Datopotamab Deruxtecan (Dato-DXd, DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer

Inclusion Criteria:

• Participants with histologically confirmed diagnosis of advanced and/or unresectableNSCLC

• Participants who received at least one line and not more than three lines of therapyand considered by the investigator as refractory to standard treatment or for whichno standard treatment is available:

1. Participants who have no known mutation or mutation without an approvedtargeted therapy: anti programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) containing therapy and a platinum-doublet regimen

2. Participants who have known EGFR, BRAF, and MET mutation or ALK, ROS1, RET,NTRK fusion: one line of an approved targeted agent and one platinum-doubletregimen

• Metastatic site easily accessible to biopsy (with exception of bone metastasis)

• Presence of at least one measurable lesion (different from the biopsy site)according to RECIST v1.1

• ECOG status should be equal or less to one

• Life expectancy should be equal or more than 3 months

• Participants must have adequate bone marrow reserve and organ function, based onlocal laboratory data within 14 days prior to Cycle 1, Day 1

• Participants with asymptomatic and clinically stable treated brain metastasis, whorequire no treatment with corticosteroids and/or anticonvulsants. Participants musthave a stable neurologic status for at least two weeks prior to Cycle 1 Day 1

• Females of reproductive/childbearing potential must have a negative serum pregnancytest at screening and must agree to use a highly effective form of contraception oravoid intercourse during the study and for at least 7 months after the last dose ofstudy drug

Contraceptive methods considered highly effective:

1. Combined (estrogen and progestogen containing) hormonal contraception associatedwith inhibition of ovulation (oral, intravaginal, transdermal)

2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

3. Intrauterine device (IUD)

4. Intrauterine hormone-releasing system (IUS)

5. Bilateral tubal occlusion

6. Vasectomized partner

7. Complete sexual abstinence during and for at least 7 months after the last dose ofstudy drug. Female participants must not donate, or retrieve for their own use, ovafrom the time of screening and for at least 7 months after the final study drugadministration

Male participants must be surgically sterile or must withhold heterosexual intercourse or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 4 months following the last dose of study drug.

Male participants must not freeze or donate sperm from screening and for at least 4 months after the final study drug administration.

• Participants must understand, sign and date the written informed consent from priorto any protocol-specific procedures performed. Participants should be able andwilling to comply with study visits and procedures as per protocol

• Participants must be affiliated to a Social Security System or beneficiary of thesame

Exclusion Criteria:

• Participants unwilling to participate to the biological investigations and toperform biopsies and blood sample collection as required in the protocol

• Participants with only bone metastasis will be excluded, except if they have anaccessible primary tumor which could be biopsied at baseline, on-treatment andend-of-treatment.

• Participant with any history of interstitial lung disease (ILD) (including pulmonaryfibrosis or radiation pneumonitis), has current ILD, or is suspected to have suchdisease by imaging during screening.

• Participant with clinically severe pulmonary compromise (based on investigator'sassessment) resulting from intercurrent pulmonary illnesses including, but notlimited to:

1. Any underlying pulmonary disorder

2. Any autoimmune, connective tissue or inflammatory disorder with pulmonaryinvolvement

3. OR prior pneumonectomy

• Participants receiving chronic systemic corticosteroids at a dose higher than 10 mgprednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1Day 1. Participants who require use of bronchodilators, inhaled steroids, or localsteroid injections may be included in the study

• Participants with evidence of any leptomeningeal disease

• Participants with evidence of clinically active spinal cord compression or brainmetastases

• Participants with a history of severe hypersensitivity reactions to either the drugsubstances or inactive ingredients (including but not limited to polysorbate 80) ofDS-1062a

• Participants with a history of severe hypersensitivity reactions to other monoclonalantibodies

• Inadequate washout period prior to Cycle 1 Day 1, defined as:

1. Whole brain radiation therapy within 14 days before treatment or stereotacticbrain radiation therapy, within 7 days before treatment

2. Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s)from a previous cancer treatment regimen or clinical study (other thanEpidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)), within 14 days before treatment or 5 half-lives, whichever is longer

3. Immune checkpoint inhibitor therapy, within 21 days before treatment

4. Major surgery (excluding placement of vascular access), within 28 days beforetreatment

5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide fieldof radiation, within 28 days before treatment or palliative radiation therapywithin 14 days before treatment

6. Chloroquine or hydroxychloroquine within 14 days before treatment

7. Live virus vaccination, within 28 days before treatment

• Prior treatment with an anti-TROP-2 antibody including study drug

• Participant previously treated with an antibody drug conjugate (ADC) containing achemotherapeutic agent targeting topoisomerase I inhibitor

• Participant with unresolved toxicities from previous anticancer therapy, defined astoxicities (other than alopecia) not yet resolved according to the NCI-CTCAE v5.0,grade 2 or more

• Any evidence of primary malignancy other than locally advanced or metastatic lungcancer within three years prior to Cycle 1 Day 1, except adequately resectednon-melanoma skin cancer, curatively treated in-situ disease, or other solid tumorscuratively treated

• Participant with clinically significant corneal disease

• Any evidence of severe or uncontrolled systemic diseases including active bleedingdiatheses, active infection, psychiatric illness/social situations, geographicalfactors, substance abuse, or other factors which in the investigator's opinion makesit undesirable for the participant to participate in the study or which wouldjeopardize compliance with the protocol

• Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1,including:

1. Corrected QT interval higher than 470 ms for females and 450 ms for malesaccording to Fridericia's formula (QTcF) and assessed based on triplicate ECGs,approximately 1 minute apart

2. Left ventricular ejection fraction (LVEF) less than 50% by either ECHO orMultigated Acquisition Scan (MUGA)

3. Uncontrolled hypertension (resting systolic blood pressure higher than 180 mmHgor diastolic blood pressure higher than 110 mmHg)

4. Myocardial infarction within six months

5. NYHA Classes 2 to 4 within 28 days before treatment

6. Uncontrolled angina pectoris within six months.

7. Cardiac arrhythmia requiring antiarrhythmic treatment. Patients with a historyof cardiac arrythmia who, at baseline, are controlled with antiarrythmictreatments can be included.

• Active hepatitis B and/or hepatitis C infection, such as those with serologicevidence of viral infection within 28 days of Cycle 1, Day 1.

Participants with past or resolved hepatitis B virus (HBV) infection are eligible if:

1. Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc)positive; OR

2. HBsAg positive and HBV DNA viral load is documented to be equal or less than 2,000IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior tothe viral load evaluation with normal transaminases (in the absence of livermetastasis); OR

3. HBsAg positive and HBV DNA viral load is documented to be equal or less than 2,000IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior tothe viral load evaluation with liver metastasis and abnormal transaminases AST/ALTless than 3 ULN

4. Participants with a history of Hepatitis C infection will be eligible for enrollmentonly if the viral load according to local standards of detection, is documented tobe below the level of detection in the absence of anti-viral therapy during theprevious 12 weeks (ie, sustained viral response according to the local product labelbut no less than 12 weeks, whichever is longer)

• Participants with known human immunodeficiency virus (HIV) or active COVID-19infection

• Female participants who are pregnant or breastfeeding or intend to becomepregnant during the study

• Participants with any psychological, familial, sociological, or geographicalcondition potentially hampering compliance with the study protocol andfollow-up schedule; those conditions should be discussed with the patientbefore registration in the trial

• Participants under guardianship or deprived of his/her liberty by a judicial oradministrative decision or incapable of giving his/her consent

• Participation in another clinical trial evaluating an experimental drug (exceptnon-interventional research)