This is a Phase II, multi-center, open-label platform study evaluating novel combination treatment options in participants with locally advanced or metastatic NSCLC. The study will consist of several sub-studies, each evaluating the safety, tolerability, and preliminary antitumour activity of various treatment combinations. This study will be conducted in approximately 80 centers globally across 10 countries.

The master protocol will include 3 sub-studies, each focused on a specific disease population.

• Sub-study 1 will investigate rilvegostomig± ramucirumab in 1L non-actionable genomic alterations (AGA) NSCLC with PD-L1 ≥50%.
• Sub-study 2 will investigate rilvegostomig + ramucirumab in 1L non-actionable genomic alterations (AGA) NSCLC with PD-L1 1-49%.
• Sub-study 3 will investigate Dato-DXd + ramucirumab ± rilvegostomig in 2/3L AGA+

Each sub-study may include 2 parts (unless stated in the individual sub study protocols): Part A: one or more Safety Run-in cohort(s), and Part B: one or more Dose Expansion cohort(s).

Inclusion Criteria for All Sub-studies:

• Participant must be ≥ 18 years of age at the time of signing the ICF
• WHO/ECOG performance status of 0 or 1
• At least 1 lesion that qualifies as a RECIST 1.1 Target Lesion (TL) at baseline.
• Adequate bone marrow and organ function
• Life expectancy ≥ 12 weeks
• Provision of acceptable tumour tissue

Specific Inclusion Criteria for Sub-Study 1 and Sub-Study 2:

• Histologically or cytologically documented advanced or metastatic NSCLC
• PD-L1 TC ≥ 1% (TC≥ 50% for sub-study 1, 1-49% for sub-study 2)
• Absence of sensitizing EGFR mutations or ALK rearrangements. No known other Actionable Genomic Alterations(AGAs)

Specific Inclusion Criteria for Sub-Study 3:

• Histologically or cytologically documented advanced or metastatic non-squamous NSCLC
• Documented positive AGA and had progressed on prior targeted therapy

Exclusion Criteria for All Sub-studies:

• As judged by the investigator, any severe or uncontrolled systemic diseases, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol
• Active or prior documented autoimmune or inflammatory disorders
• Persistent toxicities (CTCAE Grade ≥ 2) (NCI CTCAE v5.0) caused by previous anti cancer therapy, excluding alopecia.
• Spinal cord compression or leptomeningeal carcinomatosis for sub-study 1 and sub-study 2. Unstable spinal cord compression for sub-study 3
• Unstable brain metastases
• History of another primary malignancy.
• Active infection, including TB and infections with HIV, HBV (verified by known positive HBsAg result), HCV.
• Uncontrolled or significant cardiac disease
• Receipt of prior systemic chemotherapy/chemoradiation/immunotherapy for advanced NSCLC for sub-study 1 and sub-study 2.
• Prior exposure to immune-mediated therapy
• History of uncontrolled hypertension, and active bleeding diseases, and high risks of bleeding and disorders of coagulation
• Any concurrent anti-cancer treatment.
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA 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 anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.