• Aged ≥18 years at the time of giving informed consent.

• Have measurable disease defined by RECIST v1.1.

• All participants have to provide a tumor tissue sample (e.g. Formalin-fixed paraffin-embedded \[FFPE\] slides or block) from archival tissue. Alternatively, a fresh biopsy should be collected, unless medically not justifiable to be conducted.

• Have Eastern Cooperative Oncology Group performance status of 0 or 1.

• Have adequate organ and bone marrow function within 7 days before randomization/enrollment.

• Have advanced (i.e., metastatic or locally recurrent where local therapy with curative intent is not possible) non-squamous or squamous (all cohorts) or only non-squamous (Cohort D2) NSCLC.

∙ Cohort-specific inclusion criteria

∙ Part 1, 2L+, squamous or non-squamous NSCLC, AGA-negative/positive, any PD-L1

• for AGA-negative NSCLC only:

‣ Have no actionable genomic alterations, such as EGFR mutations, anaplastic lymphoma kinase (ALK) gene rearrangements, or other genomic alterations for which targeted molecular therapies are available.

⁃ Have experienced relapse or progression during or after treatment with standard systemic therapy in the advanced/metastatic setting or discontinued from prior therapy due to intolerance.

⁃ Participants must have received 1 to 3 lines of systemic treatment, which can include anti-PD-1/PD-L1 therapy, chemotherapy, and anti-angiogenic agents. These treatments may be administered concurrently or sequentially. However, chemotherapy treatment must be limited to 2 lines or less.

• for AGA-positive NSCLC only (excluding EGFR activating mutation):

‣ Have documented positive test results for one or more actionable genomic alteration: EGFR (other than activating mutations), ALK, ROS proto-oncogene 1 (ROS1), gene encoding the hepatocyte growth factor receptor (MET), human gene that encodes a protein called B-Raf (BRAF), rearranged during transfection (RET), neurotrophic tropomyosin-receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), Kirsten rat sarcoma virus (KRAS), or other genomic alteration with available targeted therapy.

⁃ Must have received at least one prior systemic therapy for advanced disease, which must have included targeted treatment for actionable genomic alterations, which include alterations such as EGFR (other than activating mutations), ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other alterations for which targeted therapies are available as a part of local SoC.

⁃ Participants may have received between 1 to 3 lines of systemic treatment of anti-PD-1/PD-L1 therapy, chemotherapy, and/or anti-angiogenic agents. These treatments may be administered concurrently (including with TKI) or sequentially. However, chemotherapy treatment must be limited to 2 lines or less.

⁃ Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

• for AGA-positive NSCLC only (with EGFR activating mutation):

‣ Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del).

⁃ Participants must have received one or two prior lines of systemic therapy for advanced and/or metastatic disease, which must include treatment with an approved EGFR TKI, with at least one being a third-generation EGFR TKI.

⁃ Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.

⁃ Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease.

⁃ Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

∙ Part 2a (Cohort A), 2L+, squamous or non-squamous NSCLC, AGA-negative/positive, any PD-L1

• for AGA-positive NSCLC only, excluding EGFR activating mutation:

‣ Have documented positive test results for one or more actionable genomic alterations: EGFR (other than activating mutations), ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other genomic alterations, with available targeted therapy.

⁃ May have received 1 to 4 lines of systemic treatment, of which one prior systemic therapy for advanced disease must have included targeted treatment for actionable genomic alterations, which include alterations such as EGFR (other than activating mutations), ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other genomic alterations for which targeted therapies are available as part of local SoC.

⁃ Other therapies may include anti-PD-1/PD-L1 therapy, chemotherapy, and anti-angiogenic agents. These treatments may be administered concurrently/in combination (including with TKI) or sequentially. However, chemotherapy treatment must be limited to 2 lines or less.

⁃ Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

• for AGA-positive NSCLC only, with EGFR activation mutation:

‣ Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del).

⁃ Participants must have received one or two prior lines of systemic therapy for advanced and/or metastatic disease, which must include treatment with an approved EGFR TKI, with at least one being a third-generation EGFR TKI.

⁃ Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.

⁃ Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease.

⁃ Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

∙ Part 2a (Cohort B), 1L, squamous or non-squamous NSCLC, AGA-negative, any PD-L1

• Have no actionable genomic alterations, such as EGFR mutations, ALK rearrangements, or other genomic alterations for which targeted molecular therapies are available.

• Have received no systemic anti-cancer treatment in the advanced/metastatic setting. May have received neoadjuvant and/or adjuvant treatment if progression to advanced/metastatic disease occurred at least 12 months after completing such therapy and have not received treatment in the advanced/metastatic setting.

∙ Part 2b (Cohort C), 2L+, squamous or non-squamous NSCLC, AGA-negative or EGFR activating mutation, any PD-L1

• for AGA-negative NSCLC only:

‣ Have no actionable genomic alterations, such as EGFR mutations, ALK rearrangements, or other genomic alterations for which targeted molecular therapies are available.

⁃ Participants should have received 1 to 4 lines of systemic treatment, which can include anti-PD-1/PD-L1 therapy, chemotherapy, and/or anti-angiogenic agents.

• for EGFR-sensitizing mutation NSCLC only:

‣ Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del).

⁃ Have received 1 or 2 prior systemic therapies for advanced and/or metastatic disease with an approved EGFR TKI, which must include one third-generation anti-EGFR TKI.

⁃ Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.

⁃ Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease.

⁃ May have received neoadjuvant and/or adjuvant treatment if progression to advanced/metastatic disease occurred at least 6 months after completing such therapy and have experienced disease progression on or after EGFR TKI treatment administered in the advanced/metastatic setting.

⁃ Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

∙ Part 2b (Cohort D1) 1L, squamous or non-squamous NSCLC, AGA-negative, PD-L1 ≥50% and Part 2b (Cohort D2) 1L, squamous or non-squamous NSCLC, AGA-negative, PD-L1 \<50%

• Have no actionable genomic alterations, such as EGFR mutations, ALK rearrangements, or other genomic alterations for which targeted molecular therapies are available.

• Did not receive prior systemic therapy for advanced and/or metastatic disease.