FDA Clears IND for NST-628 for Advanced Solid Tumors With RAS-MAPK Mutations


With the FDA clearance of an investigational new drug application, a phase 1 clinical trial evaluating NST-628 will start in mid-2024.

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  • NST-628 is a new investigational drug for patients with advanced solid tumors that have specific genetic mutations in the RAS-MAPK pathway.
  • NST-628 works differently from existing drugs by targeting RAF and MEK in the RAS-MAPK pathway and reaches tumors in the brain.
  • A phase 1 trial (NCT06326411) plans to assess the safety, effectiveness, and appropriate dosage for patients with advanced solid tumors with no other treatment options.

The FDA granted clearance to the investigational new drug application for NST-628 for the treatment of patients with advanced solid tumors with genetic alterations in the RAS-MAPK pathway.1

NST-628, a mechanistically novel, fully brain penetrant non-degrading pan-RAF/MEK molecular glue, works by targeting the RAF and MEK nodes in the RAS-MAPK pathway. In a preclinical trial, NST-628, given as either a single agent or in combination regimens, demonstrated antitumor activity and tolerability.

With this FDA clearance, a phase 1 trial plans to evaluate NST-628 in adult patients with RAS-MAPK pathway mutated/dependent advanced solid tumors who have no other treatment options. Dosing in the study is expected to begin in patients with advanced solid tumors harboring genetic alterations in the MAPK pathway in the first half of 2024.

About the Phase 1 Trial of NST-628

The phase 1 study is an open-label, single-arm, 2-part study assessing the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of single agent NST-628.2 The study will include 2 parts. Part A of the trial is the dose-escalation portion which will then be followed by part B, the dose-expansion portion.

Enrollment is open to patients aged 18 years and older who have a histologically or cytologically documented metastatic or locally advanced solid tumor, newly obtained or archived tumor tissue, adequate organ function, and a life expectancy ≥ 12 weeks.

Patients will be excluded from the study if they have conditions interfering with oral intake or with intestinal absorption. NST-628 may not be suitable for patients with significant retinal pathology, increased risk of heart problems, or pneumonitis or interstitial lung disease. Patients who have previously been treated with MEK or BRAF inhibitors, have untreated brain tumors, or have recently undergone other cancer treatments will be excluded.

Women who are pregnant or breastfeeding, or those who cannot or will not use contraception, are also advised against taking NST-628. Further, anyone with a serious or unstable medical condition that could interfere with the study should not take NST-628.

The primary end points for part A are describing the safety profile of NST-628 and establishing the recommended dose for part B of the study. For part B, the primary end point is to evaluate the objective tumor response rate. Secondary end points for part A and B are to evaluate progression-free survival, overall survival, and PK. For patients with solid tumors other than glioma, they must have an ECOG performance status of 0 or 1, and for those with glioma, they must have a Karnofsky score ≥ 70 and an ECOG performance status of 0 or 1.

The estimated study completion date is November 2029.

1. Nested Therapeutics announces FDA clearance of investigational new drug (IND) application for NST-628, a novel pan-RAF/MEK molecular glue. News release. Nested Therapeutics. March 28, 2024. Accessed March 28, 2024. https://tinyurl.com/55xvxkmb
2. A study to investigate the safety and efficacy of NST-628 oral tablets in subjects with solid tumors (NST-628). ClinicalTrials.gov. Updated March 27, 2024. Accessed March 28, 2024. https://clinicaltrials.gov/study/NCT06326411
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