Testing the Addition of a Type of Drug Called Immunotherapy to the Usual Chemotherapy Treatment for Non-small Cell Lung Cancer, ALCHEMIST Chemo-IO Study

Inclusion Criteria

• Previously registered to A151216
• Central and/or local testing of EGFR with no EGFR exon 19 deletion or EGFR L858 R mutation (applicable to non-squamous patients only)
• Central and/or local testing of ALK with no ALK rearrangement (failed testing is considered negative) (applicable to non-squamous patients only)
• Central and/or local testing of PD-L1 immunohistochemistry (IHC) using one of the following assays: DAKO 22C3, DAKO 28-8, EIL3N or SP263 * Note: Local testing results of EGFR and ALK by a local Clinical Laboratory Improvement Act (CLIA) certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, EIL3N or SP263 are acceptable for enrollment on A081801. Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration
• Completely resected stage IB (>= 4 cm), II or IIIA non-small cell lung cancer (NSCLC) (squamous or non-squamous) with negative margins (complete R0 resection). Patients will be staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2010 * Note: Patients with pathologic N2 disease, completely resected, are eligible. However, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population
• Complete recovery from surgery. Registration to A081801 must be 30-77 days following surgery
• Human immunodeficiency virus (HIV)-infected patients with a history of Kaposi sarcoma and/or multicentric Castleman disease on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8 gm/dl
• Calculated (Calc.) creatinine clearance >= 45 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

Exclusion Criteria

• No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis
• No prior allogeneic tissue/solid organ transplant
• Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements
• No current pneumonitis or history of (non-infectious) pneumonitis that required steroids
• No active auto-immune disease that has required systemic treatment within the last 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• No patients with a “currently active” second malignancy that is progressing or has required active treatment within the last 3 years. Participants with non-melanoma skin cancers or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) that have undergone potentially curative therapy are eligible
• No hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection

PRIMARY OBJECTIVES:

I. To compare the disease free survival (DFS) and overall survival (OS) (dual primary endpoints) between combination pembrolizumab plus standard of care (Arm C) versus (vs.) standard of care (Arm A) in patients with stage IB-IIIA non-small cell lung cancer.

II. To compare the DFS and OS (dual primary endpoints) between sequential pembrolizumab following standard of care (Arm B) vs. standard of care (Arm A) followed by observation in patients with stage IB-IIIA non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. To compare the DFS and OS between combination pembrolizumab with standard of care (Arm C) vs. sequential standard of care followed by pembrolizumab (Arm B) in patients with stage IB-IIIA non-small cell lung cancer.

II. To compare the adverse event rates and drug discontinuation rates due to adverse events with the addition of pembrolizumab plus standard of care (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) as well as Arm B versus Arm C in patients with stage IB-IIIA non-small cell lung cancer.

III. To compare the DFS and OS between pembrolizumab plus standard of care (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) by PD-L1 expression status (tumor proportion score [TPS] >= 50% vs TPS < 50%) in patients with stage IB-IIIA non-small cell lung cancer.

IV. To compare the DFS and OS between pembrolizumab plus standard of care (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) in patients with stage IB-IIIA non-small cell lung cancer that receive at least 2 cycles of initial adjuvant chemotherapy.

QUALITY OF LIFE OBJECTIVES:

I. To compare patient-reported quality of life (QOL) one year after randomization as assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core (C)30 between patients randomized to receive adjuvant chemotherapy followed by pembrolizumab (Arm B), and those randomized to receive adjuvant chemotherapy + observation (Arm A).

II. To compare patient reported QOL one year after randomization as assessed by EORTC QLQ-C30 between patients randomized to receive adjuvant chemotherapy + pembrolizumab concomitantly (Arm C) and those randomized to receive adjuvant chemotherapy + observation (Arm A).

III. To compare patient-reported QOL at completion of chemotherapy as assessed by the EORTC QLQ-C30 between patients randomized to receive adjuvant chemotherapy + pembrolizumab concomitantly (Arm C) and those randomized to receive adjuvant chemotherapy + observation or adjuvant chemotherapy followed by pembrolizumab (Arms A and B combined).

IV. To present longitudinal trajectories by arm of patient-reported dyspnea and coughing as assessed by the EORTC QLQ-Lung Cancer (LC13).

CORRELATIVE SCIENCE OBJECTIVES:

I. To compare the DFS and OS with the addition of pembrolizumab (combination and/or sequential) to standard of care platinum-based adjuvant therapy (Arms B and C) vs standard of care (Arm A) in the PD-L1 subgroup of patients with PD-L1 expression status (>= 1% vs < 1%).

II. To compare the DFS and OS with the addition of pembrolizumab (combination and/or sequential) to standard of care platinum-based adjuvant therapy (Arms B and C) vs. standard of care (Arm A) by tumor mutational burden status (high vs. low) in patients with stage IB-IIIA non-small cell lung cancer.

III. To identify a cell-free deoxyribonucleic acid (cfDNA) marker associated with high-risk of recurrence and improved DFS and OS with the addition of pembrolizumab to standard adjuvant chemotherapy (Arms B and C).

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A:

INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

CONTINUANCE THERAPY: Patients then undergo observation.

ARM B:

INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

CONTINUANCE THERAPY: Patients then receive pembrolizumab intravenously (IV) over 25-40 minutes on day 1. Treatment repeats every 21 days for 17 cycles or every 6 weeks for 16 cycles (patients enrolled after 10/14/2020) in the absence of disease progression or unacceptable toxicity.

ARM C:

INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice and pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 13 cycles or every 6 weeks for 12 cycles (patients enrolled after 10/14/2020) in the absence of disease progression or unacceptable toxicity.

*ACCEPTABLE REGIMENS:

DOUBLET I: Patients receive cisplatin IV over 1-2 hours and pemetrexed IV over 10 minutes on day 1 of each cycle.

DOUBLET II: Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1 of each cycle.

DOUBLET III: Patients receive cisplatin IV over 1-2 hours on day 1 of each cycle and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 of each cycle.

DOUBLET IV: Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1 of each cycle.

After completion of study treatment, patients are followed up at 6 weeks, then every 3 months for 2 years from randomization, every 6 months for years 2-4, and then annually for up to 10 years from randomization.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Alliance for Clinical Trials in Oncology

Principal Investigator
Jacob M. Sands

• Primary ID A081801
• Secondary IDs NCI-2020-00751
• Clinicaltrials.gov ID NCT04267848