HERTHENA-Lung02: A Study of Patritumab Deruxtecan Versus Platinum-based Chemotherapy in Metastatic or Locally Advanced EGFRm NSCLC After Failure of EGFR TKI Therapy

Inclusion Criteria:

1. Is a male or female subject aged ≥18 years (follow local regulatory requirements ifthe legal age of consent for study participation is >18 years old).

2. Has histologically or cytologically documented metastatic or locally advancednon-squamous NSCLC not amenable to curative surgery or radiation.

3. Has documentation of an EGFR-activating mutation detected from tumor tissue or bloodsample: exon 19 deletion or L858R at diagnosis or thereafter.

4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic orlocally advanced setting, which must include a third -generation EGFR TKI

5. May have received either neoadjuvant and/or adjuvant treatment if progression tometastatic or locally advanced disease occurred at least 12 months after the lastdose of such therapy and subsequently experienced disease progression on or afterthird-generation EGFR TKI treatment administered in the metastatic or locallyadvanced setting.

6. Has not received any other prior systemic therapies in the metastatic or locallyadvanced setting (including chemotherapy, immunotherapy etc) (even if administeredin combination with EGFR TKI).

7. Has documentation of radiographic disease progression while receiving or afterreceiving a third generation EGFR TKI for metastatic or locally advanced disease.

8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.

9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue.

10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 atScreening.

11. Has adequate bone marrow reserve and organ function based on local laboratoryevaluation within 14 days prior to randomization:

• Platelet count: ≥100,000/mm^3 or ≥100 × 10^9/L within 14 days prior to theassessment of platelet count during the Screening Period

• Absolute neutrophil count: ≥1500/mm^3 or ≥1.5 × 10^9/L within 14 days prior tothe assessment of absolute neutrophil count during the Screening Period

• Hemoglobin (Hgb): ≥9.0 g/dL within 14 days prior to the assessment ofhemoglobin during the Screening Period

• Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using theCockcroft-Gault equation or measured CrCl

×Upper limit of normal (ULN)

• Total bilirubin (TBL): TBL ≤1.5 × ULN

• Serum albumin: ≥2.5 g/dL

• Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partialthromboplastin time (PTT): ≤1.5 × ULN, except for participants receivingcoumarin-derivative anticoagulants or other similar anticoagulant therapy whomust have PT-INR within therapeutic range as deemed appropriate by theInvestigator

Exclusion Criteria:

1. Has any previous histologic or cytologic evidence of small cell OR combined smallcell/non-small cell disease in the archival tumor tissue or pretreatment tumorbiopsy, or squamous NSCLC histology

2. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis orradiation pneumonitis), has current ILD, or is suspected to have such disease byimaging during Screening

3. Has clinically severe respiratory compromise (based on the Investigator'sassessment) resulting from intercurrent pulmonary illnesses including, but notlimited to the following:

• Any underlying pulmonary disorder, restrictive lung disease, or pleuraleffusion

• Any autoimmune, connective tissue, or inflammatory disorders where there isdocumented, or a suspicion of pulmonary involvement at the time of Screening

• OR prior complete pneumonectomy

4. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone orequivalent anti-inflammatory activity or any form of immunosuppressive therapy priorto randomization

5. Has any history of or evidence of current leptomeningeal disease

6. Has evidence of clinically active spinal cord compression or brain metastases,defined as being symptomatic and untreated, or requiring therapy withcorticosteroids or anticonvulsants to control associated symptoms

7. Any prior treatment with any agent including an antibody drug conjugate (ADC)containing a chemotherapeutic agent targeting topoisomerase I, human epidermalgrowth factor receptor 3 (HER3) antibody, and any systemic therapies (other thanEGFR TKIs) in the metastatic/locally advanced setting, including chemotherapy or anyother systemic therapy in combination with an EGFR TKI

8. Has history of other active malignancy within 3 years prior to randomization, exceptfor adequately resected nonmelanoma skin cancer, adequately treated intraepithelialcarcinoma of the cervix, and any other curatively treated in situ disease

9. Has uncontrolled or significant cardiovascular disease prior to randomization

10. Has active hepatitis B and/or hepatitis C infection, such as those with serologicevidence of active viral infection within 28 days of randomization

11. Has a known human immunodeficiency virus (HIV) infection that is not well controlled

12. Has clinically significant corneal disease