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)

1. Sign and date the tissue ICF and the main ICF, prior to the start of any
study-specific
qualification procedures.
2. Male or female subjects aged >=18 years (follow local regulatory requirements
if the legal age of consent for study participation is >18 years old).
3. Histologically or cytologically documented locally advanced or metastatic
NSCLC not amenable to curative surgery or radiation.
4. Documentation of radiological disease progression while on/after receiving
most recent treatment regimen for locally advanced or metastatic disease.
Subjects must have received both of the following:
a. Prior treatment with osimertinib. Subjects 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.
b. Systemic therapy with at least 1 platinum-based chemotherapy regimen.
5. Documentation of an EGFR-activating mutation detected from tumor tissue or
blood sample: exon 19 deletion or L858R.
6. At least 1 measurable lesion confirmed by BICR as per RECIST v1.1 (please
refer to section 10.4 of the protocol)
7. Consented and willing to provide required tumor tissue of sufficient
quantity (as defined in the Laboratory Manual) and of adequate tumor tissue
content (as confirmed by hematoxylin and eosin [H&E] staining at the central
laboratory).Required tumor tissue can be provided as either:
a. Pretreatment tumor biopsy from at least 1 lesion not previously irradiated
and amenable to core biopsy
OR
b. 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.
AND consent to provide a required on-study tumor biopsy. After approximately 15
on-study tumor biopsies in each arm have been collected, the Sponsor will
notify the Investigator of a change to the requirement.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at
Screening (see Section 10.3.3 of the protocol)
9. Has adequate bone marrow reserve and organ function based on local
laboratory data within 14 days prior to Cycle 1 Day 1 (please refer to schedule
in protocol, paragraph 5.1).
10. If the subject is a female of childbearing potential, she must have a
negative serum
pregnancy test at Screening and must be willing to use highly effective birth
control, as
detailed in Section 10.3.4 of the protocol, upon enrollment, during the
Treatment Period, and for 7 months following the last dose of study drug. A
female is considered of childbearing potential following menarche and until
becoming postmenopausal (no menstrual period for a minimum of 12 months) unless
permanently sterile (undergone a hysterectomy, bilateral salpingectomy or
bilateral oophorectomy) with surgery at least 1 month before the first dose or
confirmed by follicle stimulating hormone (FSH) test. Please refer to section
8.4.2 of the protocol.
Pregnancy Test for further details regarding confirmation of post-menopausal
status.
11. Female subjects must not donate, or retrieve for their own use, ova from
the time of
screening and throughout the study treatment period, and for at least 7 months
after the
final study drug administration.
12. If male, the subject must be surgically sterile or willing to use highly
effective birth
control (Please refer to section 10.3.4) upon enrollment, during the treatment
period, and for at least 4 months following the last dose of study drug.
13. Male subjects must not freeze or donate sperm starting at Screening and
throughout the study period, and at least 4 months after the final study drug
administration.
14. Is willing and able to comply with scheduled visits, drug administration
plan, laboratory tests, other study procedures, and study restrictions.

1. Any previous or current histologic or cytologic evidence of small cell OR
combined small cell/non-small cell disease in the archival tumor tissue or
pretreatment tumor biopsy.
2. 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.
3. Clinically severe respiratory compromise (based on Investigator*s
assessment) resulting from intercurrent pulmonary illnesses including, but not
limited to:
a. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months
prior to of the study enrollment, severe asthma, severe chronic obstructive
pulmonary disease [COPD]), restrictive lung disease, pleural effusion);
b. Any autoimmune, connective tissue or inflammatory disorders with pulmonary
involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis);
OR prior complete pneumonectomy.
4. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or
equivalent anti-inflammatory or any form of immunosuppressive therapy prior to
enrollment. Subjects who require use of bronchodilators, inhaled or topical
steroids, or local steroid injections may be included in the study.
5. Evidence of any leptomeningeal disease.
6. Evidence of clinically active spinal cord compression or brain metastases,
defined as untreated and symptomatic, or requiring therapy with corticosteroids
or anticonvulsants to control associated symptoms. Subjects with clinically
inactive or treated brain metastases who are asymptomatic (ie, without
neurologic signs or symptoms and not requiring treatment with corticosteroids
or anticonvulsants) may be included in the study. Subjects must have a stable
neurologic status for at least 2 weeks prior to Cycle 1 Day 1.
7. Inadequate washout period prior to Cycle 1 Day 1, defined as:
a. Whole brain radiation therapy <14 days or stereotactic brain radiation
therapy <7 days;
b. 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;
c. Immune checkpoint inhibitor therapy <21 days;
d. Major surgery (excluding placement of vascular access) <28 days;
e. 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
f. Chloroquine or hydroxychloroquine <14 days.
8. Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3)
antibody or single-agent topoisomerase I inhibitor.
9. Prior treatment with an antibody drug conjugate (ADC) that consists of any
topoisomerase I inhibitor
10. 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. Subjects with chronic Grade 2 toxicities may be eligible at the
discretion of the Investigator after consultation with the Sponsor Medical
Monitor or designee.
11. Has history of other active malignancy within 3 years prior to enrollment,
except:
a. Adequately treated non-melanoma skin cancer;
b. Superficial bladder tumors (Ta, Tis, T1);
c. Adequately treated intraepithelial carcinoma of the cervix uteri;
d. Low risk non-metastatic prostate cancer (with Gleason score <7, and
following local treatment or ongoing active surveillance);
e. Any other curatively treated in situ disease.
12. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1,
including:
a. QT interval corrected with Fridericia*s formula (QTcF) prolongation interval
of >470 ms for females and >450 ms for males;
b. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram
(ECHO) or multigated acquisition (MUGA) scan;
c. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or
diastolic blood pressure >110 mmHg);
d. Myocardial infarction within 6 months;
e. New York Heart Association (NYHA) Classes 2 to 4 congestive heart failure
(See protocol section 10.3.2) within 28 days;
f. Uncontrolled angina pectoris within 6 months;
g. Cardiac arrhythmia requiring antiarrhythmic treatment.
13. 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.
a. Subjects with past or resolved hepatitis B virus (HBV) infection are
eligible if:
i Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody
[anti-HBc] positive; OR
ii HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented
to be <=2000 IU/mL in the absence of anti-viral therapy and during the previous
12 weeks prior to the viral load evaluation with normal transaminases values
(in the absence of liver metastasis); OR
iii HBsAg positive and HBV DNA viral load is documented to be <=2000 IU/mL, in
the absence of anti-viral therapy and during the previous 12 weeks prior to the
viral load evaluation for subjects with liver metastasis and abnormal
transaminases with a result of AST/ALT <3 × ULN.
b. Subjects with a history of hepatitis C infection will be eligible for
enrollment only if the viral load according to local standards of detection is
documented to be below the level of detection in the absence of anti-viral
therapy during the previous 12 weeks (ie, sustained viral response according to
the local product label but no less than 12 weeks, whichever is longer).
14. Subject with any human immunodeficiency virus (HIV) infection.
15. 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 it undesirable for the subject to participate in
the study or which would jeopardize compliance with the protocol. Screening
for chronic conditions is not required.
16. History of hypersensitivity to either the drug substance or any excipients
in patritumab deruxtecan.
17. Female who is pregnant or breast-feeding or intends to become pregnant
during the study.
18. Prior or ongoing clinically relevant illness, medical condition, surgical
history, physical finding, or laboratory abnormality that, in the
Investigator*s opinion, could affect the safety of the subject; alter the
absorption, distribution, metabolism or excretion of the study drug; or
confound the assessment of study results.
19. Has clinically significant corneal disease.