LAUSR

Introduction: HER2-mutant NSCLC is associated with poor prognosis. SHR-A1811 is a novel antibody-drug conjugate (ADC) consisting of a humanized HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. Here, we report data from the phase 1 portion of a phase 1/2 study with SHR-A1811 in patients with HER2-mutant NSCLC (NCT04818333). Methods: In this single-arm, dose escalation and expansion phase 1 portion, patients with advanced activating HER2-mutant NSCLC who had failed platinum-based chemotherapy in the advanced or metastatic setting or could not tolerate chemotherapy were enrolled. SHR-A1811 was assessed at doses of 3.2, 4.8, 5.6, 6.4, and 8.0 mg/kg intravenously once every 21-day cycle. Dose escalation and determination of maximum tolerated dose (MTD) was guided by Bayesian logistic regression model with overdose control. Dose selected for expansion was determined based on data from dose-escalation phase. The primary endpoints were safety, MTD and recommended phase 2 dose (RP2D). Results: At data cutoff (Nov 8, 2022), 50 patients were enrolled. All were stage IV with a median of 3 (range 1-8) prior systemic treatments, including HER2-targeted TKI (66%), immune checkpoint inhibitors (68%), and anti-angiogenic drugs (78%). 96% had a HER2 kinase domain mutation. One patient in 8.0 mg/kg dose cohort had dose-limiting toxicities (grade 4 febrile neutropenia and grade 4 thrombocytopenia). The 4.8 mg/kg dose cohort was expanded to 38 patients. The median follow-up duration was 5.6 months (95% CI 4.2-7.0). 62% of patients remained on treatment. Overall, objective response rate was 40.0% (95% CI 26.4-54.8); median duration of response was 8.3 months (95% CI 5.4-13.7); disease control rate was 86.0% (95% CI 73.3-94.2); median progression-free survival was 10.8 months (95% CI 6.7-15.0). All patients had treatment-related adverse events (TRAEs). 42% of patients experienced grade ≥3 TRAEs, with the most common ones being decreased neutrophil count (30%), decreased white blood cell count (20%), anemia (16%), and thrombocytopenia (12%). Nine patients (18%) had serious AEs deemed related to SHR-A1811. Treatment discontinuation due to AEs was reported in two patients. One death was reported to be treatment related (interstitial lung disease). After single dosing, dose exposure (Cmax and AUClast) of SHR-A1811 increased in a dose-proportional manner. PK parameters of SHR-A1811 and total antibody were similar at all dose levels, with low plasma exposure of free topoisomerase I inhibitor observed. Conclusion: SHR-A1811 showed tolerable safety profile and durable antitumor activity in heavily pretreated patients with HER2-mutant NSCLC. Dose expansion at 4.8 mg/kg and 5.6 mg/kg is ongoing to establish the RP2D. Citation Format: Shun Lu, Hong Jian, Wei Hong, Zhengbo Song, Nong Yang, Sheng Hu, Zibin Liang, Yongsheng Wang, Yan Wang, Min Peng, Yan Yu, You Li, Jiapeng Shuang, Kaijing Zhao. Safety, tolerability, pharmacokinetics, and efficacy of SHR-A1811, an antibody-drug conjugate, in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC): a multicenter, open-label, phase 1/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT204.