Olomorasib plus Pembrolizumab for the Treatment KRAS G12C+ Mutant, PD-L1 TPS 1-49% Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
• Age ≥ 18 years at the time of consent
• ECOG of 0-2
• Subjects must have previously untreated, stage IIIB-IIIC or Stage IV nonsquamous NSCLC not amenable to curative intent treatment. Staging determined according to the American Joint Committee on Cancer (AJCC) 8th edition Staging System
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 within 28 days prior to treatment
• Known KRAS G12C mutation identified on tumor tissue or circulating tumor deoxyribonucleic acid (DNA) (ctDNA) as determined by molecular testing performed in a Clinical Laboratory Improvement Act (CLIA), College of American Pathologists (CAP) or other similarly certified laboratory per local guidelines
• Subjects must have a known PD-L1 tumor proportion score (TPS) of 1-49% as determined by an immunohistochemistry (IHC) assay in a CLIA, CAP, or other similarly certified laboratory as per local guidelines
• Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (obtained within 14 days prior to initiating study treatment)
• Platelets ≥ 100 x 10^9/L (obtained within 14 days prior to initiating study treatment)
• Hemoglobin ≥ 9 g/dL (obtained within 14 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained within 14 days prior to initiating study treatment) * Except participants with a documented history of Gilbert’s syndrome who must have a total bilirubin level of ≤ 3.0 x ULN. * Direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN or < 5 x ULN if the liver has tumor involvement (obtained within 14 days prior to initiating study treatment)
• Calculated creatinine clearance ≥ 30 mL/min using a validated method such as estimation via Cockcroft/Gault, Chronic Kidney Disease Epidemiology Collaboration Formula (CKD-EPI), or Modification of Diet in Renal Disease (MDRD) equations OR direct measurement of creatinine clearance in urine (obtained within 14 days prior to initiating study treatment)
• Length of Time Since Prior Therapy: * Palliative limited-field radiotherapy ≥ 7 days (prior to start of study drug) * Brain radiotherapy ≥ 14 days (prior to start of study drug) * Major surgery ≥ 28 days (prior to start of study drug)
• Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to study treatment. * NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 4 months after last dose of pembrolizumab, or 35 days after olomorasib discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of olomorasib and pembrolizumab combination through 4 months after the last dose of pembrolizumab
• Subject is able to swallow oral medication

Exclusion Criteria

• Subject has a serious pre-existing medical condition(s) that, in the judgment of the Investigator, would preclude participation in this study, including interstitial lung disease (ILD) or severe dyspnea at rest and uncontrolled disease-related pericardial effusion or pleural effusion
• Subject has a documented additional validated targetable oncogenic driver mutation or alteration in following genes: EGFR, ALK, BRAF (V600E), HER2, MET (exon 14), ROS1, RET, or NTRK 1/2/3
• 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) or any other absolute contraindication to pembrolizumab. 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
• History of allogenic tissue/solid organ transplant or allogenic stem cell transplant
• Subject must not have had prior systemic therapy (chemotherapy, immunotherapy, or targeted therapy) for treatment of Stage IIIB-IIIC or Stage IV non-squamous NSCLC. Participants who received adjuvant, neoadjuvant, concurrent chemoradiotherapy, or consolidation therapy are eligible provided systemic treatment was completed at least 6 months prior to enrollment. Participants who received a prior inhibitor targeting KRAS are not eligible
• Have known active CNS metastases and/or carcinomatous meningitis. Exceptions: * 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. * 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 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
• Subject has an active fungal, bacterial, and/or active untreated viral infection, including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required unless mandated by local health authority, subjects with well-controlled HIV/hepatitis (HEP) viral infections are permitted)
• Subject has clinically significant, active cardiovascular disease, unstable angina, or history of myocardial infarction within 6 months prior to planned start of olomorasib
• Subject has a prolongation of the QT interval corrected for heart rate of ≥ 470 msec on screening electrocardiogram (ECG) as calculated using Fridericia’s formula (QTcF). If QTcF > 470 msec on more than 1 ECG is obtained during the screening, repeat 2 additional times and use the average of the 3 measurements to determine eligibility. Note that individuals with implanted pacemakers may enter study without meeting QTc criteria due to nonevaluable measurement
• Subject is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial
• Subject has a known allergic reaction against any of the components of study treatments