Small Cell Lung Cancer
Conditions
Keywords
Small Cell Lung Cancer, SCLC, LS-SCLC, Limited Stage, Carcinoma, Lung Cancer
Brief summary
This is a Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, International Study of Durvalumab or Durvalumab and Tremelimumab as Consolidation Treatment for Patients with LS-SCLC Who Have Not Progressed Following Concurrent Chemoradiation Therapy
Interventions
DRUGDurvalumab
Durvalumab IV (intravenous infusion)
DRUGTremelimumab
Tremelimumab IV (intravenous infusion)
OTHERPlacebo
Placebo IV (intravenous infusion)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically documented limited-stage small cell lung cancer (stage I-III). 2. Received 4 cycles of chemotherapy concurrent with radiotherapy, which must be completed within 1 to 42 days prior to randomization and the first dose of IP. Chemotherapy must contain platinum and IV etoposide. Radiotherapy must be either total 60-66 Gy over 6 weeks for the standard QD regimen or total 45 Gy over 3 weeks for hyperfractionated BD schedules. 3. PCI may be delivered at the discretion of investigator and local standard of care, and must be conducted after the end of cCRT and completed between 1 to 42 days to first dose of IP. 4 .Have not progressed following definitive concurrent chemoradiation 5 .Life expectancy ≥ 12 weeks at Day 1. 6. ECOG 0 or 1 at enrolment.
Exclusion criteria
1. Extensive-stage SCLC 2. Active or prior documented autoimmune or inflammatory disorders 3. Uncontrolled intercurrent illness, including but not limited to interstitial lung disease. 4. Active infection including tuberculosis, HIV, hepatitis B and C 5. Patients who received sequential chemotherapy and radiotherapy (no overlap of RT with chemotherapy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Durvalumab Versus Placebo: Progression-Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Response evaluations performed every 8 weeks (q8w) ± 1 week up to 72 weeks, then every 12 weeks (q12w) ± 1 week up to 96 weeks, and then every 24 weeks (q24w) thereafter until PD, up to DCO date 15 January 2024 (a maximum of approximately 1936 days) | PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective disease progression (PD) or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm) from nadir. Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method. |
| Durvalumab Versus Placebo: Overall Survival (OS) | From date of randomization until death due to any cause, up to DCO date 15 January 2024 (a maximum of approximately 1936 days) | OS was defined as the time from the date of randomization until death due to any cause. Median OS was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Durvalumab Versus Placebo: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to DCO date 15 January 2024 (a maximum of approximately 1936 days) | ORR per RECIST 1.1 assessed by BICR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) (i.e., unconfirmed response). CR was defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR was defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Objective Response Rate Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | From date of randomization until death due to any cause, up to approximately 89 months | ORR per RECIST 1.1 assessed by BICR is defined as the percentage of participants with at least 1 visit response of CR or PR (i.e., unconfirmed response). CR is defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters. |
| Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 18 Months Following Randomization (PFS18) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Month 18 | PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS18 was defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 18 months following randomization. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Progression-Free at 18 Months Following Randomization Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Month 18 | PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS18 is defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 18 months following randomization. |
| Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 24 Months Following Randomization (PFS24) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Month 24 | PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS24 was defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 24 months following randomization. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Progression-Free at 24 Months Following Randomization Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Month 24 | PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS24 is defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 24 months following randomization. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Time to Death or Distant Metastasis (TTDM) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months | TTDM per RECIST 1.1 is defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the radiation field according to RECIST 1.1 or proven by biopsy. |
| Durvalumab Versus Placebo: Percentage of Participants Alive at 24 Months From Randomization (OS24) | Month 24 | OS was defined as the time from the date of randomization until death due to any cause. The OS24 was defined as the Kaplan-Meier estimate of OS at 24 months after randomization. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Alive at 24 Months From Randomization | Month 24 | OS is defined as the time from the date of randomization until death due to any cause. The OS24 is defined as the Kaplan-Meier estimate of OS at 24 months after randomization. |
| Durvalumab Versus Placebo: Percentage of Participants Alive at 36 Months From Randomization (OS36) | Month 36 | OS was defined as the time from the date of randomization until death due to any cause. The OS36 was defined as the Kaplan-Meier estimate of OS at 36 months after randomization. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Progression-Free Survival Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months | PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Time From Randomization to Second Progression (PFS2) | Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months | PFS2 is defined as the time from the date of randomization to the earliest of the progression event subsequent to the first subsequent anticancer therapy (excluding radiotherapy) or death. The date of second progression is recorded by the Investigator in the eCRF at each assessment and defined according to local standard clinical practice and might involve any of the following: objective radiological imaging, symptomatic progression, or death. |
| Durvalumab Versus Durvalumab Plus Tremelimumab: Progression-Free Survival Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months | PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. |
| Durvalumab Versus Durvalumab Plus Tremelimumab: Objective Response Rate Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | From date of randomization until death due to any cause, up to approximately 89 months | ORR per RECIST 1.1 assessed by BICR is defined as the percentage of participants with at least 1 visit response of CR or PR (i.e., unconfirmed response). CR is defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters. |
| Durvalumab Versus Durvalumab Plus Tremelimumab: Overall Survival | From date of randomization until death due to any cause, up to approximately 89 months | OS is defined as the time from the date of randomization until death due to any cause. |
| Durvalumab Plus Tremelimumab Versus Placebo: Change From Baseline in Patient-Reported Symptoms as Assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ) | Baseline (Day 1) and up to approximately 89 months | Patient-reported outcomes for 5 disease related symptoms will be assessed using EORTC QLQ-Core 30 (C30) items questionnaire (fatigue, appetite loss) and EORTC QLQ-Lung Cancer module 13 (LC13) (dyspnea, cough and pain in chest). An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom items, functional scales, and global health status (GHS) scale with higher scores on GHS/QoL and functioning scales representing better health status/function, but higher scores on symptom scales/items representing greater symptom severity. |
| Durvalumab: Serum Concentration of Durvalumab | End of infusion on Cycle 1 Day 1, pre-infusion on Cycle 2 (Week 4), Cycle 5 (Week 16) and Cycle 26 (Week 100) and Month 3 post last dose of study treatment (Week 119) (each treatment cycle is 28 days) | Blood samples were collected to determine the concentration of durvalumab. |
| Durvalumab Plus Tremelimumab: Serum Concentration of Tremelimumab | Up to approximately 27 months | Blood samples will be collected to determine the concentration of tremelimumab. |
| Durvalumab: Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab | From first dose of study drug (Day 1) up to DCO date 15 January 2024 (a maximum of approximately 1936 days) | Blood samples were collected to determine the presence of ADAs for durvalumab using validated assays. Treatment-emergent ADA-positive was defined as either treatment-induced (post-baseline ADA-positive only) or treatment-boosted ADA (baseline positive ADA titer that was boosted to ≥4 fold during the study period). Treatment-induced ADA was defined as ADA positive post-baseline and not detected at baseline. Treatment-boosted ADA was defined as a baseline positive ADA titer that was boosted to a 4-fold or higher level (greater than the analytical variance of the assay) following drug administration. Number of participants with treatment-emergent ADA (ADA incidence) are presented. |
| Durvalumab Plus Tremelimumab: Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab | Up to approximately 30 months | Blood samples will be collected to determine the presence of ADAs for tremelimumab using validated assays. Treatment-emergent ADA-positive is defined as either treatment-induced (post-baseline ADA-positive only) or treatment-boosted ADA (baseline positive ADA titer that was boosted to ≥4 fold during the study period). Treatment-boosted ADA is defined as a baseline positive ADA titer that was boosted to a 4-fold or higher level (greater than the analytical variance of the assay) following drug administration. Treatment-induced ADA is defined as ADA positive post-baseline and not detected at baseline. |
| Durvalumab Versus Durvalumab Plus Tremelimumab: Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Status Based on Progression-Free Survival, Overall Survival, and Objective Response Rate | Up to approximately 89 months | Blood samples will be collected for clinical biomarker testing and a tumor specimen will be collected as per tumor specimen collection requirements. The specimen will be evaluated by immunohistochemistry to determine the expression of tumor specific antigens and immune markers. The PD-L1 is a biomarker and will be assessed using the VENTANA PD-L1 (SP263) assay. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Alive at 36 Months From Randomization | Month 36 | OS is defined as the time from the date of randomization until death due to any cause. The OS36 is defined as the Kaplan-Meier estimate of OS at 36 months after randomization. |
| Durvalumab Plus Tremelimumab Combination Versus Placebo: Overall Survival | From date of randomization until death due to any cause, up to approximately 89 months | OS is defined as the time from the date of randomization until death due to any cause. |
Countries
Argentina, Belgium, Canada, China, Czechia, Germany, India, Italy, Japan, Netherlands, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States, Vietnam
Participant flow
Recruitment details
This Phase III, double-blind, placebo-controlled trial studied participants with limited stage small-cell lung cancer who had not progressed after concurrent chemoradiation therapy at 164 sites in 19 countries. Interim results are based on data cut-off (DCO) date of 15 January 2024. 730 participants were randomized; the first 600 in a 1:1:1 ratio to durvalumab monotherapy (D), durvalumab plus tremelimumab combination therapy (D+T) or placebo (P), the remaining in a 1:1 ratio to D or P.
Pre-assignment details
Based on the results of the secondary objectives at the interim analysis (reviewed by an unblinded independent data monitoring committee \[IDMC\]), data for the D+T arm were to remain blinded to the Sponsor as pre-specified in the study's unblinding plan. Since the D+T arm was blinded at the time of posting the results from this interim analysis, results for that arm will be posted at the time of final analysis.
Participants by arm
| Arm | Count |
|---|---|
| Durvalumab Participants received durvalumab monotherapy (1500 mg for participants \>30 kg in weight and a weight-based dosing equivalent to 20 mg/kg for participants \<=30 kg in weight) via IV infusion once q4w, until clinical/RECIST 1.1-defined radiological progression, intolerable toxicity, or for a maximum of 24 months, whichever occurred first. | 264 |
| Durvalumab Plus Tremelimumab Participants received durvalumab in combination with tremelimumab (1500 mg durvalumab in combination with 75 mg tremelimumab for participants \>30 kg in weight and a weight-based dosing equivalent to 20 mg/kg durvalumab in combination with 1 mg/kg tremelimumab for participants \<=30 kg in weight) via IV infusion once q4w, until clinical/RECIST 1.1-defined radiological progression, intolerable toxicity, or for a maximum of 24 months, whichever occurred first. | 200 |
| Placebo Participants received matching placebo via IV infusion once q4w for 4 doses/cycles each, until clinical/RECIST 1.1-defined radiological progression, intolerable toxicity, or for a maximum of 24 months, whichever occurred first. | 266 |
| Total | 730 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 115 | 0 | 144 |
| Overall Study | Ongoing at the time of DCO | 140 | 200 | 111 |
| Overall Study | Withdrawal by Subject | 9 | 0 | 11 |
Baseline characteristics
| Characteristic | Durvalumab | Durvalumab Plus Tremelimumab | Placebo | Total |
|---|---|---|---|---|
| Age, Customized <65 years | 160 Participants | NA Participants | 162 Participants | NA Participants |
| Age, Customized >=65 years | 104 Participants | NA Participants | 104 Participants | NA Participants |
| Race/Ethnicity, Customized Asian | 131 Participants | NA Participants | 121 Participants | NA Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | NA Participants | 3 Participants | NA Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 Participants | NA Participants | 14 Participants | NA Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | NA Participants | 3 Participants | NA Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 255 Participants | NA Participants | 249 Participants | NA Participants |
| Race/Ethnicity, Customized Other | 2 Participants | NA Participants | 5 Participants | NA Participants |
| Race/Ethnicity, Customized White | 130 Participants | NA Participants | 137 Participants | NA Participants |
| Sex: Female, Male Female | 86 Participants | NA Participants | 78 Participants | NA Participants |
| Sex: Female, Male Male | 178 Participants | NA Participants | 188 Participants | NA Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 115 / 264 | 0 / 0 | 146 / 266 |
| other Total, other adverse events | 209 / 262 | 0 / 0 | 196 / 265 |
| serious Total, serious adverse events | 78 / 262 | 0 / 0 | 64 / 265 |
Outcome results
Primary
Durvalumab Versus Placebo: Overall Survival (OS)
OS was defined as the time from the date of randomization until death due to any cause. Median OS was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.
Time frame: From date of randomization until death due to any cause, up to DCO date 15 January 2024 (a maximum of approximately 1936 days)
Population: The FAS included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Overall Survival (OS) | 55.9 months |
| Placebo | Durvalumab Versus Placebo: Overall Survival (OS) | 33.4 months |
p-value: 0.0104295% CI: [0.569, 0.928]Log Rank
Primary
Durvalumab Versus Placebo: Progression-Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective disease progression (PD) or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm) from nadir. Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method.
Time frame: Response evaluations performed every 8 weeks (q8w) ± 1 week up to 72 weeks, then every 12 weeks (q12w) ± 1 week up to 96 weeks, and then every 24 weeks (q24w) thereafter until PD, up to DCO date 15 January 2024 (a maximum of approximately 1936 days)
Population: The FAS included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Progression-Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 16.6 months |
| Placebo | Durvalumab Versus Placebo: Progression-Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 9.2 months |
p-value: 0.0160895% CI: [0.606, 0.95]Log Rank
Secondary
Durvalumab: Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab
Blood samples were collected to determine the presence of ADAs for durvalumab using validated assays. Treatment-emergent ADA-positive was defined as either treatment-induced (post-baseline ADA-positive only) or treatment-boosted ADA (baseline positive ADA titer that was boosted to ≥4 fold during the study period). Treatment-induced ADA was defined as ADA positive post-baseline and not detected at baseline. Treatment-boosted ADA was defined as a baseline positive ADA titer that was boosted to a 4-fold or higher level (greater than the analytical variance of the assay) following drug administration. Number of participants with treatment-emergent ADA (ADA incidence) are presented.
Time frame: From first dose of study drug (Day 1) up to DCO date 15 January 2024 (a maximum of approximately 1936 days)
Population: The ADA population included all participants in the safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab | Durvalumab: Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab | 7 Participants |
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Objective Response Rate Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
ORR per RECIST 1.1 assessed by BICR is defined as the percentage of participants with at least 1 visit response of CR or PR (i.e., unconfirmed response). CR is defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.
Time frame: From date of randomization until death due to any cause, up to approximately 89 months
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Overall Survival
OS is defined as the time from the date of randomization until death due to any cause.
Time frame: From date of randomization until death due to any cause, up to approximately 89 months
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Alive at 24 Months From Randomization
OS is defined as the time from the date of randomization until death due to any cause. The OS24 is defined as the Kaplan-Meier estimate of OS at 24 months after randomization.
Time frame: Month 24
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Alive at 36 Months From Randomization
OS is defined as the time from the date of randomization until death due to any cause. The OS36 is defined as the Kaplan-Meier estimate of OS at 36 months after randomization.
Time frame: Month 36
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Progression-Free at 18 Months Following Randomization Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS18 is defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 18 months following randomization.
Time frame: Month 18
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Percentage of Participants Progression-Free at 24 Months Following Randomization Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS24 is defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 24 months following randomization.
Time frame: Month 24
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Progression-Free Survival Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir.
Time frame: Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Time From Randomization to Second Progression (PFS2)
PFS2 is defined as the time from the date of randomization to the earliest of the progression event subsequent to the first subsequent anticancer therapy (excluding radiotherapy) or death. The date of second progression is recorded by the Investigator in the eCRF at each assessment and defined according to local standard clinical practice and might involve any of the following: objective radiological imaging, symptomatic progression, or death.
Time frame: Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months
Secondary
Durvalumab Plus Tremelimumab Combination Versus Placebo: Time to Death or Distant Metastasis (TTDM) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
TTDM per RECIST 1.1 is defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the radiation field according to RECIST 1.1 or proven by biopsy.
Time frame: Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months
Secondary
Durvalumab Plus Tremelimumab: Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab
Blood samples will be collected to determine the presence of ADAs for tremelimumab using validated assays. Treatment-emergent ADA-positive is defined as either treatment-induced (post-baseline ADA-positive only) or treatment-boosted ADA (baseline positive ADA titer that was boosted to ≥4 fold during the study period). Treatment-boosted ADA is defined as a baseline positive ADA titer that was boosted to a 4-fold or higher level (greater than the analytical variance of the assay) following drug administration. Treatment-induced ADA is defined as ADA positive post-baseline and not detected at baseline.
Time frame: Up to approximately 30 months
Secondary
Durvalumab Plus Tremelimumab: Serum Concentration of Tremelimumab
Blood samples will be collected to determine the concentration of tremelimumab.
Time frame: Up to approximately 27 months
Secondary
Durvalumab Plus Tremelimumab Versus Placebo: Change From Baseline in Patient-Reported Symptoms as Assessed by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ)
Patient-reported outcomes for 5 disease related symptoms will be assessed using EORTC QLQ-Core 30 (C30) items questionnaire (fatigue, appetite loss) and EORTC QLQ-Lung Cancer module 13 (LC13) (dyspnea, cough and pain in chest). An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom items, functional scales, and global health status (GHS) scale with higher scores on GHS/QoL and functioning scales representing better health status/function, but higher scores on symptom scales/items representing greater symptom severity.
Time frame: Baseline (Day 1) and up to approximately 89 months
Secondary
Durvalumab: Serum Concentration of Durvalumab
Blood samples were collected to determine the concentration of durvalumab.
Time frame: End of infusion on Cycle 1 Day 1, pre-infusion on Cycle 2 (Week 4), Cycle 5 (Week 16) and Cycle 26 (Week 100) and Month 3 post last dose of study treatment (Week 119) (each treatment cycle is 28 days)
Population: The pharmacokinetic (PK) population included all participants who received at least 1 dose of study drug per the protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would have significantly affected the PK analyses. Only those participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Durvalumab | Durvalumab: Serum Concentration of Durvalumab | Cycle 1 Day 1: End of infusion | 431.00 microgram per milliliter (mcg/mL) | Standard Deviation 327.861 |
| Durvalumab | Durvalumab: Serum Concentration of Durvalumab | Cycle 2 (Week 4): Pre-infusion | 89.57 microgram per milliliter (mcg/mL) | Standard Deviation 107.228 |
| Durvalumab | Durvalumab: Serum Concentration of Durvalumab | Cycle 5 (Week 16): Pre-infusion | 159.63 microgram per milliliter (mcg/mL) | Standard Deviation 58.561 |
| Durvalumab | Durvalumab: Serum Concentration of Durvalumab | Cycle 26 (Week 100): Pre-infusion | 178.20 microgram per milliliter (mcg/mL) | Standard Deviation 65.422 |
| Durvalumab | Durvalumab: Serum Concentration of Durvalumab | Month 3 follow-up | 44.97 microgram per milliliter (mcg/mL) | Standard Deviation 36.026 |
Secondary
Durvalumab Versus Durvalumab Plus Tremelimumab: Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Status Based on Progression-Free Survival, Overall Survival, and Objective Response Rate
Blood samples will be collected for clinical biomarker testing and a tumor specimen will be collected as per tumor specimen collection requirements. The specimen will be evaluated by immunohistochemistry to determine the expression of tumor specific antigens and immune markers. The PD-L1 is a biomarker and will be assessed using the VENTANA PD-L1 (SP263) assay.
Time frame: Up to approximately 89 months
Secondary
Durvalumab Versus Durvalumab Plus Tremelimumab: Objective Response Rate Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
ORR per RECIST 1.1 assessed by BICR is defined as the percentage of participants with at least 1 visit response of CR or PR (i.e., unconfirmed response). CR is defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.
Time frame: From date of randomization until death due to any cause, up to approximately 89 months
Secondary
Durvalumab Versus Durvalumab Plus Tremelimumab: Overall Survival
OS is defined as the time from the date of randomization until death due to any cause.
Time frame: From date of randomization until death due to any cause, up to approximately 89 months
Secondary
Durvalumab Versus Durvalumab Plus Tremelimumab: Progression-Free Survival Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR is defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anticancer therapy prior to progression. PD is defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir.
Time frame: Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to approximately 89 months
Secondary
Durvalumab Versus Placebo: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
ORR per RECIST 1.1 assessed by BICR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) (i.e., unconfirmed response). CR was defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR was defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.
Time frame: Response evaluations performed q8w ± 1 week up to 72 weeks, then q12w ± 1 week up to 96 weeks, and then q24w thereafter until PD, up to DCO date 15 January 2024 (a maximum of approximately 1936 days)
Population: The FAS included all randomized participants. Only participants with measurable disease at baseline per BICR are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 30.3 percentage of participants |
| Placebo | Durvalumab Versus Placebo: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 32.0 percentage of participants |
Secondary
Durvalumab Versus Placebo: Percentage of Participants Alive at 24 Months From Randomization (OS24)
OS was defined as the time from the date of randomization until death due to any cause. The OS24 was defined as the Kaplan-Meier estimate of OS at 24 months after randomization.
Time frame: Month 24
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Percentage of Participants Alive at 24 Months From Randomization (OS24) | 68.0 percentage of participants |
| Placebo | Durvalumab Versus Placebo: Percentage of Participants Alive at 24 Months From Randomization (OS24) | 58.5 percentage of participants |
Secondary
Durvalumab Versus Placebo: Percentage of Participants Alive at 36 Months From Randomization (OS36)
OS was defined as the time from the date of randomization until death due to any cause. The OS36 was defined as the Kaplan-Meier estimate of OS at 36 months after randomization.
Time frame: Month 36
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Percentage of Participants Alive at 36 Months From Randomization (OS36) | 56.5 percentage of participants |
| Placebo | Durvalumab Versus Placebo: Percentage of Participants Alive at 36 Months From Randomization (OS36) | 47.6 percentage of participants |
Secondary
Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 18 Months Following Randomization (PFS18) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS18 was defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 18 months following randomization.
Time frame: Month 18
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 18 Months Following Randomization (PFS18) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 48.8 percentage of participants |
| Placebo | Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 18 Months Following Randomization (PFS18) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 36.1 percentage of participants |
Secondary
Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 24 Months Following Randomization (PFS24) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1
PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir. The PFS24 was defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by BICR at 24 months following randomization.
Time frame: Month 24
Population: The FAS included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab | Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 24 Months Following Randomization (PFS24) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 46.2 percentage of participants |
| Placebo | Durvalumab Versus Placebo: Percentage of Participants Progression-Free at 24 Months Following Randomization (PFS24) Assessed by Blinded Independent Central Review Per Response Evaluation Criteria in Solid Tumors Version 1.1 | 34.2 percentage of participants |