Testing the Addition of a Type of Drug Called Immunotherapy to the Usual Chemotherapy Treatment for Non-Small Cell Lung Cancer, ALCHEMIST Trial

Study Overview
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Brief Summary
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This phase III ALCHEMIST trial tests the addition of pembrolizumab to usual chemotherapy for the treatment of stage IIA, IIB, IIIA or IIIB non-small cell lung cancer that has been removed by surgery. 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, such as cisplatin, pemetrexed, carboplatin, gemcitabine hydrochloride, and paclitaxel, 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 with usual chemotherapy may help increase survival times in patients with stage IIA, IIB, IIIA or IIIB non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare the disease free survival (DFS) between Arm B versus (vs) Arm C in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. SECONDARY OBJECTIVES: I. To compare the overall survival (OS) between the two treatment arms in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. II. To compare the adverse event rates and drug discontinuation rates due to adverse events in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. III. To compare the adverse event (AE) rates for Arms B and C with A (prior to Update #7) and estimate the DFS and OS in Arm A. IV. To compare the DFS and OS in patients with stage IIA-IIIB (T3-4N2) 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 + pembrolizumab concomitantly (Arm C). II. To compare patient-reported QOL at completion of chemotherapy as assessed by the EORTC QLQ-C30 between patients randomized to receive adjuvant chemotherapy followed by pembrolizumab (Arm B) and those randomized to receive adjuvant chemotherapy + pembrolizumab concomitantly (Arm C). III. 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 in the PD-L1 subgroup of patients with PD-L1 expression status (>= 1% vs < 1%). II. To compare the DFS and OS by tumor mutational burden status (high vs. low) in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A (CLOSED AS OF UPDATE #7 on 2/1/2022): INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice of each cycle. 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 of each cycle. 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 of each cycle. 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 of each cycle and pembrolizumab IV over 25-40 minutes on day 1 of each cycle or for cycles 1 and 3 (patients enrolled after 10/14/2020). 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 of each cycle. 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. Patients also undergo echocardiogram (ECHO) as clinically indicated during screening and on the trial. Patients may undergo magnetic resonance imaging (MRI) during screening and as clinically indicated on the trial, as well as computed tomography (CT) and blood sample collection throughout the trial. *ACCEPTABLE REGIMENS: DOUBLET I: Patients receive cisplatin IV and pemetrexed IV over 10 minutes on day 1 of each cycle. DOUBLET II: Patients receive carboplatin IV over and pemetrexed IV over 10 minutes on day 1 of each cycle. DOUBLET III: Patients receive cisplatin IV on day 1 of each cycle and gemcitabine hydrochloride IV on days 1 and 8 of each cycle. DOUBLET IV: Patients receive carboplatin IV and paclitaxel IV over 1-96 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 from randomization, and then annually for up to 10 years from randomization.

Official Title
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Integration of Immunotherapy Into Adjuvant Therapy for Resected NSCLC: ALCHEMIST Chemo-IO (ACCIO)

Conditions
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Lung Non-Small Cell Carcinoma, Lung Non-Small Cell Squamous Carcinoma, Lung Non-Squamous Non-Small Cell Carcinoma, Stage II Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Carboplatin
* Drug: Cisplatin
* Procedure: Computed Tomography
* Procedure: Echocardiography
* Drug: Gemcitabine Hydrochloride
* Procedure: Magnetic Resonance Imaging
* Other: Observation
* Drug: Paclitaxel
* Biological: Pembrolizumab
* Drug: Pemetrexed Disodium
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A female of childbearing potential is a sexually mature female who: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) 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: Central testing of EGFR was discontinued as of A081801 Update 10; central testing of ALK and PD-L1 will continue. Local testing results by a local CLIA certified laboratory is required for EGFR and acceptable for ALK. 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 IIA, IIB IIIA or IIIB (T3-4N2) non-small cell lung cancer (NSCLC) (squamous or non-squamous) with negative margins (complete R0 resection). Patients will be staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2017 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 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 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (platinum doublet, observation)<br>INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician's choice of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then undergo observation. Patients also undergo ECHO as clinically indicated during screening and on the trial. Patients may undergo MRI during screening and as clinically indicated on the trial, as well as CT and blood sample collection throughout the trial. (CLOSED AS OF UPDATE #7) | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Other: Observation<br>* Undergo observation<br>* Other names: Visual Inspection;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm B (platinum doublet, sequential pembrolizumab)<br>INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice of each cycle and pembrolizumab IV over 25-40 minutes on day 1 of each cycle or for cycles 1 and 3 (patients enrolled after 10/14/2020). 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 of each cycle. 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. Patients also undergo ECHO as clinically indicated during screening and on the trial. Patients may undergo MRI during screening and as clinically indicated on the trial, as well as CT and blood sample collection throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm C (platinum doublet, combination pembrolizumab)<br>INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice of each cycle and pembrolizumab IV over 25-40 minutes on day 1 of each cycle or for cycles 1 and 3 (patients enrolled after 10/14/2020). 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 of each cycle. 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. Patients also undergo ECHO as clinically indicated during screening and on the trial. Patients may undergo a MRI during screening and as clinically indicated on the trial, as well as CT and blood sample collection throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) | Will compare DFS between the two arms (combination versus sequential pembrolizumab added to standard of care platinum-based adjuvant therapy) in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. Will be estimated using the Kaplan-Meier method, where the stratified log-rank test (using the central PD-L1 result for the PD-L1 expression status) will be used to compare the distributions across the treatment arms. DFS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. Univariable and multivariable Cox models stratified by the stratification factors (using the central PD-L1 result for the PD-L1 expression status) used in the randomization will be assessed as well. | From randomization to the first of either disease recurrence or death from any cause, assessed up to 5 years after accrual completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be estimated using the Kaplan-Meier method, where the stratified log-rank test (using the central PD-L1 result for the PD-L1 expression status) will be used to compare the distributions across the treatment arms. OS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. Univariable and multivariable Cox models stratified by the stratification factors (using the central PD-L1 result for the PD-L1 expression status) used in the randomization will be assessed as well. | From randomization to death from any cause, assessed up to completion of 5 years follow-up | 
| Incidence of adverse events | The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5. will compare the adverse event rates and drug discontinuation rates due to adverse events. To evaluate the adverse events profiles associated with each treatment arm, the maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests. In addition, we will also compute and compare the total adverse event burden for each arm | Up to 10 years | 
| DFS between each of the arms | Will compare the DFS by PD-L1 expression status (tumor proportion score [TPS] ≥ 50% versus [vs] TPS < 50% using the central PD-L1 expression status) in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. This will be assessed using the treatment arm by PD-L1 expression status (using the central PD-L1 expression status) interaction effect on DFS. Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be used as the primary analytical method, where all baseline covariates will be considered in the univariable models and subsequently in the multivariable models based on the criteria for selection for the multivariable models. Similar analyses will be performed for the correlative endpoints using the cut off of 1% for the PD-L1 expression status (using the central PD-L1 expression status), and tumor mutational burden (high vs low). | From randomization to the first of either disease recurrence or death from any cause, assessed up to 5 years after accrual completion | 
| OS between each of the arms | will compare the OS by PD-L1 expression status (TPS ≥ 50% vs TPS < 50% using the central PD-L1 expression status) in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. This will be assessed using the treatment arm by PD-L1 expression status (using the central PD-L1 expression status) interaction effect on OS. Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be used as the primary analytical method, where all baseline covariates will be considered in the univariable models and subsequently in the multivariable models based on the criteria for selection for the multivariable models. Similar analyses will be performed for the correlative endpoints using the cut off of 1% for the PD-L1 expression status (using the central PD-L1 expression status), and tumor mutational burden (high vs low). | From randomization to death from any cause, assessed up to completion of 5 years of follow-up |