The Treatment of Rare Tenosynovial Giant Cell Tumors Is Poised to Shift

R. Lor Randall, MD, FACS

In August 2024, the FDA granted priority review to the new drug application (NDA) for the investigational, oral switch-control tyrosine kinase inhibitor vimseltinib for the treatment of patients with rare tenosynovial giant cell tumors (TGCTs), signifying a potential shift in the treatment landscape of the disease.¹ R. Lor Randall, MD, FACS, noted that focusing on patient quality of life (QOL) is the most important aspect of the management of TGCTs and vimseltinib may offer a safe option with tolerable adverse effects (AEs).

“It is exciting to see another agent coming,” Randall said in an interview with OncLive®. “[Potential treatment with vimseltinib] does require at least the duality of the surgeon and the medical oncologist, [and] preferably an entire treatment board that is making decisions if and when this drug becomes available.”

The FDA has assigned a Prescription Drug User Fee Act goal date of February 17, 2025, to the NDA for vimseltinib for the treatment of patients with TGCTs.¹

Data from the phase 3 MOTION trial (NCT05059262) showed that the potent inhibitor of CSF1R significantly improved objective response rate (ORR) vs placebo. Patients in the vimseltinib arm (n = 83) achieved an ORR of 40% vs 0% among those in the placebo arm (n = 40). Clinically meaningful functional and symptomatic improvements were also observed with vimseltinib vs placebo, and cholestatic hepatotoxicity or drug-induced liver injury did not occur with vimseltinib treatment.²

Additional safety data from MOTION revealed that the most common any-grade AEs among patients treated with vimseltinib included periorbital oedema (45%), fatigue (33%), and facial oedema (31%). Grade 3 to 4 AEs in the vimseltinib arm occurring in at least 2% of patients included increased blood creatine phosphokinase (10%), hypertension (5%), periorbital oedema (4%), and pruritus (2%). Furthermore, 1 patient had a treatment-related serious treatment-emergent AE of subcutaneous abscess.

In the interview, Randall detailed how he approaches the treatment of patients with TGCTs, the potential of vimseltinib to join pexidartinib (Turalio) in the field, and more. Randall is the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California.

OncLive: How do patients with TGCTs usually present in the clinic?

Randall: [A TGCT is] not a sarcoma itself but is a locally [aggressive tumor]. We need to distinguish this from giant cell tumors of bone, which are a distinct entity. The nomenclature can be confusing. A TGCT is a soft tissue proliferation that involves joints and tendon sheets. It is a real source of morbidity for patients and has historically been a surgical disease. Orthopedic oncologists and people with similar training have been the go-to providers for this condition, but in the last decade or so there has been real progress in the medicinal aspects of the disease and emerging therapeutics.

The CSF1 receptor is a primary driver for TGCT pathogenesis. Pexidartinib is commercially available for use, and medical oncologists have brought it [forward] as a frontline or an adjuvant [therapy] for the management of patients with TGCTs. A discussion of the clinical array [of] presentations for TGCTs could burn up this whole conversation. [TGCTs are] not cancer but [are] a cancer-like condition in terms of local morbidity.

How would you approach treatment for a patient with a TGCT?

[With] medical management, you need to be very careful talking about the treatment and the AEs of the treatment vs the disease itself. We don’t want to make the disease worse than the problem. [Cancer is] a threat to the patient’s life and gives us a bit of license to say, ‘we have to cure the cancer because without curing the cancer, there’s no reason to worry about QOL’. I’m oversimplifying for brevity, but the idea is survival [outcomes are most important] and then the secondary [end point] is QOL.

Whereas [with TGCTs], we are [focused on] QOL because it’s not a life-threatening condition. When we start talking about treatments, whether they be surgical or medical, we have to take into consideration the AE profile and patient-reported outcome measures of the treatment.

There is a new agent, [vimseltinib], that is pending FDA approval. Recently, the MOTION trial findings have been published in Lancet and have shined a light on the CSF1R inhibitor vimseltinib. I encourage the audience to look at that article in more detail—the phase 3 findings are exciting.

With the potential for vimseltinib to join pexidartinib as an approved systemic agent to treat patients with TGCT, how is the relationship between patients, medical oncologists, and surgeons going to change?

As a surgeon, that’s the real issue for me. Like with desmoid tumors, I believe we may get to the point where surgery is not necessarily the frontline treatment for a large number of patients because when [a patient has] the diffuse type of TGCT, the local recurrence rates can be in excess of 50% in some cases. Recurrence rates are very high. [Vimseltinib is] a drug that has a bit more of a tolerable profile, [so we may] start seeing front loading of [the agent if it becomes available] in some patients as a first-line therapy, as opposed to trying any surgical intervention.

I do want to qualify that by saying it is very discretionary, and there are certain cases where surgery is absolutely indicated as a potentially curative [option for the tumors], especially when you have [diseases such as] nodular TGCT. This is why it’s important—like with all these sarcoma-like conditions—that patient cases are presented at multidisciplinary tumor boards, and everyone weighs in.

You mentioned the heterogeneity of TGCT, is vimseltinib an agent that can be used across all patients with TGCT?

It is a great question. It’s the heterogeneity of presentation, not the heterogeneity of biology. The discriminator here is bulk of disease, and radiologists who are familiar with reading MRIs [and] orthopedic surgeons who are familiar with the examination of the involved joint will have to weigh in heavily about that heterogeneity of bulk of disease and whether [vimseltinib could] be a frontline treatment. But, for nodular [disease] and cases where [the disease is] not quite diffuse or it could be removed with an arthroscopic procedure in the front of the knee, which is a very benign treatment itself, that may be part of the frontline therapy.

Disclosure: Dr Randall cited he is a consultant for Deciphera Pharmaceuticals, the manufacturer of vimseltinib.

References

1. U.S. Food and Drug Administration accepts for priority review Deciphera’s new drug application for vimseltinib for the treatment of patients with tenosynovial giant cell tumor (TGCT). News release. Ono Pharmaceutical, Ltd. August 16, 2024. Accessed September 3, 2024. https://www.ono-pharma.com/en/news/20240816.html
2. Gelderblom H, Bhadri V, Stacchiotti S, et al; MOTION investigators. Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10445):2709-2719. doi:10.1016/S0140-6736(24)00885-7