Abstract CT129: Preliminary results from a Phase 1a/b dose-escalation and expansion trial of the pan-RAF-MEK molecular glue NST-628 in patients (pts) with advanced or refractory RAF, KRAS, and NRAS-mutant solid tumors

Abstract 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. Citation Format: Ahmad A. Tarhini, Monica Chen, Jia Liu, Varun Monga, Victoria Atkinson, Sarina A. Piha-Paul, Bartosz Chmielowski, Benjamin Herzberg, Charlotte Lemech, Prachi Bhave, Ganessan Kichenadasse, Gerald Falchook, Janice Mehnert, Andrae Vandross, Mohamad Salkeni, Meredith McKean, David Wages, Ann Marie Kennedy, Meagan B. Ryan, John Clark, Abdulaziz Nanah, Michael J. Fossler, Philip Komarnitsky, Igor Puzanov. Preliminary results from a Phase 1a/b dose-escalation and expansion trial of the pan-RAF-MEK molecular glue NST-628 in patients (pts) with advanced or refractory RAF, KRAS, and NRAS-mutant solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT129.