pan-RAF-MEK分子胶NST-628在晚期或难治性RAF、KRAS和NRAS突变实体瘤患者中的1a/b期剂量递增和扩展试验初步结果

Background The RAS-MAPK pathway is altered in ~40% of all human cancers, yet its therapeutic inhibition has been limited by adaptive resistance, paradoxical activation, and poor CNS penetration. NST-628 is a potent non-degrading fully brain penetrant pan-RAF-MEK molecular glue that leads to inactive complex formation between MEK and all isoforms of RAF preventing activation of MEK by RAF resulting in broad anti-tumor activity preclinically. We report preliminary findings from the first-in-human Phase 1a/b study of NST-628 in pts with RAS-MAPK-altered cancers. Methods NST-628-001 is an open-label Phase 1a/b study evaluating the safety, pharmacokinetics, and preliminary efficacy of oral NST-628 in pts with refractory metastatic/advanced solid tumors with K/NRAS or RAF mutations. Dose escalation employed BOIN method, with accelerated titration. Longitudinal PK and PD were analyzed. Tumor assessments were performed with RECIST 1.1 for primary extracranial solid tumors, and with RANO 2.0 for CNS malignancies. Results As of 02/01/2026, NST-628 has been administered to 64 pts across 7 dose regimens in the dose-escalation phase and to 5 pts in the expansion phase. Most common tumors were melanoma (48%), pancreatic (14%) and colorectal (8%) cancer. Median age was 65 yrs (range 18-89); median number of prior lines of systemic therapy was 2 (range 1-8). Most common treatment related adverse events (TRAEs) included rash, diarrhea, CK elevations and retinopathy. Majority of TRAEs were Grade (G) 1-2. Most common ≥G3 TRAEs were CK elevations (N = 6) and diarrhea (N = 3). No G5 TRAEs. The PK of NST-628 was characterized by apparent clearance of 0.143 L/hr. Exposure was dose-proportional at doses < 0.4 mg, and > dose-proportional at ≥ 0.4 mg. MTD was 0.4 mg QD and recommended dose for expansion (RDE) was 0.4 mg QD x7 followed by 0.3 mg QoD. At the RDE in response-evaluable BRAF Class II/III or NRAS mutant melanoma (N = 13) response rate (RR) was 38% (one response unconfirmed); across all doses (N = 28), RR was 29% (two responses unconfirmed at data cutoff). With median follow-up of 6.4 mo. median duration of response in melanoma was not reached. In addition to melanoma, responses were observed in ovarian, cervical, thymic and colorectal cancer. Baseline ctDNA confirmed driver mutations in 86% of pts and on treatment measurements correlate changes in ctDNA with radiographic response. Conclusions NST-628 showed a manageable safety profile in pts with advanced solid tumors and promising anti-tumor activity in previously treated BRAF Class II/III or NRAS-mutant melanoma and other RAS/RAF-driven malignancies. Beyond positioning NST-628 as a promising new therapy for pts with melanoma, the safety profile and anti-tumor activity support evaluation as monotherapy and in rational combinations in other patients with RAS-RAF-driven tumors.