HERTHENA-Lung02: A Phase 3, Randomized, Open-label Study of Patritumab Deruxtecan Versus Platinum-based Chemotherapy in Metastatic or Locally Advanced Epidermal Growth Factor Receptor-mutated (EGFRm) Non-small Cell Lung Cancer (NSCLC) After Failure of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy

1. Sign and date the main ICF, prior to the start of any study-specific
qualification procedures. Consent for the optional samples for EOT tumor biopsy
and/or pharmacogenetic analysis will be covered in the main ICF.
A separate tissue screening consent will be obtained from all subjects to meet
the baseline biopsy requirement.
2. Is a male or female subject aged >=18 years (follow local regulatory
requirements if the legal age of consent for study participation is >18 years
old).
3. Has histologically or cytologically documented metastatic or locally
advanced nonsquamous NSCLC not amenable to curative surgery or radiation.
4. Has documentation of an EGFR-activating mutation detected from tumor tissue
or from blood sample: exon 19 deletion or L858R at diagnosis or thereafter.
5. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the
metastatic or locally advanced setting, which must include a
thirdgeneration EGFR TKI (ie, approved therapies designed with higher
preferential activity for mutant vs. EGFRwt and that address acquired
resistance to first- and second-generation EGFR TKI [eg, osimertinib,
lazertinib, aumolertinib, alflutinib, and others in consultation with
Medical Monitor]). If a subject has received 2 prior lines of EGFR TKI therapy,
administration of the third-generation EGFR TKI must have
been in the most recent line. Subject must have documentation of T790M mutation
if subjects had treatment with a first- or second-generation
EGFR TKI prior to treatment with a third-generation EGFR TKI. Enrollment of
subjects receiving third-generation EGFR TKIs other than
osimertinib will be a maximum of approximately 20% of the enrolled population
in each treatment arm.
6. May have received either neoadjuvant and/or adjuvant treatment if
progression to metastatic or locally advanced disease occurred at least 12
months after the last dose of such therapy and subsequently experienced disease
progression on or after third-generation EGFR TKI treatment administered in the
metastatic or locally advanced setting.
a. To provide an example, a patient who received osimertinib as adjuvant
therapy after tumor resection, then progressed to having metastatic disease
over a year following completion of adjuvant therapy must have also received a
third-generation EGFR TKI as treatment for metastatic disease to be considered
eligible for this study.
7. Has not received any other prior systemic therapies in the metastatic or
locally advanced setting (including chemotherapy, immunotherapy etc) (even if
administered in combination with EGFR TKI).
8. Has documentation of radiographic disease progression while receiving or
after a third-generation EGFR TKI for metastatic or locally advanced disease.
9. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator
assessment.
10. Is willing to provide sufficient quantity and quality of tumor tissue
content.
11. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0
or 1 at Screening.
12. Has adequate bone marrow reserve and organ function based on local
laboratory data within 14 days prior to randomization as described
in the protocol.
13. If the subject is a female of childbearing potential, must have a negative
serum pregnancy test at Screening and must be willing to use
highly effective birth control upon randomization, during the Treatment Period,
and for 7 months following the last dose of patritumab
deruxtecan. A female is considered to be of childbearing potential following
menarche and until becoming postmenopausal (no menstrual period for a minimum of
12 months) or if permanently sterile (undergone a hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) with surgery at least 1 month before
randomization or confirmed by follicle stimulating hormone (FSH) test. For
comparator drugs, the investigators should follow local practice guidelines
and/or label approved in their country.
14. 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 patritumab deruxtecan administration. For
comparator drugs, the investigators should follow local practice guidelines
and/or label approved in their country.
15. If male, must be surgically sterile or willing to use highly effective
birth control upon randomization, during the Treatment Period, and for at least
4 months following the last dose of patritumab deruxtecan. For comparator
drugs, the investigators should follow local practice guidelines and/or label
approved in their country.
16. Male subjects must not freeze or donate sperm starting at Screening and
throughout the study period and at least 4 months after the final patritumab
deruxtecan administration. For comparator drugs, the investigators should
follow local practice guidelines and/or label approved in their country.
For the full list of criteria, please see section 5.1 in protocol

1. Has 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, or squamous NSCLC histology.
2. Has any history of ILD (including pulmonary fibrosis or radiation
pneumonitis), has current ILD, or is suspected to have such disease by imaging
during Screening.
3. Has clinically severe respiratory compromise (based on the Investigator's
assessment) resulting from intercurrent pulmonary illnesses as described in the
protocol.
4. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or
equivalent anti-inflammatory activity or any form of immunosuppressive therapy
prior to randomization. Subjects who require use of bronchodilators, inhaled or
topical steroids, or local steroid injections may be included in the study.
5. Has any history of or evidence of current leptomeningeal disease.
6. Has evidence of clinically active spinal cord compression or brain
metastases, defined as being symptomatic and untreated, or requiring therapy
with corticosteroids or anticonvulsants to control associated symptoms.
Subjects with clinically inactive or treated brain metastases who are
asymptomatic (i.e., without neurologic signs or symptoms and not requiring
treatment with corticosteroids or anticonvulsants) may be included in the study
but must have a stable neurologic status for at least 2 weeks prior to
randomization. Subjects with asymptomatic brain
metastases and treated with anticonvulsants as prophylaxis are able to enrol.
7. Has had inadequate washout period prior to randomization defined as follows:
a. Whole brain radiation therapy <28 days or stereotactic brain radiation
therapy <7 days.
b. Major surgery (excluding placement of vascular access) <28 days.
c. Radiotherapy treatment to >30% of the bone marrow or with a wide field of
radiation <28 days or palliative radiation therapy <7 days.
d. Chloroquine or hydroxychloroquine <=14 days.
e. Live virus vaccination <=28 days.
8. Has had prior treatment with the following:
a. Any agent including an ADC containing a chemotherapeutic agent targeting
topoisomerase I.
b. HER3 antibody.
c. Any systemic therapies (other than EGFR TKIs) in the metastatic or locally
advanced setting, including chemotherapy or any other systemic therapy in
combination with an EGFR TKI.
9. Has unresolved toxicities from previous anticancer therapy, defined as
toxicities (other than alopecia) not yet resolved by the National Cancer
Institute - Common Terminology Criteria for Adverse Events Version 5.0
(NCI-CTCAE v5.0), Grade <=1 or baseline. Subjects with chronic Grade 2
toxicities [defined as no worsening to Grade >2 for at least 3 months prior to
randomization and managed with SoC treatment])
that the Investigator deems related to previous anticancer therapy may be
randomized.
10. Has history of other active malignancy within 3 years prior to
randomization, except the following:
a. Adequately resected nonmelanoma skin cancer.
b. Adequately treated intraepithelial carcinoma of the cervix.
c. Any other curatively treated in situ disease.
11. Has uncontrolled or significant cardiovascular disease prior to
randomization as described in the protocol.
12. Has active hepatitis B and/or hepatitis C infection, such as those with
serologic evidence of active viral infection within 28 days of randomization.
13. Has a known HIV infection that is not well controlled. All the following
criteria are required to define an HIV infection that is well controlled:
undetectable viral ribonucleic acid (RNA) load, CD4+ counts/levels of >350
cells/µL, no history of AIDS-defining opportunistic infection within the past
12 months, and stable for at least 3 weeks on same anti-HIV retroviral
medications. If an HIV infection meets the above criteria, the subject's viral
RNA load and CD4+ cell count should be monitored per local SoC (e.g., every 3
months).
14. Has any evidence of severe or uncontrolled diseases (eg, active bleeding
diatheses, active infection) psychiatric illness/social situations,
geographical factors, substance abuse, or other factors that, in the
Investigator's opinion, make it undesirable for the subject to participate
in the study or that would jeopardize compliance with the protocol. Screening
for chronic conditions is not required for eligibility.
15. Has known hypersensitivity to either the drug substance or inactive
ingredients in any of the drug products.
16. Is a female who is pregnant or breastfeeding or intends to become pregnant
during the study.
For full list of exclusion criteria, refer to section 5.2 of the protocol.