Clinical activity of TGF-β inhibitor vactosertib in combination with imatinib in desmoid tumors: a multicenter phase 1/2 study

BACKGROUND To determine to the activity and safety of TGF-β inhibitor, vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS In this investigator-initiated, open-label, multicenter, phase I/II trial, patients with desmoid tumors not amendable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase I, the vactosertib dose was set at 100 mg (level − 1) and 200 mg (level 1) to determine the recommended phase II dose. Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. The tolerability of the vactosertib and imatinib combination and pharmacokinetic parameters were also evaluated. RESULTS Twenty-eight patients were enrolled with a median follow-up of 20.7 months. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Treatment-naïve patients had longer PFS compared to those with 1–2 or 3 prior treatment modalities (1 year PFS 100% vs 90% vs 25%, P  = 0.017). The most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3–4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS Vactosertib and imatinib combination was well-tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-β inhibitor, in this rare and difficult-to-treat desmoid tumor.