Silevertinib (BDTX-1535) 4th-gen covalent EGFR TKI posts 36% ORR in EGFR C797S NSCLC

Silevertinib (BDTX-1535) is a fourth-generation covalent EGFR tyrosine kinase inhibitor designed to hit classical EGFR mutations plus non-classical EGFR mutations (including PACC) and acquired C797S, with reported high CNS penetrance; this open-label Phase 2 trial (NCT05256290) enrolled previously treated recurrent NSCLC after ≤2 prior lines and only 1 prior EGFR TKI (osimertinib preferred). At the 200mg QD dose (used for all patients after May 2024), ORR was 16.7% in the NCM cohort (n=30; PACC subset ORR 21.7% in n=23) and 36.4% in the C797S cohort (n=33), with median duration of treatment 4.8–5.0 months; 49% (NCM) and 31% (C797S) had CNS metastases, and ~20% had baseline co-alterations (MET/RET/RAS/RAF) in post hoc analysis. Safety at 200mg looked “EGFR TKI-like”: serious TRAEs in 11%, discontinuation due to TRAEs in 8%, and notable grade 3 events mainly rash (13%) and diarrhea (8%) (stomatitis/paronychia 2% each); without mature PFS/DOR yet, the clearest benchmark is that chemo in the post-osimertinib setting typically delivers low double-digit ORR and short PFS (11% ORR, mPFS ~3.5 months with docetaxel), while targeted options like amivantamab+lazertinib in a heavily pretreated post-osimertinib/post-platinum population have reported ~36% ORR and mPFS ~4.9 months (cross-trial comparisons, different populations).

(Caveat: efficacy is currently anchored to ORR and time-on-treatment; without the pending PFS/DOR—and without stratification by C797S cis/trans context, CNS response rate, and the impact of baseline bypass alterations—the real clinical “lift” vs existing post-osimertinib strategies remains hard to judge.)