Nested Therapeutics Reports Promising Early 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. 17, 2026 at 9:36pm

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An extreme close-up X-ray photograph revealing the intricate molecular structure of a brain-penetrant cancer drug, conceptually illustrating the scientific innovation behind this new therapeutic approach.A translucent X-ray view of the molecular structure of a promising new brain-penetrant cancer drug, offering hope for patients with limited treatment options.Cambridge Today

Nested Therapeutics, a clinical-stage oncology company, has reported initial results from its ongoing Phase 1 study evaluating NST-628, a brain-penetrant non-degrading pan-RAF/MEK molecular glue, in patients with advanced solid tumors. The data presented at the AACR Annual Meeting 2026 show encouraging single-agent anti-tumor activity and a favorable tolerability profile in a range of RAF and RAS-mutant tumors, including a 38% response rate and 85% disease control rate at the recommended dose in heavily pretreated NRAS and BRAF Class II/III melanoma patients.

Why it matters

These findings are particularly significant for NRAS and BRAF Class II/III melanoma patients, a population representing approximately 33% of cutaneous melanoma cases, for whom no approved targeted therapies are currently available. The early signals of clinical activity beyond melanoma, including in KRAS-mutant solid tumors and evidence of brain penetrance, further support the potential of NST-628 to address significant unmet need across RAS/MAPK-driven cancers.

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 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, NRAS/BRAF Class III-mutant colorectal cancer, and BRAF Class II-mutant thymic cancer. Additionally, a patient with high-grade astrocytoma (BRAF V600E) previously treated with multiple lines of RAF/MEK-targeted therapy showed a 70% tumor shrinkage on NST-628 monotherapy, consistent with the drug's preclinical brain penetration profile. The safety profile of NST-628 was generally favorable, with predominantly Grade 1-2 adverse events.

  • As of the data cutoff date of February 1, 2026, NST-628 has been administered to 69 patients.

The players

Nested Therapeutics

A clinical-stage oncology company developing transformative therapies for RAS/MAPK-driven disorders.

Darrin Miles

Chief Executive Officer of Nested Therapeutics.

Philip Komarnitsky

Chief Medical Officer of Nested Therapeutics.

Ahmad A. Tarhini

Presenter of the Phase 1 study data at the AACR Annual Meeting 2026 and a physician at 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, 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 initial clinical results for Nested Therapeutics' NST-628, a brain-penetrant pan-RAF/MEK molecular glue, demonstrate promising anti-tumor activity and tolerability, particularly in NRAS and BRAF Class II/III melanoma patients who currently lack approved targeted therapy options. These findings, along with the evidence of activity in other RAS/MAPK-driven tumors and the drug's brain penetrance, support the continued development of NST-628 as a potential foundational therapy for this patient population.