Initial Results of NST-628 Show Promise in Targeting Advanced Melanoma at AACR 2026
Initial Results of NST-628 Show Promise in Targeting Advanced Melanoma at AACR 2026
On April 17, 2026, Nested Therapeutics, a clinical-stage oncology firm, publicly shared promising preliminary outcomes from its ongoing Phase 1 study evaluating NST-628, a unique brain-penetrant pan-RAF/MEK molecular glue, during the AACR Annual Meeting 2026. This innovative treatment is aimed at tackling advanced solid tumors driven by RAS/MAPK signaling, boasting significant anti-tumor activity and excellent tolerability.
Key Findings from the Trial
The data showcased from the trial highlights the antitumor efficacy of NST-628. Specifically, in heavily pre-treated patients with NRAS and BRAF Class II/III melanoma—who represent approximately 33% of cutaneous melanoma patients with no available targeted therapies—the results were impressive:
- - A 38% response rate was recorded following treatment with the recommended dose.
- - The disease control rate reached an exceptional 85% within this subgroup.
- - Notably, the median follow-up period was established at 6.4 months, although the median duration of response remains unreported to date.
These findings confirm Nested Therapeutics' hypothesis that leveraging a single-agent, fully brain-penetrant therapy can yield meaningful clinical benefits while maintaining a tolerability profile favorable enough for sustained dosing. Darrin Miles, CEO of Nested Therapeutics, shared his excitement, indicating this data not only highlights durable responses in hard-to-treat melanoma subtypes but is also encouraging for clinical potential in KRAS-driven solid tumors, among others.
Broader Anti-Tumor Activity Observed
Beyond melanoma, NST-628 demonstrated an ability to provoke responses across various tumor types. For instance:
- - Responses were noted in KRAS-mutant ovarian and cervical cancers, including a noteworthy case involving a patient with KRAS G12V-mutant cervical cancer who has maintained a partial response for over a year.
- - Additionally, some cases of colorectal cancer with NRAS/BRAF Class III mutations and thymic cancer with BRAF Class II mutations exhibited promising results. For instance, a patient suffering from high-grade astrocytoma demonstrated a significant 70% tumor reduction on NST-628.
- - Importantly, reductions in circulating tumor DNA (ctDNA) correlated with radiographic responses observed, indicating a strong connection between decreases in tumor markers and actual tumor size reductions.
Safety and Tolerability
In terms of safety, the NST-628 trials yielded predominantly Grade 1-2 adverse events, with the most common being related to dermatological issues, gastrointestinal disturbances, and mild ocular events. Critically, no Grade 5 events were recorded, and serious adverse effects requiring grade ≥3 intervention were notably infrequent (the most common being CK elevation). The rate of discontinuation was low at just 9%, which is promising for a drug designed to provide continuous treatment for difficult-to-manage cancers, and the delivered dosage intensity stood at 82%.
Philip Komarnitsky, MD, PhD, Chief Medical Officer of Nested Therapeutics, noted, “The initial anti-tumor activity observed with NST-628 monotherapy is indeed encouraging.” This sentiment is pivotal, especially considering that the drug’s efficacy appears particularly promising within patient populations that currently lack approved treatment options.
Moving Forward
Nested Therapeutics continues with the Phase 1 expansion cohort enrollment, aiming to extend evaluations of NST-628 across other malignancies associated with the MAPK pathway as well as in combination therapies.
The poster presentation titled “Preliminary Results from a Phase 1a/b Dose-Escalation and Expansion Trial of the Pan-RAF-MEK Molecular Glue NST-628 in Patients with Advanced or Refractory RAF, KRAS, and NRAS-Mutant Solid Tumors,” presented by Dr. Ahmad A. Tarhini from Moffitt Cancer Center, will further detail outcomes on April 20, 2026. This ongoing research ultimately seeks to benefit a significant subset of the cancer patient population that could greatly benefit from targeted therapies addressing their unique genetic profiles.
As the field of oncology continues to evolve and innovate, NST-628 represents a hopeful advancement for tackling RAS/MAPK-driven cancers, promising to enhance patient care through tailored, effective therapies.
Topics Health）
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