NST-628 / Nested Therap - LARVOL DELTA

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 (AACR 2026) - "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."

Clinical • First-in-human • Metastases • P1 data • Brain Cancer • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • BRAF • KRAS • NRAS

A Phase 0/1 Study of NST-628 in Recurrent Grade 4 Glioma (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Nader Sanai

New P1 trial • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor

Nested Therapeutics Reports Initial Encouraging Clinical Activity and Favorable Tolerability of NST-628, a Brain-Penetrant Pan-RAF/MEK Molecular Glue, at AACR 2026 (PRNewswire) - "NST-628 monotherapy demonstrated a 38% response rate in BRAF Class II/III and NRAS-mutant melanoma (N=13) and 33% response rate overall (N=18); response rates include one unconfirmed partial response. Disease control rate was 85% in the melanoma subgroup and 72% overall. With a median follow-up of 6.4 months, the median duration of response in melanoma was not yet reached....Responses to NST-628 were observed across multiple tumor types and genotypes, including KRAS-mutant ovarian and cervical cancers...as well as NRAS/BRAF Class III-mutant colorectal cancer and BRAF Class II-mutant thymic cancer. A patient with high-grade astrocytoma (BRAF V600E)...demonstrated 70% tumor shrinkage on NST-628 monotherapy..."

P1 data • Astrocytoma • Cervical Cancer • Colorectal Cancer • Melanoma • Ovarian Cancer • Thymic Carcinoma

NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers (AACR 2024) - "Given its differentiated molecular mechanism, best-in-class drug-like properties, and superior safety profile in IND-enabling GLP studies, NST-628 is positioned to make an impact clinically to address unmet patient need. First-in-human trials of NST-628 have been initiated in early 2024"

First-in-human • Oncology • Solid Tumor • ARAF • BRAF • KRAS • NF1 • NRAS

Target identification, selectivity profiling and binding site mapping of small molecule and peptide drugs by LiP-MS (AACR 2024) - "In this study, we present target deconvolution results on four small molecule compounds and one peptide compound with very distinct pharmacological profile: 1) staurosporine, a broad-specific kinase inhibitor; 2) roniciclib, a failed clinical-stage pan-CDK inhibitor; 3) selumetinib, an allosteric, non-ATP-competitive MEK 1 and 2 inhibitor; 4) NST-628, a newly developed non-degradating molecular glue inhibiting the RAS/MAPK pathway; and 5) Acetyl-calpastatin, a 24 amino-acid polypeptide inhibitor of calpain 1 and 2. Nature Comm 2020 [2] Hendricks and Beaton et al. ACS Chem Bio 2021 [3] AACR 2022 [4] AACR 2023 [5] AACR-NCI-EORTC 2023"

Oncology • CAPN1 • CDK1 • CDK2 • CDK4 • CDK9 • MAP2K1 • MAP2K2

The novel pan-RAF-MEK glue NST-628 is highly efficacious as monotherapy and as an anchor for vertical inhibition of the RAS-MAPK pathway in KRAS-mutant cancers (EORTC-NCI-AACR 2024) - P1 | " We designed in vitro potency assays (proliferation) to address the efficacy of NST-628 alone and in combination with KRAS G12D-inhibitors RMC-9805 (RAS "ON"), MRTX1133 (RAS "OFF"), and the pan-RAS inhibitor RMC-6236 (RAS "ON"). Collectively, this study warrants further investigation of NST-628 as a vertical combination partner with both RAS "ON" and RAS "OFF" inhibitors targeting KRAS G12D and other RAS mutations. NST-628 is positioned to make an impact clinically in areas of high unmet patient need in KRAS-mutant solid tumors. First-in-human trials of NST-628 in RAS- and RAF-mutant solid tumors are underway in 2024 (NCT06326411)."

Late-breaking abstract • Monotherapy • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

A phase I, first-in-human, dose escalation and expansion study of oral pan-RAF/MEK molecular glue NST-628 in subjects with solid tumors harboring RAS-MAPK pathway alterations (ESMO 2024) - P1 | "Secondary endpoints are PFS/OS, while exploratory translational endpoints include levels of circulating tumor DNA, serum tumor markers, and tumor/blood pERK. Subjects have been treated and recruitment is ongoing."

Clinical • P1 data • Brain Cancer • CNS Tumor • Glioma • Melanoma • Oncology • Solid Tumor • BRAF • KRAS • NRAS

The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers. (PubMed, Cancer Discov) - "With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • BRAF

Nested Therapeutics Announces Oral Presentation of Preclinical Data for NST-628, a Novel, Fully Brain-Penetrant, Pan-RAF/MEK Molecular Glue, at the 2024 AACR Annual Meeting (PRNewswire) - "Nested Therapeutics...announced that preclinical data for the company's lead program, NST-628, were featured in an oral presentation...at the American Association for Cancer Research (AACR) Annual Meeting....In mouse models with an intact blood brain barrier as well as central nervous system (CNS) models with RAS-MAPK alterations, NST-628 demonstrated full intrinsic CNS permeability. These data suggest NST-628 has the potential to treat brain metastases and primary CNS malignancies with MAPK pathway alterations....Preclinical data support NST-628 as an ideal combination partner for upstream inhibitors including KRAS inhibitors by effectively preventing pathway reactivation."

Preclinical • CNS Tumor

Nested Therapeutics Announces FDA Clearance of Investigational New Drug (IND) Application for NST-628, a Novel Pan-RAF/MEK Molecular Glue (PRNewswire) - "Nested Therapeutics...announced that the U.S. Food and Drug Administration (FDA) cleared the investigational new drug (IND) application for NST-628 for the treatment of patients with advanced solid tumors harboring genetic alterations in the RAS-MAPK pathway....'With clinical trial sites already activated, we look forward to dosing the first patients in this trial in the first half of this year'....The Phase 1 open-label, single-arm, two-part study (NCT06326411) is intended to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of single agent NST-628 in adult patients with RAS-MAPK pathway mutated/dependent advanced solid tumors..."

IND • Trial status • Solid Tumor

A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors (clinicaltrials.gov) - P1 | N=230 | Recruiting | Sponsor: Nested Therapeutics, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF

A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors (clinicaltrials.gov) - P1 | N=230 | Not yet recruiting | Sponsor: Nested Therapeutics, Inc

New P1 trial • Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF

Nested Therapeutics to Present Preclinical Data for NST-628, a Novel Pan-RAF/MEK Molecular Glue, in the New Drugs on the Horizon Series at 2024 AACR Annual Meeting (PRNewswire) - "Nested Therapeutics...today announced that preclinical data from its lead program, NST-628, will be featured in an oral presentation in the 'New Drugs on the Horizon' series at the American Association for Cancer Research (AACR) Annual Meeting taking place in San Diego, California from April 5-10, 2024....The preclinical data supports NST-628's profile as a mechanistically novel, fully brain penetrant non-degrading pan-RAF/MEK molecular glue that targets RAF and MEK nodes in the RAS-MAPK pathway."

Preclinical • Brain Cancer • Oncology

Nested Therapeutics Presents First Preclinical Data for Lead Candidate, NST-628, a RAS/MAPK Pathway Inhibitor at 2023 AACR-NCI-EORTC Conference (PRNewswire) - "Nested Therapeutics...presented the first preclinical data from its lead candidate, NST-628, a mechanistically novel non-degrading molecular glue that targets multiple nodes in the RAS/MAPK pathway, outlined in three poster presentations at the 2023 AACR-NCI-EORTC International Conference taking place in Boston, Massachusetts from October 11-15, 2023. NST-628 outperformed other MAPK-targeted compounds administered as either single agents or combinations in anti-tumor activity and tolerability. Additionally, NST-628 effectively crossed the blood-brain barrier, suggesting a potential advantage for the treatment of brain metastases and primary CNS malignancies with MAPK pathway alterations....Nested Therapeutics plans to submit an IND for NST-628 following completion of ongoing preclinical and IND-enabling studies, to support first-in-human studies to start in the first half of 2024."

IND • Preclinical • CNS Tumor

Nested Therapeutics to Present Preclinical Data for Novel, Potential Best-in-Class Inhibitor of the RAS/MAPK Pathway at 2023 AACR-NCI-EORTC Conference (PRNewswire) - "Nested Therapeutics, a biotechnology company pioneering a next-generation precision medicine platform to address hard-to-treat cancers, today announced it will present preclinical data from its lead candidate, NST-628, a mechanistically novel non-degrading molecular glue that targets multiple nodes in the RAS/MAPK pathway, at the upcoming 2023 AACR-NCI-EORTC International Conference....Nested Therapeutics will be presenting three posters that validate the mechanism of action and demonstrate potential superiority of NST-628 compared to other MAPK-targeted compounds."

Preclinical • CNS Tumor • Oncology