Study JZQB is a global, multicenter, randomized (1:1), double-blind, placebo-controlled, Phase 3 study that will enroll participants with unresectable, advanced, or metastatic KRAS G12C-mutant NSCLC into one of the two parallel-running parts that will:

• Compare LY3537982 in combination with pembrolizumab to placebo in combination with pembrolizumab as first-line treatment for participants with a tumor with PD-L1 expression ≥50% (Part A).
• Compare LY3537982 in combination with pembrolizumab plus pemetrexed and platinum to placebo in combination with pembrolizumab plus pemetrexed and platinum as firstline treatment of participants with a tumor with PD-L1 expression 0 to 100% (Part B).
  Allocation of participants with PD-L1 expression ≥50% to either Part A or Part B will be at the discretion of the investigator and in line with clinical practice where first-line treatment decisionmaking is based on tumor PD-L1 expression and suitability for single agent pembrolizumab or pembrolizumab with pemetrexed and platinum. The decision to allocate a participant to Part A or B will occur prior to randomization and the reason will be collected on the electronic case report form (eCRF).

• Part A: single cycle of pembrolizumab.
• Part B: single cycle of either pemetrexed-platinum with or without pembrolizumab, or pembrolizumab monotherapy.

Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics

1. Histologically or cytologically confirmed NSCLC with Stage IIIB-IIIC or Stage IV disease not suitable for curative intent radical surgery or radiation therapy. Staging will be according to the AJCC Staging System (8th ed [AJCC Cancer Staging Manual 8th Edition. 2020]).
   a. Part B and Safety Lead-In Part B: the histology of the tumor must be predominantly non-squamous (in line with pemetrexed label).
2. Must have disease with evidence of KRAS G12C mutation in tumor or blood sample as determined by molecular testing performed in a CLIA, ISO/IEC, CAP, or other similarly certified laboratory as per local guidelines including, but not limited, to IVDR compliance as applicable (see Section 8.8).
3. Must have known PD-L1 expression (estimated percentage [0%-100%] of tumor cells (TCs) showing partial or complete membranous PD-L1 staining) as determined by an IHC assay in a CLIA, ISO/IEC, CAP, or other similarly certified laboratory as per local guidelines including, but not limited to, IVDR compliance as applicable (see Section 8.8).
   a. Dose Optimization: 0% to 100%
   i. Participants should be suitable, as per the local label, for first line
   treatment with pembrolizumab monotherapy in order to be eligible.
   b. Part A: ≥50%.
   i. Participants with PD-L1 ≥50% should be suitable for first line treatment with pembrolizumab monotherapy in order to be eligible (at the discretion of the investigator)
   c. Safety Lead-In Part B and Part B: 0% to 100%.
   i. Participants should be suitable, as per investigator’s discretion, for first line treatment with pembrolizumab, pemetrexed and platinum in order to be eligible.
4. Must have measurable disease per RECIST v1.1 (Eisenhauer et al. 2009) as assessed by the investigator. Target lesions situated in a previously irradiated area are considered measurable if progression subsequent to radiation has been shown in such lesions, and the location of previously irradiated lesions is clearly documented.
5. Must have an ECOG performance status of 0 or 1 (Oken et al. 1982)
6. Estimated life expectancy ≥12 weeks.
7. Ability to swallow capsules.
8. Must have adequate laboratory parameters, as defined in the following table
   Contraception
9. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. For the contraception requirements of this protocol, see Section 10.6 in Appendix 6.
10. Women of childbearing potential must
    a. Have a negative pregnancy test (serum preferable) at screening, followed by a negative serum or urine result 24 hours prior to treatment with study intervention.
    b. Not be breastfeeding during treatment and after study intervention for at least 180 days.
    Informed consent
11. Are capable of demonstrating an understanding of the nature, significance, and implications of participation in the trial and giving signed informed consent as described in Section 10.1.3, Appendix 1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
    Age
12. Are of an acceptable age to provide informed consent according to local regulations and are at least 18 years of age.

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

13. Have a documented additional validated targetable oncogenic driver mutation or alteration in genes such as EGFR, ALK, BRAF (V600E), HER2, MET (exon 14), ROS1, RET, or NTRK1/2/3.
14. Have known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided
    a. Any previous local treatment to treat CNS metastases must be completed at least 14 days prior to treatment. Glucocorticoid therapy (prednisone <10 mg daily or equivalent) at time of enrollment or randomization will be allowed in patients that are clinically and neurologically stable
    b. Radiologically stable (that is, without evidence of progression for ≥14 days by repeat imaging). Patients must be neurologically and clinically stable for ≥14 days prior to enrollment or randomization. Glucocorticoid therapy (equivalent of 10 mg/day of prednisone) at time of enrollment or randomization will be allowed.
    Prophylactic anticonvulsants are permitted, provided the participant is on a stable dose for ≥14 days prior enrollment or randomization.
    c. Subjects with asymptomatic untreated brain metastases (that is, no acute neurological symptoms requiring urgent CNS-directed therapy (radiation or surgery), no requirements for corticosteroids, and no lesion >1.5 cm) may participate.
    All patients with CNS metastases at baseline (asymptomatic or previously treated) will require regular imaging of the brain as a site of disease.
15. Have clinically significant active cardiovascular disease or history of myocardial infarction or unstable angina within 6 months prior to planned start of study.
16. Have prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 msec. If QTcF >470 msec on 1 ECG is obtained during the screening, repeat 2 additional times and use the average of the 3 measurements to determine eligibility.
    Note that participants with implanted pacemakers may enter study without meeting QTc criteria due to nonevaluable measurement.
17. Have uncontrolled, disease-related, pericardial effusion or pleural effusion.
18. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current clinically significant pneumonitis/interstitial lung disease.
19. Have an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
20. History of allogenic tissue/solid organ transplant or allogenic stem cell transplant.
21. Have an active fungal, bacterial, and/or active untreated viral infection, including HIV or viral (A, B, or C) hepatitis (screening is not required unless mandated by local health authority).

• HIV-infected participants must be on ART and have a well-controlled HIV infection/disease defined as:
  i. Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of Screening
  ii. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of Screening and for at least 12 weeks prior to Screening
  iii. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months.
  iv. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 28 days prior to study entry (Day 1). and agree to continue ART throughout the study.
  v. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (FDA 2023) HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are excluded.
• History of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as detectable HCV RNA [qualitative]) infection.
  i. Note: Testing for Hepatitis B or C is not required unless mandated by local health authority.
• Hepatitis C screening tests are not required unless:
  i. Known history of HCV infection
  ii. As mandated by local health authority

22. The participant has a serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study, including (but not limited to): severe dyspnea at rest, requiring oxygen therapy, known psychiatric or substance abuse disorder). Screening for chronic conditions is not required.
23. Have clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
24. Known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder,
    that have undergone potentially curative therapy are not excluded. Participants receiving adjuvant hormone therapy for breast or prostate cancer with no evidence of disease are eligible.
    Prior/Concomitant Therapy
25. Have had any of the following prior to randomization:

• Prior systemic therapy (chemotherapy, immunotherapy, targeted therapy, or biological therapy) for advanced or metastatic NSCLC.
  o 1 cycle of standard-of-care treatment prior to study enrollment in either Part A or Part B will be allowed for cases where immediate treatment is clinically indicated. Prior treatment options allowed for suitable patients, in line with local label and treatment guidelines, are:
  ▪ Part A and Dose Optimization: single cycle ofpembrolizumab
  ▪ Part B and Safety Lead-In Part B: single cycle of either pemetrexed-platinum with or without pembrolizumab, or pembrolizumab monotherapy.
  Study treatment should start approximately 21 days after Day 1 of the prior cycle of therapy (or as close as possible after this date). Start of study treatment may be delayed for a maximum of 42 days from Day 1 of the prior cycle of therapy to allow sufficient time for recovery from treatmentrelated toxicity.
• Participants who received adjuvant, neoadjuvant or consolidation therapy are eligible provided systemic treatment was completed at least 6 months prior to randomization.
• Participants who received a KRAS G12C inhibitor in the adjuvant or neoadjuvant setting are not eligible.
• Participants who received an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
  (e.g., CTLA-4, OX 40, CD137) in the adjuvant or neoadjuvant setting and were discontinued from that treatment due to a Grade 3 or higher immunerelated
  AE are not eligible.
• Major surgery within 21 days prior to the first dose of study intervention. Placement of vascular access is not considered a major surgery.
• Radiotherapy within 14 days of the first dose of study intervention. If the radiotherapy was more than 30 Gy to the lung, then the treatment must have been completed at least 6 months prior to the first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not
  require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study intervention except for alopecia and Grade 2 prior
  therapy related neuropathy.

26. A current diagnosis of immunodeficiency, or chronic high-dose systemic corticosteroid use (prednisone >10 mg daily or equivalent). Endocrine replacement therapy, e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc., is not considered a form of chronic treatment and is not excluded. The use of topical, ophthalmic, inhaled, and intranasal corticosteroids and local steroid injections is permitted.
27. Have received a live vaccine within 30 days prior to the first dose of trial treatment. Seasonal flu vaccines that do not contain live virus are permitted. Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are mRNA vaccines, adenoviral vaccines, or inactivated vaccines.
    Prior/Concurrent Clinical Study Experience
28. Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
29. Have participated, within the past 30 days (4 months for studies conducted in Japan; 3 months for studies conducted in the UK), in a clinical study involving an investigational product. If the previous investigational product has a long half-life, 5 half-lives or 30 days (4 months for studies conducted in Japan; 3 months for studies conducted in the UK [whichever is longer]) should have passed.
    Other Exclusion Criteria
30. Have a known hypersensitivity to any of the components of LY3537982, pembrolizumab, pemetrexed or platinum containing drugs.
    Exclusion Criteria for Participants receiving Pemetrexed and Platinum (Part B and Safety Lead-In Part B)
31. Squamous cell and/or mixed small cell/nonsmall cell histology is not permitted.
32. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam) around pemetrexed administration.
    a. Subjects taking NSAIDs or salicylates will not take the NSAID or salicylate (other than an aspirin dose ≤1.3 grams per day) for 2 days before, the day of, and 2 days after receiving pemetrexed.
    b. Subjects taking NSAIDs or salicylates with a long half-life will not take the NSAIDs or salicylates for 5 days before, the day of, and 2 days after pemetrexed.
33. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
34. Individual is known to be intolerant to any component of their planned treatment regimen at the dose levels specified in each combination, as evidenced by prohibitive toxicity, such as Grade 4 hematologic toxicity, any toxicity requiring transfusion support, or G-CSF, or other toxicities considered treatment related.