically because the disease is so diffuse. A lot of orthopedic surgeons say it’s like operating in mud. It can be very difficult to clear the entire process.
Over years, the diffuse type can cause a significant amount of morbidity to patients who are affected with it. It is generally something, because it’s not a malignancy, per say, that will threaten a person’s life, but it is definitely something that can change the trajectory of an individual’s life. What we mean by this is, as the process continues, it can cause a significant amount of swelling, it can cause a significant amount of pain, decrease a person’s range of motion, and cause significant disability.
Patients are often not able to function as they normally would without high amounts of narcotics. The process can also destroy the joint as well and lead to numerous surgeries like joint replacements, which can also cause morbidity. It is a very difficult process for people in a very difficult disease.
RDR®: Why are the recurrent rates so high even after surgical intervention?
Tap: It’s because it’s not necessarily like removing a tumor. It’s a really infiltrative process; that’s why the surgeons often say it’s like operating in mud. That process can be really infiltrative not only in the joints but also throughout the surrounding muscles and tissues. For example, within the area of the knee, that’s something that can be infiltrated, not only the anterior part of the knee but also the posterior part of the knee.
Consequently, patients would need very large surgeries but a significant amount of the disease would be left behind, and that would continue to grow over time. That’s why we have such high recurrence rates. People estimate that about 50% of TGCT patients have the diffuse type of the disease.
RDR®: What is some of the research and groundwork that has been done to develop pexidartinib?
Tap: There are a few things. First, about 10 years ago, it was found that the neoplastic clone cell that’s causative within this process has a translocation that usually puts 2 genes together that shouldn’t be together, and one of these genes is called colony stimulating factor 1 (CSF1). Often, this gene is placed next to the promoter of the ubiquitous collagen gene. Consequently, the promotor of that gene is always tuning on the CSF1 gene.
This gene is, for lack of a better term, the growth factor that will attract inflammatory cells to the joint. When we look at a tumor, the majority of the cells that compose those tumors are inflammatory cells. The neoplastic cells are actually the minority of the tumor. That was a very important discovery because we do have drugs that can target CSF1 and CSF1 receptors. There are drugs like imatinib and melatonin, which we use for other cancers. These are fairly weak inhibitors of CSF1, but there was some nice data to show there may be some benefits for patients with this disease.
Subsequently, what’s happened is drugs like pexidartinib were developed, and pexidartinib is a much stronger and more specific inhibitor of CSF1R, and that’s a really strong drug that blocks the process and the recruitment of the inflammatory cells. That’s why we saw the tremendous results that we saw.
RDR®: If approved down the road, what would the clinical implications be for providers and patients battling TGCT?
Tap: This would have a tremendous impact, and I think the study in and of itself already has had a tremendous impact on the community for a few reasons. One is because up until a few years ago, the medical community—with the exception of a few real experts—didn’t truly understand the ramifications of what the disease did and how the people suffered with the disease.
You can imagine, then, if all of a sudden you believe you have a drug, it can be very hard to figure out the best way to apply the drug for patients, and importantly, to understand if the results are meaningful for patients.
What was unique about this effort, and what we’re really proud of, is that the pharmaceutical companies were involved as well as the academic community, both medical oncologists and orthopedic oncologists, who often deal with this disease, and they really got together with the patient community to better understand what this disease does to them. In doing so, we were able to also develop novel patient reported outcomes (PROs) to truly understand whether or not we were seeing responses that had a meaningful impact in a patient’s life.
Because this disease is a very diffuse disease, we knew that standard imaging criteria that we often use on other clinical trials would not adequately measure how the drug was acting in the tumor. There were very specific MRI correlates done for this disease.
This trial has allowed us to help define how this disease affects people, what the normal outcomes are that we would see with strong inhibitors of this CSFR1, and what may be meaningful for the patient.
It’s setting the standard for understanding not only this disease in patients but also the best way to develop therapies for patients with TGCT. Just in those parameters alone, I think this study has made major advancements for patients with this disease. I think it was a very rare study in which patient input has really helped us develop this correctly.
If the drug gets approved, I think it would be another major advancement for TGCT patients because it would allow those with the diffuse type and aggressive variants of the disease to get tremendous improvement in their quality of life; that’s what we saw in our patients. They not only had dramatic improvements in the sizes of their tumors, but those decreases in tumor sizes also correlated with better functionality for them. It helped patients avoid amputation, get off of disability, get off of a lot of narcotics, and be able to take better care of their kids and grandkids.
The drug did have some toxicity though. There are some very common liver toxicities that we can see with this class of drugs, which are often just forms of inflammation with the delivery, which is something the medical community really knows how to deal with regarding this type of drug. There were a few patients that had more serious liver toxicities though.
That being said, we have to understand who the right patients are to use this drug in and what the right times are for the patients to use the drug. Also, are there specific health care providers that should be prescribing the drug if it gets approved? We want to make sure that the providers understand the drug, the disease, and the toxicity profile to be able to talk about the appropriate risks and benefits for their patients, which is critical, in addition to how to use and monitor the drug correctly. For the right patient, this drug can be an amazing treatment.
In our community as well, if the drug gets approved, it will also allow us how to figure out how to better apply the drug for patients in the long-term. I have had some patients on this drug dating from the early phase 1 study for over 5 years, and they have had tremendous responses to the drug, and they don’t just want to stop it because they’re afraid ceasing the treatment will cause the tumor to grow back.
However, if the drug gets approved, we can begin to answer some questions on how to best clinically use the drug. What we mean by that is [figuring out] the right dose and potentially avoiding the risk of some of the liver toxicities we may have seen in the phase 3 study. People who started out at the lower dose were observed to have less liver inflammation and possibly less liver toxicity. We could also start answering whether this a drug that we don’t have to use continuously in patients and if this is a drug we can use more intermittingly.
In patients with the diffuse form of the disease, we could investigate if the treatment could augment surgery and be able to cure patients with the disease; these are all very important questions. We are learning [more about] what happens when we stop the drug in patients; we [have seen] variability in patients who stop the drug. Some can stop the drug and maintain stability for long periods of time while others stop the drug and the tumor starts to grow. In the latter case, we have to investigate when we want to reintroduce the drug again.
However, this treatment really just opens the door for a disease that has very few treatments, and it allows us to really work with the patient community and figure out when the best time to use this treatment and how to best use this treatment is.
RDR®: Looking forward, what do you feel the next steps are?
Tap: I do think we would definitely have to wait for the NDA for this drug. In my mind, if the drug gets approved, it would really be about figuring out exactly how it should be used in patients, and that’s the most important thing. Our patient community has been really wonderful in teaming together with us and working through how best to apply the drug on an individual basis.
I do also think—and in a rare disease this is a wonderful thing—that not only has this phase 3 study and how it was designed set the standard of how to develop drugs in this disease in a very comprehensive way, but it’s opened up the door for a lot of other, similar drugs to also be tested in this disease.
Although I hope that this is the first, I do hope that it is going to allow for many more drugs and potential combinations to come into this arena for patients with TGCT.
Now that a standard for how to develop a drug and run trials is out there, I’m hoping there will be accelerated future processes. This brings a lot of hope to TGCT patients. Not only will they have a potential drug on the market to use, but there may also be a significant amount of more therapies available for them. From our standpoint, it will also help us better understand the disease, understand more of the science, and better help patients with these types of agents.