Non-small Cell Lung Cancer
Conditions
Keywords
Non-small Cell Lung Cancer, Bintrafusp alfa (proposed INN), M7824, Durvalumab, Stage III, INTR@PID LUNG 005
Brief summary
The main purpose of this study was to evaluate safety and efficacy in participants treated with concomitant chemoradiation therapy (cCRT) plus M7824 followed by M7824 compared to cCRT plus placebo followed by durvalumab.
Interventions
DRUGM7824
Participants received intravenous infusion of 1200 milligram (mg) M7824 over 1 hour every 2 weeks (q2w) during cCRT and up to 1 year after cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator.
DRUGPlacebo
Participants received intravenous infusion of placebo matched to M7824 over 1 hour q2w during cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator.
DRUGDurvalumab
Participants received intravenous infusion of durvalumab 10 milligram per kilogram (mg/Kg) over 1 hour q2w up to 1 year after cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator.
DRUGEtoposide
Participants received etoposide 50 mg/m\^2 intravenously over a minimum of 30 minutes up to 60 minutes daily on Day 1 to 5 and Day 29 to 33 during cCRT.
DRUGPemetrexed
Participants received pemetrexed at a dose of 500 mg/m\^2 intravenously over 10 minutes or according to local standards on Days 1, 22, and 43 during cCRT.
DRUGCarboplatin
Participants received carboplatin intravenously based on area under curve (AUC) 2 over 30 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 during cCRT.
DRUGPaclitaxel
Participants received paclitaxel intravenously at a dose of 45 mg/m\^2 over 60 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 during cCRT.
DRUGCisplatin
In combination with etoposide, participants received cisplatin 50 mg/m\^2 intravenously over 60 minutes on Days 1, 8, 29, and 36 during cCRT. In combination with pemetrexed, participants received cisplatin 75 mg/m2 intravenously over 60 minutes on Days 1, 22, and 43 during cCRT.
RADIATIONIntensity Modulated Radiation Therapy (IMRT)
Participants received IMRT 5 fractions per week for about 6 weeks (Total 60 gray \[Gy\]).
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology * Participants with tumor harboring an Epidermal growth factor receptor (EGFR) sensitizing (activating) mutation, Anaplastic lymphoma kinase (ALK) translocation, ROS-1 rearrangement are eligible. * Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) greater than equals to (\>=) 1.2 liters or \>= 50% of predicted normal volume measured within 3 weeks prior to randomization. * Adequate hematological, hepatic and renal function as defined in the protocol * Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies
Exclusion criteria
* Participants with Mixed small cell with non-small cell lung cancer histology * Recent major surgery within 4 weeks prior to entry into the study * Significant acute or chronic infections including human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome, Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and active tuberculosis * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization * Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) * Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody or drug targeting T-cell coregulatory proteins
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | Time from randomization to the date of first documentation of PD or death, assessed approximately up to 27 months | PFS was defined as the time from randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was analyzed by using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Time from randomization to the date of death due to any cause, assessed up to 27 months | Overall Survival was defined as the time from randomization to the date of death due to any cause. The overall survival was analyzed by using the Kaplan-Meier method. |
| Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from randomization up to data cut off (assessed up to 27 months) | ORR was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to RECIST v1.1as adjudicated by the Investigator. CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions. |
| Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from first documentation of objective response to the date of first documentation of PD or death due to any cause, assessed approximately up to 27 months | DOR was defined as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. Results were calculated based on Kaplan-Meier estimates. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Time from randomization up to data cut off (assessed up to 27 months) | Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention. |
| Serum Concentration Immediately Before Next Dosing (Ctrough) of M7824 | Pre-dose, 30 minutes after end of infusion on Day 1, 15, 29, 57, 85, 127, 157, 343 | Ctrough was the serum concentration observed immediately before next dosing. |
| Number of Participants With Positive Antidrug Antibodies (ADA) | Time from randomization up to data cut off (assessed up to 27 months) | Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported. |
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of M7824 | Pre-dose, 30 minutes after end of infusion on Day 1, 15, 29, 57, 85, 127, 157, 343 | Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed M7824 concentration-time data. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Japan, Netherlands, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
First participant signed informed consent: 16-Apr-2019, Clinical data cut-off: 21-Jul-2021.
Participants by arm
| Arm | Count |
|---|---|
| cCRT Plus M7824 Followed by M7824 Participants received Concomitant Chemoradiotherapy (cCRT): Cisplatin/Etoposide (50 milligrams per square meter (mg/m\^2) of Cisplatin intravenously over 60 minutes on Days 1, 8, 29, and 36 with 50 mg/m\^2 intravenously of Etoposide over a minimum of 30 minutes up to 60 minutes daily on Day 1 to 5 and Day 29 to 33 during cCRT or Carboplatin/Paclitaxel (carboplatin intravenously based on area under curve (AUC) 2 over 30 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 with 45 mg/m\^2 of Paclitaxel over 60 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 during cCRT or Cisplatin/Pemetrexed (50 mg/m\^2 of Cisplatin intravenously over 60 minutes on Days 1, 8, 29, and 36 with 500 mg/m\^2 of Pemetrexed intravenously over 10 minutes or according to local standards on Days 1, 22, and 43 during cCRT concomitant with Intensity Modulated Radiation Therapy 5 (IMRT 5), fractions per week for about 6 weeks (Total 60 gray \[Gy\]) in combination with intravenous infusion of 1200 mg of M7824 over 1 hour every 2 weeks (q2w) during cCRT and up to 1 year after cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator. | 75 |
| cCRT Plus Placebo Followed by Durvalumab Participants received Concomitant Chemoradiotherapy (cCRT): Cisplatin/Etoposide (50 mg/m\^2) of Cisplatin intravenously over 60 minutes on Days 1, 8, 29, and 36 with 50 mg/m\^2 intravenously of Etoposide over a minimum of 30 minutes up to 60 minutes daily on Day 1 to 5 and Day 29 to 33 during cCRT or Carboplatin/Paclitaxel, carboplatin intravenously based on area under curve (AUC) 2 over 30 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 with 45 mg/m\^2 of Paclitaxel over 60 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 during cCRT or Cisplatin/Pemetrexed, 50 mg/m\^2 of Cisplatin intravenously over 60 minutes on Days 1, 8, 29, and 36 with 500 mg/m\^2 of Pemetrexed intravenously over 10 minutes or according to local standards on Days 1, 22, and 43 during cCRT concomitant with Intensity Modulated Radiation Therapy 5 (IMRT 5), fractions per week for about 6 weeks (Total 60 gray \[Gy\]) in combination with intravenous infusion of placebo matched to M7824 over 1 hour q2w during cCRT followed by intravenous infusion of durvalumab 10 milligram per kilogram (mg/Kg) over 1 hour q2w up to 1 year after cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator. | 78 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomized but not treated | 1 | 1 |
Baseline characteristics
| Characteristic | cCRT Plus Placebo Followed by Durvalumab | Total | cCRT Plus M7824 Followed by M7824 |
|---|---|---|---|
| Age, Continuous | 64.9 Years STANDARD_DEVIATION 8.94 | 64.8 Years STANDARD_DEVIATION 9.12 | 64.7 Years STANDARD_DEVIATION 9.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants | 144 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 59 Participants | 25 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 41 Participants | 89 Participants | 48 Participants |
| Sex: Female, Male Female | 16 Participants | 36 Participants | 20 Participants |
| Sex: Female, Male Male | 62 Participants | 117 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 75 | 5 / 78 |
| other Total, other adverse events | 68 / 74 | 72 / 77 |
| serious Total, serious adverse events | 43 / 74 | 31 / 77 |
Outcome results
Primary
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator
PFS was defined as the time from randomization to the date of first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was analyzed by using the Kaplan-Meier method.
Time frame: Time from randomization to the date of first documentation of PD or death, assessed approximately up to 27 months
Population: Full Analysis Set (FAS) included all participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| cCRT Plus M7824 Followed by M7824 | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 3.7 months |
| cCRT Plus Placebo Followed by Durvalumab | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 3.7 months |
Secondary
Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
DOR was defined as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. Results were calculated based on Kaplan-Meier estimates.
Time frame: Time from first documentation of objective response to the date of first documentation of PD or death due to any cause, assessed approximately up to 27 months
Population: Due to early termination of the study, the data for this outcome measure was not collected.
Secondary
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of M7824
Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed M7824 concentration-time data.
Time frame: Pre-dose, 30 minutes after end of infusion on Day 1, 15, 29, 57, 85, 127, 157, 343
Population: Based on recommendations by an external Independent Data Monitoring Committee (IDMC), Sponsor decided to discontinue this clinical study. Subsequently, the data for this outcome measure was not collected and analyzed.
Secondary
Number of Participants With Positive Antidrug Antibodies (ADA)
Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.
Time frame: Time from randomization up to data cut off (assessed up to 27 months)
Population: Based on recommendations by an external Independent Data Monitoring Committee (IDMC), Sponsor decided to discontinue this clinical study. Subsequently, the data for this outcome measure was not collected and analyzed.
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events
Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention.
Time frame: Time from randomization up to data cut off (assessed up to 27 months)
Population: Safety (SAF) Analysis Set included all participants who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| cCRT Plus M7824 Followed by M7824 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with TEAEs | 70 Participants |
| cCRT Plus M7824 Followed by M7824 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with immunotherapy related TEAE | 48 Participants |
| cCRT Plus M7824 Followed by M7824 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with cisplatin/etoposide chemotherapy regimen related TEAE | 7 Participants |
| cCRT Plus M7824 Followed by M7824 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with carboplatin/paclitaxel chemotherapy regimen related TEAE | 46 Participants |
| cCRT Plus M7824 Followed by M7824 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with cisplatin/pemetrexed chemotherapy regimen related TEAE | 15 Participants |
| cCRT Plus M7824 Followed by M7824 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with radiotherapy related TEAE | 59 Participants |
| cCRT Plus Placebo Followed by Durvalumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with cisplatin/pemetrexed chemotherapy regimen related TEAE | 11 Participants |
| cCRT Plus Placebo Followed by Durvalumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with TEAEs | 74 Participants |
| cCRT Plus Placebo Followed by Durvalumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with carboplatin/paclitaxel chemotherapy regimen related TEAE | 47 Participants |
| cCRT Plus Placebo Followed by Durvalumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with immunotherapy related TEAE | 48 Participants |
| cCRT Plus Placebo Followed by Durvalumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with radiotherapy related TEAE | 60 Participants |
| cCRT Plus Placebo Followed by Durvalumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events | Participants with cisplatin/etoposide chemotherapy regimen related TEAE | 11 Participants |
Secondary
Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
ORR was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to RECIST v1.1as adjudicated by the Investigator. CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions.
Time frame: Time from randomization up to data cut off (assessed up to 27 months)
Population: FAS included all participants who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cCRT Plus M7824 Followed by M7824 | Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | 29.3 percentage of participants |
| cCRT Plus Placebo Followed by Durvalumab | Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | 32.1 percentage of participants |
Secondary
Overall Survival (OS)
Overall Survival was defined as the time from randomization to the date of death due to any cause. The overall survival was analyzed by using the Kaplan-Meier method.
Time frame: Time from randomization to the date of death due to any cause, assessed up to 27 months
Population: FAS included all participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| cCRT Plus M7824 Followed by M7824 | Overall Survival (OS) | 4.6 months |
| cCRT Plus Placebo Followed by Durvalumab | Overall Survival (OS) | 4.3 months |
Secondary
Serum Concentration Immediately Before Next Dosing (Ctrough) of M7824
Ctrough was the serum concentration observed immediately before next dosing.
Time frame: Pre-dose, 30 minutes after end of infusion on Day 1, 15, 29, 57, 85, 127, 157, 343
Population: Based on recommendations by an external Independent Data Monitoring Committee (IDMC), Sponsor decided to discontinue this clinical study. Subsequently, the data for this outcome measure was not collected and analyzed.