The purpose of eVOLVE-Lung02 is to test the effectiveness (efficacy) and measure the safety of volrustomig in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy as 1L treatment in participants with mNSCLC in PD-L1 < 50%.

Adult patients with a histologically or cytologically documented metastatic NSCLC, with tumors that lack activating EGFR, ALK, and ROS1 alterations are eligible for enrollment. Patients will be randomized in a 1:1 ratio to receive treatment with volrustomig + chemotherapy or pembrolizumab + chemotherapy. Tumor evaluation scans will be performed until disease progression as efficacy assessment. All patients will be followed for survival until the end of the study. An data monitoring committee (DMC) composed of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule.

Key Inclusion Criteria:

• Histologically or cytologically documented squamous or non-squamous NSCLC.
• Stage IV NSCLC (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2016), not amenable to curative surgery or radiation.
• Absence of sensitizing EGFR mutations and ALK and ROS1 rearrangements.
• Absence of documented tumor genomic alteration results from tests conducted as part of standard local practice in any other actionable driver oncogenes for which there are locally approved targeted first-line therapies.

Key Exclusion Criteria:

• Mixed small-cell lung cancer and NSCLC histology or sarcomatoid variant. Rare subtypes are excluded.

• Spinal cord compression.

• Symptomatic brain metastases. Brain metastases may be treated or untreated, but participants must be asymptomatic and off steroids for at least 14 days prior to start of study intervention. A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and study enrollment.

• History of another primary malignancy except for:

  1. Malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence.
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  3. Adequately treated carcinoma in situ without evidence of disease.

• As judged by the investigator, any condition that would interfere with evaluation of the study intervention or interpretation of participant safety or study results.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. SignedData Sharing Agreement (non-negotiable contract for data accessors) must be inplace before accessing requested information. Additionally, all users will need toaccept the terms and conditions of the SAS MSE to gain access. For additionaldetails, please review the Disclosure Statements athttps://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

None (Open Label)