A MULTICENTER, OPEN-LABEL PHASE 1 STUDY OF HE3-DXd IN SUBJECTS WITH METASTATIC OR UNRESECTABLE NON-SMALL CELL LUNG CANCER

Inclusion Criteria for Dose Escalation 1. Male or female subjects aged 18 years
and older. 2. Has histologically or cytologically documented adenocarcinoma
NSCLC. 3.Has locally advanced or metastatic NSCLC, not amenable to curative
surgery or radiation 4. Has acquired resistance to EGFR TKI according to the
Jackman criteria (PMID: 19949011): a. Historical confirmation that the tumor
harbors an EGFR mutation known to be associated with EGFR TKI sensitivity
(including G719X, exon 19 deletion, L858R, L861Q), OR b. Has experienced
clinical benefit from an EGFR TKI, followed by systemic progression of disease
(Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 or World Health
Organization [WHO]) while on continuous treatment with an EGFR TKI. 5. Is
currently receiving and able to discontinue erlotinib, gefitinib, afatinib, or
osimertinib. 6. Has been receiving erlotinib, gefitinib, afatinib, or
osimertinib for least 6 weeks with well-controlled related toxicities less than
Grade 3 in severity at the time of Screening. 7. Has radiological documentation
of disease progression while receiving continuous treatment with erlotinib,
gefitinib, afatinib, or osimertinib. 8.Has at least one measurable lesion per
RECIST version 1.1 9. Is willing to provide archival tumor tissue from a biopsy
performed within 6 months of progression during treatment with erlotinib,
gefitinib, afatinib, or osimertinib OR has at least 1 lesion, not previously
irradiated, amenable to core biopsy and is willing to undergo Screening tumor
biopsy. 10. Demonstrates absence of EGFR T790M mutation if treated with
erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if
treated with osimertinib. 11.Has Eastern Cooperative Oncology Group performance
status of 0 or 1, with no deterioration over the previous 2 weeks For
additional Inclusion criteria please refer to protocol Inclusion Criteria for
Dose Expansion only: 1. Male of female subjects aged >=18 years (follow local
regulatory requirements if the legal age of consent for study participation is
>18 years old). 2. Has locally advanced or metastatic NSCLC not amenable to
curative surgery or radiation. 3.Has received systemic therapy for locally
advanced or metastatic disease including at least 1 platinum-based chemotherapy
regimen 4.Has documented radiological disease progression during/after most
recent treatment regimen for locally-advanced or metastatic disease 5. Has at
least 1 measurable lesion per RECIST v1.1. 6.Is willing to provide archival
tumor tissue from a biopsy performed within 6 months of consent and performed
after progression during/after treatment with most recent cancer therapy
regimen OR has at least 1 lesion, not previously irradiated, amenable to core
biopsy and is willing to undergo tumor biopsy For additional inclusion criteria
please refer to protocol Additional Inclusion Criteria Specific to Cohorts 1,
3a, and 3b and 4 please refer to protocol Additional Inclusion Criteria
Specific to Cohort 2 please refer to protocol Additional Inclusion criteria
specific to Cohort 5 please refer to the protocol

Exclusion Criteria for Dose Expansion: 1. Has any evidence of small cell
histology, or combined small cell and non-small cell histology, in original
tumor biopsy or in Screening biopsy performed after progression 2. Has
previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS1
fusion, BRAF V600E mutation, RET rearrangement, HER2 mutation, MET
amplification, or MET exon 14 skipping mutation. No new testing for these
genomic alterations is required for Screening. 3.Treatment with any of the
following: a. Any cytotoxic chemotherapy, investigational agent or other
anticancer drug(s) from a previous cancer treatment regimen or clinical study
(other than EGFR TKI in Cohort 1 only), within 14 days prior to first dose of
HE3-DXd b. Immune checkpoint inhibitor therapy within 21 days prior to dose of
HE3-DXd c. Prior treatment with an anti-HER3 antibody d. Prior treatment with a
topoisomerase I inhibitor e. Prior treatment with an antibody-drug conjugate
(ADC) that consists of an exatecan derivative that is a topoisomerase I
inhibitor (eg, DS-8201a) f. Major surgery (excluding placement of vascular
access) within 4 weeks prior to first dose of HE3-DXd g. Radiotherapy treatment
to more than 30% of the bone marrow or with a wide field of radiation within 4
weeks prior to first dose of HE3-DXd 4. Has history of other active malignancy
within 3 years prior to first dose of HE3-DXd, except: a. Adequately treated
non-melanoma skin cancer OR b. Superficial bladder tumors (Ta, Tis, T1) OR c.
Curatively treated in situ disease 5. Has spinal cord compression or clinically
active central nervous system metastases, defined as untreated and symptomatic,
or requiring therapy with corticosteroids or anticonvulsants to control
associated symptoms. Participants with clinically inactive brain metastases may
be included in the study. Participants with treated brain metastases that are
no longer symptomatic and who require no treatment with corticosteroids or
anticonvulsants may be included in the study if they have recovered from the
acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed
between the end of whole brain radiotherapy and study enrollment (1 week for
stereotactic radiotherapy) 6. Has history of myocardial infarction within the
past 6 months 7. Has symptomatic congestive heart failure[New York Heart
Association (NYHA) Classes III-IV], unstable angina, or cardiac arrhythmia
requiring antiarrhythmic treatment 8. Has left ventricular ejection fraction
(LVEF) < 45% by either echocardiogram (ECHO) or multigated acquisition scan
(MUGA) 9. Has any clinically important abnormalities in rhythm, conduction or
morphology of resting electrocardiogram (ECG), eg, complete left bundle branch
block, third-degree heart block, second-degree heart block, or PR interval >
250 milliseconds (ms) 10. Has a mean corrected QT interval using Fridericia's
Correction Formula (QTcF) prolongation to > 470 ms for females and > 450 ms for
males in three successive Screening measurements 11. Unable or unwilling to
discontinue concomitant drugs that are known to prolong the QT interval 12. Has
any factors that increase the risk of corrected QT (QTc) interval prolongation
or risk of arrhythmic events, such as congenital long QT syndrome, family
history of long QT syndrome, or unexplained sudden death under 40 years of age
in first-degree relatives. 13. Has any history of interstitial lung disease
(pulmonary fibrosis or severe radiation pneumonitis)has current
ILD/pneumonitis, or is suspected to have such disease by imaging during
Screening. 14. Has any evidence of severe or uncontrolled systemic diseases
(including uncontrolled hypertension, and active bleeding diatheses or active
infection, including hepatitis B, hepatitis C, and human immunodeficiency virus
[HIV]), psychiatric illness/social situations,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. 15. Is pregnant or
breastfeeding, or is planning to become pregnant. 16. Has clinically
significant corneal disease. For Common Exclusion Criteria for Dose Expansion
please refer to protocol