A Study of LY3537982 Plus Immunotherapy With or Without Chemotherapy in Participants With Non-Small Cell Lung Cancer (NSCLC) With a Change in a Gene Called KRAS G12C

Study Overview
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Brief Summary
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The purpose of this study is to assess if adding LY3537982 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.

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

Official Title
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SUNRAY-01, A Global Pivotal Study in Participants With KRAS G12C-Mutant, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Comparing First-Line 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

Conditions
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Carcinoma, Non-Small-Cell Lung, Neoplasm Metastasis

Intervention / Treatment
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* Drug: LY3537982
* Drug: Pembrolizumab
* Drug: Placebo
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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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%. 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 and after study intervention for at least 180 days. 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) Squamous cell and/or mixed small cell/nonsmall cell histology is not permitted. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) Is unable or unwilling to take folic acid or vitamin B12 supplementation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Optimization: LY3537982 Dose Level 1 plus Pembrolizumab<br>LY3537982 Dose level 1 administered orally in combination with pembrolizumab administered intravenously (IV) in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: LY3537982<br>* Administered orally.<br>Drug: Pembrolizumab<br>* Administered IV.<br>|
| Experimental: Dose Optimization: LY3537982 Dose Level 2 plus Pembrolizumab<br>LY3537982 Dose level 2 administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: LY3537982<br>* Administered orally.<br>Drug: Pembrolizumab<br>* Administered IV.<br>|
| Experimental: Safety Lead In: LY3537982 plus Pembrolizumab, Pemetrexed and Platinum<br>LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: LY3537982<br>* Administered orally.<br>Drug: Pembrolizumab<br>* Administered IV.<br>Drug: Cisplatin<br>* Administered IV.<br>Drug: Carboplatin<br>* Administered IV.<br>Drug: Pemetrexed<br>* Administered IV.<br>|
| Experimental: Part A: LY3537982 plus Pembrolizumab<br>LY3537982 administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: LY3537982<br>* Administered orally.<br>Drug: Pembrolizumab<br>* Administered IV.<br>|
| Placebo Comparator: Part A: Placebo plus Pembrolizumab<br>Placebo administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Pembrolizumab<br>* Administered IV.<br>Drug: Placebo<br>* Administered orally.<br>|
| Experimental: Part B: LY3537982 plus Pembrolizumab, Pemetrexed, and Platinum<br>LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: LY3537982<br>* Administered orally.<br>Drug: Pembrolizumab<br>* Administered IV.<br>Drug: Cisplatin<br>* Administered IV.<br>Drug: Carboplatin<br>* Administered IV.<br>Drug: Pemetrexed<br>* Administered IV.<br>|
| Placebo Comparator: Part B: Placebo plus Pembrolizumab, Pemetrexed, and Platinum<br>Placebo administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. | Drug: Pembrolizumab<br>* Administered IV.<br>Drug: Placebo<br>* Administered orally.<br>Drug: Cisplatin<br>* Administered IV.<br>Drug: Carboplatin<br>* Administered IV.<br>Drug: Pemetrexed<br>* Administered IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Optimization and Safety Lead-In Part B: Number of Participants with a Treatment Emergent Adverse Event(s) (TEAE) | Dose Optimization and Safety Lead-In Part B: Number of Participants with a TEAE | Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year) | 
| Part A and Part B: Progression-Free Survival (PFS) | PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR) | Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Overall Survival (OS) | Part A and Part B: OS | Randomization to date of death from any cause. (Estimated as up to 3 years) | 
| Part A and Part B: Overall Response Rate (ORR): Percentage of Participants who Achieve a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) | ORR per RECIST v1.1 by BICR | Randomization to disease progression or death. (Estimated as approximately 1 year) | 
| Part A and Part B: Duration of Response (DOR) | DOR per RECIST v1.1 by BICR | Date of first evidence of CR or PR to date of disease progression or death from any cause. (Estimated as approximately 1 year) | 
| Part A and Part B: Disease Control Rate (DCR): Percentage of Participants who Achieve a BOR of CR, PR, or Stable Disease (SD) | DCR per RECIST v1.1 by BICR | Randomization to disease progression or death from any cause. (Estimated as approximately 1 year) | 
| Part A and Part B: Time to Response (TTR) | TTR per RECIST v1.1 by BICR | Time from randomization until the date that measurement criteria for CR or PR (whichever is first recorded) are first met (Estimated as approximately 1 year) | 
| Part A and Part B: PFS2 | Part A and Part B: PFS2 by Investigator | Randomization to disease progression on next line of treatment or death from any cause (Estimated as approximately 1 year | 
| Part A and Part B: Time to Worsening of NSCLC-related Symptoms as Measured by NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ) | NSCLC symptoms will be assessed using the 7-item NSCLC-SAQ. The NSCLC-SAQ measures overall symptom severity of NSCLC, including cough, pain, dyspnea, fatigue, and poor appetite. Response options range from 0) Not at all to 4) Always or from 0) Never to 4) Always. The total score ranges from 0-20. Higher scores represent worse symptoms. | Randomization through end of treatment (Estimated as approximately 1 year) | 
| Part A and Part B: Time to Deterioration in Physical Function, as Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) Physical Functioning Subscale | The EORTC QLQ-C30 is a 30-question patient-reported instrument used to assess multidimensional health-related quality of life (HRQoL) in cancer patients. Physical functioning is measured by the EORTC-QLQ-30 Physical Function Scale (five items). Response options range from 1) Not at all to 4) Very much. The sum score is linearly transformed to the range 0 - 100. Higher scores represent better physical function. | Randomization through end of treatment (Estimated as approximately 1 year) | 
| Part A and Part B: Proportion of Time with High Side-Effect Burden, as Measured by Functional Assessment of Cancer Therapy - General Item 5 (FACT-GP5) | FACT-GP5 is a single-item, patient-reported instrument for assessing overall treatment side-effect burden. Response options range from 0) Not at all to 4) Very much. Higher scores represent higher symptom burden. | Randomization through end of treatment (Estimated as approximately 1 year) | 
| Part A and Part B: Change from Baseline in Overall Health-related Quality of Life, as Measured by the EORTC QLQ-C30 Global Health Status/Quality of Life Subscale | The EORTC QLQ-C30 is a 30-question patient-reported instrument used to assess multidimensional HRQoL in cancer patients. Overall HRQoL is measured by the EORTC QLQ-30 Global Health Status/Quality of Life Subscale (two items). Response options range from 1) very poor to 7) excellent. Scores are linearly transformed to the range 0 - 100. Higher scores represent better overall HRQoL. | Randomization through end of treatment (Estimated as approximately 1 year) |