Study of SHR-A1811 Combined with Pyrotinib and Bevacizumab in Advanced Breast Cancer with Brain Metastasis

Inclusion Criteria:

• More than 18 years old;

• ECOG PS Score: 0~2;

• Patients must have a life expectancy ≥ 3 months;

• Brian metastasis confirmed by MRI, at least one measurable brain lesion based onRANO-BM with no prior radiotherapy;

• Mannitol or hormone therapy is allowed to use for brain metastasis before enrolment,but treatment dosage should be stable for one week and not need to be increased;

• Adequate organ function and marrow function;

• Has recovered from any AEs (≤ grade 1) related to prior anti-tumour treatmentsbefore first dose of study therapy, except: a. alopecia; b. hyperpigmentation;

• Willing to join in this study, able to provide written informed consent, goodcompliance and willing to cooperate with follow-up.

Exclusion Criteria:

• Has leptomeningeal metastasis or cystic metastatic lesions confirmed by MRI orlumbar puncture;

• Existence of third space fluid (e.g. massive ascites, pleural effusion, pericardialeffusion) that is not well controlled by effective methods, e.g. drainage;

• Has CNS complications with the need for emergency intervention, or brain metastasiswith poorly controlled symptoms by hormone or dehydration therapy, such asuncontrollable intracranial hypertension, mental disorder or epilepsy;

• Prior bevacizumab or EGFR-TKI is allowed, but should meet the following requirementsat the same time:

1. No disease progression during prior bevacizumab or EGFR-TKI;

2. More than 3 months from the interruption of bevacizumab or EGFR-TKI to diseaseprogression;

• Has received whole brain radiotherapy, chemotherapy, surgery within 2 weeks beforefirst dose of study therapy; has received trastuzumab-based therapy or endocrinetherapy within one week before first dose of study therapy; has received palliativeradiotherapy for bone metastasis within 2 weeks before first dose of study therapy;

• Has known clinically significant lung disease, that is, moderate-to-severe lungdisease which severely affects respiratory function, including but not limited to:idiopathic pulmonary fibrosis, pneumonitis. Prior ≥ grade 3 interstitial lungdisease is not allowed to enrolment;

• Has received full-dose anticoagulants or thrombolytics within 10 days beforeenrolment, or non-steroid anti-inflammatory drugs with platelet inhibition (exceptlow-dose aspirin (≤325mg qd) for preventive use);

• Existence of unhealed wound, active gastric ulcer, and other diseases which maycause haemorrhage risk (e.g., prior major operation within 4 weeks before enrolment,prior arterial or venous thrombotic event within one year before enrolment, priorcerebralvascular accident);

• Has known hereditary haemorrhagic tendency or coagulation disorder;

• Has joined in other clinical drug trials within 2 weeks before enrolment;

• Use of other antitumor systemic treatment during the study at the same time, exceptbisphosphonates for the treatment of bone metastasis or osteoporosis prevention;

• Other malignancy within prior 5 years unless curatively treated with no evidence ofdisease for at least recent 3 years, except: curatively treated in situ cancer ofthe cervix, skin basal cell carcinoma or skin squamous cell carcinoma;

• Cardiac insufficiency, including but not limited to: congestive heart failure,transmural myocardial infarction, angina which needs drug treatments, clinicallysignificant valvulopathy and high-risk arrhythmia, or QTc abnormity with clinicalsignificance in ECG examination during the screening period (corrected QTc >450 msec [male] or QTc >470 msec [female] under the resting state);

• Uncontrolled hypertension (under the resting state: systolic pressure >160mmHg ordiastolic pressure >100mmHg);

• Other diseases which may affect study results, including but not limited to: 1)known history of immunodeficiency, including HIV-positive, other acquired or innateimmunodeficient disease, or known history of organ transplantation; 2)HBsAg-positive and HBV DNA≥1000 IU/mL, or HCV antibody-positive, or treponemapallidum antibody-positive; 3) hypersensitivity to study therapy or any of itsexcipients; 4) severe infection requiring antibiotics, antiviral or antifungaltreatment;

• Female patients during the gestation or suckling period, of childbearing potentialand pregnancy test-positive, or unwilling to use an effective method ofcontraception during the whole study;

• Inability to swallow, intestinal obstruction or existence of other factors affectingmedication and absorption;

• Any other conditions not appropriate for study enrolment in the opinion of theinvestigator.