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).
Participants must meet all of the following criteria to be eligible for inclusion in this
- 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
- 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
- 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
Participants meeting any exclusion criteria for this study will be excluded from this
- 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
- 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
- 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.