vimseltinib (DCC-3014)

P1/2, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial completion date: Jun 2024 --> Aug 2028 | Trial primary completion date: Dec 2023 --> Jul 2026

P1, N=32, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Phase classification: P1b --> P1 | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P3, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial primary completion date: Mar 2024 --> Aug 2023

P1/2, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2022 --> Dec 2023

In Part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Pts with TGCT not amenable to surgery and no prior anti-CSF1/CSF1R therapy (previous treatment with imatinib or nilotinib was allowed) were enrolled and treated with vimseltinib 30 mg twice weekly (recommended phase 2 dose). Longer follow-up demonstrated that vimseltinib continued to be well tolerated with a manageable safety profile in pts with TGCT not amenable to surgery with no prior anti-CSF1/CSF1R therapy. Antitumor activity continued to improve with a promising overall ORR. At week 25, the majority of responders experienced ≥30% reductions in worst and average pain.

Pts with TGCT not amenable to surgery who received prior anti-CSF1/CSF1R therapy (including pexidartinib, cabiralizumab, or vimseltinib) were enrolled and treated with vimseltinib 30 mg twice weekly (recommended phase 2 dose). Longer follow-up demonstrated that vimseltinib continued to be well tolerated with a manageable safety profile in pts with TGCT not amenable to surgery who received prior anti-CSF1/CSF1R therapy. Antitumor activity continued to improve in this pretreated population, with an increased ORR. At week 25, all responders experienced ≥30% reductions in worst and average pain.

Pexidartinib is the first CSF-1 receptor inhibitor approved for the treatment of TGCT. Here, we discuss various available treatment strategies and ongoing investigations and trials targeting diffuse TGCT, which include nilotinib, lacnotuzumab, cabiralizumab, vimseltinib, and emactuzumab.

Vimseltinib demonstrated long-term tolerability in patients with TGCT not amenable to surgery. The ORR continues to improve; sustained responses were observed across all dose cohorts both within and after 6 months, demonstrating continued benefit with prolonged treatment.Previously presented at ESMO 2022, FPN: Pending, Gelderblom, et al. Reused with permission.

We report safety, efficacy, and preliminary patient-reported outcome data for patients with TGCT treated with the recommended phase 2 dose (RP2D; 30 mg twice weekly; NCT03069469). Patients with TGCT not amenable to surgery were treated in 2 cohorts: A (no prior anti-CSF1/CSF1R therapy except imatinib and/or nilotinib) and B (prior anti-CSF1/CSF1R therapy). At RP2D, vimseltinib demonstrated encouraging antitumour activity with clinical benefit (partial response + stable disease) in 100% of patients. AEs were manageable in both cohorts. Patients reported symptomatic benefit (improved BPI scores).

Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier Ltd.

Patients with TGCT not amenable to surgery were treated in 2 cohorts: A (no prior anti-CSF1/CSF1R therapy except imatinib and/or nilotinib) and B (prior anti-CSF1/CSF1R therapy). At the RP2D of vimseltinib, patients in both cohorts reported improvement in worst and average pain and joint swelling and stiffness at Week 25. Results support continued evaluation of vimseltinib at this dose level in the ongoing phase 3 MOTION trial (NCT05059262).

Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving Food and Drug Administration (FDA) approval for treatment of TGCT. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase 1 clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in initial TGCT patients.

Vimseltinib is currently being evaluated in Phase 1/2 clinical studies for the treatment of TGCT and other solid tumors (NCT03069469; NCT04242238). Initial pharmacodynamic and efficacy data in TGCT patients will be presented.