NCT06119581 - A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 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.

Outcomes

Primary Outcomes

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

Time frame: 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)

Time frame: Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year)

Secondary Outcomes

Part A and Part B: Overall Survival (OS)

Part A and Part B: OS

Time frame: Randomization to date of death from any cause. (Estimated as up to 3 years)

Part A and Part B: PFS

PFS per RECIST v1.1 by investigator

Time frame: Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year)

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 and Investigator

Time frame: 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 and Investigator

Time frame: 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 and Investigator

Time frame: 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 and Investigator

Time frame: 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: Intracranial Overall Response Rate (ORR)

Intracranial ORR per Modified RECIST (mRECIST) by BICR

Time frame: Randomization to intracranial disease progression or death. (Estimated as approximately 1 year)

Part A and Part B: Intracranial Duration of Response (DoR)

Intracranial DoR per mRECIST by BICR

Time frame: Date of first evidence of CR or PR to date of intracranial disease progression or death from any cause. (Estimated as approximately 1 year)

Part A and Part B: PFS2

Part A and Part B: PFS2 by Investigator

Time frame: Randomization to disease progression on next line of treatment or death from any cause (Estimated as approximately 1 year

Part A and Part B: Changes in NSCLC-related symptoms as measured by NSCLC-SAQ

NSCLC-related symptoms are assessed by the NSCLC-SAQ total score, which is computed as the sum of the 5 domains (7 questions) and ranges from 0 to 20. The total score will be calculated if all 7 questions are completed. Higher scores indicate more severe symptomatology.

Time frame: Randomization through end of treatment (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.