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:
- ≥ 1 prior line(s) of EGFR TKI treatment (erlotinib, gefitinib, afatinib,
dacomitinib or osimertinib). Participants receiving an EGFR TKI at the time of
signing informed should continue to take the EGFR TKI until 5 days prior to Cycle
1 Day 1. EGFR T790M mutation-positive participants (previously treated with
erlotinib, gefitinib, afatinib or dacomitinib) must have received and have
documentation of radiological disease progression following treatment with
- 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.
- ECOG PS 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 of 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.