This is a single arm, multicenter and prospective study to evaluate the efficacy and safety of T-DXd for the treatment in locally advanced, unresectable, or metastatic participants with selected HER2 positive (IHC 3+) NSCLC which are not eligible for curative therapy

Inclusion Criteria:

1. Male and female participants must be at least 18 years of age at the time of signing the ICF.
2. Histologically documented Stage III locally advanced and unresectable non-squamous NSCLC not amenable to curative surgery or radiation and/or Stage IV NSCLC.
3. Participants must have HER2 overexpression (IHC 3+).
4. progressed following at least one or two prior systemic treatment.
5. Prior anti-HER2 are eligible except for HER2 ADC.
6. At least 1 measurable lesion by the investigator based on RECIST 1.1.
7. LVEF ≥ 50% within 28 days before enrollment.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
9. Adequate organ and bone marrow function within 14 days before enrolment. All parameters must be the most recent results available.
10. Adequate treatment washout period before enrolment.
11. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner.

Exclusion Criteria:

1. Has spinal cord compression or clinically active central nervous system metastases.
2. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG.
3. 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.
4. Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals
5. Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection or active hepatitis B (hepatitis B virus surface antigen or hepatitis B virus core antibody positive, at screening) or C infection.
6. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan.
7. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
8. Known allergy or hypersensitivity to study treatment or any of the study drug excipients
9. History of severe hypersensitivity reactions to other monoclonal antibodies.
10. Pregnant or breastfeeding female participants, or participants who are planning to become pregnant.
11. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
12. Any other clinically significant medical conditions, that may, in the opinion of the investigator, interfere with the participant's participation in the clinical study or evaluation of the clinical study results.