Molecular Glue Brings New Hope for Patients with BRAF or NRAS-Mutant Melanoma or Other RAS/RAF-driven Malignancies
An interview with:
Ahmad A Tahini MD PhD, Senior Member, Professor, Director, Department of Cutaneous Oncology and Immunology, Moffitt Cancer Center and Research Institute, Tampa, USA.
SAN DIEGO, USA—Patients who have BRAF or NRAS-mutant melanoma or other RAS/RAF-driven malignancies could soon have a new option if they become refractory to current regimens, according to research discussed at the American Association for Cancer Research 2026 Annual Meeting.
The drug NST 628 is described as “non-degrading, brain penetrant, pan RAF-MEK molecular glue” that was found to have “promising anti-tumor efficacy” with manageable toxicities, by first author Ahmad A Tahini MD PhD, Director of Cutaneous Oncology at the Moffitt Cancer Center and Research Institute in Tampa, USA. After reporting his results at the AACR he gave the Audio Journal of Oncology more of the details:
AUDIO JOURNAL OF ONCOLOGY: Ahmad A Tahini MD PhD
IN: [GOODWIN]”Peter Goodwin here, in San Diego……
OUT: ………I’m Peter Goodwin” 8:25secs
AACR ABSTRACT
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
AUTHORS:
Ahmad A. Tarhini1, Monica Chen2, Jia Liu3, Varun Monga4, Victoria Atkinson5, Sarina A. Piha-Paul6, Bartosz Chmielowski7, Benjamin Herzberg8, Charlotte Lemech9, Prachi Bhave10, Ganessan Kichenadasse11, Gerald Falchook12, Janice Mehnert13, Andrae Vandross14, Mohamad Salkeni15, Meredith McKean16, David Wages17, Ann Marie Kennedy17, Meagan B. Ryan17, John Clark17, Abdulaziz Nanah18, Michael J. Fossler18, Philip Komarnitsky17, Igor Puzanov19
INSTITUTIONS:
1H. Lee Moffit Cancer Center and Research Institute, Tampa, FL,
2Memorial Sloan Kettering Cancer Center, New York, NY,
3The Kinghorn Cancer Centre, St Vincent’s Health Network Sydney, Darlinghurst, NSW, Australia,
4UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA,
5Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Woolloongabba, Qld, Australia,
6M. D. Anderson Cancer Center, Houston, TX,
7UCLA Medical Center, Los Angeles, CA,
8Columbia University, New York, NY,
9Scientia Clinical Research, Sydney, NSW, Australia,
10Cabrini Health, Melbourne, Vic, Australia,
11Southern Oncology, Bedford Park, SA, Australia,
12Sarah Cannon Research Institute at Health ONE, Denver, CO,
13NYU Langone, New York, NY,
14Next Oncology Austin, Austin, TX,
15Next Oncology Virginia, Fairfax, VA,
16Sarah Cannon Research Institute, Nashville, TN,
17Nested Therapeutics, Cambridge, MA,
18Cytel, Inc, Waltham, MA,
19Roswell Park Comprehensive Cancer Center, Buffalo, NY
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.
Ahmad A Tarhini MD PhD, AACR 2026, Audio J of Oncol. TEXT
May 19, 2026
