Non-Small Cell Lung Cancer
Conditions
Brief summary
The purpose of this study is to find out whether it is better to receive a new drug, MEDI4736, or better to receive no further treatment after surgery (and possibly chemotherapy) for lung cancer.
Interventions
DRUGMEDI4736
DRUGPlacebo
Sponsors
Chinese Thoracic Oncology Group
Canadian Cancer Trials Group
Intergroupe Francophone de Cancerologie Thoracique
Thoracic Oncology Group of Australasia (TOGA)
National Health and Medical Research Council, Australia
National Cancer Institute, Naples
Central and Eastern European Oncology Group
Dutch Society of Physicians for Pulmonology and Tuberculosis
Korean Cancer Study Group
Fundación GECP
West Japan Oncology Group (WJOG)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of primary non-small cell carcinoma of the lung. according to WHO Classification of Tumours (WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. WHO/IARC Classification of Tumours, 4th Edition, Volume 7). Patients with large-cell neuroendocrine carcinomas are not eligible. * Patients must be classified post-operatively as Stage IB (≥ 4cm in the longest diameter), II or IIIA on the basis of pathologic criteria. Note: Although T3N2M0 tumours have been reclassified to stage IIIB in the 8th edition of the IASLC staging system, these patients remain eligible (as stage IIIA under the 7th edition criteria). * Complete surgical resection of the primary NSCLC is also mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. Resection may be accomplished by open or VATS techniques Note: Patients with synchronous primary tumours will not be eligible due to the potential uncertainty regarding their appropriate PD-L1 status. Prior Systemic Therapy: * Pre-operative (neo-adjuvant) platinum based or other chemotherapy is not permissible. * Patients may have received prior post-operative platinum based chemotherapy as per standard of care. * No prior anticancer therapy for treatment of NSCLC other than standard post-operative adjuvant chemotherapy is permissible. Radiation: • Patients with N2 disease only who receive adjuvant post-operative radiation therapy are eligible provided they meet the protocol specified timing criteria for surgery, adjuvant chemotherapy and randomization. Pre-operative radiation therapy is not permissible. * The patient must have an ECOG performance status of 0, 1. * Hematology: . Absolute neutrophil count ≥ 1.5 x 109/L or ≥ 1,500/µl Platelets ≥ 100 x 109/L or ≥ 100,000/µl * Biochemistry: Total bilirubin\* ≤ institutional upper limit of normal Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal AST(SGOT) and ALT(SGPT) ≤ 2.5 x institutional upper limit of normal Creatinine Clearance ≥ 40 ml/min \* excluding Gilbert's syndrome Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft Formula: Females: GFR = 1.04 x (140-age) x weight in kg serum creatinine in μmol/L Males: GFR = 1.23 x (140-age) x weight in kg serum creatinine in μmol/L * Patient able and willing to complete the QoL, economics and other questionnaires. The baseline assessment must already have been completed within required timelines prior to randomization. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate * Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up * Protocol treatment is to begin within 2 working days of patient randomization
Exclusion criteria
* Patients with a history of other malignancies, except: * adequately treated non-melanoma skin cancer, * curatively treated in-situ cancer, or * other malignancies curatively treated with no evidence of disease for ≥ 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy. * A combination of small cell and non-small cell lung cancer, pulmonary carcinoid tumour or large-cell neuroendocrine carcinoma (LCNEC). * History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: patients with Grave's disease and/or psoriasis not requiring systemic therapy within the last two years from randomization and patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement are not excluded. * History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization\* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy. * Live attenuated vaccination administered within 30 days prior to randomization. * History of hypersensitivity to MEDI4736 or any excipient. * Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, must have a LVEF \> 50% within 12 weeks prior to randomization. * Concurrent treatment with other investigational drugs or anti-cancer therapy. * Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol. This includes but is not limited to: * known clinical diagnosis of tuberculosis; * known active hepatitis B infection (positive HBV surface antigen (HBsAg)). Patients with a past or resolved hepatitis B infection (defined as presence of hepatitis B core antibody (anti-HBc) and absence of HBSAg) are eligible; * known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA; * known human immunodeficiency virus infection (positive HIV antibodies). * known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function * Pregnant or lactating women. Women of childbearing potential must have a urine pregnancy test proven negative within 14 days prior to randomization. Men and women of child-bearing potential must agree to use adequate contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Compare Disease Free Survival (DFS) for Patients With NSCLC That is PD-L1 Expression TC ≥ 25% and Patients Without EGFR Exon 21 L858R Mutation or Exon 19 Deletions or ALK Gene Rearrangements | Up to 8.3 years | DFS in months is defined as the time from the date of randomization to the date of first documented disease relapse or the occurrence of a new invasive primary malignancy that was later confirmed or death from any cause, whichever came first. For patients who were determined to have residual disease at study entry after consensus review, the DFS were censored at the date of randomization. Patients who are alive and disease/new invasive primary malignancy-free at the data cut-off date will be censored at their last disease assessment date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival in Patients With PD-L1 Expression Levels >= 1% and Without Common Activating EGFR Mutations or ALK Gene Rearrangements. | up to 8.3 years | DFS time in months is defined as the time from the date of randomization to the date of first documented disease relapse or the occurrence of a new invasive primary malignancy that was later confirmed or death from any cause, whichever came first. For patients who were determined to have residual disease at study entry after consensus review, the DFS were censored at the date of randomization. Patients who are alive and disease/new invasive primary malignancy-free at the data cut-off date will be censored at their last disease assessment date. |
| Disease-free Survival in Patients Without Common Activating EGFR Mutations or ALK Gene Rearrangements. | up to 8.3 years | DFS is defined as the time from the date of randomization to the date of first documented disease relapse or the occurrence of a new invasive primary malignancy that was later confirmed or death from any cause, whichever came first. For patients who were determined to have residual disease at study entry after consensus review, the DFS were censored at the date of randomization. Patients who are alive and disease/new invasive primary malignancy-free at the data cut-off date will be censored at their last disease assessment date. |
| Compare Overall Survival (OS) for Patients in Patients With PD-L1 >= 25% and Without EGFR Exon 21 L858R Mutation or Exon 19 Deletion or ALK Gene Rearrangements. | All randomized patients with a minimum of 5 years follow up and up to 9.7 years. | OS is defined as the time from the date of randomization to the date of death of any cause or censored at their last known alive date before or on the data cutoff date. Analysis population is for patients in patients with PD-L1 \>= 25% and without EGFR exon 21 L858R mutation or exon 19 deletion or ALK gene rearrangements. |
| Compare Overall Survival (OS) for Patients in Patients With PD-L1 >= 1% and Without EGFR Exon 21 L858R Mutation or Exon 19 Deletion or ALK Gene Rearrangements. | All randomized patients with a minimum of 5 years follow up and up to 9.7 years. | OS is defined as the time from the date of randomization to the date of death of any cause or censored at their last known alive date before or on the data cutoff date. Patients population is for patients with PD-L1 \>= 1% and without EGFR exon 21 L858R mutation or exon 19 deletion or ALK gene rearrangements. |
| Compare Overall Survival (OS) for Patients in Patients Without EGFR Exon 21 L858R Mutation or Exon 19 Deletion or ALK Gene Rearrangements. | All randomized patients with a minimum of 5 years follow up and up to 9.7 years. | OS is defined as the time from the date of randomization to the date of death of any cause or censored at their last known alive date before or on the data cutoff date. Analysis population is all randomized patients without EGFR exon 21 L858R mutation or exon 19 deletion or ALK gene rearrangements. |
| Compare Disease Free Survival (DFS) in All Randomized Patients | up to 8.3 years | DFS is defined as the time from the date of randomization to the date of first documented disease relapse or the occurrence of a new invasive primary malignancy that was later confirmed or death from any cause, whichever came first. For patients who were determined to have residual disease at study entry after consensus review, the DFS were censored at the date of randomization. Patients who are alive and disease/new invasive primary malignancy-free at the data cut-off date will be censored at their last disease assessment date. For a special case, Patient AUAP0005 was found that the original NSCLC diagnosis was erroneous, and the patient had metastatic testicular cancer prior to randomization, confirmed retrospectively by immunophenotyping. Since the patient did not have completely resected NSCLC, the patient was censored at randomization for both DFS and OS. |
| Compare Overall Survival (OS) in All Randomized Patients | All randomized patients with a minimum of 5 years follow up and up to 9.7 years. | OS is defined as the time from the date of randomization to the date of death of any cause or censored at their last known alive date before or on the data cutoff date. |
Countries
Australia, Brazil, Bulgaria, Canada, China, France, Hungary, Italy, Japan, Netherlands, New Zealand, Poland, Romania, Singapore, South Korea, Spain, Taiwan, Ukraine, United States
Contacts
STUDY_CHAIRGlenwood Goss
Ottawa Hospital Research Institute, Ontario, Canada
Participant flow
Recruitment details
The study was activated on Oct. 9th of 2014. Accrual was completed on March 27th of 2020, with 1415 patients randomized to the trial.
Pre-assignment details
After registration but prior to randomization, tissue blocks from the surgically resected NSCLC must be submitted for PD-L1 assessment and the result must be available prior to randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Adjuvant platinum based chemotherapy < 300 mg/m2 | 184 Participants |
| Adjuvant platinum based chemotherapy >= 300 mg/m2 | 216 Participants |
| Adjuvant platinum based chemotherapy no chemotherapy | 141 Participants |
| Age, Continuous | 64 Year |
| ALK Mutation Negative | 916 Participants |
| ALK Mutation Positive | 19 Participants |
| Disease Stage IB tumor size > 4cm | 118 participant |
| Disease Stage II | 503 participant |
| Disease Stage IIIA | 543 participant |
| EGFR Mutation status Exon 21 L858R mutation or Exon 19 deletions | 149 Participants |
| EGFR Mutation status Other mutations | 15 Participants |
| EGFR Mutation status Unknown | 2 Participants |
| EGFR Mutation status Wild type | 415 Participants |
| PD-L1 expression TC level <1% | 600 Participants |
| PD-L1 expression TC level 1-<25% | 94 Participants |
| PD-L1 expression TC level 25-<50% | 64 Participants |
| PD-L1 expression TC level >=50% | 228 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 140 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 247 Participants |
| Race (NIH/OMB) White | 209 Participants |
| Region of Enrollment Australia | 31 Participants |
| Region of Enrollment Brazil | 4 Participants |
| Region of Enrollment Bulgaria | 5 Participants |
| Region of Enrollment Canada | 67 Participants |
| Region of Enrollment China | 15 Participants |
| Region of Enrollment France | 118 Participants |
| Region of Enrollment Hungary | 0 Participants |
| Region of Enrollment Italy | 78 Participants |
| Region of Enrollment Japan | 152 Participants |
| Region of Enrollment Netherlands | 14 Participants |
| Region of Enrollment New Zealand | 2 Participants |
| Region of Enrollment Poland | 2 Participants |
| Region of Enrollment Romania | 5 Participants |
| Region of Enrollment Singapore | 1 Participants |
| Region of Enrollment South Korea | 66 Participants |
| Region of Enrollment Spain | 44 Participants |
| Region of Enrollment Taiwan | 42 Participants |
| Region of Enrollment Ukraine | 11 Participants |
| Region of Enrollment United States | 17 Participants |
| Sex: Female, Male Female | 168 Participants |
| Sex: Female, Male Male | 587 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 298 / 944 | 146 / 471 |
| other Total, other adverse events | 900 / 947 | 432 / 463 |
| serious Total, serious adverse events | 197 / 947 | 72 / 463 |
Outcome results
None listed