Chemotherapy Combined With Immunotherapy vs Immunotherapy Alone for Older Adults With Stage IIIB-IV Lung Cancer, The ACHIEVE Trial

• ClinicalTrials.gov Identifier: NCT06096844
• Recruitment Status: Recruiting
• First Posted: October 24, 2023
• Last Update Posted: May 17, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: October 21, 2023
• First Posted Date: October 24, 2023
• Last Update Posted Date: May 17, 2024
• Estimated Study Start Date: November 11, 2024
• Estimated Primary Completion Date: June 1, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 21, 2023)

Overall survival [ Time Frame: From randomization to death from any cause, and patients who are alive at the time of final analysis will be censored at the last date of contact, assessed up to 5 years ]

Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios. Comparison of OS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 0.025. Other comparisons of groups will be made using the log rank test and Cox modeling.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 1, 2024)

• Progression free survival (PFS) [ Time Frame: From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 5 years ]
  Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios.
• Six month PFS [ Time Frame: From randomization to documented disease progression per RECIST 1.1 or death from any cause, whichever occurs first, assessed at 6 months ]
  Defined as the proportion of patients who remained alive and progression-free at 6 months. Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios.
• Best objective response [ Time Frame: Up to 5 years ]
  Will be evaluated via RECIST 1.1 criteria. Best objective response rate is defined as the proportion of patients with measurable disease at baseline achieved complete response (CR) or partial response (PR) as best response from the start of the treatment until disease progression/recurrence or start of non-protocol therapy. Patients who do not start treatment and patients who do not have any follow-up disease evaluation and do not meet RECIST criteria for clinical progression are coded as not evaluable. Patients who are not evaluable are included in the calculation of response rates (as non-responders).
• Incidence of adverse events [ Time Frame: Up to 2 years ]
  Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity will be assessed by summaries by CTCAE grade.
• Evaluation of quality of life (QOL) measures [ Time Frame: Baseline up to 6 months ]
  Quality of life evaluations will be conducted using questionnaires at time of disease evaluation per Functional Assessment of Cancer Therapy (FACT)-Lung version 4. QOL assessment will be gathered and the changes in QOL between the two treatment arms will be compared using Wilcoxon rank sum test. The comparison of changes in QOL using Wilcoxon rank sum test will also be done at 6 months given the high mortality rate in this population and the expectation that we may see differences in OS by that timepoint. Point estimates of all endpoints will be accompanied by the corresponding 95% confidence intervals. Point estimates of OS and the corresponding 95% confidence intervals by sex, race and ethnicity will be provided.

Original Secondary Outcome Measures (submitted: October 21, 2023)

• Progression free survival (PFS) [ Time Frame: From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 5 years ]
  Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios.
• Six month PFS [ Time Frame: From randomization to documented disease progression per RECIST 1.1 or death from any cause, whichever occurs first, assessed at 6 months ]
  Defined as the proportion of patients who remained alive and progression-free at 6 months. Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios.
• Best objective response [ Time Frame: Up to 5 years ]
  Will be evaluated via RECIST 1.1 criteria. Best objective response rate is defined as the proportion of patients achieved complete response (CR) or partial response (PR) as best response from the start of the treatment until disease progression/recurrence or start of non-protocol therapy. Patients who do not start treatment and patients who do not have any follow-up disease evaluation and do not meet RECIST criteria for clinical progression are coded as not evaluable. Patients who are not evaluable are included in the calculation of response rates (as non-responders).
• Incidence of adverse events [ Time Frame: Up to 2 years ]
  Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity will be assessed by summaries by CTCAE grade.
• Evaluation of quality of life (QOL) measures [ Time Frame: Baseline up to 6 months ]
  Quality of life evaluations will be conducted using questionnaires at time of disease evaluation per Functional Assessment of Cancer Therapy (FACT)-Lung version 4. QOL assessment will be gathered and the changes in QOL between the two treatment arms will be compared using Wilcoxon rank sum test.

Current Other Pre-specified Outcome Measures (submitted: October 21, 2023)

Gut microbe abundances [ Time Frame: Baseline and after 4 cycles of initial treatment (Cycles = 21 days) ]

Will relate gut microbe abundances to treatment outcomes, toxicity, and geriatric assessments.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Chemotherapy Combined With Immunotherapy vs Immunotherapy Alone for Older Adults With Stage IIIB-IV Lung Cancer, The ACHIEVE Trial
• Official Title: A Randomized Phase III Trial of Chemo-Immunotherapy vs Immunotherapy Alone for the Vulnerable Older Adult With Advanced Non-Small Cell Lung Cancer: The ACHIEVE Study
• Brief 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.

Detailed Description

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 including but not limited to number of additional lab draws, scan appointments, infusion visits, falls, emergency department visits, and hospitalization related to treatment toxicity.

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. Patients may also undergo stool sample collection at baseline and on 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Lung Non-Small Cell Carcinoma
• Stage IIIB Lung Cancer AJCC v8
• Stage IIIC Lung Cancer AJCC v8
• Stage IV Lung Cancer AJCC v8

Intervention

• Procedure: Biospecimen Collection
  Undergo stool sample collection
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Drug: Carboplatin
  Given IV
  Other Names:

  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • JM8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
• Procedure: Computed Tomography
  Undergo CT scan
  Other Names:

  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography
• Procedure: Magnetic Resonance Imaging
  Undergo MRI
  Other Names:

  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI
• Drug: Nab-paclitaxel
  Given IV
  Other Names:

  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • Paclitaxel Albumin
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Paclitaxel Nanoparticle Albumin-bound
  • Paclitaxel Protein-Bound
  • Protein-bound Paclitaxel
• Drug: Paclitaxel
  Given IV
  Other Names:

  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat
• Biological: Pembrolizumab
  Given IV
  Other Names:

  • BCD-201
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • Pembrolizumab Biosimilar BCD-201
  • Pembrolizumab Biosimilar QL2107
  • QL2107
  • SCH 900475
• Drug: Pemetrexed
  Given IV
  Other Names:

  • MTA
  • Multitargeted Antifolate
  • Pemfexy
• Procedure: Positron Emission Tomography
  Undergo PET
  Other Names:

  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron emission tomography (procedure)
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging
  • PT
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

• Active Comparator: Arm A (pembrolizumab)

  INDUCTION: Patients receive pembrolizumab 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.

  Patients undergo MRI at baseline and CT and/or PET on the trial at baseline and throughout the trial. Patients may also undergo stool sample collection at baseline and on the trial.

  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Computed Tomography
  • Procedure: Magnetic Resonance Imaging
  • Biological: Pembrolizumab
  • Procedure: Positron Emission Tomography
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Arm B (pembrolizumab, chemotherapy)
  See Detailed Description
  Interventions:

  • Procedure: Biospecimen Collection
  • Drug: Carboplatin
  • Procedure: Computed Tomography
  • Procedure: Magnetic Resonance Imaging
  • Drug: Nab-paclitaxel
  • Drug: Paclitaxel
  • Biological: Pembrolizumab
  • Drug: Pemetrexed
  • Procedure: Positron Emission Tomography
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 21, 2023): 304
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 1, 2026
• Estimated Primary Completion Date: June 1, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• STEP 1 REGISTRATION
• Patient must be ≥ 70 years of age
• Patient must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with PD-L1 Tumor Proportion Score (TPS) range of 1-49%
• 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
• 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
• Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2
• Patient must agree not to father children while on study and for 6 months after the last dose of protocol treatment
• 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
• Absolute neutrophil count (ANC) ≥ 1,500/mcL (obtained within 14 days prior to Step 1 registration)
• Platelets ≥ 75,000/mcL (obtained within 14 days prior to Step 1 registration)
• Hemoglobin (Hgb) ≥ 8.0 g/dL (obtained within 14 days prior to Step 1 registration)
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained within 14 days prior to Step 1 registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 × institutional ULN (obtained within 14 days prior to Step 1 registration)
• 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)
• 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
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• 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
• 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

• Patient must be English or Spanish speaking to be eligible for the QOL component of the study

  • NOTE: Sites cannot translate the associated QOL forms
• 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
• 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
• 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
• 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
• 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
• Investigator must declare their intended chemotherapy regimen should their patient be randomized to Arm B (doublet vs singlet)
• STEP 2 RANDOMIZATION
• Patient must have completed the baseline Geriatric Assessment (GA) after Step 1 registration and prior to Step 2 randomization

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 70 Years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT06096844
• Other Study ID Numbers: NCI-2023-08628; NCI-2023-08628 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA5221 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA5221 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: "NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."
• URL: https://grants.nih.gov/policy/sharing.htm

• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Megan A Baumgart; ECOG-ACRIN Cancer Research Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: March 2024