A Study of Subcutaneous Trastuzumab Deruxtecan in Participants With Metastatic Solid Tumors

Key Inclusion Criteria:

1. Sign and date the ICF, prior to the start of any trial- specific qualificationprocedures.

2. Adults ≥18 years or the minimum legal adult age (whichever is greater).

3. a) Disease State: If HER2 status is required for eligibility (for all populations,except "Pan-tumor, heavily pretreated, with no SoC"), a documented HER2 test resultmust be available. A participant population would only be considered in regionswhere T-DXd is approved for that indication and an approved or validated test isavailable, if required per country regulations. Note: for all indications, all localHR testing and HER2 testing shall be per ASCO/CAP guidelines, as applicable, in theadvanced setting, using a validated or approved test as required per localregulations. The most recent available samples should be used to confirmeligibility, if applicable. For full description of each population, see below.Breast Cancer: adults with pathologically documented unresectable or metastaticbreast cancer HER2-positive BC: have received a prior anti-HER2-based regimen. ForHER2-positive BC participants in Part 2 only, prior anti-HER2 based therapy shouldhave been received in either:

• the metastatic setting, or

• the neoadjuvant or adjuvant setting and have developed disease recurrenceduring or within 6 months of completing therapy. HR-, HER2-low BC: havereceived a prior systemic cytotoxic therapy in the metastatic setting; ordeveloped disease recurrence during or within 6 months of completing (neo)adjuvant chemotherapy. HR+, HER2-low/ultralow BC: have received previousET AND an additional line of ET must not be the next line of treatmentconsidered in the participant's best interest.

• For participants in Part 2 with HR+ HER-2low/ultralow BC, the followingcriteria also apply:

• had disease progression while receiving 1 previous line of ET with a CDK4/6iand 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 atarget therapy such as CDK4/6, mTOR or PI3-K inhibitors) administered for thetreatment of metastatic disease

• of note:

• If the 1 line was given while in the adjuvant setting, if disease recurrenceoccurred while on the first 24 months of adjuvant ET, that will be considered aline of therapy and only 1 additional line of ET will be required in themetastatic setting, with or without targeted therapy (such as CDK4/6, mTOR orPI3-K inhibitors)

• Any progression after discontinuing or completing a course of adjuvant ET willnot be considered a line of therapy

• Single agent PARP inhibitor therapy does not count as ET or as cytotoxic is notconsidered a line of ET

• Changes in dosing schedules, or discontinuations/restarting of the same drugsor the addition of a targeted therapy to an ET without progression (eg, addinga CDK4/6 inhibitor to a current aromatase inhibitor regimen) will not beconsidered separate lines of therapy.

• participants may not have received more than 2 prior lines of cytotoxic therapyin the recurrent or metastatic setting. NSCLC, HER2 mut: adults withunresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2)mutations, and who have received a prior systemic therapy. Gastric Cancer, HER2-positive: adults with locally advanced or metastaticHER2-positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junctionadenocarcinoma who have received a prior anti-HER2-based regimen Pan-tumor,HER2-positive: adults with unresectable or metastatic HER2-positive (IHC 3+) solidtumors who have received prior treatment or have no satisfactory alternativetreatment options Heavily pretreated tumors: adults with unresectable or metastaticsolid tumors (other than described above), who have received prior systemictreatment and have no satisfactory treatment alternative b) Part 2 only: At least 1RECIST 1.1 measurable lesion on CT or MRI.

4. Radiologic or objective evidence of disease progression on or after the lastsystemic therapy prior to starting trial intervention.

5. Part 2 only: confirmation of availability of the most recent available adequate FFPEarchival tumor tissue sample obtained in the advanced setting, or provision of newlyobtained tumor tissue if clinically feasible and at an acceptable risk as determinedby the Investigator.

6. ECOG PS of 0 to 1.

Key Exclusion Criteria:

1. Prior treatment with ADC that consists of an exatecan derivative that is atopoisomerase I inhibitor; NOTE exception for SDC 1 and 2, where prior exposure tosuch agents is permitted provided the following are met:

2. At least 1 year has elapsed since last dose of exatecan derivative ADC.

3. The participant did not discontinue nor reduce the dose due to toxicity.

4. The participant did not experience any drug-related Grade 3/4 toxicity.

5. The participant did not experience ILD of any grade while on or after theexatecan derivative ADC treatment.

6. Has a history of severe hypersensitivity reactions to either the drug substances orinactive ingredients in the drug products.

7. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.

8. Medical history of MI within 6 months before enrollment or symptomatic CHF (New YorkHeart Association class II to IV). Participants with troponin levels above ULN atscreening (as defined by the manufacturer), and without any MI-related symptomsshould have a cardiologic consultation during the Screening Period to rule out MI.

9. Has a corrected QT interval (QTcF) prolongation to > 480 ms (regardless ofparticipant's sex) based on average of the screening triplicate 12-lead ECG.

10. Has a history of (non-infectious) ILD/pneumonitis that required steroids, hascurrent ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out byimaging at screening.