MC# 20-40

1. Male or female ≥ 18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
3. Life expectancy ≥12 weeks
4. Subject has measurable disease based on RECIST v1.1
5. Functions of important organs meet the following standards (no blood component and cell growth factor treatment within 28 days before first time study drug administration):
   • Absolute neutrophil count (ANC) ≥1.5×10⁹/L (1,500/mm³)
   • Platelets ≥100×10⁹/L (100,000/mm³)
   • Hemoglobin (Hgb) ≥9.0 g/dL (90 g/L)
   • Albumin levels ≥2.8 g/dL
   • Total bilirubin ≤1.5× ULN
   • Prothrombin time and activated partial thromboplastin time (aPTT) ≤1.5×ULN
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; for subjects with liver metastases, ALT and AST ≤5×ULN
   • Serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min based on Cockcroft-Gault equation
   • QTcF≤ 450 msec for male, QTcF ≤ 470 msec for female;
   • LVEF ≥ 50% by either ECHO or MUGA
6. Pregnancy and Contraception:
   • Female subjects agree not to be pregnant or lactating from beginning of the study screening until 6 months after receiving the last treatment
   • Male subjects with partners of childbearing potential and female subjects of childbearing potential are willing and able to employ a highly effective method of birth control/contraception to prevent pregnancy from beginning of the study screening until 6 months after receiving the last treatment of study drug
   • A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year, when used consistently and correctly)
   • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to initiation of treatment and not be breast feeding.  Female subjects of non-childbearing potential must be surgically sterile (i.e., bilateral tubal ligation or removal of both ovaries and/or uterus at least 6 months prior to dosing) or naturally postmenopausal (spontaneous cessation of menses) for at least 24 consecutive months prior to dosing, with a follicle stimulating hormone (FSH) level at screening of ≥40 mIU/mL.
7. Subjects participate in the study voluntarily, sign the informed consent, and are willing and able to comply with clinic visits and study-related procedures

Additional inclusion criteria for Part 1-Dose Escalation:

8. Subject with HER2 expression or mutation must have a pathologically documented advanced/unresectable or metastatic solid tumor that is refractory to or intolerable with standard treatment, or for which no standard treatment is available

Additional inclusion criteria for Part 2-Indication Expansion:

9. Part 2, Cohort A: Subjects have a pathologically documented advanced/unresectable or metastatic breast cancer with HER2 overexpression (IHC3+, or ISH+) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available; Treated with trastuzumab and taxanes
10. Part 2, Cohort B: Subjects have a pathologically documented advanced/unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with HER2 overexpression (IHC3+, IHC2+ and ISH+) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available; Treated with platinum-based chemotherapy with or without trastuzumab in the recurrent/metastatic setting
11. Part 2, Cohort C: Subjects have a pathologically documented advanced/unresectable or metastatic breast cancer with HER2 low expression (IHC2+ and ISH-, IHC1+ and ISH-, or IHC 1+ and ISH untested) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available
12. Part 2, Cohort D: Subjects have a pathologically documented advanced/unresectable or metastatic NSCLC with HER2 expression or mutation (determined by next generation sequencing or other analysis techniques as appropriate) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available
13. Part 2, Cohort E: Subjects have a pathologically documented advanced/unresectable or metastatic cancer with HER2 expression or mutation (determined by next generation sequencing or other analysis techniques as appropriate) other than breast cancer, gastric or gastroesophageal junction adenocarcinoma, NSCLC (i.e colorectal cancer, urothelial carcinoma, etc.) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available

1. Active central nervous system (CNS) metastasis without surgery or radiotherapy, except for those who are stable for at least 1 month after treatment and have stopped corticosteroids for more than 2 weeks
2. Subjects with other malignant tumors in the past 5 years or at present (except for cured skin basal cell carcinoma and cervical carcinoma in situ)
3. Received mitomycin C and nitrosoureas chemotherapy within 6 weeks before first time study drug administration
4. Any surgery (eg., surgery for cancer treatment), radiotherapy, chemotherapy or molecular targeted treatment within 4 weeks; received endocrine therapy within 2 weeks before first time study drug administration
5. Received any antibody drug conjugates with the following characteristics: the components contain exatecan or its derivatives, and are topoisomerase I inhibitors, such as Enhertu (DS- 8201a), etc.
6. Any concurrent use of immunosuppressant or systemic corticosteroid treatment to achieve immunosuppression purpose (dose > 10mg/day prednisone or other therapeutic corticosteroids), and still in use within 2 weeks before first time study drug administration
7. Received CYP3A4, CYP2D6, P-gp or BCRP strong inhibitor or inducer less than 5 half-lives before first time study drug administration
8. History of autoimmune disease with the possibility of recurrence or active autoimmune disease (such as the following, but not limited to: autoimmune hepatitis, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [subjects that can be controlled only by hormone replacement therapy can be included], subjects with skin diseases without systematic treatment such as vitiligo, psoriasis, alopecia, controlled type I diabetes treated with insulin can be included; asthma completely relieved in childhood without any intervention in adult can be included, subjects that requires medical intervention with bronchodilators for asthma cannot be included)
9. History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV) or other acquired or congenital immune-deficient disease, or any active systemic viral infection requiring therapy (e.g., hepatitis B or C), or organ transplantation
10. Cardiac disease including myocardial infarction within a minimum 6 months before first time study drug administration, or unstable angina, congestive heart failure (New York Heart Association [NYHA] classes II–IV), or clinically significant supraventricular or ventricular cardiac arrhythmia requiring treatment/intervention
11. History of clinically significant lung diseases (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or suspected to have these diseases by imaging at screening period
12. Known hereditary or acquired bleeding and thrombotic tendency (such as hemophilia, coagulation dysfunction, etc.)
13. Active hepatitis B (HBsAg positive and HBV DNA ≥ 500 IU / ml), hepatitis C (hepatitis C antibody positive and HCV RNA higher than the detection limit of the analytical method), hepatic cirrhosis, or severe infections requiring antibiotic, antiviral or antifungal control
14. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI CTCAE v5.0 Grade ≤1 at baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the investigator and discussion with sponsor.
15. Known history of severe allergy to any component (antibody-drug conjugate [ADC], total antibody, unconjugated toxin SHR169265) of the SHR-A1811 product, or allergy to humanized monoclonal antibody products (such as trastuzumab, pertuzumab, etc.)
16. Any other medical (e.g., impaired liver function, specifically: Child-Pugh class B or C, pulmonary, metabolic, congenital, endocrine, drug abuse, etc.), psychiatric, or social conditions deemed by the investigator to be likely to interfere with a subject’s rights, safety, welfare or ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results