DESTINY-Breast 06

Key Inclusion Criteria:

• Patients must be ≥18 years of age.

• Pathologically documented breast cancer that:

1. is advanced or metastatic

2. has a history of HER2-low or negative expression by local test, defined as IHC 2+/ISH- or IHC 1+ (ISH- oruntested) or HER2 IHC 0 (ISH- or untested)

3. has HER2-low or HER2 IHC >0 <1+ expression as determined by central HER2 laboratory result established on a tissue sample taken in the metastatic setting

4. was never previously HER2-positive

5. is documented HR+ disease in the metastatic setting.

6. No prior chemotherapy for advanced or metastatic breast cancer.

7. Has adequate tumor samples for assessment of HER2 status

8. Must have either:

a. disease progression within 6 months of starting first line metastatic treatment with an endocrine therapy combined with a CDK4/6 inhibitor or;

b. disease progression on at least 2 previous lines of endocrine therapy with or without a targeted therapy in the metastatic setting (progression ofdisease within 24 months on adjuvant ET is considered a line of therapy)

9. Has protocol-defined adequate organ and bone marrow function.

Key Exclusion Criteria:

• Ineligible for all options in the investigator’s choice chemotherapy arm
• Uncontrolled intercurrent illness or significant cardiovascular disease
• Active or prior documented ILD/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses
• Patients with spinal cord compression or clinically central nervous system metastasis