Abstract CT009: SHR-A1811, a HER2-directed antibody-drug conjugate (ADC), in advanced HER2-mutant non-small cell lung cancer (NSCLC): Updated phase 2 results from HORIZON-Lung

Abstract Background: SHR-A1811 is a novel ADC consisting of a humanized HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. We conducted a multicenter, open-label, phase 1/2 study to evaluate SHR-A1811 in HER2-altered NSCLC. In the registrational phase 2 portion in patients (pts) with HER2-mutant NSCLC, the primary endpoint of IRC-assessed ORR was met (DCO, Jun. 14, 2024). Here, we presented an updated analysis after an additional 6-mo follow-up, focusing on survival outcomes. Methods: Pts with advanced NSCLC and centrally confirmed HER2 mutation, previously treated with (or intolerance to) platinum-based chemo and anti-PD-1/PD-L1 therapy, were enrolled. SHR-A1811 was administered at 4.8 mg/kg IV Q3W. Results: 94 pts were enrolled and treated. Median prior lines of therapy was 2 (range 1-9); all received platinum-based chemo and anti-PD-1/PD-L1 therapy and 23.4% received anti-HER2 TKI. 25.5% had BM at baseline. The most common HER2 mutation was exon 20 insertions (overall, 94.7%; A775_G776insYVMA, 72.3%). As of DCO (Dec. 14, 2024), median follow-up was 14.2 mo (range 4.7-18.2). Per IRC, ORR was 74.5% (95% CI 64.4-82.9); median DoR was 9.8 mo (95% CI 8.3-13.9). Median PFS was 11.5 mo (95% CI 9.7-15.2), with consistent benefits observed across baseline subgroups (Table 1). Efficacy per INV is shown in Table 1. Median OS was not reached; 12-mo OS rate was 88.2% (95% CI 79.8-93.3). Grade ≥3 TRAEs occurred in 63 (67.0%) pts; all with incidence ≥5% were haematological toxicities. ILD occurred in 8 (8.5%; grade 1-2, n=7; grade 3, n=1) pts. TRAEs led to dose discontinuation in 2 (2.1%) pts. There was no treatment-related death. Conclusions: At the updated analysis, SHR-A1811 continued to show clinically meaningful efficacy with a manageable safety profile in pts with previously treated HER2-mutant NSCLC, supporting it as a potential new treatment option for this population. Citation Format: Shun Lu, Ziming Li, Yan Wang, Yuping Sun, Linlin Wang, Xingya Li, Longhua Sun, Zhiyi He, Haiyan Yang, Yongsheng Wang, Qiming Wang, Zhengbo Song, Wei Hong, Yong Wang, Guohao Xia, Yan Yu, Min Peng, Yong Song, Donglin Wang, Rui Meng, Jian Fang, Yongzhong Luo, Wenhua Liang, Sheng Hu, Zhihui Wang, Haichuan Su, Zhiyong He, Liuning Li, Wei Guo, Zhentian Liu, Qitao Yu, Yun Zhao, Runxiang Yang, Peng Chen, Yiru Wang, You Li, Lulu Yang, Wei Shi. SHR-A1811, a HER2-directed antibody-drug conjugate (ADC), in advanced HER2-mutant non-small cell lung cancer (NSCLC): Updated phase 2 results from HORIZON-Lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT009.