T-DXd with HyaluronidaseA Study of Subcutaneous Trastuzumab Deruxtecan in Participants With Metastatic Solid Tumors

Key Inclusion Criteria:

1. Adults ≥18 years or the minimum legal adult age (whichever is greater).
2. a) Disease State: If HER2 status is required for eligibility (for all populations), a documented HER2 test result must be available.

Breast Cancer: adults with pathologically documented unresectable or metastatic breast cancer HER2-positive BC: have received a prior anti-HER2-based regimen. For HER2-positive BC participants in Part 2 only, prior anti-HER2 based therapy should have been received in either:

• the metastatic setting, or
• the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. HR-, HER2-low BC: have received a prior systemic cytotoxic therapy in the metastatic setting; or developed disease recurrence during or within 6 months of completing (neo)adjuvant chemotherapy. HR+, HER2-low/ultralow BC: have received previous ET AND an additional line of ET must not be the next line of treatment considered in the participant's best interest.
• For participants in Part 2 with HR+ HER-2low/ultralow BC, the following criteria also apply:
• had disease progression while receiving 1 previous line of ET with a CDK4/6i and is not expected to benefit from immediate use of a second line of ET, OR
• had disease progression on at least 2 previous lines of ET with or without a target therapy such as CDK4/6, mTOR or PI3-K inhibitors) administered for the treatment of metastatic disease
• participants may not have received more than 2 prior lines of cytotoxic therapy in the recurrent or metastatic setting. NSCLC, HER2 mut: adults with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, and who have received a prior systemic therapy.

b) Part 2 only: At least 1 RECIST 1.1 measurable lesion on CT or MRI.
3. Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting trial intervention.

Key Exclusion Criteria:

1\. Prior treatment with ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor; 4. Medical history of MI within 6 months before enrollment or symptomatic CHF (New York Heart Association class II to IV). Participants with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI-related symptoms should have a cardiologic consultation during the Screening Period to rule out MI.

5\. Has a corrected QT interval (QTcF) prolongation to > 480 ms (regardless of participant's sex) based on average of the screening triplicate 12-lead ECG. 6. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.