Nested Therapeutics Reports Promising Results for Brain-Penetrant Pan-RAF/MEK Therapy

NST-628 demonstrates 38% response rate and 85% disease control rate in advanced NRAS and BRAF Class II/III melanoma patients

Apr. 20, 2026 at 6:37am

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An extreme close-up X-ray image revealing the intricate molecular structures within a brain tumor cell, conceptually illustrating the potential of Nested Therapeutics' drug NST-628 to target RAS/MAPK-driven cancers.Nested Therapeutics' brain-penetrant cancer drug NST-628 shows promise in treating hard-to-treat brain tumors and other RAS/MAPK-driven cancers.Cambridge Today

Nested Therapeutics, a clinical-stage oncology company, reported initial results from its ongoing Phase 1 study evaluating NST-628, a brain-penetrant pan-RAF/MEK molecular glue, in patients with advanced solid tumors. The data presented at AACR 2026 showed encouraging single-agent anti-tumor activity and a favorable tolerability profile across multiple RAS/MAPK-driven tumors, including a 38% response rate and 85% disease control rate in heavily pretreated NRAS and BRAF Class II/III melanoma patients, a population with no approved targeted therapies.

Why it matters

These findings support the potential of NST-628 to address significant unmet need across RAS/MAPK-driven cancers, particularly in melanoma patients with NRAS and BRAF Class II/III mutations who currently lack effective targeted treatment options. The early evidence of clinical activity beyond melanoma, including in KRAS-mutant solid tumors, as well as the drug's brain penetrance, further highlight its versatility as a foundational therapy in both monotherapy and combination settings.

The details

In the ongoing Phase 1 study, NST-628 has been administered to 69 patients, with 64 in the dose-escalation phase and 5 in the expansion phase. At the recommended dose for expansion, NST-628 monotherapy demonstrated a 38% response rate and 85% disease control rate in BRAF Class II/III and NRAS-mutant melanoma patients. Responses were also observed across multiple other 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) also showed a 70% tumor shrinkage, consistent with NST-628's preclinical brain penetration profile. The safety profile was favorable, with predominantly Grade 1-2 adverse events and a low discontinuation rate of 9% at the recommended dose.

  • The data cutoff date for the reported results was February 1, 2026.
  • The AACR Annual Meeting 2026 where the data was presented took place on April 20, 2026.

The players

Nested Therapeutics

A clinical-stage oncology company developing transformative therapies for RAS/MAPK-driven disorders, including the brain-penetrant pan-RAF/MEK molecular glue NST-628.

Darrin Miles

Chief Executive Officer of Nested Therapeutics.

Philip Komarnitsky, MD, PhD

Chief Medical Officer of Nested Therapeutics.

Ahmad A. Tarhini, MD, PhD

Presenter of the data at the AACR Annual Meeting 2026 and a researcher from Moffitt Cancer Center.

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What they’re saying

“These initial data support our hypothesis that targeting RAF/MEK signaling with a single-agent, fully brain-penetrant pan-RAF/MEK molecular glue can deliver meaningful clinical benefit with a tolerability profile that supports sustained dosing even in comparison to what may be expected from combination regimens.”

— Darrin Miles, Chief Executive Officer of Nested Therapeutics

“The anti-tumor activity observed with NST-628 monotherapy is encouraging. A safety profile that supports continuous dosing at 82% dose intensity with a 9% discontinuation rate, combined with the response rate of 38% and disease control rate of 85% in NRAS and BRAF Class II/III melanoma patients at the recommended dose, is promising for this patient population with no approved targeted therapies.”

— Philip Komarnitsky, MD, PhD, Chief Medical Officer of Nested Therapeutics

What’s next

Nested plans to continue enrollment in the ongoing Phase 1 expansion cohort and evaluate NST-628 in additional malignant and non-malignant MAPK-driven diseases and combination settings, including mutant-selective RAS and other inhibitors.

The takeaway

The promising results with NST-628 monotherapy, including the high response and disease control rates in NRAS and BRAF Class II/III melanoma patients, as well as the evidence of activity in other RAS/MAPK-driven tumors and brain penetrance, highlight the potential of this brain-penetrant pan-RAF/MEK molecular glue to address significant unmet needs across a range of cancers.