BH-30643 (OMNI‑EGFR mutant‑selective macrocyclic TKI) shows 59% ORR in post‑osimertinib C797S NSCLC (incl CNS)

BH-30643 is a first-in-class macrocyclic, non-covalent “OMNI‑EGFR” inhibitor engineered to selectively hit EGFR driver mutations while largely sparing WT EGFR and retaining activity against C797S with or without T790M; SOLARA is a first-in-human Phase 1 BOIN dose-escalation with backfill/expansion in advanced EGFR/HER2-mutant NSCLC (NCT06706076). As of January 5, 2026, 72 patients were treated across 20–160mg total daily dose (median 3 prior lines; 65% with brain metastases); common WT EGFR-like TRAEs were mostly grade 1 (diarrhea 38%, rash 28%, stomatitis 13%), but bilirubin elevation was frequent (36%) consistent with off-target UGT1A1 inhibition and drove most grade 3 TRAEs (18% overall; bilirubin 8/15 grade 3; DLTs of bilirubin increase and mucositis at ≥60mg BID), with no pneumonitis observed. In the key resistance subgroup with C797S (n=28; 17 scan-evaluable), partial responses occurred in 10/17 (59%) with similar activity whether T790M was present (50%) or absent (66%); ctDNA also showed pharmacodynamic signal with >99% C797S VAF reduction in 7/9 baseline-positive patients—well above typical later-line docetaxel±ramucirumab benchmarks in unselected NSCLC (ORR ~14–23%, mPFS ~3.0–4.5 months in REVEL), though cross-trial comparisons are imperfect and SOLARA has not yet reported durability metrics (DoR/PFS/OS).