A Global Pivotal Study in Participants with KRAS G12C-Mutant, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Comparing FirstLine Treatment of LY3537982 and Pembrolizumab vs Placebo and Pembrolizumab in those with PD-L1 expression ≥50% or LY3537982 and Pembrolizumab, Pemetrexed, Platinum vs Placebo and Pembrolizumab, Pemetrexed, Platinum regardless of PD-L1 Expression

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 first-line 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 decision-making 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). One cycle of standard-of-care treatment prior to enrollment, 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: o Part A: single cycle of pembrolizumab o Part B: single cycle of either pemetrexed-platinum with or without pembrolizumab, or pembrolizumab monotherapy. The reason for having received a prior cycle of treatment will be collected on the eCRF. The study design contains a randomized, open-label Dose Optimization, assessing 2 different doses of LY3537982 in combination with pembrolizumab as well as a single arm, open-label Safety Lead-In of LY3537982 in combination with pembrolizumab, pemetrexed and platinum. The Dose Optimization and the Safety Lead-In Part B may start at the same time and run in parallel, or they may start in a staggered fashion.

Inclusion

5.1. Inclusion Criteria 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% 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. Part B and Safety Lead-In 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/site. 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: specimens must be collected within 14 days before the start of study intervention. Approved on 22 Aug 2024 GMT CONFIDENTIAL J3M-MC-JZQB(f) 67 System Laboratory Value Hematologica ANC ?1.5 × 109 /L Platelets ?100 × 109 /L Hemoglobin ?9.0 g/dL (or ≥5.6 mmol/L)a Note: transfusions to increase a participant’s hemoglobin or platelets level or initiation of erythropoietin or G-CSF therapy to meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug. Hepatic Total bilirubin ?1.5× ULN Except participants with a documented history of Gilbert syndrome who must have a total bilirubin level of ≤3.0× ULN Direct bilirubin ≤ULN for participants with total bilirubin levels >1.5×ULN ALT and AST ≤2.5× ULN OR ?5× ULN if the liver has tumor involvement Renal Measured creatinine clearance OR Part A and Dose Optimization ≥30 mL/min Part B and Safety Lead-In Part B ≥45 mL/min Calculated creatinine clearance as calculated per Cockcroft-Gault CrCl formulab or institutional standards Coagulation International normalized ratio (INR) or prothrombin time (PT) Activated partial thromboplastin time (aPTT) or PTT ≤1.5x ULN unless the participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; dL = deciliter; G-CSF = granulocyte-colony-stimulating factor; g = gram; L = liter; mL = milliliter; min = minute; ULN = upper limit of normal. a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. b Cockcroft-Gault CrCl formula = [[140 – age (yr)] × weight(kg)] / [72 × serum Cr (mg/dL) × 0.85 for females]. 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 negative serum or urine pregnancy test result within 72 hours prior to first dose of study intervention. b. Not be breastfeeding during treatment. Approved on 22 Aug 2024 GMT CONFIDENTIAL J3M-MC-JZQB(f) 68 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.

Exclusion

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. Note: testing for these alterations is not required. 14. Have known active CNS metastases and/or carcinomatous meningitis. Exceptions: a. Individuals with small 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. b. Individuals with previously treated CNS metastases may participate provided: ? Any previous local treatment for CNS metastases is completed at least 14 days prior to enrollment. AND ? Participants are radiologically stable (that is, without evidence of progression for ≥14 days by repeat imaging). AND ? Participants are 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. Note: All patients with CNS metastases at baseline (asymptomatic or previously treated) will require regular imaging of the brain as a site of disease (Section 1.3). 15. Have clinically significant active cardiovascular disease or history of myocardial infarction or unstable angina within 6 months prior to planned start of study treatment. 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 Approved on 22 Aug 2024 GMT CONFIDENTIAL J3M-MC-JZQB(f) 69 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. (Note: Criteria #17 has been removed) 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, uncontrolled systemic 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) vi. 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. ? Hepatitis B or C screening tests are not required unless: i. Known history of HBV or 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. Approved on 22 Aug 2024 GMT CONFIDENTIAL J3M-MC-JZQB(f) 70 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, with the following exception: o 1 cycle of standard-of-care treatment prior to study enrollment 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 of pembrolizumab ? 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 standard-of-care treatment to allow sufficient time for recovery from treatment-related toxicity. ? Participants who received adjuvant, neoadjuvant, concurrent chemoradiotherapy, or consolidation therapy are eligible provided systemic treatment was completed at least 6 months prior to randomization. ? Participants who received a prior KRAS G12C inhibitor 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, neoadjuvant or consolidation setting and were discontinued from that treatment due to a Grade 3 or higher immune-related 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 for palliation within 1 week 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 radiationrelated toxicities and not require corticosteroids. Approved on 22 Aug 2024 GMT CONFIDENTIAL J3M-MC-JZQB(f) 71 ? Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study intervention. Exceptions: alopecia, Grade 2 prior therapy related neuropathy, endocrine adverse events considered clinically stable and maintained on appropriate replacement therapy. 26. A current diagnosis of immunodeficiency or is receiving chronic high-dose systemic corticosteroid use (prednisone >10 mg daily or equivalent) or any other form of systemic immunosuppressive therapy within 7 days prior to first dose of study intervention. 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 (see Section 6.8.1). 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. Have squamous cell histology for NSCLC or have small cell elements present in mixed tumors categorized by the predominant cell type. 32. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of 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.