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CHICAGO -- An oral investigational agent effectively shrank tenosynovial giant cell tumors (TGCTs) while demonstrating functional and symptomatic benefits for patients, the phase III MOTION trial showed.

In 83 patients with the non-malignant tumors for whom surgery would potentially worsen functional limitations or cause severe morbidity, the study's primary endpoint showed a 40% overall response rate with twice-weekly vimseltinib at week 25 (including complete responses in 5%) versus none with placebo (P<0.0001), reported William Tap, MD, of Memorial Sloan Kettering Cancer Center in New York City.

And using the TGCT-specific tumor volume score for assessment of response showed that two-thirds of vimseltinib-treated patients had a 50% reduction in tumor volume versus none of the placebo recipients (P<0.0001), according to findings presented here at the American Society of Clinical Oncology annual meeting.

Additionally, said Tap, the novel colony stimulating factor-1 receptor (CSF1R) inhibitor demonstrated statistically significant and clinically meaningful improvements in key secondary endpoints, including measures of active range of motion and self-reported physical function, health status, joint stiffness, and pain.

"Importantly, the functional and symptomatic benefit was achieved regardless of whether there was an objective tumor response," said Tap.

He added that vimseltinib was well tolerated, with no evidence of cholestatic hepatotoxicity, drug-induced liver injury, or hair/skin hypopigmentation -- all of which are known side effects of pexidartinib (Turalio), the only approved therapy for TGCT.

"If approved, vimseltinib offers a systemic treatment to people with tenosynovial giant cell tumor and provides proven functional health and symptomatic benefit to a population living with substantial morbidity and limited treatment options," said Tap.

Findings of the global trial were simultaneously published in .

TGCTs, also called tendon sheath or pigmented villonodular synovitis, are rare non-malignant neoplasms caused by dysregulation in the CSF1 gene, leading to overproduction of the CSF1 protein, explained Tap. The tumors arise in the synovium covering the surface of joint spaces and in tendon sheaths and can lead to swelling, pain, and stiffness in patients' joints.

"Surgical resection is standard of care, but not all people have disease that is amenable to surgery, and recurrence rates are as high as 40% to 50% in some of the more recalcitrant subtypes," said Tap.

For these patients, only pexidartinib is approved for TGCT based on an objective response rate of 39% and improvements in patient-reported outcomes from the similarly designed . But that drug, a CSF1R multikinase inhibitor, showed a clear signal for liver injury in trials and as a result is only accessible under a Risk Evaluation and Mitigation Strategy (REMS) program that monitors for drug-associated liver damage.

Vimseltinib is a tyrosine kinase inhibitor that selectively and potently targets CSF1R, which is thought to promote abnormal cell proliferation in the synovium. The drug had previously shown promise for TGCT in a , paving the way for MOTION.

"Vimseltinib is a potential treatment option for patients with TGCT not amenable to surgery, and if this drug is approved, surgeons will need to assess whether drug treatment is a better option than surgery," wrote Hiroshi Urakawa, MD, PhD, and Shiro Imagama, MD, PhD, both of Nagoya University Hospital in Japan, in an accompanying the publication in The Lancet.

While noting that the results compare favorably to pexidartinib, with a similar response rate but improved safety, the editorialists pointed to some limitations in the data set, including the fact that the median duration of response was not yet available for either type of response assessment and that "there is little information about tumor control after drug discontinuation, response after drug resumption, and recurrence after surgery for responding tumors, which would be useful information to have for what is likely to be a long-term treatment, given that TGCT is a benign tumor."

Trial Details

MOTION is an ongoing international phase III trial that enrolled adults with a confirmed symptomatic TGCT diagnosis who were not amenable to surgery.

Patients were randomized 2:1 to vimseltinib (n=83) at a dose of 30 mg twice weekly or matching placebo (n=40) during a 24-week double-blind phase, after which the primary endpoint of tumor response and key secondary endpoints were assessed -- the focus of Tap's presentation. This was followed by an open-label period where placebo patients could cross over to study treatment.

Participants had a median age of 43-45 years, a majority were women, and about two-thirds were white. The knee was the most common tumor location (67-68%) followed by the ankle and hip. More than two-thirds of the patients had a prior surgery or procedure for their TGCT, and 23% had previous treatment with nilotinib (Tasigna) or imatinib (prior CSF1R inhibition was an exclusion criteria).

The primary endpoint of objective response was assessed with RECIST version 1.1 at week 25 by independent radiological review. Secondary endpoints included response via tumor volume score; active range of motion on goniometry assessments; physical function on the TGCT-specific Patient-Reported Outcomes Measurement Information System physical function (PROMIS-PF); health status on the EuroQoL Visual Analogue Scale; worst stiffness numeric rating scale score; and the worst pain response rate on the Brief Pain Inventory.

Vimseltinib was well tolerated, with predictable and manageable toxicities, said Tap. Treatment discontinuation occurred in 6% of vimseltinib-treated patients. There was one treatment-related serious event in the vimseltinib arm (subcutaneous abscess), but no evidence of cholestatic hepatotoxicity or drug-associated liver injury.

"The authors of ENLIVEN argued at the time that the hepatotoxicity caused by pexidartinib was a class effect of CSF1R inhibitors, whereas the authors of MOTION consider it to be an adverse event specific to pexidartinib," noted Urakawa and Imagama.

The most common treatment-emergent adverse events (TEAEs) with vimseltinib, most of which were grade 1/2, included periorbital edema (45%), fatigue (33%), face edema (31%), pruritus (29%), headache (28%), asthenia (27%), and increases in blood creatine phosphokinase (CPK; 24%) and aspartate aminotransferase (23%).

Grade 3 or higher TEAEs in the vimseltinib arm included increases in blood CPK (10%), hypertension (5%), periorbital edema (4%), and pruritus (2%), along with face edema, headache, asthenia, and maculopapular rash each in 1% of patients.