The study is an open-label, randomized clinical trial comparing the efficacy of adagrasib administered in combination with pembrolizumab versus pembrolizumab alone in the first-line treatment setting in patients with advanced NSCLC (squamous or nonsquamous) with KRAS G12C mutation and PD-L1 ≥ 50%. Secondary and exploratory objectives include evaluation of secondary efficacy endpoints, safety and tolerability, adagrasib PK, PROs, and correlative genomic biomarkers for the combination regimen in the study population.

• Patients will be randomized 1:1 to:

Investigational arm (cohort 3): adagrasib 300 mg BID + pembrolizumab 200 mg Q3W
Comparator arm (cohort 4): pembrolizumab 200 mg Q3W

• Randomization will be stratified by:

1. Known history of treated or untreated metastases
2. ECOG performance score
3. Region

• Study treatment will be expressed in 3-week cycles.
• The presence of KRAS G12C mutation and PD-L1 ≥ 50% for the purpose of patient eligibility must be established using sponsor-approved local or central test.
• Adagrasib will be administed orally on a continuous basis at a starting dose of 400 mg BID.
• Pembrolizumab will be administer by IV infusion.
• Disease progression will be monitored through RECIST v1.1

• Histologically or cytologically confirmed diagnosis of NSCLC (squamous or nonsquamous) with KRAS G12C mutation and PD-L1 ≥ 50% confirmed using sponsor-approved testing
• Unresectable or metastatic disease
• Not a candidate for definitive therapy
• Measurable disease per RECIST v1.1
• A representative tumor specimen (histology!)
• Life expectancy of at least 3 months
• Recovery from the AE of prior locoregional therapy to baseline or Grade 1 (excluding alopecia)
• ECOG 1 or 1
• No evidence of brain metastases (untreated symptomatic brain metastases ≤ 2.0 cm no needing immediate local therapy) or previously treated brain metastases not needing immediate local therapy

• Prior systemic treatment for locally advanced or metastatic NSCLC including chemotherapy, immune CIT or a therapy targeting KRAS G12C mutation.
• Radiation to the lung > 30 Gy within 6 months prior to first dose of study treatment
• Patients with known CNS lesion must not have any of the following:
  • Any untreated or symptomatic brain lesions > 2.0 cm in size
  • Any brainstem lesions
  • Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a total daily dose of >10 mg of prednisone
  • Poorly controlled generalize or complex partial seizures, or manifest neurologic progression due to brain lesions notwithstanding CNS-directed therapy
• Carcinomatous meningitis
• Active or prior documented autoimmune or inflammatory disease
• Immunocompromising conditions
• Receipt of a live vaccine within 30 days prior to first dose of study treatment
• Known severe hypersensitivity to study drugs and/or any of its excipients
• Known HIV, HBV or HBC infection
• Major surgery within 4 weeks prior to first dose of study treatment
• History of intestinal disease or major gastric surgery, likely to alter absorption of study treatment
• Cardiac abnormalities
• History or stroke or transient ischemic attack within 6 months prior to first dose
• Ongoing need for treatment with concomitant medication known to cause prolonged Qtc interval
• Known or suspected presence of another malignancy
• Pregnancy, breastfeeding
• Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history which could interfere with the patient’s participation in the study.