HER3-DXd (Patritumab Deruxtecan; U3-1402) in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer

Inclusion Criteria:

Inclusion Criteria Specific to Dose Escalation and Second-line Dose Expansion:

• Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue

• Must have received osimertinib for locally advanced or metastatic disease at a doseof 80 mg once daily (QD) for at least 6 weeks and must not miss more than two dosesduring the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1)

• Must not have received any other prior systemic cancer therapies in the locallyadvanced/metastatic setting

• Has documentation of radiological disease progression following first-line treatmentwith osimertinib in the locally advanced or metastatic setting

Inclusion Criteria Specific to First-line Dose Expansion:

• The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC knownto be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessedby Clinical Laboratory Improvement Amendments (CLIA)-certified (United States [US]sites), accredited (outside of the US), local laboratory or central laboratory. Onlytissue-based testing will be accepted.

• Participants must have previously untreated locally advanced or metastatic NSCLC andmust be eligible to receive first-line treatment with osimertinib, according to thejudgment of the investigator. Prior adjuvant or neo-adjuvant therapy (chemotherapy,radiotherapy, investigational agents; except with osimertinib) is permitted.

All Participants:

Participants must meet all criteria to be eligible for inclusion in this study:

• Histologically or cytologically documented locally advanced or metastatic NSCLC notamenable to curative surgery or radiation.

• At least 1 measurable lesion as assessed by Investigator as per Response EvaluationCriteria in Solid Tumors (RECIST v1.1)

• Tissue requirements

• For Dose Escalation (all cohorts): provide an optional pre-treatment tumortissue of sufficient quantity, as defined in the laboratory manual. Theoptional pre-treatment tumor tissue can be provided as either:

• Pre-treatment tumor biopsy from at least 1 lesion not previouslyirradiated and amenable to core biopsy OR

• Archival tissue collected from a biopsy performed prior to signing of thetissue consent, and since progression while on treatment with the mostrecent cancer therapy

• For First-line Dose Expansion (Cohorts 3, 4a, and 4b): provide an optionalpre-treatment and optional on-treatment tumor tissues of sufficient quantity,as defined in the laboratory manual. The optional pre-treatment tumor tissuecan be provided as either:

• Pre-treatment tumor biopsy from at least 1 lesion not previouslyirradiated and amenable to core biopsy OR

• Archival tissue collected from a biopsy performed at the time of initialdiagnosis or later

• For Second-line Dose Expansion (Arm 1, Arm 2, and Arm 1b): provide a requiredpre-treatment and required on-treatment tumor tissues of sufficient quantity,as defined in the laboratory manual. The required pre-treatment tumor tissuecan be provided as either:

• Pre-treatment tumor biopsy from at least 1 lesion not previouslyirradiated and amenable to core biopsy OR

• Archival tissue collected from a biopsy performed prior to signing of thetissue consent, and since progression while on treatment with the mostrecent cancer therapy regimen

• Note: For all participants who consent to a pre-treatment biopsy, inorder to ensure an adequate amount of tissue is available, a coreneedle biopsy is required.

• Has adequate bone marrow reserve and organ function based on local laboratory datawithin 14 days prior to Cycle 1, Day 1 (Dose Escalation and First-line DoseExpansion) or within 14 days prior to randomization (Second-line Dose Expansion):

• Platelet count: ≥100 000/mm^3 or ≥100 × 10^9/L (platelet transfusions are notallowed within 14 days prior to the assessment of platelets during thescreening period in order to meet the study inclusion criterion)

• Hemoglobin: ≥9.0 g/dL (transfusion of red blood cells and/or growth factorsupport is not allowed within 14 days prior to the assessment of hemoglobinduring the screening period in order to meet the study inclusion criterion)

• Absolute neutrophil count (ANC): 1500/mm^3 or ≥1.5 × 10^9/L (granulocyte colonystimulating factor support is not allowed within 14 days prior to theassessment of ANC during the screening period in order to meet the studyinclusion criterion)

• Creatinine clearance (CrCl): CrCl ≥30 mL/min as calculated using theCockcroft-Gault equation or measured CrCl

• Aspartate aminotransferase/ alanine aminotransferase: ≤3 × ULN (if livermetastases are present, ≤5 × ULN)

• Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence ofdocumented Gilbert's syndrome [unconjugated hyperbilirubinemia] or livermetastases)

• Serum albumin: ≥2.5 g/dL

• Alkaline phosphatase (ALP) and Gamma-glutamyl transferase (GGT): ≤2.5 × ULN ofboth ALP and GGT

• Prothrombin time (PT) or PT-international normalized ratio (INR) and Activatedpartial thromboplastin time (aPTT) / Partial thromboplastin time (PTT): ≤1.5 ×ULN, except for subjects on coumarin-derivative anticoagulants or other similaranticoagulant therapy, who must have PT-INR within therapeutic range as deemedappropriate by the Investigator.

Exclusion Criteria:

• Any previously documented histologic or cytologic evidence of small cell OR combinedsmall cell/non-small cell disease

• Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis thatrequired corticosteroid therapy, has current ILD, or is suspected to have suchdisease by imaging during screening.

• Clinically severe pulmonary compromise (based on Investigator's assessment)resulting from intercurrent pulmonary illnesses including, but not limited to:

• Any underlying pulmonary disorder (eg, pulmonary emboli within three months ofthe study enrollment or randomization, severe asthma, severe chronicobstructive pulmonary disease, restrictive lung disease, pleural effusion);

• Any autoimmune, connective tissue or inflammatory disorders with pulmonaryinvolvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); ORprior complete pneumonectomy.

• Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone orequivalent anti-inflammatory activity or any form of immunosuppressive therapy priorto Cycle 1, Day 1. Participants who require use of bronchodilators, inhaled ortopical steroids, or local steroid injections may be included in the study.

• Evidence of any leptomeningeal disease.

• Has spinal cord compression or clinically active central nervous system metastases,defined as symptomatic, or requiring therapy with corticosteroids or anticonvulsantsto control associated symptoms. Participants with clinically inactive brainmetastases may be included in the study. Participants with treated brain metastaseswho are no longer symptomatic and who require no treatment with corticosteroids oranticonvulsants may be included in the study, but must have a stable neurologicstatus for at least 4 weeks prior to Cycle 1, Day 1. Participants with asymptomaticbrain metastases and treated with anticonvulsants as prophylaxis are able to enrollfollowing a 14-day washout period. Note: A CT or MRI scan of the brain at baselineis required for all participants.

• Inadequate washout period prior to Cycle 1, Day 1 defined as:

• Whole brain radiation therapy <28 days or stereotactic brain radiation therapy <7 days;

• Any systemic anticancer therapy (excluding osimertinib in all Dose EscalationCohorts and in Second-line Dose Expansion [Arm 1, Arm 2, and Arm 1b]),including investigational agents, <14 days or 5 half-lives, whichever is longer

• Immune checkpoint inhibitor therapy ≤21 days

• Major surgery (excluding placement of vascular access) <4 weeks

• Radiotherapy treatment to more than 30% of the bone marrow or with a wide fieldof radiation < 28 days or palliative radiation therapy <7 days

• Chloroquine or hydroxychloroquine ≤14 days

• Medications or herbal supplemented known to be strong inducers of cytochromeP450 (CYP) 3A4 <21 days.

• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute CommonTerminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, Grade ≤1 orbaseline. Subjects with chronic Grade 2 toxicities may be eligible per thediscretion of the Investigator after consultation with the Sponsor Medical Monitoror designee.

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow osimertinib, or previous significant bowel resection that would precludeadequate absorption of osimertinib.

• Has any primary malignancy other than locally advanced or metastatic NSCLC within 3years prior to Cycle 1, Day 1 (Dose Escalation and First-line Dose Expansion) orwithin 3 years prior to randomization (Second-Line Dose Expansion), exceptadequately resected non-melanoma skin cancer, curatively treated in situ disease, orother solid tumors curatively treated.

• Uncontrolled or significant cardiovascular disease prior to Cycle 1, Day 1including:

• Mean corrected QT interval using Fridericia's formula (QTcF) interval of >450ms in 3 successive central screening measurements

• Left ventricular ejection fraction (LVEF) ≤50% by either echocardiogram (ECHO)or multigated acquisition (MUGA) scan

• Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg

• Myocardial infarction within 6 months

• New York Heart Association (NYHA) Classes 2 to 4 congestive heart failurewithin 28 days

• Uncontrolled angina pectoris within 6 months

• Has cardiac arrhythmia requiring antiarrhythmic treatment

• Complete left or right bundle branch block within 6 months

• History of second- or third-degree heart block or PR interval >250 ms within 6months

• History of clinically relevant ventricular arrhythmias, such as ventriculartachycardia, ventricular fibrillation, or Torsade de Pointes

• Has any factors that increase the risk of corrected QT (QTc) prolongation orrisk of arrhythmic events, such as heart failure, hypokalemia, congenital longQT syndrome, family history of long QT syndrome, or unexplained sudden deathunder 40 years of age in first-degree relatives, or any concomitant medicationknown to prolong the QT interval

• Has clinically significant corneal disease

• Any evidence of severe or uncontrolled diseases including active bleeding diatheses,active infection, psychiatric illness/social situations, geographical factors,substance abuse, or other factors which in the Investigator's opinion makes itundesirable for the subject to participate in the study or which would jeopardizecompliance with the protocol. Screening for chronic conditions is not required.

• Has a known human immunodeficiency virus (HIV) infection that is not wellcontrolled.