Abstract CT301: SHR-A1811 ± adebrelimab as first-line (1L) treatment for advanced HER2-mutant NSCLC: A randomized phase 2 cohort from a phase 1b/2 study

Abstract Background: Trastuzumab rezetecan (SHR-A1811) is a novel HER2-directed ADC approved for pretreated HER2-mutant NSCLC (Lancet Oncol, 2025). ADCs may enhance antitumor immunity and synergize with immunotherapy. We conducted an open-label, phase 1/2 (dose-escalation/efficacy-exploration) study (NCT05482568) to evaluate SHR-A1811 in combination therapy for HER2-altered NSCLC and here report data from phase 2 Cohort D of 1L SHR-A1811 ± adebrelimab (anti-PD-L1 mAb) for HER2-mutant NSCLC. Methods: Patients (pts) were randomized (1:1) to receive SHR-A1811 (4.8 mg/kg, iv, Q3W) + adebrelimab (1200 mg, iv, Q3W) or SHR-A1811 (4.8 mg/kg, iv, Q3W) alone, stratified by PD-L1 expression (TPS, <1% vs ≥1%). The primary endpoint was ORR per investigator. Results: 68 pts (PD-L1 TPS <1%/1-49%/≥50%, 50.0%/41.2%/8.8%; exon 20 insertions/A775_G776insYVMA, 89.7%/55.9%) were treated. At data cutoff (Oct 20, 2025), median follow-up was 16.7 mo. Confirmed ORR was 69.4% (95% CI 51.9-83.7) with SHR-A1811 + adebrelimab (combo) vs 81.3% (95% CI 63.6-92.8) with SHR-A1811; median DoR was not reached (NR) and 16.6 mo (95% CI 8.5-NR), respectively. PFS events occurred in 10 pts (27.8%) with combo vs 13 (40.6%) with SHR-A1811; median PFS was NR (95% CI 15.3-NR) vs 17.9 mo (95% CI 9.7-NR; HR 0.65, 95% CI 0.28-1.47). Efficacy by PD-L1 TPS is shown in Table 1. A trend toward improved PFS with addition of adebrelimab was seen across subgroups. All grade ≥3 TRAEs occurring in ≥10% were hematologic in both arms. ILD occurred in 2 (5.6%) pts with combo and 1 (1.3%) with SHR-A1811. TRAEs led to discontinuation of SHR-A1811 in 2 (5.6%) and adebrelimab in 4 (11.1%) in combo arm and SHR-A1811 in 2 (6.3%) in monotherapy arm. Conclusions: SHR-A1811 ± adebrelimab as 1L therapy showed robust activity with manageable safety in HER2-mutant NSCLC. Early data suggest clinical benefits with addition of adebrelimab, regardless of PD-L1 expression, driven by durablity of disease control. Citation Format: Shun Lu, Zhengbo Song, Ziming Li, Haiyong Wang, Yan Yu, Qitao Yu, Shaozhang Zhou, Zhiyong He, Yan Wang, Yiping Zhang, Songyan Han, Rui Meng, Guoqun Zhang, Longhua Sun, Xueqin Chen, Yong Mao, Yongsheng Li, Yongzhong Luo, Kangsheng Gu, Xuhong Min, Bo Jin, Runxiang Yang, Yanqiu Zhao, Liqiang Zhong, Jun Wang, Zhiguo Zhou, Chengzhi Zhou, Kaijun Zhang, Xiaotong Li, Xinjing Ma, Liju Zong, You Li. SHR-A1811 ± adebrelimab as first-line (1L) treatment for advanced HER2-mutant NSCLC: A randomized phase 2 cohort from a phase 1b/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT301.