TH-4000, a hypoxia-activated EGFR/Her2 inhibitor to treat EGFR-TKI resistant T790M-negative NSCLC.

e13548 Background: TH-4000 is a clinical-stage hypoxia-activated prodrug that releases an irreversible tyrosine kinase inhibitor (TKI) of wild type (WT) EGFR, mutant (Δ19) EGFR and Her2. Hypoxia tumor targeting may allow for greater intratumoral dose intensity without dose limiting systemic toxicity. Tumor hypoxia upregulates WT EGFR signaling through several HIF-dependent mechanisms. Clinical studies indicate that mutant EGFR NSCLC with WT EGFR present (heterozygous) is associated with limited response to EGFR-TKIs. NSCLC is known to be a hypoxic tumor; thus, hypoxia-induced activation of WT EGFR signaling may be a mechanism of current EGFR-TKI resistance. Phase 1 clinical trial established the MTD of TH-4000 at 150 mg/m2/wk. Here we report translational studies supporting initiation of a Phase 2 trial. Methods: The activity of TH-4000 and erlotinib were assessed in a heterozygous (WT/ Δ19) EGFR PC9 tumor xenograft model (n = 6-9/grp). Erlotinib was dosed daily at a human-matched plasma PK equivalent (10...