Summary

This phase III trial compares the effect of adding chemotherapy to immunotherapy (pembrolizumab) versus immunotherapy alone in treating patients with stage IIIB-IV lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab and chemotherapy may help stabilize lung cancer.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate whether there is an improvement in overall survival (OS) with chemotherapy combined with pembrolizumab compared to single agent pembrolizumab in this vulnerable older adult patient population.

SECONDARY OBJECTIVES:
I. To evaluate any difference in progression free survival (PFS) with chemotherapy combined with pembrolizumab as compared to single agent pembrolizumab.
II. To evaluate the difference in PFS rate at 3 months and at 6 months with chemotherapy combined with pembrolizumab as compared to single agent pembrolizumab.
III. To evaluate the difference in best objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to assess whether chemotherapy combined with pembrolizumab results in improved response rates compared to treatment with single agent pembrolizumab.
IV. To evaluate toxicity in those treated with chemotherapy combined with pembrolizumab compared to those treated with single agent pembrolizumab.
V. To evaluate patient reported quality of life (QOL) evaluations between treatment arms.

EXPLORATORY OBJECTIVES:
I. To compare safety and tolerability between treatment arms.
II. To explore factors within the pre-treatment geriatric assessment (GA) as predictors of toxicity and outcomes. To describe changes between the intended chemotherapy treatment planned versus treatment given and referrals placed by treating provider based on GA results.
III. To evaluate the assessment of a novel, composite fPFS score using disease progression/functional impairment assessment as a potential correlate to OS in this vulnerable population.
IV. To evaluate the correlation of 3-months PFS with OS as a potential surrogate of OS benefit.
V. To evaluate the correlation of 6-months PFS with OS as a potential surrogate of OS benefit.
VI. To assess elective dose intensity of chemotherapy of patients who receive doublet chemotherapy versus single agent chemotherapy.

EXPLORATORY CORRELATIVE OBJECTIVE:
I. To relate gut microbe abundances to treatment outcomes, toxicity, and geriatric assessments.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A:

INDUCTION: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 or 42 days for 2 years in the absence of disease progression or unacceptable toxicity.

ARM B:

INDUCTION: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Patients also receive investigator's choice of a chemotherapy regimen: 1) Pemetrexed IV over 10 minutes + carboplatin IV over 30-60 minutes on day 1 of each cycle; 2) Nab-paclitaxel IV over 30 on days 1, 8, and 15 of each cycle + carboplatin IV over 30-60 minutes on day 1 of each cycle; 3) Paclitaxel IV over 1 hour on day 1, 8, and 15 of each cycle or over 3 hours on day 1 of each cycle + carboplatin IV over 30-60 minutes on day 1 of each cycle; 4) Nab-paclitaxel IV over 30 minutes on days 1, 8 and 15 of each cycle; 5) Paclitaxel IV over 3 hours on day 1 of each cycle or over 1 hour on days 1, 8, and 15 of each cycle; or 6) Pemetrexed IV over 10 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 or 42 days for 2 years in the absence of disease progression or unacceptable toxicity.

All patients undergo magnetic resonance imaging (MRI) at baseline and computed tomography (CT) and/or positron emission tomography (PET) on the trial at baseline and throughout the trial.

After completion of study treatment, patients are followed up every 3 months if < 2 years from randomization and every 6 months if 2-5 years from Step 1 registration.

Eligibility

1. STEP 1 REGISTRATION
2. Patient must be = 70 years of age
3. Patient must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with PD-L1 Tumor Proportion Score (TPS) range of 1-49%
4. Patient must have Stage IIIB, IIIC or IV disease and not be candidates for combined chemo-radiation. NOTE: Prior chemo-radiation therapy (RT) for stage III with recurrence is allowed
5. Patient must have a tumor that is negative for EGFR mutation/ALK translocations or other actionable first line mutations in which patients would receive first-line oral tyrosine kinase inhibitors
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2
7. Patient must agree not to father children while on study and for 6 months after the last dose of protocol treatment
8. Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
9. Absolute neutrophil count (ANC) = 1,500/uL (obtained within 14 days prior to Step 1 registration)
10. Platelets = 75,000/uL (obtained within 14 days prior to Step 1 registration)
11. Hemoglobin (Hgb) = 8.0 g/dL (obtained within 14 days prior to Step 1 registration)
12. Total bilirubin = 1.5 x institutional upper limit of normal (ULN) (obtained within 14 days prior to Step 1 registration)
13. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) = 3.0 × institutional ULN (obtained within 14 days prior to Step 1 registration)
14. Creatinine clearance (CrCL) = 45 mL/min (estimated using Cockcroft-Gault method with actual body weight or measured) (obtained within 14 days prior to Step 1 registration)
15. Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months of Step 1 registration are eligible for this trial
16. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
17. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have undetectable HCV viral
18. 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
19. Patient must be English or Spanish speaking to be eligible for the QOL component of the study * NOTE: Sites cannot translate the associated GA or QOL forms
20. Patient must not have symptomatic central nervous system disease (CNS) metastases. Patients with a clinical history of CNS metastases or cord compression are eligible if they have been definitively treated and are clinically stable for at least 14 days prior to Step 1 registration and off all steroids for at least 24 hours prior to Step 1 registration. Patients with asymptomatic CNS metastases are eligible
21. Patient must not have had any prior cytotoxic chemotherapy regimen for metastatic disease. Chemotherapy given in the setting of adjuvant therapy or locally advanced disease is allowed as long as treatment was completed, and they have fully recovered from treatment related adverse events prior to Step 1 registration
22. Patient must not have had any prior immunotherapy for metastatic disease. Immunotherapy given in the setting of adjuvant therapy or locally advanced disease is allowed as long as treatment was completed greater than 6 months prior to Step 1 registration
23. Patient must not have a history of uncontrolled autoimmune conditions with the following exceptions, which are allowed: alopecia, vitiligo, rheumatoid arthritis, psoriasis/psoriatic arthritis, Hashimoto’s thyroiditis, lupus, inflammatory bowel disease
24. Patient must not be on immunosuppressive medication, including steroids (if doses exceed the equivalent of prednisone 10 mg daily). Short courses of steroids which are discontinued prior to randomization are acceptable. Patients on inhaled, intranasal and/or topical steroids are eligible
25. Patient must have baseline imaging done assessing all measurable or non-measurable sites of disease within 45 days prior to Step 1 registration
26. Investigator must declare their intended chemotherapy regimen should their patient be randomized to Arm B (doublet versus[vs] singlet)
27. STEP 2 RANDOMIZATION
28. Patient must have completed the baseline Geriatric Assessment (GA) after Step 1 registration and prior to Step 2 randomization

Treatment Sites in Georgia