HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for inclusion in this study.

* Sign and date the tissue informed consent form (ICF) and the main ICF, prior to the start of any study-specific qualification procedures.
* Male or female participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
* Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiation.
* Documentation of radiological disease progression while on/after receiving most recent treatment regimen for locally advanced or metastatic disease. Participants must have received both of the following:

  * Prior treatment with osimertinib. Participants receiving an EGFR TKI at the time of signing informed consent should continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1. Participants in South Korea known to harbor a clinically actionable genomic alteration in addition to EGFR mutation (e.g., anaplastic lymphoma kinase \[ALK\] or ROS1 protocol oncogene 1 \[ROS1\] fusion) for which treatment is available must have also received prior treatment with at least 1 approved genotype-directed therapy, unless unable (i.e., if contraindicated). No new testing for these genomic alterations (e.g., ALK or ROS1 fusion) is required for Screening.
  * Systemic therapy with at least 1 platinum-based chemotherapy regimen.
* Documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R.
* At least 1 measurable lesion confirmed by BICR as per RECIST v1.1
* Consented and willing to provide required tumor tissue of sufficient quantity and of adequate tumor tissue content. Required tumor tissue can be provided as either:

  * Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
  * Archival tumor tissue collected from a biopsy performed within 3 months prior to signing of the tissue consent and since progression while on or after treatment with the most recent cancer therapy regimen.
* Eastern Cooperative Oncology Group Performance Standard of 0 or 1 at Screening.
* Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to Cycle 1 Day 1:

  * Platelet count : ≥100,000/mm\^3 or ≥100 × 10\^9/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
  * Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
  * Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L
  * Serum creatinine (SCr) or creatinine clearance (CrCl): SCr ≤1.5 × upper limit of normal (ULN), OR CrCl ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl
  * Aspartate aminotransferase/alanine aminotransferase: ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
  * Total bilirubin: ≤1.5 × ULN if no liver metastases (\<3 × ULN in the presence of documented Gilbert's syndrome \[unconjugated hyperbilirubinemia\] or liver metastases)
  * Serum albumin: ≥2.5 g/dL
  * Prothrombin time (PT) or PT-International normalized ratio (INR) and activated partial thromboplastin time (aPTT)/PTT: ≤1.5 × ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator

Exclusion Criteria:

Participants meeting any exclusion criteria for this study will be excluded from this study.

* Any previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy.
* Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such disease by imaging during screening.
* Clinically severe respiratory compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:

  * Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior to the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\]), restrictive lung disease, pleural effusion);
  * Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior complete pneumonectomy.
* Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory or any form of immunosuppressive therapy prior to enrollment. Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
* Evidence of any leptomeningeal disease.
* Evidence of clinically active spinal cord compression or brain metastases.
* Inadequate washout period prior to Cycle 1 Day 1, defined as:

  * Whole brain radiation therapy \<14 days or stereotactic brain radiation therapy \<7 days;
  * Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), \<14 days or 5 half-lives, whichever is longer;
  * Monoclonal antibodies, other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) \<28 days;
  * Immune checkpoint inhibitor therapy \<21 days;
  * Major surgery (excluding placement of vascular access) \<28 days;
  * Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \<28 days or palliative radiation therapy \<14 days; or
  * Chloroquine or hydroxychloroquine \<14 days.
* Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3) antibody or single-agent topoisomerase I inhibitor.
* Prior treatment with an antibody drug conjugate (ADC) that consists of any topoisomerase I inhibitor
* Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline. Participants with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee.
* Has history of other active malignancy within 3 years prior to enrollment, except:

  * Adequately treated non-melanoma skin cancer;
  * Superficial bladder tumors (Ta, Tis, T1);
  * Adequately treated intraepithelial carcinoma of the cervix uteri;
  * Low risk non-metastatic prostate cancer (with Gleason score \<7, and following local treatment or ongoing active surveillance);
  * Any other curatively treated in situ disease.
* Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1
* Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1.
* Participant with any human immunodeficiency virus (HIV) infection.