This is a Phase 1/1b, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical activity of etrumadenant in combination with carboplatin/pemetrexed with or without an anti PD-1 antibody (pembrolizumab or zimberelimab), in participants with non-squamous Non-Small Cell Lung Cancer (NSCLC).
Objectives is to evaluate the safety and tolerability of etrumadenant combination therapy in participants with non-small cell lung cancer (NSCLC).
Trial methods
1)Dose-escalation Phase
-Arm A: Participants will receive etrumadenant orally QD at escalating doses in combination with standard doses of carboplatin/pemetrexed. 
-Arm B: Participants will receive etrumadenant orally QD at escalating doses in combination with standard doses of carboplatin/pemetrexed and pembrolizumab. 
2) Dose-expansion Phase
- Arm 1: Participants will receive zimberelimab in combination with carboplatin/pemetrexed. 
-Arm 2: Participants will receive etrumadenant in combination with carboplatin/pemetrexed and zimberelimab at the RDE determined during dose escalation in Arm B.

Treatment

Drug: Etrumadenant (AB928), Carboplatin, Pemetrexed, Pembrolizumab, Zimberelimab (AB122)
Dose escalation of etrumadenant in combination with carboplatin/pemetrexed and etrumadenant in combination with carboplatin/pemetrexed plus pembrolizumab at standard doses will be assessed in participants with advanced metastatic non-squamous Non-Small Cell Lung Cancer. In this dose escalation combination study, participants will receive oral administration of etrumadenant as well as IV infused carboplatin/pemetrexed with or without pembrolizumab.
Dose expansion of zimberelimab in combination with carboplatin/pemetrexed and AB928 in combination with carboplatin/pemetrexed plus zimberelimab at standard doses may be assessed in participants with advanced metastatic non-squamous Non-Small Cell Lung Cancer. The dose of AB928 used will be determined based on the findings from the dose escalation phase.
Overall duration of treatment will depend on how well the treatment is tolerated.
Treatment may continue until unacceptable toxicity or progressive disease or other reasons specified in the protocol.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. The dose expansion dose level will be determined in this part with escalating doses of etrumadenant in combination with standard doses of carboplatin/pemetrexed chemotherapy regimen in participants with Non-Small Cell Lung Cancer

Arm Label

Target Number of Participant

Arm Type

Arm Description

Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. The dose expansion dose level will be determined in this part with escalating doses of etrumadenant in combination standard doses of carboplatin/pemetrexed chemotherapy regimen and pembrolizumab in participants with Non-Small Cell Lung Cancer.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Zimberelimab will be administered in combination with standard carboplatin/pemetrexed chemotherapy regimen in participants with Non-Small Cell Lung Cancer.

Arm Label

Target Number of Participant

Arm Type

Arm Description

The dose administered in expansion will be determined during dose escalation. Etrumadenant will be administered in combination with standard carboplatin/pemetrexed chemotherapy regimen and zimberelimab in participants with Non-Small Cell Lung Cancer.

Gender

Age

Description

1. Male or female participants; age ≥ 18 years
2. Pathologically confirmed nonsquamous NSCLC that is metastatic, locally advanced, or recurrent with progression.
3. Arm 1 and Arm 2 participants must have a sensitizing epidermal growth factor receptor (EGFR) mutation with disease progression or treatment intolerance after one or more approved TKIs. Previous treatment with chemotherapy or PD-1/L1 therapy is not allowed.
4. No TKI therapy within 5 days of Cycle 1 Day 1
5. The last dose of previous investigational therapy is at least 4 weeks or 5 half-lives prior to Cycle 1 Day 1
6. Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
8. Confirm that an archival tissue sample is available and ≤ 24 months old; if not, a new biopsy of a tumor lesion must be obtained at screening.
9. Adequate organ and marrow function

1. Use of any live vaccines against infectious diseases within 4 weeks (28 days) of initiation of investigational product.
2. Underlying medical conditions that, in the Investigator's or Sponsor's opinion, will make the administration of investigational product(s) hazardous
3. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
4. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 90 days after the last dose of etrumadenant or zimberelimab, or 6 months after the last dose of pemetrexed or carboplatin, whichever is longer.
5. 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.
6. 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.
7. Prior use of an adenosine pathway targeting agent.
8. Due to potential for drug-drug interactions with etrumadenant, participants must not have had:
- Treatment with breast cancer resistance protein substrates (BCRP) or P-glycoprotein (P-gp) with a narrow therapeutic window, administered orally within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
- Treatment with known strong cytochrome P450 3A4 (CYP3A4) inducers and strong CYP3A4 inhibitors within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.

Percentage of Participants with Adverse Events

From first study treatment administration until up to 90 days after the last dose (Approximately 1 year)

Percentage of participants who experience a Dose Limiting Toxicity

From first study treatment administration through Day 21

Percentage of Participants with Disease Control (complete response, partial response, or stable disease) for >6 months

From study enrollment until disease progression or loss of clinical benefit (up to app. 3-5 years)

Percentage of participants with Objective Response

From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (up to approximately 3-5 years)

Percentage of participants with anti-drug antibodies to zimberelimab

Recorded at Baseline (Screening), during the first 4 cycles of treatment (4 months) and 30 days post last dose (i.e. in total approximately 5 months)

Progression Free Survival (PFS)

From start of treatment up to the first occurrence of progressive disease or death from any cause, whichever occurs first (up to approximately 3-5 years)

Plasma concentration of etrumadenant

Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 days post last dose (i.e. in total approximately 5 months)

Serum concentration of zimberelimab

Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 days post last dose (i.e. in total approximately 5 months)

Overall Survival (OS)

From study start of treatment up to death from any cause (up to approximately 3-5 years)

Duration of Response

From the date of first occurrence of a documented objective response to first documentation of disease progression or death from any cause, whichever occurs first (up to app. 3-5 years)