METHODS OF USING A BISPECIFIC ANTIGEN-BINDING CONSTRUCT TARGETING HER2 IN COMBINATION WITH CDK4/6 INHIBITORS FOR THE TREATMENT OF BREAST CANCER

1 - 17 . (canceled)

18 . A method of treating a patient with human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer, the method comprising administering to the patient:

I) 15 mg/kg to 20 mg/kg of a bispecific anti-HER2 antigen-binding construct every 2 weeks (Q2W) or 15 mg/kg to 50 mg/kg of a bispecific anti-HER2 antigen-binding construct every 3 weeks (Q3W);

II) fulvestrant administered at 250 mg-500 mg Q2W for the first 3 doses, then once every 4 weeks (Q4W), and

III) Ribociclib;

wherein the bispecific anti-HER2 antigen-binding construct comprises a heavy chain H 1 , a heavy chain H 2 , and a light chain L1,

wherein:

a) heavy chain H 1 comprises the CDR sequences set forth in SEQ ID NO:39, SEQ ID NO:40, and SEQ ID NO:41;

b) heavy chain H 2 comprises the CDR sequences set forth in SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, and SEQ ID NO:72; and

c) light chain L1 comprises the CDR sequences set forth in SEQ ID NO:27, SEQ ID NO:28, and SEQ ID NO:29.

19 . The method according to claim 18 , wherein the breast cancer is resectable, partially resectable, or unresectable.

20 . The method according to claim 18 , wherein the breast cancer is locally advanced and/or metastatic.

21 . The method according to claim 18 , wherein the bispecific anti-HER2 antigen-binding construct comprises a heavy chain H 1 comprising the amino acid sequence set forth in SEQ ID NO:36, a heavy chain H 2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a light chain L1 comprising the amino acid sequence set forth in SEQ ID NO:24.

22 . The method according to claim 18 , wherein the effective amount of the bispecific anti-HER2 antigen-binding construct is 20 mg/kg every two weeks.

23 . The method according to claim 18 , wherein the effective amount of the bispecific anti-HER2 antigen-binding construct is 30 mg/kg every three weeks.

24 . The method according to claim 18 , wherein the administrations of I, II and III result in a complete response (CR), partial response (PR) or stable disease (SD) in the patient.

25 . The method according to claim 18 , wherein the disease control rate in a group of patients administered I, II, and III is greater than 60%, 70%, or 80%.

26 . The method according to claim 18 , wherein the administrations of I, II and III are administered following at least one, two, or three first-line therapies.

27 . The method according to claim 18 , wherein the patient has prior progression or intolerance following prior trastuzumab, pertuzumab and T-DM1 treatment.

28 . The method according to claim 18 , wherein the method further comprises administration of one or more chemotherapeutic agents.

29 . The method according to claim 28 , wherein the one or more chemotherapeutic agents is gemcitabine and/or cisplatin.

30 . The method according to claim 18 , wherein the method further comprises administration of gonadotropin-releasing hormone analogue.

31 . A method of treating a patient with human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer, the method comprising administering to the patient:

I) 20 mg/kg of a bispecific anti-HER2 antigen binding construct thereof every 2 weeks (Q2W);

II) fulvestrant administered at 500 mg Q2W for the first 3 doses, then once every 4 weeks (Q4W); and

III) Ribociclib;

wherein the bispecific anti-HER2 antigen-binding construct comprises a heavy chain H 1 , a heavy chain H 2 , and a light chain L1,

wherein:

a) heavy chain H 1 comprises the CDR sequences set forth in SEQ ID NO:39, SEQ ID NO:40, and SEQ ID NO:41;

b) heavy chain H 2 comprises the CDR sequences set forth in SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, and SEQ ID NO:72; and

c) light chain L1 comprises the CDR sequences set forth in SEQ ID NO:27, SEQ ID NO:28, and SEQ ID NO:29.

32 . The method according to claim 31 , wherein the bispecific anti-HER2 antigen-binding construct comprises a heavy chain H 1 comprising the amino acid sequence set forth in SEQ ID NO:36, a heavy chain H 2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a light chain L1 comprising the amino acid sequence set forth in SEQ ID NO:24.

33 . The method according to claim 31 , wherein the administrations of I, II, and III result in a complete response (CR), partial response (PR) or stable disease (SD) in the patient.

34 . The method of claim 18 , wherein the bispecific anti-HER2 antigen-binding construct is an antibody drug conjugate (ADC).

35 . The method of claim 31 , wherein the bispecific anti-HER2 antigen-binding construct is an antibody drug conjugate (ADC).