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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.27:["$","$L29",null,{"trial":{"nctId":"NCT04619004","briefTitle":"HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer","officialTitle":"HERTHENA-Lung01: A Phase 2 Randomized Open-Label Study of Patritumab Deruxtecan (U3-1402) in Subjects With Previously Treated Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)","briefSummary":"This study is designed to evaluate the antitumor activity of patritumab deruxtecan in participants with metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R) who have received and progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen.","detailedDescription":"This study will initially randomize participants to one of 2 arms in a 1:1 ratio to receive either a 5.6 mg/kg fixed dose regimen or an up-titration dose regimen of patritumab deruxtecan (HER3-DXd, U3-1402).","overallStatus":"ACTIVE_NOT_RECRUITING","phase":"PHASE2","studyType":"INTERVENTIONAL","conditions":["Non-Small Cell Lung Cancer Metastatic","Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor"],"interventions":[{"type":"DRUG","name":"Patritumab Deruxtecan (Fixed dose)","description":"Patritumab deruxtecan will be dosed at 5.6 mg/kg as an intravenous (IV) infusion administered on Day 1 of each 21-day cycle."},{"type":"DRUG","name":"Patritumab Deruxtecan (Up-Titration)","description":"Patritumab deruxtecan will be dosed as an intravenous (IV) infusion administered at Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and subsequent cycles, 6.4 mg/kg administered on Day 1 of each 21-day cycle."}],"keywords":["Non-Small Cell Lung Cancer Metastatic","Non-Small Cell Lung Cancer with Mutation in Epidermal Growth Factor Receptor","Epidermal growth factor receptor","HER3-DXd","Patritumab Deruxtecan","U3-1402"],"locations":[{"facility":"Banner MD Anderson Cancer Center","city":"Gilbert","state":"Arizona","country":"United States","zip":"85234","lat":33.35283,"lng":-111.78903},{"facility":"City of Hope","city":"Duarte","state":"California","country":"United States","zip":"91010","lat":34.13945,"lng":-117.97729},{"facility":"Moores Cancer Center at the UC San Diego Health","city":"La Jolla","state":"California","country":"United States","zip":"92093","lat":32.84727,"lng":-117.2742},{"facility":"Pacific Shores Medical Group","city":"Long Beach","state":"California","country":"United States","zip":"90813","lat":33.76696,"lng":-118.18923},{"facility":"USC Norris Comprehensive Cancer Center","city":"Los Angeles","state":"California","country":"United States","zip":"90033","lat":34.05223,"lng":-118.24368},{"facility":"University of California at Irvine","city":"Orange","state":"California","country":"United States","zip":"92868","lat":33.78779,"lng":-117.85311},{"facility":"Cedars Sinai","city":"West Hollywood","state":"California","country":"United States","zip":"90048","lat":34.09001,"lng":-118.36174},{"facility":"University of Colorado Denver - Anschutz Medical Campus","city":"Aurora","state":"Colorado","country":"United States","zip":"80045","lat":39.72943,"lng":-104.83192},{"facility":"Florida Cancer Specialists - South","city":"Fort Myers","state":"Florida","country":"United States","zip":"33901","lat":26.62168,"lng":-81.84059},{"facility":"AdventHealth Orlando","city":"Orlando","state":"Florida","country":"United States","zip":"32804","lat":28.53834,"lng":-81.37924},{"facility":"Memorial Healthcare System","city":"Pembroke Pines","state":"Florida","country":"United States","zip":"33021","lat":26.00315,"lng":-80.22394},{"facility":"Florida Cancer Specialist-North","city":"St. Petersburg","state":"Florida","country":"United States","zip":"33770","lat":27.77086,"lng":-82.67927},{"facility":"Florida Cancer Specialists-Panhandle","city":"Tallahassee","state":"Florida","country":"United States","zip":"32308","lat":30.43826,"lng":-84.28073},{"facility":"H. 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What this study is about