Vimseltinib Demonstrates Encouraging Preliminary Efficacy, Tolerability in TGCT

Hans Gelderblom, MD

Vimseltinib (DCC-3014) was well tolerated and demonstrated promising preliminary efficacy in patients with tenosynovial giant cell tumors (TGCT) whose tumors are not amendable to surgical resection, according to results from a phase 1/2 study (NCT03069469) presented during the 2021 ESMO Congress.¹

Results from the phase 1 portion of the study showed that vimseltinib induced an overall response rate (ORR) of 50% in this patient population (n = 32), with durable responses observed across all dose cohorts, including 1 complete response (CR) in cohort 5 (n = 8). Moreover, in cohort A (n = 19) of the phase 2 portion of the study, the agent elicited an ORR of 42%, which was comprised of partial responses (PRs). Notably, 10 of the 19 evaluable patients in cohort A had more than 1 follow-up imaging assessment and 2 responses were reported at later scans.

“These results support further evaluation of vimseltinib in MOTION, a randomized, placebo-controlled, phase 3 trial in patients with TGCT not amenable to surgical resection,” lead study author Hans Gelderblom, MD, of Leiden University Medical Center, and colleagues, wrote in a poster on the data.

TGCT is a rare, locally aggressive neoplasm, in which overexpression of colony-stimulating factor 1 (CSF1) drives recruitment of macrophages, which results in local inflammation and joint destruction. Patients with TGCT often experience debilitating symptoms, with significant disease burden, and an unmet need for treatment options remains for those whose tumors are not amenable to surgery.

Vimseltinib is an oral, investigational, highly selective, switch-control kinase inhibitor of the CSF1 receptor. To further explore the safety and efficacy of vimseltinib in patients with TGCT who are not amenable to surgery, investigators launched a multicenter, open-label study comprised of 2 phases.

The phase 1 dose-escalation portion of the research utilized a pharmacologically-guided 3+3 design and sought to identify both the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD) of the agent. The phase 2 expansion portion of the research aimed to evaluate the safety, tolerability, and preliminary efficacy of vimseltinib in 2 cohorts.

Cohort A enrolled patients who did not previously receive anti–CSF1/CSF1 receptor therapy; however, prior therapy with imatinib (Gleevec) or nilotinib (Tasigna) was permitted. Cohort B included those who received prior anti–CSF1/CSF1 receptor therapy; in this cohort, prior imatinib or nilotinib alone was not allowed.

A total of 32 patients were examined on the phase 1 portion of the trial. Cohort 5 comprised 5 patients who received vimseltinib at a loading dose of 30 mg daily for 5 days, and 30 mg twice weekly thereafter. Cohort 8 comprised 12 patients who received the agent at a loading dose of 30 mg daily for 3 days, and 10 mg daily thereafter. Finally, cohort 9 comprised 12 patients who received vimseltinib at a loading dose of 20 mg daily for 3 days, and 6 mg daily thereafter.

The RP2D was identified to be a twice weekly dose of 30 mg, and this was administered to the 37 patients enrolled to cohort A of the phase 2 portion of the study. Among those patients enrolled to cohort A, 19 were determined to be evaluable of efficacy, as of the data cutoff of June 7, 2021.

Among the patients enrolled to both the phase 1 and 2 portions of the study, the median age was 47.5 years (range, 21-73). The majority of patients in both phase 1 and 2 of the study were female (53% and 72%, respectively), White (97% and 78%), and had disease located in the knee (63% and 56%).

Thirty-eight percent of patients on the phase 1 portion of the research had received at least 1 prior surgery vs 89% of those included in the phase 2 portion. Thirteen percent of patients included in the phase 1 portion of the trial had received prior imatinib or nilotinib and 3% received prior lacnotuzumab (MCS-110). Six percent of patients included in the phase 2 portion of the research received prior imatinib or nilotinib.

Additional data showed that 15 patients on the phase 1 portion of the study experienced a PR (47%) with vimseltinib, and 16 achieved stable disease (50%). In the phase 2 portion, 8 patients achieved a PR (42%) with the agent, and 11 patients had stable disease (58%).

In terms of safety, 63% of all patients in the phase 1 group (n = 32) experienced a treatment-emergent adverse effect (TEAE), and 31% reported a grade 3/4 event. The most frequently reported grade 3/4 TEAEs in the phase 1 group included increased aspartate aminotransferase (13%), increased lipase (9%), increased amylase (6%), and hypertension (6%).

Moreover, 59% of patients in the phase 1 portion of the research reported a TEAE that led to a dose modification; 56% experienced a TEAE that led to a dose interruption, and 41% experienced a TEAE that required a dose reduction. TEAEs led to treatment discontinuation in 6% of patients.

In the phase 2 group (n = 36), 53% of patients reported a TEAE of any grade, and 25% experienced TEAEs that were grade 3/4 in severity. Additionally, in this group, TEAEs led to a dose modification in 28% of patients; 25% of patients experienced a dose interruption due to TEAEs, 8% required a dose reduction, and 3% of patients experienced effects that resulted in treatment discontinuation.

“In patients with TGCT not amenable to surgical resection, vimseltinib was well tolerated in both phase 1 and phase 2 cohort A,” the study authors wrote. “The safety profile remains manageable with longer-term follow-up across all phase 1 dose cohorts.”

Reference

1. Gelderblom H, Abdul Razak AR, Sánchez-Gastaldo A, et al. Safety and preliminary efficacy of vimseltinib in tenosynovial giant cell tumor (TGCT). Ann Oncol. 2021;32(5):S1233-S1234. doi:10.1016/j.annonc.2021.08.275