Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)

Inclusion criteria:

1. Male and female participants must be at least 18 years of age. Other agerestrictions may apply as per local regulations

2. Disease Characteristics:

3. Locally advanced, unresectable, or metastatic disease based on most recentimaging

4. For Part 1, 2, 3a, 4a pathologically documented adenocarcinoma of thestomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on localtissue testing results

5. For Part 3b,4b and Part 5, pathologically documented adenocarcinoma of thestomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on localtissue testing results

6. For Part 1, progression on or after at least one prior trastuzumabcontaining regimenFor Part 2, Part 3, Part 4 and Part 5, previously untreated for unresectable ormetastatic adenocarcinoma of the stomach/GEJ/ esophagus with with HER2-positive (Part 2 and Part 3 [Arm 3A] and Part 4 [Arm 4A]) or HER2-low (Part 3 [Arm 3B], Part 4 [Arm 4B] and Part 5)) status

7. Has measurable target disease assessed by the Investigator based on RECIST version 1.1

8. Has protocol defined adequate bone marrow and organ function including cardiac,renal and hepatic function

9. If of reproductive potential, agrees to use a highly effective form of contraceptionor avoid intercourse during and upon completion of the study.

Exclusion criteria:

1. Part 1 to 4: History of active primary immunodeficiency, known HIV, active chronic,or past hepatitis B infection, or hepatitis C infection. Part 5: evidence of active,uncontroled HIV, HBV or HCV infection.

2. Uncontrolled intercurrent illness.

3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD thatcannot be ruled out by imaging at screening.

4. Lung-specific intercurrent clinically significant severe illnesses.

5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, orantifungals.

6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritonealshunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).

7. Has spinal cord compression or clinically active central nervous system metastases.