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

Abstract

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 mg/kg, po). TH-4000 was dosed weekly (15 mg/kg, ip) as a single-agent or added to erlotinib at Day 14. Multi-time point detection of plasma and tumor TH-4000 and TKI were measured by LC/MS/MS. Tumor biomarkers were assessed by western blot. Results: PC9 was 8% hypoxic. All PC9 tumors progressed on erlotinib while all tumors regressed on TH-4000 alone or when added 14 days into erlotinib therapy, suggesting an ability to prevent or overcome resistance to TKI treatment. In the same model, single-dose administration of 15 mg/kg (ip) TH-4000 achieved a plasma AUC equivalent to 32 mg/m2 (IV) in humans, well below the MTD defined in Phase 1 trial. Preclinical PK/PD studies of single-dose TH-4000 (15 mg/kg) showed prolonged prodrug residency in tumor tissue (T½39 h) releasing TKI steadily over 7 days with EGFR shut down maintained for a week. Conclusions: TH-4000 was more effective than erlotinib in a heterozygous (WT/Δ19) EGFR PC9 model either upfront as a single-agent or when added to erlotinib after progression. Based on these data, once weekly administration of TH-4000 (150 mg/m2) is proposed in a Phase 2 trial planned in EGFR activating-mutation confirmed NSCLC patients who have progressed on TKI therapy and are T790M-negative.