The study aims to determine maximum tolerated dose (MTD) or recommended combination dose of the MTA-cooperative PRMT5 inhibitor Anvumetostat administered in combination with other therapies in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-deleted thoracic tumors. The study also aims to determine the safety profile of Anvumetostat administered in combination with other therapies in adult participants with metastatic or locally advanced MTAP-deleted thoracic tumors.

Inclusion Criteria

Subprotocol A, B, and C

• Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
• Tumor tissue (formalin-fixed, paraffin-embedded sample) or an archival block must be available. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before Anvumetostat dosing.
• Homozygous MTAP-deletion
• Able to swallow and retain PO administered study treatment.
• Disease measurable as defined by RECIST v1.1.

Subprotocol A - Histologically or cytologically confirmed diagnosis of NSCLC.

Arm A (Anvumetostat + carboplatin + paclitaxel + pembrolizumab):

- Predominantly squamous histology.

Arm B (Anvumetostat + carboplatin + pemetrexed + pembrolizumab):

- Predominantly non-squamous histology.

Arm C (Anvumetostat + pembrolizumab):

- PD-L1 positive.

Subprotocol B - Histologically confirmed NSCLC with homozygous MTAP-deletion and KRAS p.G12C mutation.

Subprotocol C

• Histologically or cytologically confirmed diagnosis of NSCLC with brain metastases.
• Brain lesion meeting RANO-BM criteria for measurable disease.

Exclusion Criteria

Subprotocol A, B, and C

• Cardiovascular and pulmonary exclusion criteria as defined in the protocol.
• Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
• History of solid organ transplant.
• Major surgery within 28 days of first dose of Anvumetostat.
• Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
• Radiation therapy within 28 days of first dose.

Subprotocol A

- Autoimmune disease or immunodeficiency disease as defined in the protocol'

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of reevaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.