Cisplatin (CIS) Administered As Dry Powder for Inhalation (DPI) in Patients with Stage IV Non-Small Cell Lung Cancer

Inclusion Criteria:

• The patient must be ≥18 years of age at the time of signing the informed concentform (ICF).

• The patient must have a pathologically or cytologically confirmed Stage IV NSCLCthat could be treated with pembrolizumab alone or combined withcarboplatin/pemetrexed or paclitaxel.

• The patient must have measurable disease according to RECIST 1.1.

• The patient must be treatment naïve for stage IV NSCLC at the time of studyenrolment. Patients having received, at least 6 months before D1, platinumderivatives adjuvant after (i) surgery or (ii) concomitant chemotherapy-radiotherapyfor unresectable locally advanced NSCLC are eligible.

• The patient must have an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0-1.

• The patient must have adequate organ function values as follows:

1. Haematology:

2. Platelet count >100,000 cells/mm3.

3. Absolute neutrophil count >1,500 cells/mm3.

4. Haemoglobin >9 g/dL.

5. Serum creatinine less or equal to upper limit of normal (ULN) or creatinineclearance >60 mL/min/1.73 m2 on the basis of Cockcroft-Gault glomerularfiltration rate estimation.

6. Coagulation:

7. International normalised ratio (INR) ≤1.5; for patients treated withcoumarins INR ≤3 is acceptable.

8. Prothrombin time (PTtest) and activated partial thromboplastin time (aPTT) <1.6 x ULN unless therapeutically warranted.

9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x ULN.In case of hepatic metastasis, AST and ALT <5 x ULN.

10. Bilirubin ≤1.5 x ULN, except for patients with known familialhyperbilirubinemia (such as Gilbert syndrome); for patients with documentedGilbert's syndrome (Gilbert-Meulengracht syndrome) total bilirubin of ≤3 x ULNis acceptable.

• The patient must have a resting oxygen saturation of at least 90%, a FEV1 ≥50% ofpredicted values as determined by spirometry and a DLCO of at least 50%.

• The patient is able to manipulate adequately the refillable single-dose (RS01)capsule-based device.

• Women of childbearing potential should have a negative serum pregnancy test, and benot pregnant or breastfeeding at screening.

• Male patients that are able to father children and female patients of childbearingpotential must agree to use highly effective methods of contraception throughout thestudy and for at least 6 months after the last dose of CIS-DPI.

• The patient has given written informed consent prior to any study-specificprocedures.

• The patient has the willingness and ability to comply with scheduled visits,treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

• Patients with contraindication to or unwillingness to undergo contrast-enhancedcomputed tomography (CT) scans and chest X-rays according to the protocolrequirements.

• Patients who are participating in an investigational drug or device study within 4weeks prior to the planned day for the first study treatment administration (D1).

• Patients who have been treated by any anti-neoplastic agent within 6 months prior tothe planned day for the first study treatment administration (D1).

• Patients who have received prior therapy with an immune checkpoint inhibitor.

• Patients who have received prior radiotherapy (head, neck, thorax, or abdomen)within 4 weeks prior to the planned day for the first study treatment administration (D1) except palliative radiotherapy (2 weeks). Patients must have recovered from allradiation-related toxicities, not require corticosteroids (see criterion 2425) andnot have had radiation pneumonitis >grade 2.

• Patients with concurrent thoracic irradiation for the treatment of lung cancer.

• Patients who underwent major surgery within 4 weeks before the planned day for thefirst study treatment administration (D1).

• Patients with EGFR activating mutation or ALK translocation, or any other activablemolecular alterations that in the opinion of the investigator could be moreeffectively treated with targeted therapies (Note: This exclusion criterion must bechecked before the first SoC administration).

• Non-smoking patients without results of Epidermal growth factor receptor (EGFR)mutation and anaplastic large-cell lymphoma kinase (ALK) translocation before theplanned day for the first study treatment administration (D1).

• Patients with known pre-existing hearing impairment due to VIII nerve alteration.

• Patients presenting a history of previous severe intolerance to or sensitivity tocisplatin, vitamin E or lactose.

• Patients with mouth problems (e.g. cleft palate) or other abnormalities that wouldprevent tight fit of the mouth seal.

• Patients with uncontrolled symptomatic pleural effusion or uncontrolledpneumothorax.

• Patients having undergone pneumonectomy or bilobectomy (except if bilobectomyincludes the right middle lobe).

• Patients with a known history of severe cough/bronchospasm upon inhalation of drypowder inhalation products.

• Patients with a known history or current evidence of any chronic upper or lowerrespiratory conditions (other than asthma and allergic or non-allergic rhinitis).History of mild acute upper or lower respiratory conditions are allowed, providedthat the condition has been resolved at least 3 months before the planned day forthe first study treatment administration (D1) and provided that, in theinvestigator's judgement, this occurrence poses no additional risk for this subject.

• Patients with a known history of idiopathic pulmonary fibrosis, organizingpneumonia, drug-induced pneumonitis, idiopathic pneumonitis, acute exacerbation ofchronic obstructive pulmonary disease (COPD) in the last 3 months before D1 (even ifmanaged in an outpatient setting), known history of interstitial lung disease (ILD),or (non-infectious) pneumonitis that require steroids or that have currentpneumonitis.

• Patients with uncontrolled asthma, as defined in the Global Initiative for Asthma (GINA) 2020 guidelines. Patients with (i) a history of asthma or (ii) controlledactive asthma treated with long-acting beta-2 mimetics with or without inhaledcorticosteroids and having less than one asthma crisis per month, are eligible.

• Patients with uncontrolled or severe active infection.

• Known positivity for human immunodeficiency virus (HIV) or history of HIV (HIVtesting is not mandatory):

• Active hepatitis B virus (HBV; chronic or acute) defined as having a positivehepatitis B surface antigen (HBsAg) test at screening. Patients with past orresolved HBV infection (defined as having a negative HBsAg test and a positivehepatitis B core antigen antibody test) are eligible.

• Active hepatitis C virus (HCV) infection defined as having a positive HCV antibodytest followed by a positive HCV ribonucleic acid (RNA) test at screening. The HCVRNA test will be performed only for patients who have a positive HCV antibody test.Patients who are positive for HCV antibodies are eligible only if polymerase chainreaction (PCR) is negative for HCV RNA.

• Positivity for Coronavirus Disease 2019 (COVID-19) by PCR testing. PCR result mustnot be older than 72 hours prior to the planned day for the first study drugadministration (D1). Completed vaccination or prior COVID-19 infection does notexempt patients from PCR testing.

• Live virus vaccine within 30 days prior to the planned day for the first studytreatment administration (D1) (Note: inactivated seasonal flu vaccine isacceptable).

• Patients using oral corticosteroids within 4 weeks1 week prior to the planned dayfor the first study treatment administration (D1) above daily dose of 10 mg or anysingle dose of 16 mg. Patients receiving inhaled or topical corticosteroids areeligible.

• Patients who are presenting persistent toxicities greater than or equal to CommonTerminology Criteria for Adverse Events (CTCAE version 5.0) grade 2 caused byprevious cancer therapy (except for clinically non-significant toxicities, such asalopecia).

• Patients having a current active malignancy with the exception of adequately-treatedbasal or squamous cell carcinoma of the skin, preinvasive carcinoma of the cervix,in situ carcinoma of the breast or low-grade prostate cancer with no plan fortreatment intervention. Patients with previous history of malignancy provided thatpatient has been free of disease for at least 3 years may be included.

• Patients with a known history of arterial thromboembolic event (ATE) or venousthromboembolic event (VTE) within 3 months prior to the planned day for the firststudy treatment administration (D1).

• Patients with a known history of any of the following conditions: presyncope orsyncope of either unexplained or cardiovascular etiology, uncontrolled ventriculararrhythmia (including but not limited to ventricular tachycardia and ventricularfibrillation) or sudden cardiac arrest.

• Patients with significant or uncontrolled congestive heart failure (CHF) with LeftVentricular Ejection Fraction Assessment (LVEF) of less than 40%, significant oruncontrolled myocardial infarction or significant ventricular arrhythmias within thelast 6 months prior to the planned day for the first study treatment administration (D1).

• Patients who have uncontrolled hypertension defined as systolic blood pressure ≥150mmHg or diastolic blood pressure ≥90 mmHg despite standard medical management with ≥2 anti-hypertensive drugs.

• Patients with a known history of organ transplant or current activeimmunosuppressive therapy (such as cyclosporine, tacrolimus).

• Patients with known history or presence of clinically relevant central nervoussystem (CNS) pathology, any autoimmune disease or significant coagulation disorder.

• Patients with carcinomatous meningitis or CNS metastases, except where suchmetastases are stable and already irradiated.

• Patients with peripheral neuropathy >grade 1.

• Patients with any significant medical condition that in the opinion of theinvestigator makes participation in the trial against the patients' best interests.

• Patients who are unwilling or unable to comply with the study protocol for any otherreason.