What does this research mean for the field?

The novel macrocyclic EGFR inhibitor BH-30643 demonstrates clinical efficacy and safety in advanced EGFR-mutant non-small cell lung cancer, including being the first TKI monotherapy to elicit responses against C797S resistance mutations regardless of T790M status. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This trial aims to evaluate the safety and efficacy of the novel macrocyclic EGFR inhibitor BH-30643 in patients with EGFR-mutant non-small cell lung cancer (NSCLC).

May 29, 2026

First-in-human trial of BH-30643, a novel macrocyclic, non-covalent, mutant-selective OMNI-EGFR inhibitor, in EGFR -mutant ( EGFR m) NSCLC.

Key Points

This trial aims to evaluate the safety and efficacy of the novel macrocyclic EGFR inhibitor BH-30643 in patients with EGFR-mutant non-small cell lung cancer (NSCLC).
Phase 1 dose escalation study using a Bayesian Optimal Interval Design (BOIN) with backfill at potentially efficacious doses.
Patients with advanced NSCLC with detectable EGFR and/or HER2 mutations were enrolled, including those with measurable disease and asymptomatic, untreated brain metastases.
Plasma next-generation sequencing (NGS) was performed at baseline and during treatment to assess mutation response.
Among 72 enrolled patients, common treatment-related adverse events (TRAEs) included diarrhea (38%), rash (28%), and fatigue (15%), primarily grade 1.
Half of the participants with C797S mutation experienced a significant reduction of C797S variant allele frequency (VAF) on treatment, indicating efficacy.
High plasma exposure levels achieved over 10x target concentrations suggested potential for effective treatment response, particularly in CNS.

Abstract

3014 Background: Macrocyclic next-generation tyrosine kinase inhibitors (TKIs) have transformed outcomes in ALK- and ROS1-positive NSCLC; such creatively designed medicines are similarly needed to improve outcomes in EGFR-mutant NSCLC. Using a novel, mutant-selective macrocyclic structure, BH-30643 was designed for super-potency against driver EGFRm, largely sparing wildtype (WT) EGFR, and with unique invulnerability to resistance from C797S with or without T790M. Here we report emerging first-in-human dose-escalation data from the SOLARA trial (NCT06706076). Methods: Phase 1 dose escalation used a BOIN design with backfill at potentially efficacious doses. Expansion cohorts targeted populations of interest. Patients (pts) had advanced NSCLC with EGFR and/or HER2 mutations detected on local testing (tissue or plasma). Measurable disease was required; asymptomatic untreated brain metastases (BM) were permitted. Objectives included safety, PK, and RECIST response rate (ORR). Plasma NGS was performed at baseline and on treatment. Results: As of 01/05/2026, 72 pts enrolled into dose escalation and backfill across 7 dose levels at a total daily dose of 20mg -160mg, median age 62, 44% Asian, 65% with history of BM, median of 3 prior lines of treatment (range 1-12). EGFR mutations included classical (38 pts), exon20ins (14 pts) and other/atypical (18 pts) or HER2 mutations (2 pts). Plasma exposures at doses of 40mg BID and above achieved > 10x coverage over target EC90 and exceeded exposure levels of most contemporary EGFR TKIs. Common TRAE ( > 10%) were WT EGFR-associated, including diarrhea (38%), rash (28%), fatigue (15%), stomatitis (13%), and were predominantly grade 1. Bilirubin elevation was seen in 26 pts (36%) related to off-target UGT1A1 inhibition (Gilbert’s-like). Grade 3 TRAE were seen in 15 pts (18%), most commonly bilirubin (8/15); DLTs included bilirubin increase and mucositis, occurring at doses ≥ 60mg BID. No pneumonitis was observed. Responses were observed across diverse EGFRm subsets, including in CNS. Including expansion pts, 28 pts enrolled with C797S on their most recent informative molecular testing (6 with concurrent MET+ or KRAS+), with 23 still on therapy. Of 17 with on-treatment scans, partial responses (confirmed or ongoing) were seen in 10 (59%); ORR was comparable with (50%) or without (66%) T790M. Of 9 pts with baseline C797S detected in ctDNA (3 with T790M), 7 had > 99% reduction of C797S VAF on treatment. Conclusions: Leveraging a novel macrocyclic scaffold, BH-30643 is the first TKI monotherapy to demonstrate clinical responses against C797S both with or without T790M. High plasma exposures combined with super-potency, CNS activity, and favorable safety offers potential for deep and durable EGFR inhibition. Enrollment into backfill and expansion cohorts is ongoing to better characterize activity in both TKI-naïve and resistant pts. Clinical trial information: NCT06706076 .

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First-in-human trial of BH-30643, a novel macrocyclic, non-covalent, mutant-selective OMNI-EGFR inhibitor, in EGFR -mutant ( EGFR m) NSCLC.

Key Points

Abstract

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