Izalontamab Brengitecan and Adagrasib for the Treatment of KRAS G12C Mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer Refractory to KRAS G12C Inhibitors, IZA-A Trial

Inclusion Criteria

• Patients must have histologically or cytologically confirmed diagnosis of NSCLC or NSCLC predominant histology
• Patients must have a diagnosis of metastatic or locally advanced NSCLC not amenable to curative therapy
• Tumor must harbor a KRAS G12C mutation. Testing available through multigene NGS panels performed in the Molecular Diagnostics Laboratory in University of Texas (UT) MD Anderson Cancer Center and can be performed using either tissue or blood assays. Use of standard of care (SOC) results are allowed to meet this requirement
• Patients must have progressed on a prior KRAS G12C inhibitor as monotherapy or as combination therapy
• Patients must have received at least one prior line of therapy and up to 3 prior lines of therapy
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Age ≥ 18 years - no dosing or adverse event data are currently available on the use of izabren and adagrasib in patients < 18 years of age; children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or, investigational agent) discontinued at least 2 weeks before first dose date
• Most recent radiation treatment discontinued at least 1 week prior to first dose date (includes brain radiation)
• Hemoglobin ≥ 9.0g/dL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ institutional upper limit of normal (ULN) (if associated with liver metastases or Gilbert's disease, ≤ 3 x ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (if associated with liver metastases, ≤ 5 x ULN)
• Creatinine ≤ 1.5 mg/dL or creatinine clearance (CrCl) ≥ 45 mL/min (calculated using a validated prediction equation - e.g., Cockcroft-Gault, Modification of Diet in Renal Disease Formula [MDRD], or 24-hour urine CrCl)
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable
• Patients with a history of hepatitis C virus (HCV) infection must have documentation of undetectable HCV viral load
• Patients with treated brain metastases are eligible if patients are neurologically stable for at least 1 week prior to the first dose of study treatment without the use of corticosteroids or are on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent)
• Patients 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
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Because adagrasib and iza-bren are known to be teratogenic, women of child-bearing potential (WCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 (men) and 7 (WCBP) months after completion of study treatment administration. This includes all female patients less than 55 years of age unless the patient presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months) * History of hysterectomy or bilateral salpingo-oophorectomy * Ovarian failure (follicle stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy) * History of bilateral tubal ligation or another surgical sterilization procedure
• Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal Ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of study treatment administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) except for alopecia and parameters superseded by other eligibility criteria (e.g., laboratory parameters)
• Patients who are receiving any other investigational agents
• Patients with active untreated brain metastases or carcinomatous meningitis
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to adagrasib and iza-bren
• Patients with prior history of pneumonitis or interstitial lung disease. Patients with prior history of radiation pneumonitis which was asymptomatic or resolved with steroid treatment, and without evidence of clinically active radiation pneumonitis are eligible
• Human immunodeficiency virus (HIV)-infected patients. Those on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant and actively breastfeeding woman due to concerns for teratogenicity and infant toxicity
• 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 or inability to swallow oral medications
• Prolonged corrected QT (QTc) interval (> 470 milliseconds for women and > 450 milliseconds for men), or immediate family or medical history of congenital long QT syndrome
• History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment
• History of unstable angina, myocardial infarction, and symptomatic atrial fibrillation within 6 months prior to first dose of study treatment
• Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the investigator’s opinion, would be likely to interfere with the patient’s participation in the study, or with the interpretation of the results