DZD6008 (4th-gen EGFR TKI) posts 60% ORR at 60mg in EGFR C797X+ post–osimertinib NSCLC

DZD6008 is an oral, fourth-generation EGFR tyrosine kinase inhibitor designed to inhibit EGFR exon19del/L858R plus resistant double (T790M) and triple mutations including C797X, with reported BBB penetration and WT-sparing selectivity. In the ongoing Phase 1/2 TIAN-SHAN1 (US/Australia; NCT06905197) and TIAN-SHAN2 (China; NCT06813365/CTR20241790), 24 EGFR C797X+ metastatic NSCLC patients with ≥1 post-baseline scan (median 2 prior lines after EGFR TKI exposure; 91.7% Asian) received DZD6008 QD (20/40/60mg) and achieved 41.7% ORR overall with tumor shrinkage in 75%; at the RP2Ds, ORR was 23.1% (40mg; n=13) and 60.0% (60mg; n=10), with median DoR and PFS not reached and 9-month PFS rates of 54.5% and 64.8%. Safety was mostly grade 1–2 with no DLTs; grade ≥3 TRAEs included lymphocyte count decreased (8.3%) and anemia/malaise/fatigue/amylase increased (each 4.2%) with no grade 5 TRAEs—numerically competitive with current common post-osimertinib options like amivantamab + carboplatin/pemetrexed (reported ORR ~50–60% range and PFS benefit vs chemo in MARIPOSA-2), though cross-trial comparisons are especially fragile here given the tiny n and dose-cohort imbalances. Take Home: If the 60mg signal holds up in a larger, biomarker-defined C797X cohort (and especially if CNS activity is confirmed), DZD6008 could become a cleaner “resistance-on-resistance” oral option after 3rd-gen EGFR TKIs—potentially differentiating vs antibody-based regimens that bring infusion burden and EGFR/MET on-target toxicity.