NST-628 Shows Early Promise in NRAS/BRAF+ Melanoma, Other Solid Tumors

NST-628, a brain-penetrant pan-RAF/MEK molecular glue, demonstrated favorable disease control in patients with NRAS and BRAF class II/III–mutant melanoma, according to results presented at the American Association for Cancer Research Annual Meeting 2026 in San Diego, California.¹

Findings from an ongoing phase 1 study (NCT06326411) suggest encouraging antitumor activity and a manageable tolerability profile across multiple RAS/MAPK-driven solid tumors, with the most notable findings being a 38% response rate and 85% disease control rate (DCR) in patients with heavily pretreated NRAS- and BRAF class II/III–mutant melanoma.

“The clinical evidence of activity in malignancies with BRAF class III mutations, an emerging resistance mechanism to RAS inhibitors, and of brain penetrance consistent with preclinical findings is particularly noteworthy,” Philip Komarnitsky, MD, PhD, MBA, chief medical officer of Nested Therapeutics, stated in a news release.²

Study Background

The single-arm 2-part study includes dose escalation followed by dose expansion of single-agent NST-628, given orally once daily in 28-day cycles.³ The primary end point in the dose-escalation portion is to determine a recommended dose for expansion (RDE) and dose-limiting toxicities. Secondary end points include objective tumor response rate, pharmacokinetics, and progression-free survival. In the dose-expansion portion, there are separate melanoma cohorts for patients with activating NRAS mutations and select BRAF alterations, and nonmelanoma cohorts of patients, including those with solid tumors with NRAS activating mutations, KRAS activating mutations, select BRAF mutations, and glioma with BRAF alterations.

Key Efficacy Results

At the RDE of 0.4 mg once daily for 7 days followed by 0.3 mg every other day, NST-628 achieved a 38% response rate and an 85% DCR in response-evaluable patients with BRAF class II/III or NRAS-mutant melanoma (n = 13). Across all evaluable patients at the RDE (n = 18), the overall response rate was 33%, and the DCR was 72%. One response in each group was unconfirmed as of the data cutoff on February 1, 2026. At a median follow-up of 6.4 months, the median duration of response in the melanoma cohort had not yet been reached.¹

These results carry particular clinical weight because NRAS- and BRAF class II/III–mutant melanomas collectively affect approximately 33% of patients with cutaneous melanoma or approximately 8000 new diagnoses annually in the United States, and no approved targeted therapies exist for this population following treatment with immune checkpoint inhibitors.

Across all dose levels in the dose-escalation phase, the response rate in melanoma was 29% (n = 28) with 2 unconfirmed responses at data cutoff.

Activity Beyond Melanoma and Early CNS Evidence

Responses were observed in tumor types beyond melanoma, including KRAS-mutant ovarian and cervical cancers, NRAS/BRAF class III–mutant colorectal cancer, and BRAF class II–mutant thymic cancer. A patient with KRAS G12V–mutant cervical cancer had an ongoing partial response exceeding 1 year of treatment duration at the time of data cutoff.¹

A particularly notable finding involved a patient with high-grade astrocytoma harboring a BRAF V600E mutation who had previously received multiple lines of RAF/MEK-targeted therapy. That patient demonstrated 70% tumor shrinkage on NST-628 monotherapy, providing early clinical corroboration of the drug's preclinical brain penetration profile. Central nervous system (CNS) tumor response was assessed using RANO 2.0 criteria.

Circulating tumor DNA (ctDNA) analysis reinforced the radiographic data: Baseline ctDNA confirmed driver mutations in 86% of patients, and on-treatment measurements of ctDNA changes correlated with radiographic response.

Safety and Tolerability

As of the data cutoff, NST-628 had been administered to 69 patients—64 in dose escalation across 7 dose regimens and 5 in the expansion phase. Median age was 65 years (range, 18-89), and patients had received a median of 2 prior lines of systemic therapy (range, 1-8).¹

Treatment-related adverse events (TRAEs) were predominantly grade 1 or 2. The most common TRAEs included rash, diarrhea, creatine kinase (CK) elevation, constitutional symptoms, and retinopathy. Grade 3 or higher TRAEs were infrequent; the most common were CK elevation (n = 6) and diarrhea (n = 3). No grade 5 TRAEs were reported.

At the RDE, the discontinuation rate was 9%, and dose intensity was 82% of the intended dose, suggesting that most patients were able to sustain treatment at or near full doses.

Mechanism and Development Context

NST-628 is designed to stabilize inactive RAF-MEK complexes, preventing MEK activation across all RAF isoforms. This mechanism aims to avoid pathway reactivation and adaptive resistance, which have limited the durability of existing RAS/MAPK-targeted agents. The drug's full brain penetrance addresses a long-standing gap in the field, as CNS metastases are common in advanced melanoma and other RAS-driven malignancies.

The expansion phase is currently enrolling at the RDE. Nested Therapeutics, the sponsor, indicated plans to evaluate NST-628 in additional malignant and nonmalignant MAPK-driven diseases and in combination with mutant-selective RAS inhibitors and other targeted agents.²

REFERENCES

1. Tarhini AA, Chen M, Liu J, et al. 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. Cancer Res. 2026;86(suppl 8):CT129. doi:10.1158/1538-7445.AM2026-CT129

2. Nested Therapeutics reports initial encouraging clinical activity and favorable tolerability of NST-628, a brain-penetrant pan-RAF/MEK molecular glue, at AACR 2026. News release. Nested Therapeutics. April 17, 2026. Accessed April 20, 2026. https://tinyurl.com/4vhsyts4

3. A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors (NST-628). ClinicalTrials.gov. Updated April 20, 2026. Accessed April 24, 2026. https://clinicaltrials.gov/study/NCT06326411