The redesigned study is a phase 3, randomized, global, open-label, pivotal, study of the efficacy and safety of REGN2810/ipilimumab versus REGN2810/chemotherapy/ipilimumab versus pembrolizumab monotherapy in patients with stage IIIB or stage IV squamous or non squamous NSCLC whose tumors express PD L1 in ≥50% of tumor cells and who have received no prior systemic treatment for their advanced disease. In the redesigned study, the study arms A and C remain the same; arm B will evaluate REGN2810 in combination with ipilimumab instead of chemotherapy. Rationale revised to reflect the new study design. Due to a new statistical design, enrollment of approximately 585 subjects is needed to generate enough progression free survival (PFS) events. Therefore, the approximate number of planned subjects is reduced to 585 from 675. An interim analysis for secondary endpoint of OS will be performed at the time of primary analysis for PFS

The current text of Key Secondary Endpoint “A patient who has not died will be censored at the last known date of contact" has been revised to "A patient who is lost to follow-up will be censored at the last date that the patient was known to be alive", following European Union (EU) regulatory review; Revised the exclusion criteria concerning human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) to clarify that patients with uncontrolled infection are excluded, but patients with controlled infection are permitted, as requested following EU regulatory review; The current text: “REGN2810 C2P1 drug product is supplied as a sterile liquid solution of 5.6 or 7.4 mL in a 10 or 20 mL glass vial for IV administration.” is revised to “REGN2810 C2P1 drug product is supplied as a sterile liquid solution of 5.6 mL in a 10 mL glass vial for IV administration.” as requested following EU regulatory review.

The following text added to exclusion criterion #10 “patients with HIV or hepatitis must have their disease reviewed by the specialist (e.g., infectious disease or hepatologist) managing this disease prior to commencing and throughout the duration of their participation in the trial” following European Union (EU) regulatory review.

Clarified: Patients on treatment Arm C, pemetrexed maintenance is not allowed; Clarified: Patients in follow-up may be offered retreatment up to an additional 108 wks; Revised secondary endpoint text: To assess predictive utility of baseline PD L1 tumor expression levels on clinical response; Clarified list of Other Secondary Objectives; Inclusion criterion revised to add stage IIIC patient eligibility & clarified histologic diagnosis of NSCLC may be confirmed by central lab; Gemcitabine options for platinum-based doublet deleted; Chemotherapy cycles changed to 4 cycles; Text deleted regarding brain scans during treatment & follow-up periods; PK/ADA sample collection time points revised; Clarified: If possible, a tumor biopsy should be collected at time of progressive disease; Clarified exclusion criteria #3, #23; Exclusion criteria #24 & #25 added based on a health authority feedback; Clarified: Tumor tissue samples will also be tested for EGFR mutations & ALK translocations as well as for ROS1 fusions by a central lab, unless testing already performed & results available from other Regeneron NSCLC immunotherapy studies; Text deleted from Biomarker procedures; Text revised in screening visit assessments; Electrocardiogram text revised; Text added on request by regulatory authority: If necessary, samples may also be used for ADA assessments of ipilimumab; Text revised: Each vial will contain withdrawable cemiplimab at a concentration of 50 mg/mL; Clarified: Pre-medications are not required prior to first administration of cemiplimab & pre-treatment with vitamin supplementation is to start within 3 days of randomization for patients with non-squamous NSCLC; Text added: Pemetrexed maintenance therapy should be given according to local prescribing information & practice guidelines; Deleted “standard-of-care” in regard to platinum-based chemotherapy(ies); Changed REGN2810 to cemiplimab & other minor editorial changes made throughout protocol.