An open-label phase 1 dose-escalation and dose-expansion trial to evaluate the safety, tolerability, and efficacy of TQ-B3234 in adults with neurofibromatosis type 1 (NF1).

Abstract

3108 Background: NF1 is an autosomal-dominant genetic disease that can manifest as neurofibromas, including cutaneous neurofibromas (cNFs) affecting almost all NF1 patients (pts), and plexiform neurofibromas (PNs, up to 50%), which are benign nerve sheath tumors. However, PNs can cause substantial pain, disfigurement and impairment in pts and are at risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs). Currently, there is no medical cure for adult pts with NF1-related PN (NF1-PN), and fewer options for adult pts with cNFs. TQ-B3234 is a highly selective MEK1/2 inhibitor. A phase 1 dose-escalation and dose-expansion trial (NCT05107037) evaluated the safety and efficacy of TQ-B3234 in adult pts with inoperable NF1-PN, MPNSTs or cNFs. Methods: Eligible adult pts with inoperable NF1-PN, MPNSTs or cNFs were included in the dose-escalation phase using a 3+3 design, while only NF1-PN pts proceeded to the dose-expansion phase. TQ-B3234 was administered as a capsule, with doses ranging from 5 mg to 100 mg, once daily in 28-day cycles during the dose-escalation phase. A dose of 50mg was chosen for the dose-expansion phase. The primary endpoints were safety and objective response rate (ORR). ORR was assessed by investigators using REiNS for NF1- PN pts, RECIST 1.1 for MPNSTs pts, and paper frames for the cNF population. Results: As of September 30, 2024, 40 adult pts (31 pts of PNs, 7 pts of cNFs, and 2 MPNSTs) were enrolled. The distribution of doses was as follows: 4 pts at 5 mg, 1 at 10 mg, 3 at 15 mg, 24 at 50 mg, 5 at 70 mg, and 3 at 100 mg. One patient, a cNF case, experienced dose-limiting toxicity (DLT), in the form of G3 diarrhea (16.7%) at the 100 mg dose during the dose-escalation phase. After a median follow-up of 12 months, treatment-emergent adverse events (TEAEs) were observed in 39 pts (97.5%), with the majority were grade 1 or 2. Grade 3 TEAEs were reported in 17.5% of pts; the principal reasons for dose reductions (15.0%) TEAEs included rash acneiform (5.0%), diarrhea (2.5%), and edema (2.5%). No death occurred during the study. Among the 30 pts with NF1-PN who had at least one tumor assessment, 29 pts (96.7%) experienced tumor size reduction, and 11 (36.7%) achieved partial response (PR) based on REiNS criteria. The largest reduction in tumor size was 37.7%. For the 6 cNF pts who had at least one tumor assessment using paper frames, all 6 pts (100%) experienced reduced tumor size, with the largest reduction being 85.2%. Conclusions: TQ-B3234 demonstrated manageable safety and a significant ORR in adult NF1- PN pts. These results support the potential of TQ-B3234 to become a new treatment option for NF1- PN pts. Additionally, TQ-B3234 showed deep and durable volume reduction in adult cNF pts, as assessed by paper frames. This method could serve as a valuable tool in clinical research for achieving accurate quantitative phenotype for NF1. Clinical trial information: NCT05107037 .