Carfilzomib in Combination With Sotorasib for the Treatment of Patients With KRAS G12C Mutated Advanced or Metastatic Non-small Cell Lung Cancer

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Histologically confirmed NSCLC that is metastatic or advanced. The tumor mustexhibit evidence of KRASG12C mutation which is determined by either a ClinicalLaboratory Improvement Act (CLIA) certified ctDNA assay or by a CLIA certified tumortissue assay

• Measurable disease by RECIST v1.1

• Failed prior KRAS inhibitor

• Fully recovered from the acute toxic effects (except alopecia) from prioranti-cancer therapy

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate central nervous system (CNS) specific treatment is not required and isunlikely to be required during the first cycle of therapy

• Absolute neutrophil count (ANC) ≥ 1,500/mm^3 (performed within 14 days prior to day 1 of protocol therapy)

• NOTE: Growth factor is not permitted within 14 days of ANC assessment unlesscytopenia is secondary to disease involvement

• Hemoglobin (Hb) ≥ 9 g/dL (performed within 14 days prior to day 1 of protocoltherapy)

• Platelets ≥ 100,000/mm^3 (performed within 14 days prior to day 1 of protocoltherapy)

• NOTE: Platelet transfusions are not permitted within 14 days of plateletassessment unless cytopenia is secondary to disease involvement

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 14 days prior to day 1 of protocol therapy)

• Aspartate aminotransferase (AST) ≤ 3 x ULN (or ≤ 5 x ULN in the setting of livermetastatic disease) (performed within 14 days prior to day 1 of protocol therapy)

• Alanine aminotransferase (ALT) ≤ 5 x ULN (or ≤ 5 x ULN in the setting of livermetastatic disease) (performed within 14 days prior to day 1 of protocol therapy)

• Creatinine clearance of ≤ 1.5 x ULN or glomerular filtration rate (GFR) ≥ 60mL/min/1.73 m^2 (performed within 14 days prior to day 1 of protocol therapy)

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (performed within 14 days prior to day 1 of protocol therapy)

• If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 120 days after the last dose of protocol therapy.

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Chemotherapy or immunotherapy within 21 days prior to day 1 of protocol therapy

• Radiation therapy within 14 days prior to day 1 of protocol therapy

• KRAS inhibitor within 14 days prior to day 1 of protocol therapy

• Investigational therapy within 28 days prior to day 1 of protocol therapy (or 5half-lives, use whichever is shorter)

• Inability to previously tolerate (240 mg, QD) sotorasib

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agent

• Clinically significant uncontrolled illness

• Evidence of chronic hepatitis B virus (HBV) infection and HBV viral load detectable

• Evidence of untreated chronic hepatitis C virus (HCV) infection. Patients with HCVinfection currently on treatment are eligible if they have an undetectable HCV viralload

• Active infection requiring antibiotics (not to be completed by day 1 of protocoltherapy)

• Known history of immunodeficiency virus (HIV) with detectable viral load

• Prior or concurrent malignancy whose natural history or treatment has the potentialto interfere with the safety or efficacy assessment of the investigational regimen

• New York Heart Association (NYHA) class III or IV heart failure, myocardialinfarction in the preceding 6 months, conduction abnormalities uncontrolled bymedications

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)