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Channing Yu



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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.06 - Preliminary Phase 1 Results of U3-1402 — A Novel HER3-Targeted Antibody–Drug Conjugate—in EGFR TKI-Resistant, EGFR-Mutant NSCLC   (Now Available) (ID 1720)

      14:30 - 16:00  |  Author(s): Channing Yu

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitors (TKIs), in particular osimertinib. Overall, 57%–83% of NSCLC tumors express human epidermal growth factor receptor 3 (HER3). Because signaling through HER3 is not an established mechanism of resistance to EGFR TKIs, treatment with an anti-HER3 antibody–drug conjugate (ADC) presents an approach to targeting diverse resistance mechanisms in EGFR-mutant NSCLC. U3-1402 is a HER3-targeted ADC with a fully humanized antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Here, we present the safety/tolerability and antitumor activity data from the dose-escalation phase of an ongoing, multicenter, phase 1 study (NCT03260491).

      Method

      Patients had locally advanced or metastatic EGFR TKI-resistant, EGFR-mutant NSCLC. Patients with stable brain metastases were eligible. Dose escalation was based on dose-limiting toxicities (DLTs) guided by a Bayesian logistic regression model. U3-1402 was administered every 3 weeks via intravenous infusion. Pretreatment tumor tissue was required for retrospective HER3 immunohistochemistry analysis. Next-generation sequencing analysis was performed on available tumor tissue. Primary objectives included safety, tolerability, and identification of the recommended dose for expansion (RDE).

      Result

      As of May 2019, 30 patients were enrolled across 4 doses (3.2 [n=4], 4.8 [n=9], 5.6 [n=12], and 6.4 [n=5] mg/kg). Thirteen patients (43%) have discontinued (progressive disease [n=9], clinical progression [n=1], consent withdrawal [n=2], adverse event [AE; n=1]). All 30 patients received prior EGFR TKIs, of which 28 (93%) received prior osimertinib, and 15 (50%) prior chemotherapy. Activating EGFR mutations were reported in all patients (Ex19del: 57%; L858R: 40%; L861Q: 3%). All 25 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score, 183 [range, 56–290]). History of central nervous system (CNS) metastases was reported in 15 patients (50%). Treatment-emergent AEs were reported in 29 patients (97%; 13 patients [43%] reported grade 3/4). Two DLTs (grade 3 febrile neutropenia and grade 4 platelet count decrease) were reported in 1 patient (5.6 mg/kg) and 3 DLTs (all grade 4 platelet count decrease) in 3 patients (6.4 mg/kg). Of patients with a history of CNS metastases, 9 have progressed (2 with CNS progression; 3 with both CNS and non-CNS progression). One patient without a history of CNS metastasis progressed with new CNS disease. Of 26 efficacy-evaluable patients, 6 had confirmed partial responses (2 each at 4.8, 5.6, and 6.4 mg/kg), including 2 patients with an EGFR C797S mutation. Median best percentage change in sum of diameters (SoD) was −25.7% (range, −82.6% to 13.3%), including decreases in SoD in patients with CDK4 amplification (–25.7% and –17.8%), HER2 amplification (–28.6%), and both CCNE1 amplification and PIK3CA mutation (–28.8%).

      Conclusion

      U3-1402 demonstrated tolerable safety and antitumor activity in this ongoing study. Antitumor activity of U3-1402 was seen in cancers with EGFR-mediated and other resistance mechanisms. These findings support the hypothesis that targeting HER3 with U3-1402 may provide clinical benefit to patients with EGFR-mutant NSCLC with diverse mechanisms of resistance. RDE evaluation is ongoing.

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