Abstract PS8-08: Efficacy and safety of SHR-A1811, an anti-HER2 antibody-drug conjugate (ADC), in 391 heavily pretreated multiple solid tumors with HER2-expression or mutations: a global, multi-center, first-in-human, phase 1 study

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Abstract Background: SHR-A1811, an anti-HER2 ADC comprising trastuzumab, a cleavable linker, and the topoisomerase I inhibitor payload SHR169265, has shown substantial tumor response and a manageable safety profile in heavily treated multiple solid tumors with HER2 expression or mutations (Yao. et al., JCO, 2024). Here we present for the first time the progression-free survival (PFS) analysis results of SHR-A1811 and updated safety results, including an additional 1-year of follow-up and an expanded cohort from 307 to 391 patients. Methods: Patients eligible for this study had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every 3 weeks. Primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. Results: Between Sep 7, 2020 and Jan 12, 2024, 391 patients received SHR-A1811 treatment, including 136 HER2-positive breast cancers, 110 HER2 low-expressing breast cancers, 42 biliary tract cancers, 39 urothelial carcinomas, 22 gynecological cancers, 14 colorectal cancers (CRC), 13 gastric or gastro-esophageal junction adenocarcinomas (GC/GEJ), 4 non-small cell lung cancers (NSCLC), and 11 other types of solid tumor. These patients had undergone a median of 3 (IQR 2–5) prior treatment regimens for metastatic disease. Of these, 261 (66.8%) had an ECOG performance status of 1, 196 (50.1%) had liver metastasis, and 186 (47.6%) had lung metastasis. As of data cutoff (Feb 29, 2024), the median follow-up for HER2-positive breast cancer, HER2-low breast cancer, and non-breast tumor was 13.4, 9.5, and 6.3 months (mo), respectively. The adverse events remained consistent with previous findings in terms of frequency, severity, and specificity. No new safety signals were identified. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 247 patients (63.2%) and 26 patients (6.6%) discontinued treatment due to TRAEs. Incidence of interstitial lung disease was limited, occurring in only 10 patients (2.6%), predominantly at grade 1–2. Of the patients whose tumor responses were evaluable, the confirmed objective response rate (ORR) was 79.1% (95% CI 71.2–85.6) in HER2-positive breast cancer, 62.0% (95% CI 52.2–71.2) in HER2-low breast cancer, and 40.0% (95% CI 31.5–49.0) in non-breast tumor. Responses were durable, with median duration of response (DoR) of 23.6 mo (95% CI 15.6–NE), 12.2 mo (95% CI 7.3–NE), and 15.2 mo (95% CI 9.9–20.9), respectively. Median PFS was 20.0 mo (95% CI 15.1–NE) in HER2-positive breast cancer, 11.0 mo (95% CI 8.2–13.7) in HER2-low breast cancer, and ranged 3.4–8.5 mo in various non-breast tumor types. In breast cancer patients with liver metastasis, the median DoR and PFS (HER2-positive: not reached for DoR, 20.0 mo for PFS; HER2-low: 10.8 mo for DoR, 10.9 mo for PFS) were consistent with the total breast cancer population. Similarly, for breast cancer patients with visceral metastasis, the median DoR and PFS (HER2-positive: 23.7 mo for DoR, 21.9 mo for PFS; HER2-low: 9.9 mo for DoR, 9.8 mo for PFS) also aligned with the overall breast cancer population. Additionally, patients with HER2-positive non-breast tumors showed a trend of better efficacy compared to the overall non-breast tumor cohort in terms of ORR (45.1%), DoR (median 15.2 mo), and PFS (median 7.9 mo). Conclusions: This updated analysis reaffirms the manageable safety profile and promising efficacy of SHR-A1811 in heavily pretreated multiple solid tumors with HER2 expression or mutations. Pivotal study results are highly expected in HER2-positive breast cancer, HER2-low breast cancer, CRC, GC/GEJ, and NSCLC. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Yongmei Yin, Min-Hee Ryu, John J. Park, Tao Dai, Yiming Zhao, Jee Hyun Kim, Shouman Wang, Yahua Zhong, Mark Voskoboynik, Jian Zhang, Andreas Kaubisch, Caigang Liu, Yu Chen, Seock-Ah Im, Lingying Wu, Yingbin Liu, Vinod Ganju, Minal Barve, Hui Li, Guangyu Yao, Lequn Bao, Kaijing Zhao, Yu Shen, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Efficacy and safety of SHR-A1811, an anti-HER2 antibody-drug conjugate (ADC), in 391 heavily pretreated multiple solid tumors with HER2-expression or mutations: a global, multi-center, first-in-human, phase 1 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS8-08.

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