There’s a specific subset of melanoma patients who have zero targeted therapy options.
If you’ve got BRAF V600E melanoma, you’ve got options. Multiple approved drugs. Combination regimens. You can go from diagnosis to durable response in a lot of cases.
But if your melanoma is driven by NRAS, or by BRAF Class II or Class III mutations, you’re basically out of luck after checkpoint inhibitors fail. That’s roughly a third of all cutaneous melanoma. About 8,000 new US diagnoses per year. Nobody has ever approved a targeted therapy for this group.
Yesterday at AACR 2026, Nested Therapeutics reported the first Phase 1 clinical data for NST-628. It’s a brain-penetrant pan-RAF/MEK molecular glue.
38% response rate. 85% disease control rate. In that exact population.
NST-628 Phase 1: NRAS and BRAF Class II/III melanoma
38%
85%
0
Heavily pretreated patients at recommended Phase 2 dose. 82% dose intensity, 9% discontinuation rate.
Molecular glues are having a moment. They’re different from traditional kinase inhibitors because they don’t block an active site. Instead, they physically hold two proteins together in a way that either degrades one or prevents it from doing its job. Kymera, Neomorph, and others have been validating the degrader thesis across immunology and oncology.
NST-628 does something slightly different. It’s a non-degrading molecular glue that locks RAF and MEK together in a catalytically inactive complex. The MAPK pathway gets shut down without either protein being destroyed.
Why that matters: RAF and MEK inhibitors as separate agents have been tried for years. They have tolerability issues. They cause pathway reactivation. Their responses don’t last. Nested’s approach is designed to sidestep all of that by stabilizing the inactive state instead of fighting it.
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Early-stage biotech signals, personalized.
The signals that matter to you. Contextualized and written directly to you. So you cut through the noise and immediately understand why it matters.
The brain penetration matters too. One evaluable patient with high-grade astrocytoma showed tumor shrinkage. That’s the first concrete signal that NST-628 does what Nested has been saying it does since their first Cancer Discovery paper in 2024.
The company has been quietly building. Founded in 2021 out of Cambridge with Klaus Hoeflich as CSO. Raised $125M in Series A back in October 2022. Got FDA IND clearance in March 2024. Started the Phase 1 trial. Until yesterday, basically nothing public.
16 employees. $125M. One program. First-in-class data.
And activity in KRAS-mutant cancers too, by the way. Nested mentioned that in the readout almost as an aside. Single-agent activity across multiple RAS/MAPK-driven tumor types including KRAS, with BRAF Class III activity emerging as a potential resistance mechanism for the growing wave of RAS inhibitors.
That’s the second act.
If the Phase 1 expansion holds up, this is going to be one of the bigger early-stage clinical stories of 2026.
