Risk-Adapted, Proteomic-Guided (PROphet CB, and CARG-TT) Systemic Therapy for the Treatment of Previously Untreated Unresectable or Metastatic Non-small Cell Lung Cancer

PRIMARY OBJECTIVE:

I. To evaluate 12-month progression free survival (PFS) of systemic therapy informed by PROphet CB and CARG-TT (intervention arm) versus standard of care systemic therapy.

SECONDARY OBJECTIVES:

I. To evaluate treatment-related adverse events of systemic therapy informed by PROphet CB and CARG-TT (intervention arm) versus standard of care systemic therapy.

II. To evaluate time to treatment discontinuation of systemic therapy informed by PROphet CB and CARG-TT (intervention arm) versus standard of care systemic therapy.

III. To evaluate overall PFS of systemic therapy informed by PROphet CB and CARG-TT (intervention arm) versus standard of care systemic therapy.

IV. To evaluate overall survival (OS) among participants treated with systemic therapy informed by PROphet CB and CARG-TT (intervention arm) versus standard of care systemic therapy.

EXPLORATORY OBJECTIVES:

I. To evaluate the performance of the PROphet immune-related adverse event (irAE assay) assay for predicting irAE risk in both arms.

II. To evaluate the performance of PROphet chemotherapy risk assay for predicting chemotherapy risk in both arms.

III. To evaluate the performance of CARG-TT clinical chemotherapy toxicity tool for predicting chemotherapy risk in both arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (INTERVENTION): Patients undergo PROphet CB and CARG-TT testing and are assigned to a treatment based on immune checkpoint inhibitor (ICI) benefit and chemotherapy toxicity risk.

Patients with a lower likelihood of benefit and high risk for toxicity are assigned to 1 of 2 treatments. Patients with PD-L1 ≥ 50% are assigned to Treatment I and patients with PD-L1 < 50% are assigned to Treatment II.

TREATMENT I (ICI AND DOSE-REDUCED CHEMOTHERAPY): Patients receive carboplatin, pemetrexed, and pembrolizumab or carboplatin, pemetrexed, and cemiplimab or carboplatin, paclitaxel and pembrolizumab or carboplatin, paclitaxel and cemiplimab in the absence of disease progression or unacceptable toxicity.

TREATMENT II (DUAL ICI): Patients receive nivolumab and ipilimumab in the absence of disease progression or unacceptable toxicity.

Patients with a lower likelihood of benefit and low to intermediate risk for toxicity are assigned to 1 of 2 treatments. Patients with PD-L1 ≥ 50% are assigned to Treatment III and patients with PD-L1 < 50% are assigned to Treatment IV.

TREATMENT III (ICI AND STANDARD DOSE CHEMOTHERAPY): Patients receive carboplatin, pemetrexed and pembrolizumab or carboplatin, pemetrexed and cemiplimab or carboplatin, paclitaxel and pembrolizumab or carboplatin, paclitaxel and cemiplimab in the absence of disease progression or unacceptable toxicity.

TREATMENT IV (DUAL ICI AND STANDARD DOSE CHEMOTHERAPY): Patients receive nivolumab, ipilimumab, carboplatin and pemetrexed or durvalumab, tremelimumab, carboplatin and pemetrexed or nivolumab, ipilimumab, carboplatin and paclitaxel or durvalumab, tremelimumab, carboplatin and gemcitabine or durvalumab, tremelimumab, carboplatin, and albumin-bound paclitaxel in the absence of disease progression or unacceptable toxicity.

Patients with a higher likelihood of benefit and high risk for toxicity are assigned to 1 of 2 treatments. Patients with PD-L1 ≥ 50% are assigned to Treatment V, patients with PD-L1 < 1% are assigned to Treatment VI and patients with PD-L1 1-49% are assigned to Treatment VII.

TREATMENT V (ICI): Patients receive pembrolizumab or atezolizumab or cemiplimab in the absence of disease progression or unacceptable toxicity.

TREATMENT VI (DUAL ICI): Patients with PD-L1 < 1% receive nivolumab and ipilimumab in the absence of disease progression or unacceptable toxicity.

TREATMENT VII (ICI): Patients with PD-L1 1-49% receive pembrolizumab or atezolizumab or cemiplimab in the absence of disease progression or unacceptable toxicity.

Patients with a higher likelihood of benefit and low to intermediate risk for toxicity are assigned to 1 of 2 treatments. Patients with PD-L1 ≥ 50% are assigned to Treatment VII, patients with PD-L1 < 50% are assigned to Treatment IX.

TREATMENT VIII (ICI): Patients with PD-L1 ≥ 50% receive pembrolizumab or atezolizumab or cemiplimab in the absence of disease progression or unacceptable toxicity.

TREATMENT IX (ICI AND STANDARD DOSE CHEMOTHERAPY): Patients receive carboplatin, pemetrexed and pembrolizumab or carboplatin pemetrexed and cemiplimab or carboplatin, paclitaxel and pembrolizumab or carboplatin, paclitaxel and cemiplimab in the absence of disease progression or unacceptable toxicity.

ARM II (STANDARD OF CARE): Patients are assigned to 1 of 2 treatments types per treating investigator discretion.

TREATMENT X (ICI MONOTHERAPY): Patients receive pembrolizumab, atezolizumab or cemiplimab in the absence of disease progression or unacceptable toxicity.

TREATMENT XI (ICI AND CHEMOTHERAPY): Patients receive carboplatin, pemetrexed and pembrolizumab or carboplatin, pemetrexed and cemiplimab or carboplatin, paclitaxel and pembrolizumab or carboplatin, paclitaxel and cemiplimab in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo blood sample collection and radiographic imaging throughout the study.

After completion of study treatment, patients are followed every 6 months for up to 5 years.