The purpose of this study is to assess if adding LY3537982 (olomorasib) in combination with standard of care anti-cancer drugs is more effective than standard of care in participants with untreated advanced NSCLC. NSCLC must have a change in a gene called KRAS G12C. Study participation, including follow-up, could last up to 3 years, depending on how you and your lung cancer are doing.

Dose Optimization, Part A, and Part B are randomized. Safety Lead-In for Part B is single arm, non-randomized. Part C is non-randomized.

Inclusion Criteria:

• Histologically or cytologically confirmed NSCLC with Stage IIIB-IIIC or Stage IV disease, not suitable for curative intent radical surgery or radiation therapy.

• Part B and Safety Lead-In Part B: the histology of the tumor must be predominantly non-squamous (in line with pemetrexed label).

• Must have disease with evidence of KRAS G12C mutation.

• Must have known programmed death-ligand 1 (PD-L1) expression

  • Part A: Greater than or equal to (≥)50 percent (%).
  • Part B: 0% to 100%.
  • Part C: <50%.

• Must have measurable disease per RECIST v1.1.

• Must have an ECOG performance status of 0 or 1.

• Estimated life expectancy ≥12 weeks.

• Ability to swallow capsules.

• Must have adequate laboratory parameters.

• Contraceptive use should be consistent with local regulations for those participating in clinical studies.

• Women of childbearing potential must

  • Have a negative pregnancy test.
  • Not be breastfeeding during treatment

Exclusion Criteria:

• Have a documented additional validated targetable oncogenic driver mutation or alteration in genes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), BRAF (V600E), human epidermal growth factor receptor 2 (HER2), MET (exon 14), ROS1, rearranged during transfection (RET), or neurotrophic tyrosine receptor kinase (NTRK)1/2/3.

• Have had any of the following prior to randomization:

  -- Prior systemic therapy (chemotherapy, immunotherapy, targeted therapy, or biological therapy) for advanced or metastatic NSCLC.

  --- 1 cycle of standard-of-care treatment prior to study enrollment will be allowed for cases where immediate treatment is clinically indicated:

• Have known active central nervous system metastases and/or carcinomatous meningitis.

Exclusion Criteria for Participants receiving Pemetrexed and Platinum (Part B and Safety Lead-In Part B)

• Have predominantly squamous cell histology for NSCLC
• Only for participants with mild to moderate renal insufficiency: Unable to avoid aspirin, ibuprofen, or other nonsteroidal anti-inflammatory drugs (NSAIDs) two days before (5 days for long acting NSAIDs), day of, and two days after administration of pemetrexed
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.

Parts A and B are double blind. Dose Optimization, Safety Lead-In for Part B and Part C are open label.