This is a phase III, randomized, open-label, multicenter, global study to determine the efficacy and safety of combining durvalumab ± tremelimumab with platinum based chemotherapy (EP) followed by durvalumab ± tremelimumab maintenance therapy versus EP alone as first-line treatment in patients with extensive-stage small-cell lung cancer
Primary objective of this study is to assess the efficacy of durvalumab + tremelimumab + EP treatment compared with EP and the efficacy of durvalumab + EP treatment compared with EP in terms of OS. All patients will be randomized in a 1:1:1 ratio in a stratified manner according to the planned platinum-based therapy for Cycle 1 (cisplatin or carboplatin) to receive treatment with durvalumab + tremelimumab + EP (Arm 1), durvalumab + EP (Arm 2), or standard of care- EP (Arm 3). Arm 1 and Arm 2 patients receive the treatment until confirmed disease progression while Arm 3 patients receive up to 6 cycles of EP and prophylactic cranial irradiation if clinically indicated, at the Investigators' discretion.Patients who have discontinued treatment due to toxicity or symptomatic deterioration, clinical progression, or who have commenced subsequent anticancer therapy will be followed up until confirmed disease progression and for survival. Targeted population are adult patients (aged ≥18 years) with histologically or cytologically documented extensive disease (American Joint Committee on Cancer Stage (7th edition) IV SCLC \[T any, N any,M1 a/b\]), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan. Patients must have WHO/ECOG performance status of 0 or 1. Tumor assessments will be performed at Screening as baseline with follow-up at Week 6 ±1 week from the date of randomization, at Week 12 ±1 week from the date of randomization, and then every 8 weeks ±1 week until confirmed objective disease progression. An independent data monitoring committee (IDMC) comprised of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule of durvalumab ± tremelimumab in combination with platinum based chemotherapy at two early stages of enrolment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
987
IV infusions every 3 weeks for 12 weeks (4 cycles) and every 4 weeks thereafter until PD or other discontinuation criteria.
IV infusions every 3 weeks for 12 weeks(4 cycles). An additional dose of tremelimumab will be administered in the week 16.
up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3
Overall Survival (OS) in the Global Cohort; Assessed at Global Cohort Interim Analysis; D + EP Compared With EP
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An interim analysis of OS in the global cohort was pre-specified after approximately 318 OS events occurred each between the D + EP and EP groups (60% maturity), and between the D + T + EP and EP groups (60% maturity). At the global cohort interim analysis DCO (11 March 2019), comparison of OS in the D + EP versus (vs) EP groups had crossed the pre-specified boundary. Since these results were considered final in terms of formal statistical testing, they are presented here as a primary outcome measure. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the global cohort final analysis is presented separately in the subsequent primary outcome measure.
Time frame: From baseline until death due to any cause. Assessed until global cohort interim analysis DCO (maximum of approximately 23 months).
OS in the Global Cohort; Assessed at Global Cohort Final Analysis; D + EP Compared With EP and D + T + EP Compared With EP
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This primary outcome measure presents OS for the analysis of D + EP vs EP and D + T + EP vs EP at the time of the global cohort final analysis DCO (27 January 2020). Analysis of D + EP vs EP at the global cohort interim analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (global cohort final analysis) is presented as a secondary outcome measure.
Time frame: From baseline until death due to any cause. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
OS in the China Cohort; Assessed at China Cohort First Analysis; D + EP Compared With EP
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + EP vs EP in the China cohort was pre-specified at approximately 60% maturity (to ensure a similar maturity to the interim analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP at the China cohort first analysis DCO (06 January 2020), and is comparable in terms of maturity with the interim analysis of OS for D + EP vs EP in the Global cohort. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the China cohort second analysis is presented separately in the subsequent primary outcome measure.
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up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3
up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3
Research Site
Birmingham, Alabama, United States
Research Site
Scottsdale, Arizona, United States
Research Site
Rogers, Arkansas, United States
Research Site
Santa Monica, California, United States
Research Site
New Haven, Connecticut, United States
Research Site
Athens, Georgia, United States
Research Site
Fort Wayne, Indiana, United States
Research Site
Muncie, Indiana, United States
Research Site
Leawood, Kansas, United States
Research Site
Wichita, Kansas, United States
...and 197 more locations
Time frame: From baseline until death due to any cause. Assessed until China cohort first analysis DCO (maximum of approximately 19 months).
OS in the China Cohort; Assessed at China Cohort Second Analysis; D + EP Compared With EP and D + T + EP Compared With EP
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + T + EP vs EP in the China cohort was pre-specified at approximately 80% maturity (to ensure a similar maturity to the final analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP and D + T + EP vs EP at the time of the China cohort second analysis DCO (02 November 2020), and is comparable in terms of maturity with the final analysis of OS for D + EP vs EP and D + T + EP vs EP in the Global cohort. Analysis of D + EP vs EP at the China cohort first analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (China cohort second analysis) is presented as a secondary outcome measure.
Time frame: From baseline until death due to any cause. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
OS in the Global Cohort; D + T + EP Compared With D + EP
OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP in the global cohort. The alternative treatment comparisons in the global cohort were performed as primary outcome measures.
Time frame: From baseline until death due to any cause. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Progression-Free Survival (PFS) in the Global Cohort
PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 \[RECIST 1.1\] using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, 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) and an absolute increase of ≥5 millimeters (mm) for the sum from nadir. For evaluation of non-target lesions (NTLs), PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Objective Response Rate (ORR) in the Global Cohort
ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR). 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) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size \[\<10 mm short axis\]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Percentage of Patients Alive and Progression Free at 6 Months (APF6) in the Global Cohort
The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 6 months post-randomization.
Percentage of Patients Alive and Progression Free at 12 Months (APF12) in the Global Cohort
The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 12 months post-randomization.
Percentage of Patients Alive at 18 Months (OS18) in the Global Cohort
OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.
Time frame: At 18 months post-randomization. Assessed at the global cohort final analysis DCO (27 January 2020).
Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations in the Global Cohort
To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time frame: Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the global cohort final analysis DCO (27 January 2020).
PK of Tremelimumab; Peak and Trough Serum Concentrations in the Global Cohort
To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time frame: Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the global cohort final analysis DCO (27 January 2020).
Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab in the Global Cohort
Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of neutralizing antibody (nAb) was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.
Time frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, durvalumab). Assessed at the global cohort final analysis DCO (27 January 2020).
Number of Patients With ADA Response to Tremelimumab in the Global Cohort
Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.
Time frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, tremelimumab). Assessed at the global cohort final analysis DCO (27 January 2020).
Time to Deterioration of Health-Related Quality of Life (HRQoL) and Patient Reported Outcome (PRO) Symptoms, Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) in the Global Cohort
The EORTC QLQ-Core 30 version 3 (QLQ-C30 v3) was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) in the Global Cohort
The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until global cohort final analysis DCO (maximum of approximately 33 months).
Change From Baseline in Primary PRO Symptoms as Assessed by EORTC QLQ in the Global Cohort; D + T + EP Compared With EP
A mixed model repeated measures (MMRM) analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs P. Analysis of D + EP vs EP is presented in a separate outcome measure.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
Change From Baseline in Primary Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the Global Cohort; D + EP Compared With EP
A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
OS in the China Cohort; D + T + EP Compared With D + EP
OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP at the China cohort second analysis DCO (02 November 2020). The alternative treatment comparisons were performed as primary outcome measures.
Time frame: From baseline until death due to any cause. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
PFS in the China Cohort
PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, 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) and an absolute increase of ≥5 mm for the sum from nadir. For evaluation of NTLs, PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
ORR in the China Cohort
ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of CR or PR. 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) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size \[\<10 mm short axis\]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
APF6 in the China Cohort
The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 6 months post-randomization.
APF12 in the China Cohort
The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline, Week 6, Week 12 then every 8 weeks relative to the date of randomization until RECIST 1.1-defined progression. Assessed until 12 months post-randomization.
OS18 in the China Cohort
OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.
Time frame: At 18 months post-randomization. Assessed at the China cohort second analysis DCO (02 November 2020).
PK of Durvalumab; Peak and Trough Serum Concentrations in the China Cohort
To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time frame: Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the China cohort second analysis DCO (02 November 2020).
PK of Tremelimumab; Peak and Trough Serum Concentrations in the China Cohort
To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
Time frame: Samples were collected post-dose on Day 1 (Week 0), and pre-dose on Weeks 3 and 12. Assessed at the China cohort second analysis DCO (02 November 2020).
Number of Patients With ADA Response to Durvalumab in the China Cohort
Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.
Time frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, durvalumab). Assessed at the China cohort second analysis DCO (02 November 2020).
Number of Patients With ADA Response to Tremelimumab in the China Cohort
Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.
Time frame: Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of IP (ie, tremelimumab). Assessed at the China cohort second analysis DCO (02 November 2020).
Time to Deterioration of HRQoL and PRO Symptoms, Assessed Using EORTC QLQ in the China Cohort
The EORTC QLQ-C30 v3 was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-LC13 in the China Cohort
The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed until China cohort second analysis DCO (maximum of approximately 29 months).
Change From Baseline in Primary PRO Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the China Cohort; D + T + EP Compared With EP
A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs EP. Analysis of D + EP vs EP is presented in a separate outcome measure.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.
Change From Baseline in Primary Symptoms as Assessed by EORTC QLQ in the China Cohort; D + EP Compared With EP
A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.
Time frame: At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever comes first). Assessed up to 12 months.