Safety and Efficacy of Zimberelimab (AB122) in Combination With Domvanalimab (AB154) and Etrumadenant (AB928) in Patients With Previously Treated Non-Small Cell Lung Cancer

Inclusion Criteria:

• Histologically confirmed metastatic squamous or non-squamous non-small cell lungcancer.

• Previously treated with at least one line of therapy including an immune checkpointblocker and no more than 2 prior lines in the metastatic setting.

• Documented PD-L1 expression of at least 1% by a US FDA-approved PD-L1 assay or usingthe clone 22C3 antibody from archival biopsy or fresh tumor tissue.

• At least one measurable lesion per RECIST 1.1 criteria.

• At least 18 years of age.

• ECOG performance status ≤ 1.

• Normal bone marrow and organ function as defined below:

• Absolute neutrophil count ≥ 1,500/µL

• Platelets ≥ 100,000/µL

• Hemoglobin ≥ 9.0 g/dL

• Total bilirubin ≤ 2.0 x IULN (except participants with Gilbert's syndrome whomust have total bilirubin < 3.0 mg/dL)

• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN without hepatic metastasis and ≤ 5.0 x IULNwith hepatic metastasis

• Creatinine ≤2 x ULN or Creatinine clearance calculated by Cockcroft-Gaultformula ≥45 ml/min

• Patients with brain or meningeal metastases are eligible provided they meet thefollowing criteria:

• No evidence of progression by neurologic symptoms or signs for at least 4 weeksprior to first dose of study treatment

• Metastatic brain lesions that do not require immediate intervention

• No use of corticosteroids with dose above 10 mg prednisone (or equivalent)

• The effects of the study drugs on the developing human fetus are unknown. For thisreason, women of childbearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control, abstinence) prior tostudy entry, for the duration of study participation, and for 100 days aftercompletion of study treatment. Should a woman become pregnant or suspect she ispregnant while participating in this study, she must inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of the study, and 100days after completion of study treatment.

• Ability to understand and willingness to sign an IRB approved written informedconsent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• A history of other malignancy with the exception of:

• Malignancies for which all treatment was completed at least 2 years beforeregistration and the patient has no evidence of disease.

• Carcinoma of the skin without melanomatous features.

• Patients with actionable EGFR mutation, ALK rearrangement, ROS1 fusion or RET fusionare excluded from the study.

• Currently receiving any other investigational agents or having received anyinvestigational agents within 28 days or 5 half-lives of first dose of trialtreatment.

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to zimberelimab, domvanalimab, etrumadenant, or other agentsused in the study. Known hypersensitivity to recombinant proteins or any excipientcontained in the trial formulations.

• Use of any live vaccines against infectious diseases within 28 days of first dose oftrial treatment.

• Any gastrointestinal condition that would preclude the use of oral medications (e.g.difficulty swallowing, nausea, vomiting, or malabsorption).

• History of trauma or major surgery within 28 days prior to the first dose of studytreatment.

• Underlying medical conditions that in the investigator's opinion will make theadministration of study treatment hazardous, including but not limited to:

• Interstitial lung disease, including history of interstitial lung disease ornoninfectious pneumonitis

• Active viral, bacterial or fungal infection requiring parenteral treatmentwithin 14 days of the initiation of study treatment

• Clinically significant cardiovascular disease

• A condition that may obscure the interpretation of toxicity determination orAEs

• History of prior solid organ transplantation

• Concurrent medical condition requiring the use of supra-physiologic doses ofcorticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressivemedications (with the exception of absorbable topical corticosteroids).

• Positive test results for hepatitis B surface antigen, hepatitis C virus antibody,hepatitis C qualitative RNA, or human immunodeficiency virus-1 antibody atscreening.

• Known psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the trial.

• Any active autoimmune disease or documented history of autoimmune disease orsyndrome that required systemic treatment in the past 2 years (i.e. with use ofdisease-modifying agents, corticosteroids, or immunosuppressive drugs) except forvitiligo or resolved childhood asthma/atopy.

• Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency) is not considered aform of systemic treatment

• Participants with asthma who require intermittent use of bronchodilators,inhaled corticosteroids, or local corticosteroid injections will not beexcluded from this study. Participants on chronic systemic corticosteroids willbe excluded.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativepregnancy test within 14 days of study entry.

• Due to the potential risk for drug-drug interactions with etrumadenant, participantsmust not have had:

• Oral treatment with strong inhibitors of breast cancer resistance protein (BCRP) (e.g., cyclosporin A, eltrombopag) or BRCP substrates with a narrowtherapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4weeks or 5 drug-elimination half-lives of the drug (whichever is longer) priorto initiation of study treatment.

• Oral treatment with strong inhibitors of P-glycoprotein (P-gp) substrates (e.g., itraconazole, quinidine, verapamil, dronedarone, ranolazine) or P-gpwith a narrow therapeutic window, administered orally (e.g., digoxin) within 4weeks or 5 drug-elimination half-lives of the drug (whichever is longer) priorto initiation of study treatment.

• Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin,carbamazepine, phenobarbital, and St. John's Wort) or strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole,posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 half-livesof the drug (whichever is longer) prior to initiation of study treatment.

• Treatment with known strong UDP-glucuronosyltransferases (UGTs) of UGT1A1, 1A4, 1A9 and 2B4 inhibitors (e.g., atazanavir) within 4 weeks or 5 half-lives of thedrug, whichever is longer, prior to the initiation of study treatment

• Treatment with known sensitive substrates of BSEP within 4 weeks or 5half-lives of the drug, whichever is longer, prior to the initiation ofstudy treatment

• Treatment with known sensitive substrates of OCT2 within 4 weeks or 5half-lives of the drug, whichever is longer, prior to the initiation ofstudy treatment

• Treatment with known sensitive substrates of MATE1 within 4 weeks or 5half-lives of the drug, whichever is longer, prior to the initiation ofstudy treatment