In a randomised, placebo-controlled, phase III MOTION study, the efficacy and safety of vimseltinib was evaluated in a population of patients with symptomatic tenosynovial giant cell tumour whose disease is not amenable to surgery. Treatment with vimseltinib provided significant and clinically meaningful improvements versus placebo for the primary and all key secondary endpoints.
The antitumour effect of vimseltinib was robust; treatment produced a significant objective response rate (ORR), clinically meaningful functional and symptomatic improvements and showed a favourable safety profile. The findings were reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Prof. Hans Gelderblom of the Department of Medical Oncology, Leiden University Medical Center in Leiden, Netherlands, and colleagues on 3 June 2024 in The Lancet.
Tenosynovial giant cell tumour, previously known as pigmented villonodular synovitis or giant cell tumour of the tendon sheath, is a locally aggressive neoplasm affecting the synovium, bursae, and tendon sheath. Tenosynovial giant cell tumours are driven by dysregulation of the CSF1 gene. CSF1 overexpression promotes tumour growth and expansion by recruiting and inducing local proliferation of CSF1R-dependent inflammatory macrophages.
Surgical resection is the standard-of-care for most patients with tenosynovial giant cell tumour, but not all patients have disease that is amenable to surgery. Recurrence rates are approximately 50% for diffuse tenosynovial giant cell tumour, and patients who have a recurrence are significantly more likely to have future recurrences than those who do not have recurrence following surgery.
Although tenosynovial giant cell tumour is not life-threatening, it is associated with a substantial reduction in quality-of-life (QoL) for this patient population, for whom the mean age at diagnosis is 35–50 years. Patients can have joint damage requiring total joint replacement and, in extreme cases, amputation might be necessary.
Treatment options for patients with tenosynovial giant cell tumour not amenable to surgery are scarce. One systemic agent, pexidartinib, is approved in the USA, Taiwan, and South Korea, but in the USA, it can only be prescribed under a risk evaluation mitigation strategy due to its associated rare, but potentially fatal, off-target cholestatic hepatoxicity. Pexidartinib did not receive regulatory approval in Europe due to these safety risks and concerns over the extent and durability of symptomatic improvements.
Patients with tenosynovial giant cell tumour require long-term treatment and need therapeutic options that can improve the symptoms of tenosynovial giant cell tumour and overall QoL with manageable toxicity profiles.
Vimseltinib is an investigational, oral, switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R. In a phase I/II study, vimseltinib was well tolerated and showed promising antitumour activity and clinically meaningful changes in patient-reported outcomes (PROs) in patients with tenosynovial giant cell tumour. The MOTION study compared the efficacy and safety of vimseltinib versus placebo in patients with tenosynovial giant cell tumour not amenable to surgery.
MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase III study done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of tenosynovial giant cell tumour for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier.
The primary endpoint was ORR by independent radiological review using RECIST v1.1 at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The enrolment into study is complete.
Between 21 January 2022 and 21 February 2023, 123 patients were randomly assigned, of whom 83 to vimseltinib and 40 to placebo; 73 patients (59%) were female and 50 (41%) were male. Nine of 83 patients (11%) assigned to vimseltinib and five of 40 patients (13%) assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. ORR per RECIST was 40% (33 of 83 patients) in the vimseltinib group versus 0% (none of 40) in the placebo group (difference 40%; 95% confidence interval 29–51; p <0.0001).
Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase in eight of 83 patients (10%). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted.
With a mean age at diagnosis of 35–50 years, long-term QoL should be a priority when evaluating treatment options in these young patients. Vimseltinib provided statistically significant and clinically meaningful improvements in active range of motion, physical function, stiffness, health status, and pain compared with placebo. PROs reported are of high quality due to the robust collection and high completion rates for all PRO measures.
In the phase I portion of the ongoing phase I/II study of vimseltinib, the median treatment duration was 25.1 months (IQR 9.4–33.4), with approximately 4 years being the longest time on treatment. The optimal treatment duration with anti-CSF1R agents for patients with tenosynovial giant cell tumour remains to be determined. The MOTION study is ongoing and results from the open-label period (part 2) and long-term extension are forthcoming and expected to support the continued efficacy and safety of vimseltinib.
Overall, vimseltinib showed significant antitumour activity versus placebo, with a favourable safety profile in patients with tenosynovial giant cell tumour not amenable to surgery. Patients had statistically significant and clinically meaningful improvement in active range of motion, which could provide relief from mobility-related limitations in this young population. Patients treated with vimseltinib reported significantly improved stiffness, physical function, health status, and pain. If approved, vimseltinib will offer an effective systemic treatment option to patients with tenosynovial giant cell tumour and provide functional health and symptomatic benefit to a population living with substantial morbidity and few treatment options.
In an accompanied comment, Drs. Hiroshi Urakawa of the Department of Advanced Medicine, Nagoya University Hospital and Shiro Imagama of the Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, both in Nagoya, Japan wrote that one of the strengths of the MOTION study is that it is a well-designed study despite tenosynovial giant cell tumour being a rare tumour.
However, data regarding duration of response (DoR) are immature. An update regarding DoR and duration of treatment would be useful for clinicians, even if the median DoR is still not reached at sufficient follow-up. The study is also limited by the fact that there is little information about tumour control after drug discontinuation, response after drug resumption, and recurrence after surgery for responding tumours, which would be useful information to have for what is likely to be a long-term treatment, given that tenosynovial giant cell tumour is a benign tumour.
Elevated liver enzymes were less common in the vimseltinib group of the MOTION study than in the pexidartinib group of the ENLIVEN study. Pharmacological elucidation of the difference in hepatotoxicity caused by the two CSF1R inhibitors is needed.
The study was funded by Deciphera Pharmaceuticals.
References
- Gelderblom H, Bhadri V, Stacchiotti S, et al. on behalf of the MOTION investigators. Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet; Published online 3 June 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00885-7
- Urakawa H, Imagama S. Vimseltinib for tenosynovial giant cell tumour. The Lancet; Published online 3 June 2024. DOI: https://doi.org/10.1016/S0140-6736(24)01113-9