Vimseltinib

TGCT is a rare disease caused by a genetic translocation in the colony-stimulating factor 1 (CSF1) gene resulting in overproduction of CSF1, triggering migration of inflammatory cells including CSF1R-expressing tumor-associated macrophages (TAMs) to tumor sites. TGCT is also known as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS), a diffuse-type of TGCT. These tumors can grow and cause damage to surrounding tissues and structures inducing pain, joint stiffness, restricted mobility, joint damage, and negative quality of life impact swelling. Surgery is the main treatment option; however, these tumors tend to recur. If untreated, or if the tumor continually recurs, damage and degeneration may occur in the affected joint and surrounding tissues, which may cause significant disability.

Due to the slow-growing nature of TGCT and symptoms similar to other conditions such as sports injuries and arthritis, patients may have a longer path to diagnosis. Patients may visit multiple doctors before receiving a definite diagnosis and treatment plan. Once properly diagnosed with TGCT, patients are referred to an orthopedic oncologist and medical oncologist specializing in sarcomas, especially if they have diffuse disease.

We are currently studying vimseltinib in an international, multicenter, open-label Phase 1/2 study to assess its safety, efficacy, pharmacokinetics, and pharmacodynamics in patients with advanced tumors and TGCT. At the European Society for Medical Oncology (ESMO) Congress in September 2021, we announced updated preliminary results from the ongoing Phase 1/2 study of vimseltinib in patients with TGCT.

The data was from patients with TGCT in both the Phase 1 dose escalation portion of the study and from cohort A in the Phase 2 expansion portion of the study. Of the 51 efficacy-evaluable patients in Phase 1 across all dose cohorts and in the Phase 2, cohort A who had follow-up scans as of the June 7, 2021 cutoff date, 24 patients had a RECIST response resulting in a 47% objective response rate.

• Of the 32 patients in Phase 1, 16 patients achieved an objective response for an ORR of 50% with durable responses observed across all dose cohorts, including one complete response in cohort 5. The median duration of treatment for all patients was 10.1 months. 72% of patients remain active in the study as of the data cutoff date.

• Of the 36 patients enrolled in Phase 2 cohort A, 19 patients were evaluable for efficacy, of which there were eight patients with an objective response for an ORR of 42%. Of the 19 patients, 10 had more than one follow-up imaging assessment and two responses occurred at later scans. The median duration of treatment for all patients was 1.9 months. The study is ongoing and follow-up evaluation is continuing with 83% of patients remaining active as of the data cutoff date.

In both Phase 1 and Phase 2 cohort A, treatment with vimseltinib was generally well tolerated in patients with TGCT. The majority of the common (≥15%) TEAEs were Grade 2 or lower. Two patients (6%) discontinued treatment due to a TEAE in Phase 1 and one patient (3%) discontinued treatment due to an TEAE in Phase 2 cohort A. Two patients experienced SAEs at least possibly related to vimseltinib, including metabolic encephalopathy and vaginal hemorrhage in Phase 1; no treatment-related SAEs were reported in Phase 2 cohort A. Observed transaminase, pancreatic, and creatine phosphokinase enzyme elevations were mostly low grade, asymptomatic, and consistent with mechanism of action of CSF1R inhibitors. No abnormalities in bilirubin levels were reported.

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We plan to advance vimseltinib into a pivotal Phase 3 study in patients with TGCT. The MOTION study is two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with symptomatic TGCT who are not amenable to surgery. In Part 1 of the study, eligible study participants will be assigned 2:1 to receive either vimseltinib or matching placebo for 24 weeks. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib for Part 2 of the study. Part 2 is a long-term treatment phase in which all participants receive open-label vimseltinib. The primary endpoint of the study is ORR at 25 weeks as measured by RECIST v1.1 by blinded independent central review.

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