Safety and preliminary antitumor activity of U3-1402: A HER3-targeted antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC.

person Pasi A. Janne Dana-Farber Cancer Institute, Boston, MA info_outline Pasi A. Janne, Helena Alexandra Yu, Melissa Lynne Johnson, Conor Ernst Steuer, Michele Vigliotti, Corinne Iacobucci, Shuquan Chen, Channing Yu, Dalila B. Sellami

Authors person Pasi A. Janne Dana-Farber Cancer Institute, Boston, MA info_outline Pasi A. Janne, Helena Alexandra Yu, Melissa Lynne Johnson, Conor Ernst Steuer, Michele Vigliotti, Corinne Iacobucci, Shuquan Chen, Channing Yu, Dalila B. Sellami Organizations Dana-Farber Cancer Institute, Boston, MA, Memorial Sloan Kettering Cancer Center, New York, NY, Sarah Cannon Research Institute, Nashville, TN, Winship Cancer Institute of Emory University, Atlanta, GA, Daiichi Sankyo, Inc., Basking Ridge, NJ Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Treatment options are limited for EGFRm NSCLC resistant to EGFR TKIs. HER3 is expressed in a majority of NSCLC tumors. U3-1402 is a HER3-targeted antibody drug conjugate with a fully human HER3-targeted antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Methods: An ongoing multicenter phase 1 dose escalation and expansion study is assessing U3-1402 safety/tolerability and preliminary activity in metastatic or unresectable EGFRm NSCLC patients (pts) who are T790M negative after disease progression while on erlotinib, gefitinib or afatinib; or develop disease progression while on osimertinib regardless of T790M status. Dose escalation is based on dose-limiting toxicities (DLTs) and guided by the modified Continuous Reassessment Method. U3-1402 is administered via intravenous infusion in 21-day cycles. Pretreatment tumor tissue is required. Results: As of 11 Nov 2018, 15 pts (6 M; 9 F) were enrolled across 3 dose levels (3.2, 4.8, 6.4 mg/kg). Median age was 63 y; 10 pts had EGFR exon 19 deletion and 5 EGFR L858R mutation. Median sum of longest diameters (SLD) at baseline was 69 (range 22–143) mm. All pts had prior EGFR TKIs; 14 had 2nd line or later osimertinib. Six had prior chemotherapy. All 11 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score 188, range 150–290). Five pts discontinued treatment: 4 due to progressive disease, 1 due to adverse event (AE). All Grade (Gr) treatment-emergent AEs (TEAEs) in ≥20% of pts were nausea (60%), vomiting (40%), fatigue (33%), decreased appetite (27%), and alopecia (20%). Gr≥3 TEAEs were nausea (1/15; Gr3; related), hypoxia (1/15; Gr3; unrelated), and platelet count decreased (2/15; both Gr4 at 6.4 mg/kg and considered DLTs). In 13 evaluable pts, all but 1 had a decrease in SLD (median best change −29%, range +10% to −67%), 2 had confirmed partial response per RECIST v1.1 (best changes −44%, −67%). Conclusions: U3-1402 showed a manageable safety profile and preliminary antitumor activity in EGFR TKI-resistant EGFRm NSCLC. Evaluation of candidate biomarkers, including HER3 expression, which correlate with U3-1402 response is ongoing. Clinical trial information: NCT03260491