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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.

Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. Here we assessed SHR-A1811 in HER2-expressing/mutated unresectable, advanced, or metastatic solid tumors. Methods: Pts were eligible if they had HER2 positive breast cancer (BC), HER2 positive gastric/GEJ carcinoma, HER2 low-expressing BC, HER2-expressing/mutated NSCLC, or other HER2-expressing/mutated solid tumors, and were refractory or intolerant to standard therapy. SHR-A1811 at doses of 1.0-8.0 mg/kg was given Q3W (IV). The primary endpoints were DLT, safety, and the RP2D. Results: From Sep 7, 2020 to Sep 28, 2022, 250 pts who had undergone a median of 3 prior treatment lines in the metastatic setting received at least one dose of SHR-A1811 in dose escalation, PK expansion, and indication expansion part. As of data cutoff on Sep 28, 2022, 1 pt experienced DLT. Treatment-related adverse events (TRAEs) were reported in 243 (97.2%) pts. Grade ≥3 TRAEs, serious TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) pts, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) pts. Exposures of SHR-A1811, total antibody, and the payload were generally proportional to dose from 3.2 to 8.0 mg/kg. ORR was 61.6% (154/250, 95% CI 55.3-67.7) in all pts. Objective responses were observed in pts with HER2 positive BC (88/108, ORR 81.5%, 95% CI 72.9-88.3), HER2-low BC (43/77, ORR 55.8%, 95% CI 44.1-67.2), urothelial carcinoma (7/11), colorectal cancer (3/10), gastric/GEJ carcinoma (5/9), biliary tract cancer (5/8), NSCLC (1/3), endometrial cancer (1/2), and H&N cancer (1/1). Subgroup analyses of ORR are shown in Table 1. The 6-month PFS rate was 73.9% in all pts. Conclusions: SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors. Table 1. Subgroup analyses of ORR No. of prior treatment lines in metastatic setting in all pts (N=250) HER2 positive BC (N=108) HER2-low BC (N=77) Other tumor types (N=65) ≤3 81.8% (45/55) 58.7% (27/46) 36.7% (18/49) >3 81.1% (43/53) 51.6% (16/31) 31.3% (5/16) Prior anti-HER2 therapies in pts with BC (N=185)* HER2 positive BC (N=108) HER2-low BC (N=77) All BC (N=185) Any 82.2% (88/107, 73.7-89.0) 68.8% (11/16, 41.3-89.0) 80.5% (99/123, 72.4-87.1) Trastuzumab 81.9% (86/105, 73.2-88.7) 75.0% (9/12, 42.8-94.5) 81.2% (95/117, 72.9-87.8) Pertuzumab 83.0% (39/47, 69.2-92.4) 100% (5/5, 47.8-100) 84.6% (44/52, 71.9-93.1) Pyrotinib 86.9% (53/61, 75.8-94.1) 71.4% (5/7, 29.0-96.3) 85.3% (58/68, 74.6-92.7) Lapatinib 80.0% (28/35, 63.1-91.6) 100% (1/1, 2.5-100) 80.6% (29/36, 64.0-91.8) T-DM1 82.4% (14/17, 56.6-96.2) 100% (3/3, 29.2-100) 85.0% (17/20, 62.1-96.8) Other HER2-ADC (except T-DM1)** 60.0% (9/15, 32.3-83.7) 50.0% (2/4, 6.8-93.2) 57.9% (11/19, 33.5-79.8) ORR in pts with tumor types other than BC (N=65) HER2 IHC3+ or IHC2+/ISH+ (N=36) HER2 IHC2+/ISH- or IHC1+ or unknown (N=29) All other tumor types (N=65) % (n/N) 38.9% (14/36) 31.0% (9/29) 35.4% (23/65) ORR was shown as % (n/N, 95% CI) or % (n/N). *ORR is calculated using the number of subjects previously treated with anti-HER2 cancer therapy in advanced/metastatic setting as denominator; 2-sided 95% CIs are estimated using Clopper-Pearson method. **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, Jee Hyun Kim, John Park, Yahua Zhong, Weiqing Han, Caigang Liu, Mark Voskoboynik, Qun Qin, Jian Zhang, Minal Barve, Ana Acuna-Villaorduna, Vinod Ganju, Seock-Ah Im, Changsheng Ye, Yongmei Yin, Amitesh C. Roy, Li-Yuan Bai, Yung-Chang Lin, Chia-Jui Yen, Hui Li, Ki Young Chung, Shanzhi Gu, Jun Qian, Yuee Teng, Yiding Chen, Yu Shen, Kaijing Zhao, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human 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 CT175.