SHR-A1811, a novel HER2-targeting antibody-drug conjugate, in advanced solid tumors (HORIZON-X): a global phase 1 trial.

Introduction
Human epidermal growth factor receptor 2 (HER2), a pivotal tyrosine kinase receptor, critically regulates various signaling pathways involved in cell proliferation, differentiation, and survival.1 Aberrant activation of HER2 has been implicated in the pathogenesis of several solid tumors, making it an important therapeutic target.2–4 In recent years, substantial advancements have been achieved with the clinical approval of various agents targeting HER2, including monoclonal antibodies,5–7 tyrosine kinase inhibitors,8–11 and antibody‒drug conjugates,12–14 for the treatment of HER2-overexpressing or mutated solid tumors, predominantly in breast cancer.15 Antibody‒drug conjugates represent an evolving therapeutic strategy, merging the target specificity of monoclonal antibodies with the cytotoxic efficacy of chemotherapy, offering a targeted approach to deliver potent payloads selectively to cancer cells with mutated or overexpressed HER2.16
One of the groundbreaking advancements in anti-HER2 antibody–drug conjugates is the use of trastuzumab deruxtecan, which consists of the HER2-targeted antibody trastuzumab linked to a potent topoisomerase I inhibitor conjugate. Trastuzumab deruxtecan has subsequently received clinical approval for heavily treated patients with unresectable or metastatic HER2-positive or low-expressing breast cancer,17,18
HER2-mutated non-small cell lung cancer,19 HER2-positive gastric or gastroesophageal junction adenocarcinoma,20 and unresectable or metastatic HER2-positive solid tumors.21 This represents a significant milestone in the expansion of HER2-targeted therapy beyond breast cancer to non-breast cancers. Despite these advancements, challenges and limitations still exist in the field of antibody‒drug conjugate therapy. One notable concern is the potential risk of antibody‒drug conjugate–associated interstitial lung disease, which can be life-threatening.22 Additionally, the emergence of resistance mechanisms poses a significant hurdle in achieving durable responses in various types of solid tumors.23 Addressing these limitations is crucial for optimizing the clinical use of anti-HER2 antibody‒drug conjugates.
SHR-A1811 (trastuzumab rezetecan) is a novel antibody‒drug conjugate composed of the antibody trastuzumab, which targets HER2 and is conjugated via a cleavable linker to the topoisomerase I inhibitor payload SHR169265.24 Preclinical studies have demonstrated the superior membrane permeability and cell-killing efficacy of SHR169265 compared with the payload used in trastuzumab deruxtecan.24 Moreover, SHR-A1811 exhibited sustained inhibition of HER2-dependent tumor growth, an enhanced bystander effect, and excellent stability, with a payload release rate of less than 1%.24 The moderate drug‒antibody ratio of 6 and the minimal amount of released toxin in circulation collectively support the favorable safety profile of SHR-A1811.24 SHR-A1811 has shown encouraging efficacy and a favorable safety profile as a neoadjuvant therapy in locally advanced or early HER2-positive breast cancer25 and as a second-line treatment in advanced non-small cell lung cancer,26 with multiple ongoing clinical trials exploring its therapeutic potential across broader oncology indications.
In the first-in-human, global, multicenter, phase 1 trial, SHR-A1811 demonstrated a favorable tolerability profile, with interstitial lung disease occurring in 2.6% of patients, and led to substantial tumor responses (59.9%, 184/307) in heavily pretreated patients with HER2-expressing or mutated advanced breast cancer and non-breast cancer.27 As of February 28, 2023, with a short median follow-up duration of 7.5 months (IQR 3.7–11.5), the median progression-free survival and duration of response data were immature and not reported, and the safety and objective response rate results were still preliminary. With ongoing patient enrollment beyond this cutoff date, we present the final results of the key secondary endpoints of progression-free survival and duration of response, as well as an updated analysis of the overall response and safety data of SHR-A1811. This final analysis included an additional 2-year follow-up period following the previous analysis and involved a cohort expanded from 307 to 396 patients.

Results

Patients
From September 7, 2020, to June 4, 2024, 588 patients underwent screening, among whom 396 eligible patients were enrolled in the study, including 35 and 361 patients in the dose escalation and study expansion (pharmacokinetics expansion and indication expansion) stages, respectively. Following the previous report,27 89 newly enrolled patients were allocated to the 4.8 mg/kg, 5.6 mg/kg, or 6.4 mg/kg dose groups. In total, the tumor type cohorts in this final analysis included HER2-positive breast cancers (n = 136), HER2-low expressing breast cancers (n = 110), biliary tract cancers (n = 47), urothelial carcinomas (n = 39), gynecological cancers (n = 22, including 8 ovarian cancers, 7 cervical cancers, 5 endometrial cancers, 1 fallopian tube cancer, and 1 primary peritoneal cancer), colorectal cancers (n = 14), gastric or gastro-esophageal junction adenocarcinomas (n = 13), non-small cell lung cancers (n = 4), and other cancer types (n = 11, including 3 pancreatic cancers, 2 esophageal squamous-cell carcinomas, 2 major salivary gland cancers, 1 head and neck cancer, 1 appendiceal cancer, 1 duodenal cancer, and 1 extramammary paget’s disease).
The patient population had a median age of 55 years (IQR 49–62), with females comprising the majority (79.0%). With respect to the Eastern Cooperative Oncology Group performance status, 33.3% of the patients had a score of 0, and 66.7% had a score of 1. Prior to the study, patients had received a median of 4 (IQR 2–6) treatment regimens in the metastatic setting for HER2-positive breast cancer, 3 (IQR 2–5) for HER2-low expressing breast cancer, and 2–3.5 for non-breast cancers (Table 1 and supplementary Table 1). In the HER2-positive breast cancer cohort, 99.3%, 43.4%, and 14.7% of patients had received prior trastuzumab, pertuzumab, and trastuzumab emtansine, respectively; in the HER2-low breast cancer cohort, the percentages were 13.6%, 5.5%, and 2.7%, respectively (supplementary Table 2). In the gastric or gastroesophageal junction carcinoma cohort, all patients had previously received HER2-targeted therapy. As of the data cutoff date on March 12, 2025, the median follow-up duration was 17.1 months (IQR 9.7–28.1) in HER2-positive breast cancer patients, 10.6 months (IQR 6.9–22.1) in HER2 low-expression breast cancer patients, and ranged from 4.3 to 8.2 months in non-breast cancer patients. Treatment was discontinued in 342 patients (86.4%), primarily because of radiographic progression (n = 219, 55.3%; Fig. 1).

Safety
The median duration of drug exposure to SHR-A1811 (trastuzumab rezetecan) was 13.9 months (IQR 6.1–26.3) in HER2-positive breast cancer, 8.3 months (IQR 4.5–19.3) in HER2-low expressing breast cancer, and ranged from 2.8 to 5.9 months in non-breast cancers. The safety profile in this final analysis, as of the data cutoff on March 12, 2025, remained consistent with that of the previous report up to February 28, 2023, in terms of the frequency, severity, and specificity of adverse events. The extended follow-up period, which included newly enrolled patients, revealed no emergent safety signals.
Among the 396 patients, 395 (99.7%) experienced adverse events (Table 2), with grade 3–5 adverse events occurring in 289 patients (73.0%; Table 2). Treatment-related adverse events of any grade were reported in 391 patients (98.7%), with the most common being decreased neutrophil count (308 patients, 77.8%), anemia (292 patients, 73.7%), and decreased white blood cell count (273 patients, 68.9%; supplementary Table 3). Grade 3–5 treatment-related adverse events were noted in 261 patients (65.9%; supplementary Table 4), with serious adverse events reported in 80 patients (20.2%), primarily decreased platelet count (36 patients, 9.1%), anemia (17 patients, 4.3%), and decreased neutrophil count (15 patients, 3.8%; supplementary Table 5).
Adverse events led to dose reductions in 138 patients (34.8%) and treatment interruptions in 226 patients (57.1%). Treatment-related adverse events caused dose reductions in 138 patients (34.8%) and treatment interruptions in 162 patients (40.9%). Forty-two patients (10.6%) discontinued treatment due to adverse events, 34 (8.6%) of whom discontinued treatment related to SHR-A1811 (supplementary Table 6). Additionally, 12 patients (3.0%) died from adverse events, with 4 (1.0%) attributable to treatment-related events (supplementary Table 7).
Interstitial lung disease occurred in 10 patients (2.5%), with 7 patients classified as having low-grade disease (grades 1–2; Table 2 and supplementary Table 8). The remaining 3 patients consisted of one grade 3 event in the 4.8 mg/kg group, one grade 3 event in the 5.6 mg/kg group, and one fatal event in the 8.0 mg/kg group.
The immunogenicity analysis revealed that no patient had positive results for treatment-induced anti-drug antibody after the baseline assessment.

Efficacy
The median progression-free survival in the total 396 HER2 expressing or mutated advanced solid tumor population was 11.1 months (95% CI 10.3–13.8), varying by tumor type: 25.0 months (95% CI 17.2–33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2–13.8) for HER2-low expressing breast cancer, 5.5 months (95% CI 4.2–8.2) for biliary tract cancer, 8.1 months (95% CI 4.4–12.4) for urothelial carcinoma, 8.5 months (95% CI 5.5–16.4) for gynecological cancer, 7.4 months (95% CI 1.2–16.8) for colorectal cancer, 3.5 months (95% CI 1.2–16.7) for gastric or gastroesophageal junction adenocarcinoma, 17.2 months (95% CI 4.0–17.2) for non-small cell lung cancer, and 5.5 months (95% CI 2.5–not evaluable) for other cancers (Table 3, Fig. 2, Fig. 3). The 12-month progression-free survival rates were 66.5%, 45.3%, 19.5%, 36.7%, 38.6%, 37.5%, 30.8%, 66.7%, and 30.7%, respectively.
For HER2-positive non-breast cancers, the progression-free survival was 7.9 months (95% CI 4.3–11.0) in biliary tract cancer, 7.0 months (95% CI 1.3–12.4) in urothelial carcinoma, 13.6 months (95% CI 5.5–not evaluable) in gynecological cancer, 14.4 months (95% CI 0.6–23.6) in colorectal cancer, 3.4 months (95% CI 1.2–16.7) in gastric or gastroesophageal junction adenocarcinoma, not reached (95% CI 4.0–not evaluable) in non-small cell lung cancer, and 11.1 months (95% CI 2.5–not evaluable) in other tumor cohorts, with 12-month progression-free survival rates of 25.8%, 29.6%, 60.0%, 60.0%, 30.8%, not reached, and 37.5%, respectively (Supplementary Tables 9 and Table 10).
Among the 246 enrolled breast cancer patients, 205 underwent central laboratory HER2 testing. The median progression-free survival was 26.3 months (95% CI 19.6–38.7) for HER2-positive patients (n = 108), 11.3 months (95% CI 8.5–24.7) for HER2-low patients (n = 43), and 9.8 months (95% CI 7.2–13.8) for patients with HER2-ultralow or HER2-null disease (n = 54; supplementary Table 11).
The tumor response duration was durable, with a median duration of response of 16.2 months (95% CI 12.6–20.6) in the total population, 25.1 months (95% CI 16.8–37.5) in HER2-positive breast cancer, 12.4 months (95% CI 8.1–22.1) in HER2-low expressing breast cancer, 9.7 months (95% CI 4.2–14.7) in biliary tract cancer, 10.1 months (95% CI 6.1–17.0) in urothelial carcinoma, 7.3 months (95% CI 4.4–not evaluable) in gynecological cancer, 17.5 months (95% CI 10.9–not evaluable) in colorectal cancer, 15.9 months (95% CI 4.4–not evaluable) in gastric or gastroesophageal junction adenocarcinoma, and 14.3 months (95% CI not evaluable-not evaluable) in non-small cell lung cancer. The median duration of response was not reached for the other tumor cohorts (Table 3, Fig. 2, Fig. 3).
In breast cancer patients with liver metastases, a condition associated with a high risk of disease progression, the tumor response is also durable. This was notably demonstrated by the sustained duration of response (30.4 months [95% CI 11.5–not evaluable] for HER2-positive breast cancer patients and 10.8 months [95% CI 8.1–22.1] for HER2-low expressing breast cancer patients; supplementary Fig. 1a, c) and progression-free survival (27.8 months [95% CI 11.0–38.7] for HER2-positive breast cancer patients and 10.9 months [95% CI 7.8–13.6] for HER2-low expressing breast cancer patients; supplementary Fig. 1b, d), which closely aligns with the outcomes observed in the total breast cancer cohort.
The objective response rates of the total population and each tumor type in this final analysis were generally consistent with those in the previous report. Across the total population, 232 patients (58.6%, 95% CI 53.6–63.5) achieved confirmed objective responses, with complete responses in 12 patients (3.0%) and partial responses in 220 patients (55.6%). The confirmed objective response rate was 78.7% (95% CI 70.8–85.2) in HER2-positive breast cancer patients and 61.8% (95% CI 52.1–70.9) in HER2-low-expressing breast cancer patients. Among the 150 non-breast cancer patients, the confirmed objective response rate varied by tumor type: 38.3% (95% CI 24.5–53.6) for biliary tract cancer, 46.2% (95% CI 30.1–62.8) for urothelial carcinoma, 28.6% (95% CI 8.4–58.1) for colorectal cancer, 46.2% (95% CI 19.2–74.9) for gastric or gastroesophageal junction adenocarcinoma, 31.8% (95% CI 13.9–54.9) for gynecological cancer, and 50.0% (95% CI 6.8–93.2) for non-small cell lung cancer (Table 3 and supplementary Fig. 2). The best percent change from baseline in the sum of the diameters of the target lesions in HER2-positive breast cancer, HER2-low-expressing breast cancer, and HER2-overexpressing or HER2-mutated non-breast solid tumors is shown in supplementary Fig. 3.

Discussion
This is the first-in-human trial of SHR-A1811 (trastuzumab rezetecan), a novel antibody‒drug conjugate comprising the HER2-targeted antibody trastuzumab, a topoisomerase I inhibitor payload, via a cleavable linker in heavily prior-treated unresectable, advanced, or metastatic solid tumors with diverse tumor types. The toxicities of SHR-A1811 were manageable, with interstitial lung disease reported in only 2.5% of patients. The tumor response was robust, and the clinical benefit was durable. This final analysis further underscores the promising clinical outcomes of SHR-A1811 in terms of both safety and efficacy, highlighting its potential as an alternative treatment option across a spectrum of heavily prior-treated HER2-expressing or mutated solid tumors.
Toxicities are critical considerations in the development of new oncologic therapies. The safety data from this trial revealed that SHR-A1811 was well tolerated, with manageable adverse events. The final safety analysis reveals that the safety profile of SHR-A1811 remains consistent with the prior report,27 with no new safety signals identified during the extended follow-up period. Hematologic toxicity is the most commonly reported treatment-related adverse event, which aligns with the known toxicity profiles of HER2 antibody‒drug conjugates.12,17,18,21,26,28,29 These findings are also consistent with the antibody- and payload-driven myelosuppression commonly observed with antibody–drug conjugates.30 Treatment-related adverse events prompted discontinuation in 8.6% of patients, which is numerically lower than that of trastuzumab deruxtecan in solid tumors (14.4% to 25%).12,17,18,28,29,31 This underscores the manageable nature of the toxicities associated with SHR-A1811, enabling more patients to sustain treatment, thereby expanding the therapeutic timeframe and ultimately enhancing the antitumor efficacy. Interstitial lung disease occurred in only 2.5% of patients, with the majority of events being low grade in this study. While direct comparisons should be interpreted with caution because of heterogeneous dosing, prior therapy, ethnic differences, and patient eligibility, trastuzumab deruxtecan reported incidences of interstitial lung disease ranging from 9.6% to 26.4% across clinical trials in advanced or metastatic solid tumors.12,14,17,18,21,28,29 New evidence suggests that trastuzumab deruxtecan-associated interstitial lung disease is an off-target toxicity driven by alveolar macrophages. These cells internalize the antibody–drug conjugate through fc–fcγr interactions, triggering a phenotypic switch from an immunosuppressive state to a proinflammatory, profibrotic state that underlies interstitial lung disease development.32 The low risk of interstitial lung disease in SHR-A1811 is likely due to its moderate drug‒antibody ratio and the chiral cyclopropyl modification at the α-carbonyl position of the exatecan derivative. This modification preserves topoisomerase I inhibition while enhancing plasma stability, minimizing toxin release into the circulation, and accelerating systemic clearance,24 thereby reducing systemic exposure and off-target toxicity, suggesting that SHR-A1811 might be a relatively safe alternative for patients with potential risk of interstitial lung disease. The overall safety profile of SHR-A1811 in this final analysis supports its further investigation in subsequent phase 3 trials with a larger patient population.
The efficacy data from this final analysis further underscore the clinically meaningful potential of SHR-A1811. Durable tumor responses were observed, with median duration of response ranging from 7.3 to 25.1 months and progression-free survival spanning 3.5 to 25.0 months, suggesting potential for sustained clinical benefit. Despite the inherent limitations of cross-trial analyses, SHR-A1811 demonstrated substantial antitumor activity in HER2-positive breast cancer, with efficacy comparable to that of trastuzumab deruxtecan.17 When our HER2-positive breast cancer cohort (n = 136, median 4 prior regimens, HER2 immunohistochemistry [IHC] 3 + : 66.2%) was compared with trastuzumab deruxtecan in the DESTINY-Breast01 (n = 184, median 6 prior regimens including mandatory trastuzumab emtansine exposure, HER2 IHC 3 + : 83.7%),28 SHR-A1811 demonstrated similar efficacy outcomes: median progression-free survival of 25.0 months (95% CI 17.2–33.6) with SHR-A1811 versus 16.4 months (95% CI 12.7–not reached) with trastuzumab deruxtecan and an objective response rate of 78.7% (95% CI 70.8–85.2) versus 60.9% (95% CI 53.4–68.0). Even in HER2-low-expressing breast cancer, SHR-A1811 also exhibited progression-free survival benefits, with similar efficacy observed in exploratory analyses of centrally confirmed HER2-expressing tumors (supplementary Table 11). Notably, SHR-A1811 demonstrated a median progression-free survival of 11.0 months in HER2-low patients, whereas it was 9.9 months in patients treated with trastuzumab deruxtecan.18 Among patients with baseline brain metastases, SHR-A1811 exhibited a longer progression-free survival in HER2-positive breast cancer, with a median progression-free survival of 14.1 months versus 8.5 months for those with HER2-low-expressing breast cancer (supplementary Table 12). This result aligns with the REIN trial, where SHR-A1811 monotherapy achieved a median progression-free survival of 13.2 months in HER2-positive breast cancer patients with brain metastases.33 Considering the heavily pretreated nature of the patient population, the findings of this study highlight the potential of SHR-A1811 to overcome resistance mechanisms, thereby leading to clinically meaningful outcomes in heavily prior-treated solid tumors.
Exploratory analyses of centrally confirmed HER2-expressing tumors identified 54 patients whose tumors were classified as HER2 ultralow/null. Despite this minimal expression level, SHR-A1811 exhibited promising efficacy in this subgroup, achieving a confirmed objective response rate of 59.3% and a median progression-free survival of 9.8 months. These findings align with the efficacy observed with trastuzumab deruxtecan in the HER2-ultralow cohort (0< IHC < 1 + ) of DESTINY-Breast06.34 Notably, our HER2 ultralow/null population specifically included patients with an IHC 0 status, a group typically excluded from conventional HER2-targeted therapies. The most plausible mechanistic explanation centers on the bystander effect of SHR-A1811, where its membrane-permeable payload diffuses into adjacent tumor cells with HER2 levels below standard IHC detection thresholds,24 expanding its therapeutic potential beyond traditional HER2-positive or HER2-low classifications.
The expansion of anti-HER2 therapy into non-breast cancers represents a significant milestone. The objective response rates observed with SHR-A1811 across different tumor types were encouraging and generally align with the previous report of SHR-A181125–27,33 and the efficacy profile of trastuzumab deruxtecan.17,18
While our study offers important evidence regarding the efficacy and safety of SHR-A1811, several limitations should be considered. First, owing to the single-arm design of this study, subsequent randomized trials including a well-established comparator are needed to further validate the clinical outcomes of SHR-A1811. Second, the heterogeneity of the tumor types included in the study warrants further investigation into the efficacy of SHR-A1811 in specific cancer subtypes with larger sample sizes. Third, the analysis of the correlation of HER2 expression with treatment efficacy, particularly for expression assessed by a central laboratory, remains exploratory in nature. Biomarker studies to identify patients most likely to benefit from SHR-A1811 will be essential in personalizing treatment and maximizing therapeutic efficacy.
The development of SHR-A1811 is progressing rapidly. Several phase 2 and 3 clinical trials are currently underway to further evaluate its efficacy in both early and advanced breast cancer settings. However, a randomized, head-to-head comparison with trastuzumab deruxtecan in advanced breast cancer is not currently planned. Addressing this evidence gap through future comparative research will be crucial for defining the optimal positioning of SHR-A1811 in the evolving treatment landscape for HER2-targeted therapies.
In conclusion, the final analysis from this first-in-human phase 1 trial reaffirms the potential of SHR-A1811 as a highly effective and safe treatment option for patients with HER2-expressing and HER2-mutated solid tumors. The favorable safety profile, coupled with encouraging efficacy across a range of solid tumors, positions SHR-A1811 as a promising alternative to HER2-targeted therapies. Future studies will be pivotal in confirming these findings and optimizing treatment strategies to fully explore the potential of SHR-A1811 in improving clinical outcomes for patients with heavily prior-treated advanced solid tumors.

Materials and methods

Study design and participants
This study was designed as a global, multicenter, first-in-human, phase 1 trial conducted at 38 centers and consisted of three parts: dose escalation, pharmacokinetics expansion, and indication expansion.
Eligible patients were 18 years or older (20 years or older in Taiwan and 19 years or older in Korea) with unresectable, advanced, or metastatic solid tumors refractory or intolerant to standard therapies. Eligible patients enrolled in the dose escalation and pharmacokinetics expansion parts had histologically confirmed HER2-expressing (IHC 1 + , 2 + , and 3 + ) or mutated solid tumors. Patients in the indication expansion part had HER2-positive breast cancer (IHC 3+ or in situ hybridization [ISH]-positive; cohort A), HER2-positive gastric or gastroesophageal junction adenocarcinoma (IHC 3 + , or IHC 2 + and ISH-positive; cohort B), HER2-low expressing breast cancer (IHC 2 + and ISH-negative, IHC 1 + and ISH-negative, or IHC 1+ and ISH untested; cohort C), HER2-expressing or mutated non-small cell lung cancer (HER2-positive is defined as IHC 3 + , or ISH + ; cohort D), and other HER2-expressing or mutated solid tumors (HER2-positive is defined as IHC 3 +, or ISH + ; cohort E). HER2 status was retrospectively reconfirmed at a central laboratory (Q2 Solutions, IQVIA RDS [India] Private Limited) for all patient cohorts. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with active central nervous system metastases, other malignancies, and a history of clinically significant lung diseases (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or those suspected to have these diseases by imaging during the screening period were excluded. Complete eligibility criteria are provided in the protocol (Data Supplement).
The trial protocol and its subsequent amendments were approved by the ethics committee at each participating center (supplementary Table 13). The study was conducted in compliance with the Declaration of Helsinki and with Good Clinical Practice guidelines. Written informed consent was obtained from all enrolled patients.

Procedures
SHR-A1811 was administered intravenously every three weeks (one cycle) until disease progression, unacceptable toxicity, death, consent withdrawal, or investigator decision. Treatment interruptions (up to four weeks) and dose reductions were allowed to manage toxicities, as detailed in the protocol.
In the dose escalation part, patients were recruited via an “i3 + 3” design. Three patients per dose were evaluated for dose-limiting toxicity until day 21 by a safety monitoring committee before escalation to the next dose. Starting at 1.0 mg/kg (one-twelfth of the highest non-severely toxic dose in cynomolgus monkeys), the dose was sequentially escalated to 2.0 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 6.4 mg/kg, and 8.0 mg/kg. On the basis of the safety, tolerability, and pharmacokinetics data obtained from the dose escalation part, two to four dose groups (approximately 15 patients per group) were selected for the pharmacokinetics expansion at Asian sites. The indication expansion part followed Simon’s two-stage design, with sample sizes ranging from 121 to 190, as detailed in the protocol (Data Supplement).
Safety was assessed at each visit, with detailed schedules in the protocol. Adverse events were graded per the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0. Tumor responses were assessed at baseline, every six weeks for 24 weeks, and then every 12 weeks via high-resolution CT or MRI per RECIST v1.1. Complete and partial responses required confirmation at least four weeks later.

Outcomes
The primary endpoints were dose-limiting toxicity, safety, and the recommended phase 2 dose. The secondary endpoints included the objective response rate (proportion of patients with complete or partial response), duration of response (time from first response to progression or death), progression-free survival (time from treatment initiation to progression or death), disease control rate (proportion of patients with complete response, partial response, or stable disease), pharmacokinetics, and immunogenicity.
The short-term safety, objective response, pharmacokinetics, and immunogenicity results have been previously reported.27 Here, we present the final analysis of SHR-A1811, with a specific focus on the duration of response and progression-free survival. Additionally, we report an updated long-term assessment of safety and objective response outcomes.

Statistical analysis
The sample size in the dose escalation and pharmacokinetics expansion parts was determined on the basis of the Simon two-stage minimax design. In the indication expansion part, which consisted of two stages, the sample size for each cohort was specified with a 10% one-sided type I error and 90% power. In cohorts A and D, if no less than eight of the 28 patients achieved a best overall response of complete or partial response in the first stage, an additional 11 patients would be enrolled in the second stage. In cohorts B and C, if no less than four of the 19 patients achieved a best overall response of complete or partial response in the first stage, an additional 17 patients would be enrolled in the second stage. In cohort E, if no less than three of the 27 patients achieved a best overall response of complete or partial response in the first stage, an additional 13 patients were enrolled in the second stage.
Efficacy was assessed in the full analysis set, which included all eligible patients who received at least one dose of SHR-A1811. The efficacy analysis was based on local laboratory assessments, with central laboratory results provided in the appendix for reference. The HER2 subtypes in breast cancer were classified as follows, per central laboratory assessment: HER2-positive was IHC 3+ or ISH + ; HER2-low expression was IHC 2+ and ISH-negative, or IHC 1+ and ISH-negative or ISH untested; HER2-ultralow expressing or null was IHC 0 and ISH-negative or IHC 0 and ISH untested. Safety was assessed in the safety set, which also included all patients who received at least one dose of SHR-A1811. Baseline demographics and safety results were summarized descriptively. Time-to-event endpoints (progression-free survival and duration of response) were analyzed via the Kaplan-Meier method, with two-sided 95% confidence intervals (CIs) calculated using the Brookmeyer-Crowley method. Response rates were presented with two-sided 95% CIs using the Clopper-Pearson exact method. All analyses were performed using SAS (SAS Institute, Cary, US) version 9.4 or higher.

Supplementary information