Non Small Cell Lung Cancer

Primary Objectives: To determine the response to treatment with AB122 monotherapy, AB154 in combination with AB122, and AB154 in combination with AB122 and AB928 Secondary Objectives: 1. To determine the clinical activity of AB122 monotherapy, AB154 in combination with AB122, and AB154 in combination with AB122 and AB928 2. To assess the safety and tolerability of AB122 monotherapy, AB154 in combination with AB122, and AB154 in combination with AB122 and AB928 3. To describe the pharmacokinetic (PK) profile of AB122, AB154, and AB928 per treatment arm 4. To describe the immunogenicity of AB122 and AB154.

AB122, AB154 and AB928

AB122
AB154
AB928

IVT
IVT
capsule

30mg / mL
20mg / mL
25mg / mL

Primary Outcome Measures :
Objective response rate (ORR) [ Time Frame: From randomization until death from any cause (up to approximately 3-5 years) ]
ORR as assessed by RECIST v1.1

Progression-free survival (PFS) [ Time Frame: From randomization until death from any cause (up to approximately 3-5 years) ]
PFS as assessed by RECIST v1.1


Secondary Outcome Measures :
Duration of response (DoR) [ Time Frame: From the date of first occurence of a documented objective response to first documentation of disease progression or death from any cause, whichever occurs first (up to approximately 3-5 years) ]
DoR as assessed by RECIST v1.1

Disease control rate (DCR) [ Time Frame: From the date of first occurence of a documented objective response to first documentation of disease progression on death from any cause, whichever occurs first (up to approximately 3-5 years) ]
DCR as assessed by RECIST v1.1

Adverse Events [ Time Frame: From Screening until up to 100 days after the last dose (approximately 2 years) ]
The number and percentage of participants that experience an adverse event (AE)

Pharmacodynamics of zimberelimab [ Time Frame: Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, 60 and 100 days post last dose (in total, an average of 2 years). ]
Plasma concentration of zimberelimab

Pharmacodynamics of domvanalimab [ Time Frame: Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, 60 and 100 days post last dose (in total, an average of 2 years). ]
Plasma concentration of domvanalimab

Pharmacodynamics of etrumadenant [ Time Frame: Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, 60 and 100 days post last dose (in total, an average of 2 years). ]
Plasma concentration of etrumadenant

Immunogenicity of zimberelimab [ Time Frame: Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, and 100 days post last dose (in total, an average of 2 years). ]
Percentage of participants who develop treatment-emergent anti-drug antibodies to zimberelimab

Immunogenicity of domvanalimab [ Time Frame: Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, and 100 days post last dose (in total, an average of 2 years). ]
Percentage of participants who develop treatment-emergent anti-drug antibodies to domvanalimab

1. Male or female participants; age ≥ 18 years, or regionally approved age of consent, at the time of screening.
2. Willing and able to comply with the requirements and restrictions in this protocol.
3. Histologically confirmed, treatment naïve, metastatic squamous or non-squamous NSCLC with documented high PD-L1 expression (TPS ≥ 50% by PharmDx 22C3 or tumor cell membrane ≥ 50% by Ventana SP263) as determined by a US FDA-approved PD-L1 assay, with no EGFR or ALK genomic tumor aberrations.
4. ECOG PS of 0-1
5. At least 1 measurable lesion per RECIST v1.1
6. Adequate organ and marrow function, as defined below:
a. Neutrophils ≥ 1500/μL
b. Platelets ≥ 100 x 103/μL
c. Hemoglobin ≥ 9.0 g/dL
d. Aspartate aminotransferase ≤ 2.5 x upper limit of normal (ULN) without hepatic metastasis and ≤ 5 x ULN with hepatic metastasis
e. Alanine aminotransferase ≤ 2.5 x ULN without hepatic metastasis and ≤ 5 x ULN with hepatic metastasis
f. Bilirubin ≤ 2 x ULN (except participants with Gilbert’s syndrome who must have total bilirubin < 3.0 mg/dL)
7. If a participant has brain or meningeal metastases, the participant must meet the following criteria:
a) Have no evidence of progression by neurologic symptoms or sign for at least 4 weeks prior to the first dose.
b) Metastatic brain lesions that do not require immediate intervention.
c) Carcinomatous meningitis is excluded regardless of clinical stability.
8. Women of childbearing potential (WOCBP), defined as not surgically sterilized and between menarche and 1-year post menopause, must have a negative serum or urine pregnancy test.
9. WOCBP and male participants with WOCBP sexual partners must agree to use highly effective methods of contraception from the time of consent through 100 days after the last dose of IP. Contraceptive requirements may be extended depending on local regulatory requirements.
10. WOCBP must not be breast feeding.

1. Use of any live vaccines against infectious diseases within 28 days of first dose of IP(s).
2. Any gastrointestinal condition that would preclude the use of oral medications (eg, difficulty swallowing, nausea, vomiting, or malabsorption).
3. History of trauma or major surgery within 28 days prior to the first dose of IP.
4. Underlying medical conditions that, in the Investigator’s or Sponsor’s opinion, will make the administration of IP(s) hazardous, including but not limited to
a. Interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis,
b. Active viral, bacterial or fungal infections requiring parenteral treatment within 14 days of the initiation of the IP,
c. Clinically significant cardiovascular disease,
d. A condition that may obscure the interpretation of toxicity determination or AEs,
e. History of prior solid-organ transplantation.
5. Concurrent medical condition requiring the use of supra-physiologic doses of corticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressive medications (absorbable topical corticosteroids are not excluded).
6. Positive test results for hepatitis B surface antigen, hepatitis C virus antibody or hepatitis C qualitative RNA or human immunodeficiency virus-1 antibody at screening
7. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
8. Has significant dementia or other mental condition that precludes the participant’s ability to consent to the study.
9. Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy.
a. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
b. Participants with asthma who require intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections will not be excluded from this study. Participants on chronic systemic corticosteroids will be excluded from the study.
10. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer.
11. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of IP.
12. Known hypersensitivity to recombinant proteins, or any excipient contained in the IP formulations.