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

Stage IV Lung Cancer AJCC v8 Clinical 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06096844
• Other study ID #: NCI-2023-08628
• Secondary ID: NCI-2023-08628EA
• Status: Recruiting
• Phase: Phase 3
• Start date: November 11, 2024
• Est. completion date: June 1, 2026

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 304
• Est. completion date: June 1, 2026
• Est. primary completion date: June 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Lung Non-Small Cell Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• 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

Drug:
• Carboplatin
Given IV

Procedure:
• Computed Tomography
Undergo CT scan
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Nab-paclitaxel
Given IV
• Paclitaxel
Given IV

Biological:
• Pembrolizumab
Given IV

Drug:
• Pemetrexed
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	ThedaCare Regional Cancer Center	Appleton	Wisconsin
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	ThedaCare Cancer Care - Berlin	Berlin	Wisconsin
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Aultman Health Foundation	Canton	Ohio
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Miami Valley Hospital South	Centerville	Ohio
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	University of Illinois	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	Carle at The Riverfront	Danville	Illinois
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Premier Blood and Cancer Center	Dayton	Ohio
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Durham VA Medical Center	Durham	North Carolina
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Mount Carmel Grove City Hospital	Grove City	Ohio
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Memorial Hospital	Marysville	Ohio
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Aspirus Medford Hospital	Medford	Wisconsin
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Community Medical Center	Missoula	Montana
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	ThedaCare Regional Medical Center - Neenah	Neenah	Wisconsin
United States	ThedaCare Cancer Care - New London	New London	Wisconsin
United States	Licking Memorial Hospital	Newark	Ohio
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	Lake Regional Hospital	Osage Beach	Missouri
United States	ThedaCare Cancer Care - Oshkosh	Oshkosh	Wisconsin
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Mercy Health Perrysburg Cancer Center	Perrysburg	Ohio
United States	ECOG-ACRIN Cancer Research Group	Philadelphia	Pennsylvania
United States	Phoenixville Hospital	Phoenixville	Pennsylvania
United States	Penn Medicine Princeton Health	Plainsboro	New Jersey
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	Dartmouth Cancer Center - North	Saint Johnsbury	Vermont
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	ThedaCare Cancer Care - Shawano	Shawano	Wisconsin
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Springfield Regional Cancer Center	Springfield	Ohio
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Mercy Health - Saint Anne Hospital	Toledo	Ohio
United States	Upper Valley Medical Center	Troy	Ohio
United States	Carle Cancer Center	Urbana	Illinois
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	ThedaCare Cancer Care - Waupaca	Waupaca	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Wilmot Cancer Institute at Webster	Webster	New York
United States	Reading Hospital	West Reading	Pennsylvania
United States	William E Kahlert Regional Cancer Center/Sinai Hospital	Westminster	Maryland
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Gut microbe abundances	Will relate gut microbe abundances to treatment outcomes, toxicity, and geriatric assessments.	Baseline and after 4 cycles of initial treatment (Cycles = 21 days)
Primary	Overall survival	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.	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
Secondary	Progression free survival (PFS)	Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios.	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
Secondary	Six month PFS	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.	From randomization to documented disease progression per RECIST 1.1 or death from any cause, whichever occurs first, assessed at 6 months
Secondary	Best objective response	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).	Up to 5 years
Secondary	Incidence of adverse events	Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity will be assessed by summaries by CTCAE grade.	Up to 2 years
Secondary	Evaluation of quality of life (QOL) measures	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.	Baseline up to 6 months