Hyperprogression in PD-L1 ≥ 50% NSCLC: a Biomarker Guided Phase 2 Trial

Inclusion Criteria: 1. The participant (or legally acceptable representative) has provided documented informed consent to participation to the study and data protection consent form. 2. Male or female aged 18 years or older. 3. ECOG Performance Status of 0 - 2. 4. Pathologically (histologically or cytologically) confirmed diagnosis of stage IV NSCLC (TNM 8th edition), who received no prior systemic treatment for recurrent or metastatic NSCLC. Mixed squamous/non-squamous tumors are eligible. 5. PD-L1 TPS ≥ 50% (by local test). 6. Absence of targetable oncogene alterations (EGFR, ALK, ROS1). 7. Circulating CD10- LDNs \>30.5% at screening. LDNs will be defined as CD11b+CD15+ cells among live PBMC. Flow cytometry raw data will be centrally analyzed by the coordinating center. 8. Measurable disease (RECIST 1.1) on two CT scans performed before randomization. The following criteria must be fulfilled: * Participants must have at least one measurable lesion that has not been previously treated with radiotherapy. * Chest and abdomen scans are mandatory * Availability of measurable disease scans to be anonymized and sent for central independent confirmation by a radiologist of the coordinating center. * A minimum 2-week interval and a maximum 12-week interval will be acceptable between the two pre-treatment CT scans. * Availability to perform the baseline scan within a maximum 4-week interval before treatment start. 9. Patient's willingness to undergo blood draws to provide plasma and blood samples for analysis according to study objectives. 10. Adequate organ and marrow function as defined below: * Absolute neutrophil count \> 1.5 x 109/L (1500/mm3) * Platelets ≥100 x 109/L (100 000/mm3) * Haemoglobin ≥9.0 g/dL (5.59 mmol/L) * Estimated glomerular filtration rate (according to CDK-EPI equation): ≥ 60ml/min/1.73 m2 for patients receiving cisplatin; ≥30 ml/min/1.73 m2 for patients receiving carboplatin. * Serum bilirubin ≤1.5 x upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology) who will be allowed in consultation with their physician. * AST and ALT ≤2.5 x ULN. 11. Absence of a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or cemiplimab and/or to any of their excipients Exclusion Criteria: 1. Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication 2. Known uncontrolled infection with HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent). No serological testing is required unless mandated by local health authority. 3. Administration of live or live-attenuated vaccines within 30 days before the baseline LDNs assessment. Administration of killed vaccines is allowed. Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication. 4. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management. 5. Administration of radiotherapy within 7 days prior to the baseline LDNs assessment. 6. Administration of colony-stimulating factors (e.g., G-CSF, GM-CSF) or recombinant erythropoietin within 28 days prior to the baseline LDNs assessment. Primary prophylaxis with G-CSF and pegylated G-CSF is not allowed. Secondary prophylaxis is not recommended and required case-by-case discussion with the coordinator center before G-CSF administration. 7. Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment. 8. Female patients who are pregnant, breast-feeding, male, or female patients of reproductive potential who are not employing an highly effective method of birth control. 9. Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results. 10. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment (Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable). 11. Allogenic tissue/solid organ transplant.