A global, multicenter, randomized, two-part, phase 2/3 study.
Phase 2 Dose Selection will be randomized, blinded to the investigators and participants, and will evaluate the efficacy and safety of two different doses of BMS-986504 in combination with pembrolizumab and chemotherapy versus placebo with pembrolizumab and chemotherapy.
Phase 3 will be randomized, blinded to investigators, participants, and the Sponsor, and will evaluate the efficacy of the selected dose of BMS-986504 in combination with pembrolizumab and chemotherapy versus placebo with pembrolizumab and chemotherapy. The study will enroll previously untreated participants with MTAP-deleted mNSCLC. All participants in Phase 2 and Phase 3 will complete up to 4 study periods:
pre-screening, screening, treatment, and follow-up.

In the Phase 2 Dose Selection portion of the study, approximately 90 eligible participants will be randomized 2:2:1:1 to the following arms:

• Arm A (n = approximately 30): BMS-986504 400 mg QD in 21-day cycles + pembrolizumab + chemotherapy
• Arm B (n = approximately 30): BMS-986504 600 mg QD in 21-day cycles + pembrolizumab + chemotherapy
• Arm C (n = approximately 15): BMS-986504 400 mg matching placebo QD in 21-day cycles + pembrolizumab + chemotherapy
• Arm D (n = approximately 15): BMS-986504 600 mg matching placebo QD in 21-day cycles + pembrolizumab + chemotherapy

In the Phase 3 portion of the study, approximately 500 eligible participants will be randomized 1:1 to the following arms:

• Arm E (n = approximately 250): selected dose of BMS-986504 QD in 21-day cycles + pembrolizumab + chemotherapy
• Arm F (n = approximately 250): selected dose of BMS-986504 matching placebo QD in 21- day cycles + pembrolizumab + chemotherapy

To compare PFS of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion

Key Inclusion Criteria:

• Metastatic (Stage IV or recurrent) NSCLC (as defined by the American Joint Committee on Cancer, Ninth Edition) with no prior systemic anti-cancer therapy for metastatic disease.
• Histologically confirmed diagnosis of NSCLC and homozygous MTAP deletion or MTAP loss detected in tumor tissue using a Sponsor-provided central test or a Sponsor pre-approved local test.
• Any PD-L1 expression (0 to 100%) as determined by the Sponsor pre-approved local PD-L1 IHC assays (VENTANA PD-L1 [SP263] assay, Agilent PD-L1 IHC 22C3 pharmDx, or Agilent PD-L1 IHC 28-8 pharmDx), from tissue collected within 6 months prior to signing the pre-screening informed consent, performed in accordance with the intended use of the assays. If, despite best efforts, a quantifiable result is not possible, non-evaluable or non-quantifiable results may be acceptable upon Medical Monitor (or designee) approval for a maximum of 10% of total participants. Testing must comply with local diagnostic regulations, and documentation of which PD-L1 test used must be provided.
• At least 1 measurable lesion as per RECIST v1.1.

Key Exclusion Criteria:

• Participants with nonsquamous histology with documented targetable oncogenic mutations or AGAs (eg, EGFR, ALK, ROS1) eligible for an approved targeted therapy in 1L, as deemed appropriate by the investigator
• Symptomatic brain metastases or spinal cord compression.
• Prior systemic therapy (chemotherapy, immunotherapy, targeted therapy, or biological therapy) for mNSCLC. Note: One cycle of SoC treatment prior to randomization will be allowed for participants who require immediate treatment if clinically indicated.