Pexidartinib Shakes Up TGCT Treatment, But Questions Remain

John A. Abraham, MD, FACS

Patients with tenosynovial giant cell tumor (TGCT) should be referred to an orthopedic oncologist who possesses the appropriate surgical experience to perform the procedure the right way, according to John A. Abraham, MD, FACS, but for those who are ineligible for surgery, pexidartinib (Turalio) serves as another weapon in the treatment arsenal.

“We still believe that surgery is the [go-to approach for] first-line [treatment of this disease],” said Abraham. “However, for patients who cannot have surgery, have extensive disease, or have undergone several prior surgeries, this drug changes the way they are treated. Now, we have something to give them that is new.”

In August 2019, the FDA approved pexidartinib for the treatment of adult patients with symptomatic TGCT that is associated with severe morbidity or functional limitations and not responsive to improvement with surgery. The regulatory decision was based on data from the phase 3 ENLIVEN trial, in which treatment with the small molecule, CSF1R receptor inhibitor led to a 38% overall response rate (95% CI, 28%-52%) with pexidartinib versus 0% (95% CI-0%-6%; P <.0001) with placebo following 25 weeks of treatment based on central review of MRI scans.

However, pexidartinib is not without adverse events (AEs). The drug was associated with increases in alanine aminotransferase (67%), aspartate aminotransferase (90%), and total bilirubin (12%); these events reached grade ≥3 severity in one-third of patients. As with all drugs, the risks must be weighed with the benefits, according to Abraham.

Now, efforts are being made to better understand how best to use pexidartinib in patients with TGCT. “Now that we have a weapon, we have to figure out how to use it. That's probably the next phase of discovery in this disease,” said Abraham. “Right now, we're using [pexidartinib] in patients who either cannot have surgery, failed surgery, or don’t have the surgical option. But we don’t know if that's the best way of using this drug.”

Additionally, investigators are examining monoclonal antibodies and other small molecule inhibitors to see whether they can add more treatment options to the arsenal against the disease that are at least as effective as pexidartinib, but with less toxicities.

In an interview with OncLive, Abraham, founder of the Orthopaedic Oncology Service at the Rothman Orthopaedic Institute, and attending surgeon of Orthopaedic Surgery at Fox Chase Cancer Center, discussed associated symptoms to look out for in practice, the role of surgery in the treatment of TGCT, key challenges faced in this space, and the emergence of pexidartinib.

OncLive: What are the latest updates in TGCT?

Abraham: People need to recognize that this is an entity, because [this disease is] rare, it may not be the first thing you think about, and several explanations exist for knee pain. However, you should have this in the back of your mind when you see a patient with those classic types of symptoms.

The second thing is that the workup is generally based on symptoms and imaging, so you don't have to necessarily run out and get a whole molecular panel for every patient who experiences knee pain. Going back to the basics of medicine is the most important thing, which is history, physical, and basic imaging.

In terms of treatment, the take-home point is that surgery is really the main option. However, that doesn't mean that every time someone has TGCT, that they need to be sent to a medical oncologist immediately. The start is sending them to someone who is comfortable with doing a TGCT-type surgery. The final point is that there is a medical therapy that is now available and that’s important to know because if you have a patient who continues to have a problem, even after surgery, then there is another line of treatment.

Since this is a rare disease, what are some of the key symptoms associated with the disease to be aware of?

TGCT can occur in any joint, or even outside of a joint, so the symptoms are based on where it occurs. Because it’s a disease of the synovium which is the lining of the joint that aligns most of the joints in our bodies, the synovium gets thick and then it becomes friable, which means that it breaks apart easily. The way I describe it to patients is, if you take a leaf from a tree in the spring, that's what normal synovium is like and if you pick a leaf off the ground in the fall that is what friable synovium is like; it crunches and breaks apart and that causes bleeding. One of the most primary symptoms is a lot of bleeding into the joint and the patient experiences the effects of bleeding into the joint. The joint swells, blood fills the joint, and then they experience a lot of irritation and pain from that. When the joint is blown up like that, you lose range of motion and it causes stiffness. Another thing to not is that those symptoms come and go; there may be periods when they feel fine and all of a sudden, without any kind of inciting event, they suddenly have this blow up, with loss of range of motion and pain. Those are the kind of [symptoms they experience] no matter what joint it is.

Chronic effects are also experienced, such as the disease eroding into the bone, which could cause long-term chronic pain; it’s less of that intermittent symptom but more of a real pain in which the knee hurts all the time. The other thing is the extra-articular disease, so disease in the tendon sheaths. Most of the time we see that in the distal extremities, such as in the hand and foot; those are nodules that are painful. The tendon sheath is like a tunnel so it's not a big joint space. When you get a mass in a tunnel, then it is going to cause problems of the tendon moving normally and it can block motion. People’s fingers might get stuck in a certain position. In the hands and feet, when you experience even a little bit of swelling, it causes dramatic symptoms. In your hip, you can tolerate a certain amount of swelling without even knowing it’s there but in a little pinky finger, you cannot. The symptoms are somewhat dependent on where it is, but those are the general overview of symptoms patients experience.

You mentioned that surgery is the best option available. Could you speak to what surgery entails?

There are different forms of surgery and, again, it depends on where [the disease] is or what kind of joint it is; however, in general, we want to get rid of the synovium through the use of surgery. We can never really get rid of all the synovium. While you need your synovium, you only need a small percentage of what is actually there. Our goal is to remove the diseased synovium. The reason TGCT was originally called pigmented villonodular synovitis (PVNS), is because pigment comes in the form of blood and there's a lot of bleeding involved with this kind of disease. Blood products get taken away by the body and leave a deposition of hemosiderin behind, and hemosiderin contains iron and so it gives a rust-colored look, so a brownish/purplish discoloration.

Fortunately, that is somewhat useful to us because when we open to joint, we can see where the disease is because we just look for the purple. Orthopedic surgeons like to keep things simple. You open a joint, just look for the purple. Surgery can be extensive because you want to take out all of the diseased synovium and each joint has particular techniques of how you can do that but for every joint the techniques are specialized and extensive. You need to have someone who is familiar with doing an anterior and posterior operation in the knee, or doing a surgical dislocation of the hip or shoulder, or opening up an ankle joint to be able to see the whole thing.

These are all specialty procedures that orthopedist oncologists may have been trained to perform, but it’s not something that an average orthopedic surgeon will be comfortable doing. That’s another important point. The surgery has to be done the right way and the best chance of getting it done the right way is getting someone who is comfortable with doing those kind of procedures.

You mentioned that a novel agent has emerged in the TGCT treatment paradigm. Could you discuss the approval of pexidartinib and its utility in this space?

It's an interesting story because it shows how approaches are in oncology these days, which is very different [from those of] the past. In the past, [everyone focused on] chemotherapy. I tell patients that chemotherapy is an approach that wipes everything out, both the good and the bad. The good stuff grows back, but the bad stuff doesn't; however, when the good stuff is removed, then you experience all of the AEs, such as your hair falling out and mucositis. Any rapidly dividing cell is going to be affected, whether it’s a good cell or a bad cell.

That whole model has changed because now the way we approach it, is to figure out what is causing the problem and then target that problem; that is why the agents are called targeted agents. In about 2006 or so, it was discovered that this particular mutation is what drives TGCT and then we looked for that mutation, and that's when we figured out that TGCT and PVNS were the same thing, because have the same mutation. The story starts to unfold, because now we know what the mutation is, and we can actually define the disease better because we now know about that mutation. Then, the natural next thing is to try to target that particular mutation.

Many approaches were explored, including monoclonal antibodies and small molecules. There was somewhat of a race to develop the first agent to receive regulatory approval. The ENLIVEN trial is the one that showed that pexidartinib, which is the current approved agent, did have excellent results. The bottom line is, it causes a reduction of the volume of the disease and significant improvement in the symptoms. That being shown, we now have an agent that we know can be used, but it has AEs. Nothing is without AEs; we always have to weigh the risks and benefits.

Are any other notable agents under investigation?

Some of the new clinical trial agents that are currently being studied include both monoclonal antibodies as well as small molecule inhibitors. Now that there's an established benchmark, it won't be enough to just show that something works. We will have to show that it has a significant benefit, a benefit that at least approaches or surpasses that of pexidartinib. It's unlikely that there's going to be something that comes out anytime soon that shows dramatically improved results over pexidartinib, but there may be agents that come out that have fewer AEs, which would be beneficial. That is where the drive of the newer agents is going to be focused because the results from pexidartinib are very good. The clinical trials are ongoing because it does have AEs so we are trying to look for an agent that will have the same effect or a better effect, but also less AEs.

What other challenges are still faced in treating patients with TGCT?

Decision making is probably one of the hardest things to do. Surgeries are difficult, no matter which joint you're talking about, but once you have experience with those then it’s not necessarily the operation that becomes difficult; it’s deciding who gets what operation and when. To give an example, I’ll use the knee, as it’s the most common joint. For diffused disease, the approach is front or back synovectomies; that involves an incision in the front and back of the knee and opening up the knee on both sides and getting the synovium out. One of the problems is that the back of the knee is where all the important stuff is, so nerves, blood vessels, and lymphatic vessels. The original techniques were fraught with complications because of potential nerve injury or potential lymphatic disruption, and people would experiencing swelling and a significant range of motion problems. Patients would sometimes experience leakage of the lymphatics and wound problems because of that.

I remember when I started doing this work, we would stage all the operations and do the front side and the back side sometimes even 2 weeks apart to avoid problems with major swelling. We had patients try to limit their range of motion because we didn't want the wounds to fall apart so it was a really big deal. Now, improved surgical techniques are used and one of my former colleagues from Brigham and Women’s Hospital where I used to work, came up with a technique that avoids many of those complications and that's the technique I use. Although it's not necessarily a standard technique, in my opinion, it’s a better technique. We have been able to get to the point where we have very limited swelling and we can do both sides of the operation on the same day and have excellent access to the joint. That's a surgical evolution that has happened and just highlights how things like decision making and keeping up to date with the surgical techniques can impact the patient's outcome.

That's why it's important for your average practitioner who is seeing this kind of patient to hand it off to the people who are comfortable doing it because your average orthopedic surgeon may not know about that particular technique for this disease and it was designed for this disease in particular. Things like that make it very important you get patients to the right person and the right place. That’s why I say that it’s not necessarily the surgery; it’s the decision-making surrounding surgery that is the real difficult part of this disease.

Where will future research focus?

Now that we have a drug, what's the best way to use it? It could be that everyone should receive it for 3 months prior to surgery, as we do with neoadjuvant chemotherapy. Or, maybe we do surgery first and then put everyone on the drug for 6 months, and that will cut down the recurrence rate significantly, or it could be that we just use the drug and only when patients [progress on the drug], then we will do surgery. These are all remaining questions, and we really just don’t know. Future research in this disease will be focused on answering those.

Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019;394(10197):478-487. doi:10.1016/S0140-6736(19)30764-0.