Urothelial Cancer
Conditions
Keywords
Urothelial Cancer, Phase III
Brief summary
A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV Urothelial Cancer
Detailed description
This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and MEDI4736 (Durvalumab) in combination with tremelimumab versus SoC (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines. The patients enrolled in the study will be randomized 1:1:1 to receive treatment with combination therapy, monotherapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility). Patients will be treated with MEDI4736 (Durvalumab) or MEDI4736 (Durvalumab) with tremelimumab, or treated with SoC until progressive disease (PD) is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.
Interventions
IV infusion
DRUGTremelimumab
IV infusion
DRUGCisplatin
IV infusion
DRUGCarboplatin
IV infusion
DRUGGemcitabine
IV infusion
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma of the urothelium who have not been previously treated with first-line chemotherapy. * Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria: • Creatinine clearance (calculated or measured) \<60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection for determination • Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss • CTCAE Grade ≥2 peripheral neuropathy • New York Heart Association ≥Class III heart failure. * Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference laboratory, must be known prior to randomization.
Exclusion criteria
* Prior exposure to immune-mediated therapy, including but not limited to, other anti cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment. * History of allogenic organ transplantation that requires use of immunosuppressive agents. * Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement • Any chronic skin condition that does not require systemic therapy • Patients without active disease in the last 3 years may be included but only after consultation with AstraZeneca • Patients with celiac disease controlled by diet alone may be included but only after consultation with AstraZeneca. * Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status. * Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). * Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). The following are exceptions to this criterion: • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). * Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set | From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set | From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OS, Full Analysis Set - Durvalumab Monotherapy vs SoC | From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC | From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| Alive at 24 Months (OS24), Full Analysis Set | From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020). | Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months. |
| Alive at 24 Months (OS24), PD-L1-High Analysis Set | From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020). | Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months. |
| Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set | From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020). | Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months. |
| PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. |
| PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. |
| PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. |
| Alive and Progression-free at 12 Months (APF12), Full Analysis Set | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). | Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months. |
| Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). | Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months. |
| Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). | Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months. |
| PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique. |
| PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique. |
| PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique. |
| Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. |
| Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. |
| Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. |
| Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years). | Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. unconfirmed responses are excluded. |
| Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020). | Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment. |
| Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020). | Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment. |
| Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020). | Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment. |
| Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020) | Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment. |
| Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). | Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment. |
| Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). | Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment. |
| Duration of Response (DoR), Full Analysis Set | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). |
| Duration of Response (DoR), PD-L1-High Analysis Set | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). |
| Duration of Response (DoR), PD-L1-Low/Negative Analysis Set | Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). |
| Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3. | Blood samples were collected to determine the serum concentration of durvalumab. |
| Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3. | Blood samples were collected to determine the serum concentration of tremelimumab. |
| Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | At week 0, 4, 12 and 24, and at follow-up Month 3. | Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline. |
| Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | At week 0, 4, 12 and at follow-up Month 3. | Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline. |
| Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse outcome. |
| Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse |
| Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4. Higher score represent worse |
| Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL. |
| Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL. |
| Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). | Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL. |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Denmark, France, Germany, Greece, Israel, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy MEDI4736 (Durvalumab) + Tremelimumab | 342 |
| Monotherapy MEDI4736 (Durvalumab) | 346 |
| Standard of Care Standard of Care Chemotherapy Treatment | 344 |
| Total | 1,032 |
Baseline characteristics
| Characteristic | Combination Therapy | Monotherapy | Standard of Care | Total |
|---|---|---|---|---|
| Age, Continuous Age (years) | 66.4 years STANDARD_DEVIATION 9.6 | 66.3 years STANDARD_DEVIATION 9.9 | 67.0 years STANDARD_DEVIATION 9.32 | 66.5 years STANDARD_DEVIATION 9.6 |
| Age, Customized Age Group (Years) <50 | 19 Participants | 22 Participants | 14 Participants | 55 Participants |
| Age, Customized Age Group (Years) >= 50 - < 65 | 118 Participants | 115 Participants | 119 Participants | 352 Participants |
| Age, Customized Age Group (Years) >= 65 - < 75 | 132 Participants | 141 Participants | 137 Participants | 410 Participants |
| Age, Customized Age Group (Years) >= 75 | 73 Participants | 68 Participants | 74 Participants | 215 Participants |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 15 Participants | 14 Participants | 17 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 320 Participants | 329 Participants | 322 Participants | 971 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 7 Participants | 3 Participants | 5 Participants | 15 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 72 Participants | 60 Participants | 76 Participants | 208 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 3 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 13 Participants | 4 Participants | 8 Participants | 25 Participants |
| Race/Ethnicity, Customized Race Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 253 Participants | 278 Participants | 260 Participants | 791 Participants |
| Sex: Female, Male Sex Female | 86 Participants | 97 Participants | 70 Participants | 253 Participants |
| Sex: Female, Male Sex Male | 256 Participants | 249 Participants | 274 Participants | 779 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 255 / 342 | 263 / 346 | 270 / 344 |
| other Total, other adverse events | 306 / 340 | 312 / 345 | 299 / 313 |
| serious Total, serious adverse events | 179 / 340 | 139 / 345 | 125 / 313 |
Outcome results
Primary
To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set | 14.4 Months |
| Standard of Care | To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set | 12.1 Months |
p-value: 0.303996.99% CI: [0.695, 1.139]Log Rank
Primary
To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set | 15.1 Months |
| Standard of Care | To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set | 12.1 Months |
p-value: 0.075198.66% CI: [0.688, 1.063]Log Rank
Secondary
Alive and Progression-free at 12 Months (APF12), Full Analysis Set
Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Alive and Progression-free at 12 Months (APF12), Full Analysis Set | 21.4 percentage of participants |
| Standard of Care | Alive and Progression-free at 12 Months (APF12), Full Analysis Set | 16.8 percentage of participants |
| Standard of Care | Alive and Progression-free at 12 Months (APF12), Full Analysis Set | 15.3 percentage of participants |
Secondary
Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set
Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set | 25.6 percentage of participants |
| Standard of Care | Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set | 21.2 percentage of participants |
| Standard of Care | Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set | 15.0 percentage of participants |
Secondary
Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set
Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set | 15.2 percentage of participants |
| Standard of Care | Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set | 9.7 percentage of participants |
| Standard of Care | Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set | 15.6 percentage of participants |
Secondary
Alive at 24 Months (OS24), Full Analysis Set
Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time frame: From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Alive at 24 Months (OS24), Full Analysis Set | 39.0 percentage of participants |
| Standard of Care | Alive at 24 Months (OS24), Full Analysis Set | 31.5 percentage of participants |
| Standard of Care | Alive at 24 Months (OS24), Full Analysis Set | 29.0 percentage of participants |
Secondary
Alive at 24 Months (OS24), PD-L1-High Analysis Set
Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time frame: From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Alive at 24 Months (OS24), PD-L1-High Analysis Set | 43.7 percentage of participants |
| Standard of Care | Alive at 24 Months (OS24), PD-L1-High Analysis Set | 36.0 percentage of participants |
| Standard of Care | Alive at 24 Months (OS24), PD-L1-High Analysis Set | 29.3 percentage of participants |
Secondary
Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set
Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
Time frame: From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set | 32.1 percentage of participants |
| Standard of Care | Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set | 24.5 percentage of participants |
| Standard of Care | Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set | 28.6 percentage of participants |
Secondary
Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items I feel weak all overall and I feel light-headed (dizzy). The range of each item is 0-4. Higher score represent worse outcome.
Time frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -5.5 Scores on a scale | Standard Error 0.87 |
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -3.7 Scores on a scale | Standard Error 0.7 |
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -7.2 Scores on a scale | Standard Error 1.19 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -3.9 Scores on a scale | Standard Error 0.95 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -3.1 Scores on a scale | Standard Error 0.76 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -4.7 Scores on a scale | Standard Error 1.3 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -5.2 Scores on a scale | Standard Error 0.82 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -8.8 Scores on a scale | Standard Error 1.39 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -7.2 Scores on a scale | Standard Error 1.02 |
Comparison: NFBLSI- 18 score (Average overall visits)p-value: 0.161795% CI: [-0.6, 3.59]Mixed Models Analysis
Comparison: NFBLSI- 18 score (Average overall visits)p-value: 0.057895% CI: [-0.07, 4.29]Mixed Models Analysis
Comparison: FACT-BL TOI (Average overall visits)p-value: 0.200395% CI: [-0.91, 4.32]Mixed Models Analysis
Comparison: FACT-BL TOI (Average overall visits)p-value: 0.017895% CI: [0.57, 6]Mixed Models Analysis
Comparison: FACT-BL Total score (Average overall visits)p-value: 0.376595% CI: [-1.96, 5.17]Mixed Models Analysis
Comparison: FACT-BL Total score (Average overall visits)p-value: 0.0395% CI: [0.4, 7.81]Mixed Models Analysis
Secondary
Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items I feel weak all overall and I feel light-headed (dizzy). The range of each item is 0-4. Higher score represent worse
Time frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -5.8 Scores on a scale | Standard Error 1.09 |
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -3.9 Scores on a scale | Standard Error 0.85 |
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -8.0 Scores on a scale | Standard Error 1.47 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -2.6 Scores on a scale | Standard Error 1.11 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -2.0 Scores on a scale | Standard Error 0.87 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -2.7 Scores on a scale | Standard Error 1.51 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -5.7 Scores on a scale | Standard Error 0.95 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -10.1 Scores on a scale | Standard Error 1.65 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -8.0 Scores on a scale | Standard Error 1.22 |
Comparison: NFBLSI- 18 score (Average overall visits)p-value: 0.137395% CI: [-0.6, 4.36]Mixed Models Analysis
Comparison: NFBLSI- 18 score (Average overall visits)p-value: 0.003495% CI: [1.26, 6.27]Mixed Models Analysis
Comparison: FACT-BL TOI (Average overall visits)p-value: 0.177495% CI: [-1, 5.39]Mixed Models Analysis
Comparison: FACT-BL TOI (Average overall visits)p-value: 0.001195% CI: [2.19, 8.65]Mixed Models Analysis
Comparison: FACT-BL Total score (Average overall visits)p-value: 0.349495% CI: [-2.27, 6.38]Mixed Models Analysis
Comparison: FACT-BL Total score (Average overall visits)p-value: 0.001195% CI: [2.96, 11.71]Mixed Models Analysis
Secondary
Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score. All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104). NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items I feel weak all overall and I feel light-headed (dizzy). The range of each item is 0-4. Higher score represent worse
Time frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -4.9 Scores on a scale | Standard Error 1.18 |
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -3.4 Scores on a scale | Standard Error 1.01 |
| Combination Therapy | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -5.7 Scores on a scale | Standard Error 1.62 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -5.0 Scores on a scale | Standard Error 1.39 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -3.8 Scores on a scale | Standard Error 1.18 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -6.5 Scores on a scale | Standard Error 1.9 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | NFBLSI - 18 Score (Average overall visits) | -2.0 Scores on a scale | Standard Error 1.16 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL Total score (Average overall visits) | -3.2 Scores on a scale | Standard Error 1.86 |
| Standard of Care | Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | FACT-BL TOI (Average overall visits) | -3.0 Scores on a scale | Standard Error 1.36 |
Comparison: NFBLSI- 18 score (Average overall visits)p-value: 0.386595% CI: [-4.35, 1.69]Mixed Models Analysis
Comparison: NFBLSI- 18 score (Average overall visits)p-value: 0.28495% CI: [-5.05, 1.49]Mixed Models Analysis
Comparison: FACT-BL TOI (Average overall visits)p-value: 0.29795% CI: [-5.41, 1.66]Mixed Models Analysis
Comparison: FACT-BL TOI (Average overall visits)p-value: 0.302695% CI: [-5.85, 1.83]Mixed Models Analysis
Comparison: FACT-BL Total score (Average overall visits)p-value: 0.316895% CI: [-7.29, 2.38]Mixed Models Analysis
Comparison: FACT-BL Total score (Average overall visits)p-value: 0.217995% CI: [-8.51, 1.96]Mixed Models Analysis
Secondary
Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020)
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 38.0 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 28.0 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 50.6 percentage of participants |
p-value: 0.000895% CI: [0.432, 0.802]Regression, Logistic
p-value: <0.000195% CI: [0.27, 0.512]Regression, Logistic
Secondary
Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 47.3 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 30.6 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 48.8 percentage of participants |
p-value: 0.771795% CI: [0.639, 1.394]Regression, Logistic
p-value: 0.000195% CI: [0.303, 0.682]Regression, Logistic
Secondary
Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 24.1 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 24.1 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 53.3 percentage of participants |
p-value: <0.000195% CI: [0.151, 0.439]Regression, Logistic
Comparison: monotherapy as reference.p-value: 0.969295% CI: [0.556, 1.759]Regression, Logistic
Secondary
Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 41.5 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 31.8 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 55.5 percentage of participants |
p-value: 0.000295% CI: [0.41, 0.759]Regression, Logistic
p-value: <0.000195% CI: [0.267, 0.5]Regression, Logistic
Secondary
Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 49.8 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 34.4 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 53.1 percentage of participants |
p-value: 0.495995% CI: [0.59, 1.291]Regression, Logistic
p-value: 0.000195% CI: [0.305, 0.679]Regression, Logistic
Secondary
Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 29.2 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 27.7 percentage of participants |
| Standard of Care | Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 59.1 percentage of participants |
p-value: <0.000195% CI: [0.16, 0.448]Regression, Logistic
Comparison: monotherapy as reference.p-value: 0.807495% CI: [0.623, 1.836]Regression, Logistic
Secondary
Duration of Response (DoR), Full Analysis Set
Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Duration of Response (DoR), Full Analysis Set | 11.1 Months |
| Standard of Care | Duration of Response (DoR), Full Analysis Set | 9.3 Months |
| Standard of Care | Duration of Response (DoR), Full Analysis Set | 5.7 Months |
Secondary
Duration of Response (DoR), PD-L1-High Analysis Set
Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Duration of Response (DoR), PD-L1-High Analysis Set | 10.0 Months |
| Standard of Care | Duration of Response (DoR), PD-L1-High Analysis Set | 18.5 Months |
| Standard of Care | Duration of Response (DoR), PD-L1-High Analysis Set | 5.8 Months |
Secondary
Duration of Response (DoR), PD-L1-Low/Negative Analysis Set
Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1).
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Duration of Response (DoR), PD-L1-Low/Negative Analysis Set | 12.9 Months |
| Standard of Care | Duration of Response (DoR), PD-L1-Low/Negative Analysis Set | 5.6 Months |
| Standard of Care | Duration of Response (DoR), PD-L1-Low/Negative Analysis Set | 5.7 Months |
Secondary
Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Fatigue will be based on the question of I have a lack of energy and pain will be based on the question of I have pain, according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 38 Participants |
| Combination Therapy | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 142 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 37 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 130 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 24 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 83 Participants |
Comparison: Patients with improvement in fatiguep-value: 0.241995% CI: [0.8, 2.6]Regression, Logistic
Comparison: Patients with improvement in fatiguep-value: 0.155395% CI: [0.9, 2.8]Regression, Logistic
Comparison: Patient with deterioration in painp-value: 0.000395% CI: [1.4, 2.8]Regression, Logistic
Comparison: Patient with deterioration in painp-value: 0.014895% CI: [1.1, 2.3]Regression, Logistic
Secondary
Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Fatigue will be based on the question of I have a lack of energy and pain will be based on the question of I have pain, according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 23 Participants |
| Combination Therapy | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 78 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 24 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 71 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 14 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 51 Participants |
Comparison: Patients with improvement in fatiguep-value: 0.247395% CI: [0.7, 3.4]Regression, Logistic
Comparison: Patients with improvement in fatiguep-value: 0.014895% CI: [0.8, 3.8]Regression, Logistic
Comparison: Patient with deterioration in painp-value: 0.00995% CI: [1.2, 3]Regression, Logistic
Comparison: Patient with deterioration in painp-value: 0.15195% CI: [0.9, 2.3]Regression, Logistic
Secondary
Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Fatigue will be based on the question of I have a lack of energy and pain will be based on the question of I have pain, according to GP1 and GP4 in PWB, respectively. Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL. Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.
Time frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 15 Participants |
| Combination Therapy | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 64 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 13 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 59 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patients with improvement in fatigue | 10 Participants |
| Standard of Care | Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | Patient with deterioration in pain | 32 Participants |
Comparison: Patients with improvement in fatiguep-value: 0.676395% CI: [0.5, 3.2]Regression, Logistic
Comparison: Patients with improvement in fatiguep-value: 0.653995% CI: [0.5, 3.3]Regression, Logistic
Comparison: Patient with deterioration in painp-value: 0.009295% CI: [1.2, 4]Regression, Logistic
Comparison: Patient with deterioration in painp-value: 0.032495% CI: [1.1, 3.5]Regression, Logistic
Secondary
Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients
Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
Time frame: At week 0, 4, 12 and 24, and at follow-up Month 3.
Population: ADA evaluable patients is defined as patients in the safety analysis set who have a non-missing baseline ADA and at least one non-missing post-baseline result
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA evaluable patients | 293 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA positive at any visit (ADA Prevalence) | 37 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-emergent ADA positive (ADA Incidence) | 28 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-boosted ADA | 0 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-induced ADA (Positive Post-baseline only) | 28 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA Positive at Baseline only | 8 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA Positive Post-baseline and Positive at Baseline | 1 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Persistently Positive | 15 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Transiently Positive | 14 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | nAb Positive at any visit | 3 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Persistently Positive | 8 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA evaluable patients | 302 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA Positive at Baseline only | 18 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA positive at any visit (ADA Prevalence) | 31 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | nAb Positive at any visit | 2 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-emergent ADA positive (ADA Incidence) | 11 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | ADA Positive Post-baseline and Positive at Baseline | 3 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-boosted ADA | 1 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Transiently Positive | 5 Participants |
| Standard of Care | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-induced ADA (Positive Post-baseline only) | 10 Participants |
Secondary
Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients
Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
Time frame: At week 0, 4, 12 and at follow-up Month 3.
Population: ADA evaluable patients is defined as patients in the safety analysis set who have a non-missing baseline ADA and at least one non-missing post-baseline result
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | ADA evaluable patients | 292 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | ADA positive at any visit (ADA Prevalence) | 64 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-emergent ADA positive (ADA Incidence) | 54 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-boosted ADA | 1 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | Treatment-induced ADA (Positive Post-baseline only) | 53 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | ADA Positive at Baseline only | 8 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | ADA Positive Post-baseline and Positive at Baseline | 3 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | Persistently Positive | 31 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | Transiently Positive | 25 Participants |
| Combination Therapy | Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients | nAb Positive at any visit | 50 Participants |
Secondary
Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population
Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR. unconfirmed responses are excluded.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years).
Population: Durvalumab Cisplatin Ineligible Population include all patients who had received D monotherapy and were not eligible for cisplatin treatment at baseline (per eCRF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population | 23.0 percentage of participants |
| Standard of Care | Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population | 17.9 percentage of participants |
| Standard of Care | Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population | 21.0 percentage of participants |
Secondary
Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 36.3 percentage of participants |
| Standard of Care | Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 25.7 percentage of participants |
| Standard of Care | Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 49.1 percentage of participants |
p-value: 0.000595% CI: [0.422, 0.788]Regression, Logistic
p-value: <0.000195% CI: [0.253, 0.485]Regression, Logistic
Secondary
Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 46.8 percentage of participants |
| Standard of Care | Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 27.8 percentage of participants |
| Standard of Care | Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 48.3 percentage of participants |
p-value: 0.770895% CI: [0.639, 1.394]Regression, Logistic
p-value: <0.000195% CI: [0.268, 0.61]Regression, Logistic
Secondary
Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 20.4 percentage of participants |
| Standard of Care | Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 22.6 percentage of participants |
| Standard of Care | Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 50.4 percentage of participants |
p-value: <0.000195% CI: [0.135, 0.406]Regression, Logistic
Comparison: monotherapy as reference.p-value: 0.619595% CI: [0.469, 1.566]Regression, Logistic
Secondary
OS, Full Analysis Set - Durvalumab Monotherapy vs SoC
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | OS, Full Analysis Set - Durvalumab Monotherapy vs SoC | 13.2 Months |
| Standard of Care | OS, Full Analysis Set - Durvalumab Monotherapy vs SoC | 12.1 Months |
p-value: 0.863795% CI: [0.83, 1.169]Log Rank
Secondary
OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC | 17.9 Months |
| Standard of Care | OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC | 12.1 Months |
p-value: 0.009195% CI: [0.589, 0.928]Log Rank
Secondary
OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Time frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 11.8 Months |
| Standard of Care | OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 10.9 Months |
| Standard of Care | OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 12.2 Months |
p-value: 0.759995% CI: [0.799, 1.359]Log Rank
Comparison: monotherapy as reference.p-value: 0.442495% CI: [0.692, 1.175]Log Rank
Secondary
PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 14.6 Months |
| Standard of Care | PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 11.9 Months |
| Standard of Care | PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 11.5 Months |
p-value: 0.047795% CI: [0.683, 0.998]Log Rank
p-value: 0.788595% CI: [0.809, 1.175]Log Rank
Secondary
PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 17.2 Months |
| Standard of Care | PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 13.4 Months |
| Standard of Care | PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 11.3 Months |
p-value: 0.005395% CI: [0.549, 0.901]Log Rank
p-value: 0.133695% CI: [0.651, 1.059]Log Rank
Secondary
PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1). Median PFS2 was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 10.7 Months |
| Standard of Care | PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 9.4 Months |
| Standard of Care | PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 11.6 Months |
p-value: 0.814895% CI: [0.772, 1.391]Log Rank
Comparison: monotherapy as reference.p-value: 0.268495% CI: [0.636, 1.134]Log Rank
Secondary
PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC
Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 3.7 Months |
| Standard of Care | PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 2.3 Months |
| Standard of Care | PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC | 6.7 Months |
p-value: 0.257995% CI: [0.931, 1.304]Log Rank
p-value: 0.000895% CI: [1.124, 1.567]Log Rank
Secondary
PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC
Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-High as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~≥25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control OR ≥25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 4.1 Months |
| Standard of Care | PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 2.4 Months |
| Standard of Care | PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC | 5.8 Months |
p-value: 0.239595% CI: [0.705, 1.091]Log Rank
p-value: 0.243195% CI: [0.917, 1.406]Log Rank
Secondary
PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy
Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
Time frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
Population: The PD-L1-Low/Negative analysis set will include the subset of patients in the FAS whose PD-L1 status is PD-L1-Low/negative as defined by an Immunohistochemistry (IHC) assay developed by Ventana as:~\<25% tumor cell membrane positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control AND \<25% tumor associated immune cell positivity for PD-L1 at any intensity above background staining as noted on the corresponding negative control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 2.0 Months |
| Standard of Care | PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 2.0 Months |
| Standard of Care | PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy | 7.2 Months |
p-value: 0.001495% CI: [1.177, 1.99]Log Rank
Comparison: monotherapy as reference.p-value: 0.623695% CI: [0.729, 1.209]Log Rank
Secondary
Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set
Blood samples were collected to determine the serum concentration of durvalumab.
Time frame: Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.
Population: Pharmacokinetic analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol and had at least one post dose evaluable PK data of durvalumab or tremelimumab
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 0 - Predose | NA μg/mL | — |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 0 - Postdose | 511 μg/mL | Standard Deviation 338 |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 4 - Predose | 75.3 μg/mL | Standard Deviation 84.4 |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 12 - Predose | 125 μg/mL | Standard Deviation 97.7 |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 12 - Postdose | 594 μg/mL | Standard Deviation 298 |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 24 - Predose | 150 μg/mL | Standard Deviation 94.4 |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 24 - Postdose | 604 μg/mL | Standard Deviation 249 |
| Combination Therapy | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Follow-up Month 3 | 23.3 μg/mL | Standard Deviation 50 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Follow-up Month 3 | 19.9 μg/mL | Standard Deviation 18.4 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 0 - Predose | NA μg/mL | — |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 12 - Postdose | 576 μg/mL | Standard Deviation 233 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 0 - Postdose | 484 μg/mL | Standard Deviation 162 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 24 - Postdose | 600 μg/mL | Standard Deviation 244 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 4 - Predose | 78.9 μg/mL | Standard Deviation 56.5 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 24 - Predose | 163 μg/mL | Standard Deviation 82.5 |
| Standard of Care | Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set | Week 12 - Predose | 144 μg/mL | Standard Deviation 82.5 |
Secondary
Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set
Blood samples were collected to determine the serum concentration of tremelimumab.
Time frame: Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.
Population: Pharmacokinetic analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol and had at least one post dose evaluable PK data of durvalumab or tremelimumab
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Week 12 - Postdose | 28.1 μg/mL | Standard Deviation 13.2 |
| Combination Therapy | Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Week 0 - Predose | NA μg/mL | — |
| Combination Therapy | Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Week 0 - Postdose | 24.0 μg/mL | Standard Deviation 11.5 |
| Combination Therapy | Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Week 4 - Predose | 3.75 μg/mL | Standard Deviation 3.18 |
| Combination Therapy | Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Week 12 - Predose | 5.43 μg/mL | Standard Deviation 4.01 |
| Combination Therapy | Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set | Follow-up Month 3 | 0.943 μg/mL | Standard Deviation 1.4 |