R. Lor Randall, MD, FACS, discusses the outcomes of combining surgery and pexidartinib in patients with tenosynovial giant cell tumors, what investigators still need to learn about sequencing the CSF1R inhibitor around surgery, and what the combination approach could mean for patients with TGCT.
R. Lor Randall, MD, FACS
Treatment with pexidartinib (Turalio) in combination with surgery demonstrated effective local control and positive outcomes in patients with previously unresectable or inoperable diffuse tenosynovial giant cell tumors (TGCTs), according to a case study of 3 patients published in the Case Reports in Orthopedics.1
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.2 In the case study, a 29-year-old man with TGCT in the hip, a 35-year-old woman with TGCT in the foot, and a 55-year-old man with TGCT the knee. received the combination of surgery and the CSF1R inhibitor, demonstrating the potential benefit of this approach for patients with TGCT, according to R. Lor Randall, MD, FACS.
“[This case study] illustrates the concept that medical oncologists and orthopedic oncologists need to be working together around the topic of [TGCT] to improve patient outcomes,” Randall explained.
In an interview with OncLive®, Randall discussed the outcomes of combining surgery and pexidartinib in patients with TGCT, what investigators still need to learn about sequencing the CSF1R inhibitor around surgery, and what the combination approach could mean for patients with TGCT. Randall is the David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California.
Randall: TGCT has gone by former names of “pigmented villonodular synovitis” and “giant cell tumor tendon sheath.” These are soft tissue growths that arise in and around joints, and they are all the same entity now. The nomenclature is TGCT.
I want to point out that [TGCTs] are distinct from giant cell tumors of bone. They both have the [phrase] “giant cell tumor” in them, so it is important that medical oncologists or anyone who is not as familiar with these types of entities understand that giant cell tumor of bone is very distinct from TGCT.
It is known that CSF-1 is involved with the pathogenesis of this tumor. There are now CSF-1 inhibitors that have proven to have some good efficacy in managing this condition.
Data from the phase 3 ENLIVEN trial [NCT02371369], which [evaluated pexidartinib in patients with TGCT] has been published by William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, and his colleagues. There is also the ongoing phase 3 MOTION trial [NCT05059262] with a different CSF-1 inhibitor [vimseltinib (DCC-3014)]. Moreover, there is a forthcoming trial looking at the intra-articular use of one of these CSF-1 inhibitors. These are exciting agents that can help reduce this malignant non-malignancy, in terms of its effects on patients’ lives.
There is a different way of thinking about [treating TGCT] vs thinking about cancer. With cancer, it is survival at all costs. However, these conditions [with TGCT] do not threaten the life directly. TGCT can sometimes indirectly threaten a patient’s life when they are so far locally advanced, but they’re non-metastatic. There are case reports of multi-focal disease, however, for the most part, [TGCT involves] primary site control, and that primary site control can be highly morbid. Sometimes the surgical options are as morbid, if not more morbid, than the disease itself.
Fortunately, there are new agents that have come on board. One that is FDA approved and, on the market, now is pexidartinib. Pexidartinib has been shown to have a good effect in terms of improving patient's physical function and pain interference, as well as reduced tumor bulk.
The real question now becomes how to employ this in the armamentarium of providers who care for TGCT. Like many of the sarcoma conditions, it does require a multidisciplinary approach. The orthopedic oncologist is central to it because as orthopedic oncologists, we understand the scope of the problem in terms of functionality and the biology, as well as the use of surgery and controlling the disease. We have now partnered with our medical oncologists to advance the crusade to improve the quality of life for these patients.
Now [we turn to the] conundrum of what to do with a patient with advanced TGCT. Do we give them medication for a certain period, and then take them to local control, extricate the tumor, and consider adjuvant treatment? This is the ‘surgery sandwich’ that we see in a lot of sarcomas.
Or do we try to treat up-front? If a patient is controlled and they are not having many [adverse effects] from the drug, do we treat them in perpetuity? What about a drug holiday schedule and that potential? There are no data around that.
For cases that are refractory, do we consider pulsing with a CSF-1 inhibitor around surgery in a neoadjuvant or adjuvant setting when surgery is going to be the mainstay? These are unanswered questions.
There are many small studies that are coming out, and we just published a series of 3 cases where we did treat refractory tenosynovial giant cell tumor with pexidartinib in combination with surgery. We had good, effective local control and [good] outcomes. It's a case series of 3 that was not particularly rigorous.
Patient-reported outcomes [PROs] are the key indicator here because what the patient experiences [is most important]. When the size of a tumor is reduced on an MRI because of the drug, but the patient is no happier, that's not a win. In the cancer world, that's considered a relative win as a surrogate for survival, potentially. In this case, if a patient [with TGCT] is just as miserable with a reduced size tumor, we haven't done them any good.
Good [results are measured by] PROs. The patients subjectively report that their physical function has improved, that their pain interference is better, and things such as depression are improved based upon either drug therapy [alone], or the combination of surgery and drug therapy.
There have not been any formal guidelines. There have been expert opinions, and we've had some gatherings around potentially formulating [guidelines]. The NCCN has had discussions around this where they will say things to the effect of considering up-front CSF-1 inhibition, but we don't have guidelines. That is the next step. We will probably get a consensus panel together to narrate that guideline proposal.
I would like for a clinical trial. Many of us orthopedic oncologists have been advocating for a clinical trial. The issue is that once something comes to market and is approved, it's hard to then do another clinical trial. With pexidartinib, it's been a wonderful advent, but we have not been able to get a lot of traction on a neoadjuvant trial randomizing patients. It's difficult in that regard because it's not an oncologic scenario.
It is important to emphasize that medical oncologists may have patients [with TGCT] referred to see them. When they see a tumor that looks intra-articular, or around a joint, please check with the radiologist and the radiology report for TGCT. These do warrant histologic diagnosis, so biopsy is appropriate.
Bring in your orthopedic oncologist sooner rather than later. If it is a diagnosis of TGCT, medical oncologists need to know that they're a part of the equation in treating these patients. Orthopedic oncologists are hesitant to manage these drugs themselves, with a caveat being that this intra-articular injection form that may change that. However, these are an emerging area where medical oncologists will see more and more involvement.