In the dose escalation of the first-in-human SOLARA study, BH-30643 was administered to 39 previously treated EGFR-mutant NSCLC patients across 20–160 mg total daily doses. At candidate doses, plasma exposures exceeded EC90 targets, and case-level tumor regressions were observed across hard-to-treat genotypes, including C797S with exon 19 deletion, C797S plus T790M with exon 19 deletion, G724A with exon 19 deletion, T790M with exon 20 insertion, and exon 20 insertion in a patient with brain metastases. No aggregate objective response rate, duration, CNS response rate, or safety incidence data were disclosed.
BlossomHill Therapeutics presented the preliminary Phase 1 readout at the AACR-NCI-EORTC Molecular Targets meeting and opened expansion cohorts in its global, open-label Phase 1/2 trial. The program is testing a macrocyclic, non-covalent, mutant-selective EGFR inhibitor designed to spare wild-type EGFR/HER2 while targeting classical, atypical (including PACC), and resistance mutations such as C797S and T790M. Expansion cohorts will evaluate single-agent ORR across mutation-defined populations, enrolling both targeted therapy–naïve and pretreated patients with EGFR or HER2 alterations.
Strategically, the company is positioning BH-30643 as a breadth-first, “OMNI-EGFR” solution in a post-osimertinib landscape defined by heterogeneous resistance. Non-covalent binding and a macrocyclic scaffold are intended to neutralize C797S and other liabilities of covalent third-generation TKIs, while the selectivity claim aims to mitigate wild-type EGFR toxicity that often constrains dose intensity. The emphasis on PK exceeding EC90 suggests a potency cushion that sponsors hope will translate into consistent activity across the long tail of rare alleles. The risk is that breadth on paper must be borne out in clinically meaningful, mutation-stratified responses, including in cis/trans C797S/T790M configurations and exon 20 variants, where competing pathways and structural heterogeneity often blunt monotherapy efficacy.
For sites and CROs, expansion into rare EGFR subtypes means screening-heavy operations: central confirmation of specific alleles via tissue or ctDNA, protocol agility for less common genotypes, and careful CNS assessments given the prevalence of brain metastases. Sponsors will need to streamline molecular logistics to prevent screen failures as competing studies vie for the same post-osimertinib pool, which is already fragmented by bispecific regimens and next-generation TKIs. Regulators have signaled that accelerated pathways in this setting hinge on robust single-arm ORR with durable responses, supported by clear safety profiles and subgroup consistency. If the wild-type sparing design holds, tolerability could support higher exposures and longer treatment duration, but absent AE rates and discontinuation data, that promise is unproven.
The competitive context is unforgiving. Multiple fourth-generation EGFR inhibitors and antibody-based combinations are pursuing the same resistance niches, with some already generating randomized or combination data. BH-30643 will need to show not just anecdotal activity but a repeatable signal across defined resistance cohorts, CNS activity commensurate with real-world disease patterns, and a safety profile that enables outpatient dosing without dose-limiting rash or diarrhea. Operationally, the breadth of cohorts requires tight biomarker operations, clear RP2D selection from the 20–160 mg range, and proactive DDI and QT monitoring typical for the class.
The next inflection is the first expansion cohort update expected in 2026. Key watch items include confirmed ORR and duration in C797S±T790M populations, exon 20 insertion activity, intracranial responses, and adverse event rates versus class benchmarks. Evidence that activity spans atypical alleles without safety trade-offs could justify a registrational path in post-osimertinib disease; a patchy signal would push the asset into niche, genotype-specific use, or combination strategies. As a private company, BlossomHill will also face timing decisions on partnership and financing to support a multi-cohort global program in a crowded field.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
