Vimseltinib Improves 25-Week ORR Vs Placebo in TGCT

Hans Gelderblom, MD, PhD

Vimseltinib (DCC-3014) elicited a statistically significant and clinically meaningful improvement in 25-week overall response rate (ORR) vs placebo in patients with tenosynovial giant cell tumor (TGCT) that was not amenable to surgery, meeting the primary end point of the phase 3 MOTION trial (NCT05059262).¹

Topline data showed that patients in the intention-to-treat population given vimseltinib (n = 83) achieved a 25-week ORR of 40% (95% CI, 29%-51%) vs 0% (95% CI, 0%-9%) for those given placebo (n = 40). The 25-week ORR response difference between the 2 arms was 40% (95% CI, 29%-51%; P < .0001).

As of the August 22, 2023, data cutoff, the trial also met all key secondary end points, including an 25-week ORR by tumor volume score (TVS) of 67% (95% CI, 56%-77%) with vimseltinib vs 0% (95% CI, 0%-9%) with placebo (P < .0001) and an improvement from baseline active range of motion (ROM) at week 25 of 18.4% with vimseltinib vs 3.8% with placebo (P = .0077). Other key secondary end points were stiffness, physical function, pain, and quality of life.

“Patients suffering from TGCT are in need of a new treatment option that offers both strong clinical benefit and a well-tolerated safety profile,” Hans Gelderblom, MD, PhD, chair of the Department of Medical Oncology at Leiden University Medical Center in the Netherlands, stated in a press release. “TGCT has a significant negative impact on the daily life of patients who face substantial pain, stiffness, and impaired mobility. Success across both the primary and all key secondary end points in MOTION underscores vimseltinib’s ability to help [patients with] TGCT feel and function better.”

MOTION is a 2-part, randomized, double-blind trial assessing the efficacy and safety of vimseltinib, an oral, selective CSF1R switch-control kinase inhibitor, in patients at least 18 years of age with TGCT not amenable to surgery who are naïve to prior CSF1/CSF1R inhibitors.1,2 Patients who had previously received imatinib (Gleevec) or nilotinib (Tasigna) were allowed. Other eligibility criteria included symptomatic disease defined as at least moderate stiffness or at least moderate pain; receipt of a stable analgesic regimen for at least 2 weeks prior to the first dose of the study drug; measurable disease per RECIST v1.1 criteria with at least 1 measurable lesion of at least 2cm; and adequate organ and bone marrow function.²

In part 1 of MOTION, 123 patients were randomly assigned 2:1 to receive either 30 mg of vimseltinib or placebo twice weekly for 24 weeks. The primary end point of this trial was ORR at week 25 per RECIST v1.1 criteria by blinded independent radiologic review (IRR).

Part 2 of MOTION, in which patients from both arms of the trial have the option to receive 30 mg of vimseltinib, is ongoing.^1,2

The safety profile of vimseltinib in MOTION was consistent with previously reported data.¹ Investigators observed no evidence of cholestatic hepatotoxicity in the vimseltinib arm. In the vimseltinib arm, the most common treatment-emergent adverse effects (TEAEs) were periorbital edema (any-grade, 45%; grade 3/4, 4%), fatigue (33%; 0%), face edema (31%; 1%), pruritus (29%; 2%), headache (28%; 1%), asthenia (27%; 1%), nausea (25%; 0%), increased creatinine phosphokinase (CPK; 24%; 10%), increased aspartate aminotransferase (AST; 24%; 0%), arthralgia (19%; 0%), rash (19%; 0%), maculopapular rash (19%; 1%), peripheral edema (18%; 0%), hypertension (17%; 5%), and diarrhea (12%; 0%).

In the placebo arm, the most common TEAEs were periorbital edema (any-grade, 13%; grade 3/4, 0%), fatigue (15%; 0%), face edema (8%; 0%), pruritus (8%; 0%), headache (26%; 0%), asthenia (23%; 1%), nausea (21%; 3%), increased AST (3%; 0%), arthralgia (15%; 3%), rash (5%; 0%), peripheral edema (8%; 0%), hypertension (10%; 3%), and diarrhea (21%; 3%). The only grade 4 AEs observed were increased CPK, which occurred in 2 patients in the vimseltinib arm.

A total of 6% of patients who received vimseltinib experienced TEAEs leading to treatment discontinuation. Additionally, 53% of patients had TEAEs leading to dose interruption, and 42% of patients experienced TEAEs leading to dose reduction.

The efficacy and safety of vimseltinib in patients with advanced tumors or TGCT was also evaluated in a phase 1/2, multicenter, open-label trial (NCT03069469), results from which will be presented at the 2023 Connective Tissue Oncology Society Annual Meeting, taking place in Dublin, Ireland, from November 1 through November 4, 2023.^1,3

At a cutoff date of June 27, 2023, this study had enrolled 97 total patients. Phase 1 enrolled 32 patients with malignant solid tumors or TGCT in 3 cohorts across multiple doses. This dose-escalation phase required patients to be at least 18 years of age and have at least 1 measurable lesion per RECIST v1.1 criteria; an ECOG performance score of 0 or 1 (patients with malignant solid tumors only); and adequate organ and bone marrow function.

Patients were excluded if they had received prior anticancer therapy or therapy for TGCT, including investigational therapy, within 2 weeks (or 28 days for therapies with a half-life longer than 3 days) prior to the initiation of the study drug; unresolved toxicity from previous anticancer of TGCT therapy, excluding alopecia; known active central nervous system metastases; a presence or history of clinically relevant cardiovascular abnormalities; and any other clinically significant comorbidities.³

Phase 2 enrolled 65 patients with TGCT in 2 cohorts at the recommended phase 2 dose of vimseltinib of 30 mg twice weekly.¹ Cohort A of this dose-expansion phase included 46 patients with TGCT who had received no prior CSF1/CSF1R inhibitors but could have received prior imatinib or nilotinib. Cohort B included 19 patients with TGCT who had received prior CSF1/CSF1R inhibitors, excluding those who had received prior imatinib or nilotinib and those who discontinued systemic therapy with CSF1/CSF1R inhibitors because of drug-induced liver injury.1,3 Patients were required to have adequate bone marrow and organ function and at least 1 measurable lesion per RECIST v1.1 criteria.3 Patients were excluded if they had received therapy for TGCT, including investigational therapy, within 2 weeks (or 28 days for therapies with a half-life longer than 3 days) prior to the initiation of the study drug or known metastatic TGCT or other active cancer treatment requiring concurrent therapy.

At data cutoff, 93 patients across both phases were evaluable for efficacy per RECIST v1.1 criteria by IRR. In phase 1, patients achieved a best ORR of 72%; the median duration of response (DOR) was not reached (NR; range, 3.8+ to 45.2+ months), the median duration of treatment was 25.1 months (range, 0.7-46.9), and 47% of patients were active on treatment at the cutoff date. In phase 2 cohort A, patients achieved a best ORR of 64%, including a best ORR of 38% at week 25. The median DOR was NR (range, 0.03+ to 25.4+ months), the median duration of treatment was 21.0 months (range, 0.2-30.3), and 48% of patients were active on treatment at data cutoff. In phase 2 cohort B, patients achieved a best ORR of 44% with a median DOR of NR (range, 4.0+ to 21.0+ months) and a median duration of treatment of 7.3 months (range, 0.7-27.4). Notably, 74% of patients were active on treatment at the cutoff date.

Moreover, updated data from both cohorts of the phase 2 portion of the trial showed that patients achieved clinically meaningful symptomatic benefit at week 25 across several secondary efficacy measures, including active ROM, stiffness, physical function, and pain, as well as best ORR per TVS in cohort A.

Furthermore, the safety findings with vimseltinib in the phase 1/2 trial were consistent with previously reported data and demonstrated that the agent was well tolerated. Investigators observed no evidence of cholestatic hepatotoxicity. Additionally, 9% of patients discontinued treatment because of TEAEs.

“The topline results from MOTION, together with the impressive data announced today from the phase 1/2 study showing that the response rates with vimseltinib continue to increase over time, and that patients continue to receive long-term clinical benefit as evidenced by the median duration of treatment, demonstrates vimseltinib’s potential to become a best-in-class agent,” Gelderblom said in the press release.

“We are excited about the potential for vimseltinib to become our next approved medicine, supporting our continued evolution to a company with multiple marketed products,” Steve Hoerter, president and chief executive officer of Deciphera Pharmaceuticals, added in the news release. “The totality of data shown today demonstrate the potential for vimseltinib to offer a new and differentiated treatment option for patients with TGCT. We look forward to working with regulatory agencies worldwide as we focus on delivering this important new treatment option to patients with TGCT.”

Deciphera expects to submit a new drug application for vimseltinib in the second quarter of 2024 and a marketing authorization application for the agent in the third quarter of 2024. Additional efficacy and safety findings from part 1 of MOTION will be presented at an upcoming medical meeting.

References

1. Deciphera Pharmaceuticals announces positive top-line results from MOTION pivotal phase 3 study of vimseltinib in patients with tenosynovial giant cell tumor (TGCT). News Release. Deciphera Pharmaceuticals LLC. October 30, 2023. Accessed October 30, 2023. https://investors.deciphera.com/news-releases/news-release-details/deciphera-pharmaceuticals-announces-positive-top-line-results-0
2. Study of vimseltinib for tenosynovial giant cell tumor (MOTION). ClinicalTrials.gov. Updated March 16, 2023. Accessed October 30, 2023. https://clinicaltrials.gov/study/NCT05059262
3. Study of DCC-3014 in patients with advanced tumors and tenosynovial giant cell tumor. ClinicalTrials.gov. Updated October 10, 2023. Accessed October 30, 2023. https://clinicaltrials.gov/study/NCT03069469