Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC).
Authors: Janne Pasi A. , Baik Christina S , Su Wu-Chou , Johnson Melissa Lynne , Hayashi Hidetoshi , Nishio Makoto , Kim Dong-Wan , Koczywas Marianna , Gold Kathryn A. , Steuer Conor Ernst , Murakami Haruyasu , Yang James Chih-Hsin , Kim Sang-We , Vigliotti Michele , Qi Zhenhao , Qiu Yang , Zhao Lihui , Sternberg David W. , Yu Channing , Yu Helena Alexandra 
Published: June 2021

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Background: Patients (pts) with advanced EGFRm NSCLC have limited treatment options after failure of EGFR TKI and platinum-based chemotherapy (PBC). HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We previously presented efficacy/safety data (median follow-up, 5.4 mo) from an ongoing study of HER3-DXd in EGFRm NSCLC after failure of EGFR TKI therapy. We now present extended follow-up of pts receiving the recommended dose for expansion (5.6 mg/kg IV Q3W). Methods: This Ph 1 dose-escalation/expansion study included pts with locally advanced or metastatic EGFRm NSCLC with prior EGFR TKI therapy (NCT03260491). Pts with stable brain metastases (BM) were allowed. The primary endpoint was confirmed ORR by blinded independent central review (BICR) per RECIST v1.1; secondary endpoints included DOR, PFS and safety. Results: At data cutoff (Sept 24, 2020), 57 pts were treated with HER3-DXd 5.6 mg/kg IV Q3W; median follow-up, 10.2 mo (range, 5.2-19.9 mo). Median number of prior anticancer regimens was 4 (range, 1-10). 100% had prior EGFR TKI (86% prior osimertinib [OSI]) and 91% had prior PBC. 47% had a history of BM. Median treatment duration was 5.5 mo (range, 0.7-18.6 mo); treatment was ongoing in 18 pts (32%). Confirmed ORR by BICR was 39% (22/57; 95% CI, 26.0%-52.4%; 1 CR, 21 PR, 19 SD) with 14/22 responses occurring within 3 mo of starting HER3-DXd. DCR was 72% (95% CI, 58.5%-83.0%). Median DOR was 6.9 mo (95% CI, 3.1 mo-NE), and median PFS was 8.2 mo (95% CI, 4.4-8.3 mo). Antitumor activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 ( EGFR C797S, MET or HER2 amp, and BRAF fusion). Among pts with prior PBC, ORR was 37% (19/52; 95% CI, 23.6%-51.0%); in pts with prior OSI and PBC, ORR was 39% (17/44; 95% CI, 24.4%-54.5%). Among 43 pts evaluable for HER3 expression, nearly all expressed HER3; median membrane H-score by IHC was 180 (range, 2-280). Median H-score (range; N) was 195 (92-268; 15) in pts with CR/PR, 180 (4-280; 15) with SD, 126.5 (2-251; 6) with PD, and 180 (36-180; 7) in pts unevaluable for best overall response. The most common grade ≥3 adverse events (AEs) were thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (7%; 1 grade ≥3 [2%]; no grade 5). 6/57 pts (11%) had AEs associated with treatment discontinuation (none were due to thrombocytopenia). Conclusions: HER3-DXd 5.6 mg/kg IV Q3W demonstrated antitumor activity across various EGFR TKI resistance mechanisms in heavily pretreated metastatic/locally advanced EGFRm NSCLC. The safety profile was consistent with previous reports. A Ph 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC has been initiated (NCT04619004). Clinical trial information: NCT03260491.