Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Lung Neoplasms

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Small Cell

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Etoposide

Carboplatin

Cisplatin

Durvalumab

Etoposide phosphate

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Induction:

Durvalumab + Platinum Chemotherapy (Carboplatin or cisplatin \& Etoposide)

Maintenance:

AZD2811 + Durvalumab

IV infusions through induction phase.

IV infusions through maintenance phase until PD or other discontinuation criteria.

IV infusions through maintenance phase until PD or other discontinuation criteria.

AZD2811

IV infusions through induction phase if chosen by Investigator.

A Phase II Multicenter, Open-Label, Single Arm Study to Determine the Efficacy, Safety and Tolerability of AZD2811 and Durvalumab Combination as Maintenance Therapy After Induction with Platinum-Based Chemotherapy Combined with Durvalumab, for the First-Line Treatment of Patients with Extensive Stage Small-Cell Lung Cancer.

Primary objective of this study is to evaluate the efficacy of AZD2811 and durvalumab in patients who have not progressed following induction therapy with platinum-based chemotherapy combined with durvalumab.

This is an open-label, single arm study. Patients will be treated in an induction phase with platinum-based induction therapy and durvalumab. At the end of this induction period, participants will be assessed for disease progression, per RECIST v1.1.

Participants who have not progressed per RECIST v1.1 at the end of the induction phase will roll over into the maintenance phase of the trial, where patients will commence AZD2811 and durvalumab combination.

Participants will be treated with AZD2811 and durvalumab as maintenance therapy until confirmed progressive disease, start of non-protocol defined anticancer therapy, unacceptable toxicity, or withdrawal of consent.

If study intervention is permanently discontinued, the participant will remain in the study to be evaluated for safety assessment, as well as for confirmed disease progression and for survival.

Targeted population are adult patients (aged ≥18 years) with histologically or cytologically documented extensive disease (American Joint Committee on Cancer Stage (7th edition) IV SCLC \[T any, N any,M1 a/b\]), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan. Patients must have WHO/ECOG performance status of 0 or 1.

Tumor assessments will be performed at Screening as baseline with follow-up every 6 weeks ± 1 week for the first 36 weeks, and then every 8 weeks ±1 week until confirmed objective disease progression.

Study of AZD2811 + Durvalumab in ES-SCLC

A Phase II Multicenter, Open-Label, Single Arm Study to Determine the Efficacy, Safety and Tolerability of AZD2811 and Durvalumab Combination as Maintenance Therapy After Induction With Platinum-Based Chemotherapy Combined With Durvalumab, for the First-Line Treatment of Patients With Extensive Stage Small-Cell Lung Cancer

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Incidence of adverse events as measured by CTCAE 5.0

The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), 6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a global measure of health status. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 Scoring Manual.

Quality of life issues are assessed using a four-point scale (1= not at all, 2 = a little, 3 = quite a bit, 4 = very much), apart from two questions which are measured between 1 (Very Poor) to 7 (Excellent).

The EORTC QLQ-LC13 is a 13-item questionnaire comprised of 1 symptom scale assessing dysponea, and a series of single questions assessing cough, haemoptysis, sore mouth, dysphagis, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, pain in other parts, and use of pain medication. All items are assessed using a Likert four-point scale (1= not at all to 4 = very much).

Scoring will be done according to the EORTC QLQ-C30 Scoring Manual (Fayers et al., 2001). A high score for a symptom scale or single item represents a high level of symptomology or problems.

AstraZeneca

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Tremelimumab

durvalumab+tremelimumab+EP (carboplatin or cisplatin + etoposide)

durvalumab+EP (carboplatin or cisplatin + etoposide)

EP (carboplatin or cisplatin + etoposide)

IV infusions every 3 weeks for 12 weeks (4 cycles) and every 4 weeks thereafter until PD or other discontinuation criteria.

IV infusions every 3 weeks for 12 weeks(4 cycles). An additional dose of tremelimumab will be administered in the week 16.

up to 4 cycles every 3 weeks in Arm 1 and 2, up to 6 cycles every 3 weeks in Arm 3

Haiyi Jiang, M.D.

This is a phase III, randomized, open-label, multicenter, global study to determine the efficacy and safety of combining durvalumab ± tremelimumab with platinum based chemotherapy (EP) followed by durvalumab ± tremelimumab maintenance therapy versus EP alone as first-line treatment in patients with extensive-stage small-cell lung cancer

Primary objective of this study is to assess the efficacy of durvalumab + tremelimumab + EP treatment compared with EP and the efficacy of durvalumab + EP treatment compared with EP in terms of OS.

All patients will be randomized in a 1:1:1 ratio in a stratified manner according to the planned platinum-based therapy for Cycle 1 (cisplatin or carboplatin) to receive treatment with durvalumab + tremelimumab + EP (Arm 1), durvalumab + EP (Arm 2), or standard of care- EP (Arm 3). Arm 1 and Arm 2 patients receive the treatment until confirmed disease progression while Arm 3 patients receive up to 6 cycles of EP and prophylactic cranial irradiation if clinically indicated, at the Investigators' discretion.Patients who have discontinued treatment due to toxicity or symptomatic deterioration, clinical progression, or who have commenced subsequent anticancer therapy will be followed up until confirmed disease progression and for survival.

Targeted population are adult patients (aged ≥18 years) with histologically or cytologically documented extensive disease (American Joint Committee on Cancer Stage (7th edition) IV SCLC \[T any, N any,M1 a/b\]), or T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan. Patients must have WHO/ECOG performance status of 0 or 1.

Tumor assessments will be performed at Screening as baseline with follow-up at Week 6 ±1 week from the date of randomization, at Week 12 ±1 week from the date of randomization, and then every 8 weeks ±1 week until confirmed objective disease progression.

An independent data monitoring committee (IDMC) comprised of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule of durvalumab ± tremelimumab in combination with platinum based chemotherapy at two early stages of enrolment.

Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer (CASPIAN)

A Phase III, Randomized, Multicenter,Open-Label, Comparative Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination With Platinum-Based Chemotherapy for the First-Line Treatment in Patients With Extensive Disease Small-Cell Lung Cancer (SCLC) (CASPIAN)

OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An interim analysis of OS in the global cohort was pre-specified after approximately 318 OS events occurred each between the D + EP and EP groups (60% maturity), and between the D + T + EP and EP groups (60% maturity). At the global cohort interim analysis DCO (11 March 2019), comparison of OS in the D + EP versus (vs) EP groups had crossed the pre-specified boundary. Since these results were considered final in terms of formal statistical testing, they are presented here as a primary outcome measure. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the global cohort final analysis is presented separately in the subsequent primary outcome measure.

OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This primary outcome measure presents OS for the analysis of D + EP vs EP and D + T + EP vs EP at the time of the global cohort final analysis DCO (27 January 2020). Analysis of D + EP vs EP at the global cohort interim analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (global cohort final analysis) is presented as a secondary outcome measure.

OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + EP vs EP in the China cohort was pre-specified at approximately 60% maturity (to ensure a similar maturity to the interim analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP at the China cohort first analysis DCO (06 January 2020), and is comparable in terms of maturity with the interim analysis of OS for D + EP vs EP in the Global cohort. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the China cohort second analysis is presented separately in the subsequent primary outcome measure.

OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + T + EP vs EP in the China cohort was pre-specified at approximately 80% maturity (to ensure a similar maturity to the final analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP and D + T + EP vs EP at the time of the China cohort second analysis DCO (02 November 2020), and is comparable in terms of maturity with the final analysis of OS for D + EP vs EP and D + T + EP vs EP in the Global cohort. Analysis of D + EP vs EP at the China cohort first analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (China cohort second analysis) is presented as a secondary outcome measure.

OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP in the global cohort. The alternative treatment comparisons in the global cohort were performed as primary outcome measures.

PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 \[RECIST 1.1\] using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir) and an absolute increase of ≥5 millimeters (mm) for the sum from nadir. For evaluation of non-target lesions (NTLs), PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.

ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR). CR was defined as disappearance of all TLs since baseline (any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size \[\<10 mm short axis\]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).

The APF6 was defined as the percentage of patients who were alive and progression free at 6 months from randomization (ie, PFS rate at 6 months). PFS was calculated using the Kaplan-Meier technique.

The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PFS was calculated using the Kaplan-Meier technique.

OS18 was defined as the percentage of patients who were alive at 18 months after randomization per the Kaplan-Meier estimate of OS at 18 months.

To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.

To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.

Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of neutralizing antibody (nAb) was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.

Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA (or ADA incidence) was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to tremelimumab for each indicated category.

The EORTC QLQ-Core 30 version 3 (QLQ-C30 v3) was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.

The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and side effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (an increase in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.

A mixed model repeated measures (MMRM) analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs P. Analysis of D + EP vs EP is presented in a separate outcome measure.

A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + EP vs EP. Analysis of D + T + EP vs EP is presented in a separate outcome measure.

OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This secondary outcome measure presents OS for the analysis of D + T + EP vs D + EP at the China cohort second analysis DCO (02 November 2020). The alternative treatment comparisons were performed as primary outcome measures.

PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Progression (ie, PD) was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir) and an absolute increase of ≥5 mm for the sum from nadir. For evaluation of NTLs, PD was defined as unequivocal progression of existing NTLs. Median PFS was calculated using the Kaplan-Meier technique.

ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of patients with at least 1 visit response of CR or PR. CR was defined as disappearance of all TLs since baseline (any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm) or disappearance of all NTLs since baseline (all lymph nodes must be non-pathological in size \[\<10 mm short axis\]). PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters).

Serum sampling for ADA assessment was conducted utilizing a tiered approach (screen, confirm, titer). ADA positive post-baseline only was also referred to as treatment-induced ADA. Treatment-emergent ADA was defined as the sum of treatment-induced ADA and treatment-boosted ADA (defined as baseline positive ADA titer that was boosted to ≥4-fold during the study period). Persistently positive was defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks between first and last positive, or an ADA positive result at the last available assessment. Transiently positive was defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of nAb was tested for all ADA positive samples. Results are reported as number of patients with ADA responses to durvalumab for each indicated category.

The EORTC QLQ-C30 v3 was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration (calculated using the Kaplan-Meier technique) was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in score from baseline of ≥10) that is confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.

A MMRM analysis of EORTC QLQ-C30 and EORTC QLQ-LC13 was performed for 5 primary PRO symptoms (cough, dyspnea, chest pain, fatigue and appetite loss), and considered all data from baseline to PD or 12 months, excluding visits with excessive missing data (defined as \>75% missing data). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, with higher scores representing greater symptom severity. An improvement in symptoms was indicated by a negative change from baseline. A positive change from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as an absolute change from baseline of ≥10. This outcome measure presents change from baseline for primary PRO symptoms (reported as adjusted means) for analysis of D + T + EP vs EP. Analysis of D + EP vs EP is presented in a separate outcome measure.

TEAEs included those from first administration of study treatment up to and including 90 days after last dose of study treatment or up to date of initiation of the first subsequent anticancer therapy (whichever occurred first). Data from the global cohort and China cohort safety analysis sets was summarised separately. 6 patients in the China cohort were also included in the global cohort.

During Chemotherapy:

Patients received durvalumab (D) 1500 mg in combination with tremelimumab (T) 75 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m\^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m\^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg IV infusion post-chemotherapy (in combination with durvalumab) at Week 16 if they completed all 4 doses of durvalumab + tremelimumab during chemotherapy.

Global Cohort: D + T + EP

During Chemotherapy:

Patients received durvalumab (D) 1500 mg IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). For chemotherapy (EP), patients received etoposide (80-100 mg/m\^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m\^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9).

Post-Chemotherapy:

Patients then continued to receive durvalumab 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

Global Cohort: D + EP

For chemotherapy (EP), patients received etoposide (80-100 mg/m\^2) with either carboplatin (area under the curve 5-6) or cisplatin (75-80 mg/m\^2) IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). An additional 2 doses of EP (at Weeks 12 and 15) could be given at the investigators' discretion if clinically indicated.

Global Cohort: EP

China Cohort: D + T + EP

China Cohort: D + EP

China Cohort: EP

All Patients: D + T + EP

All Patients: D + EP

All Patients: EP

Total

Al Patients

Global Cohort

China Cohort

Baseline data is presented for all patients, as well as separately for the global and China cohorts.

Age, Customized

All Patients

Sex: Female, Male

Ethnicity (NIH/OMB)

Race

Baseline analysis was based on the global full analysis set (FAS) (all patients randomized prior to the end of global recruitment) plus the China FAS (all randomized patients in the China cohort). Patients included in both cohorts are not double-counted for the baseline analysis represented by 'All Patients'.

Analysis of the China cohort was performed to evaluate the consistency of efficacy and safety in Chinese patients with the global cohort in order to meet regulatory requirements and was not powered for a formal assessment of statistical significance.

Global Clinical Lead

D + EP vs EP. The global cohort interim analysis of OS was based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary, using the actual number of events observed as a proportion of the planned total. Boundary for declaring statistical significance was 0.0178 for a 4% overall alpha. Hazard Ratio (HR) \<1 favors D + EP to be associated with a longer OS than EP.

The global FAS included all patients randomized prior to the end of global recruitment. Interim analysis for OS in the global cohort was performed for comparison of the D + EP vs EP groups only.

Overall Survival (OS) in the Global Cohort; Assessed at Global Cohort Interim Analysis; D + EP Compared With EP

D + EP vs EP. HR \<1 favors D + EP to be associated with a longer OS than EP.

D + T + EP vs EP. The alpha level applied at the global cohort final analysis was adjusted (using a generalized Haybittle-Peto method) to account for actual alpha spent at the interim analysis based on the actual final total number of events, and thus maintain control of overall Type I error. Boundary for declaring statistical significance was 0.0418 for a 5% overall alpha.

HR \<1 favors D + T + EP to be associated with a longer OS than EP.

The global FAS included all patients randomized prior to the end of global recruitment.

OS in the Global Cohort; Assessed at Global Cohort Final Analysis; D + EP Compared With EP and D + T + EP Compared With EP

D + EP vs EP. HR \<1 favors D + EP to be associated with a longer OS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

The China FAS included all randomized patients in the China cohort. China cohort first analysis for OS was performed for comparison of the D + EP vs EP groups only.

OS in the China Cohort; Assessed at China Cohort First Analysis; D + EP Compared With EP

D + T + EP vs EP. HR \<1 favors D + T + EP to be associated with a longer OS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

The China FAS included all randomized patients in the China cohort.

OS in the China Cohort; Assessed at China Cohort Second Analysis; D + EP Compared With EP and D + T + EP Compared With EP

D + T + EP vs D + EP. HR \<1 favors D + T + EP to be associated with a longer OS than D + EP.

OS in the Global Cohort; D + T + EP Compared With D + EP

D + EP vs EP. HR \<1 favors D + EP to be associated with a longer PFS than EP.

D + T + EP vs EP. HR \<1 favors D + T + EP to be associated with a longer PFS than EP.

D + T + EP vs D + EP. HR \<1 favors D + T + EP to be associated with a longer PFS than D + EP.

Progression-Free Survival (PFS) in the Global Cohort

D + EP vs EP. An odds ratio \>1 favors D + EP.

D + T + EP vs EP. An odds ratio \>1 favors D + T + EP.

The global FAS included all patients randomized prior to the end of global recruitment. The denominator was a subset of the FAS population who had measurable disease at baseline.

Objective Response Rate (ORR) in the Global Cohort

Percentage of Patients Alive and Progression Free at 6 Months (APF6) in the Global Cohort

Percentage of Patients Alive and Progression Free at 12 Months (APF12) in the Global Cohort

Percentage of Patients Alive at 18 Months (OS18) in the Global Cohort

Week 0: peak concentration

Week 3: trough concentration

Week 12: trough concentration

The global PK analysis set included all patients randomized prior to the end of global recruitment who received at least 1 dose of investigational product (IP), per the protocol for whom any post-dose PK data were available. PK for durvalumab was performed for the D + T + EP and D + EP groups only.

Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations in the Global Cohort

The global PK analysis set included all patients randomized prior to the end of global recruitment who received at least 1 dose of IP, per the protocol for whom any post-dose PK data were available. PK for tremelimumab was performed for the D + T + EP group only.

PK of Tremelimumab; Peak and Trough Serum Concentrations in the Global Cohort

ADA positive at any visit (ADA prevalence)

Treatment-emergent ADA positive (ADA incidence)

Treatment-boosted ADA

Treatment-induced ADA (ADA positive post-baseline only)

ADA positive at baseline only

ADA positive post-baseline and positive at baseline

Persistently positive

Transiently positive

nAb positive at any visit

The global ADA evaluable patients included those in the global safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for durvalumab was performed for the D + T + EP and D + EP groups only. The denominator was durvalumab ADA evaluable patients.

Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab in the Global Cohort

The global ADA evaluable patients included those in the global safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for tremelimumab was performed for the D + T + EP group only. The denominator was tremelimumab ADA evaluable patients.

Number of Patients With ADA Response to Tremelimumab in the Global Cohort

QLQ-C30 Global Health Status / HRQoL

QLQ-C30 Cognitive Functioning

QLQ-C30 Emotional Functioning

QLQ-C30 Physical Functioning

QLQ-C30 Role Functioning

QLQ-C30 Social Functioning

QLQ-C30 Fatigue

QLQ-C30 Nausea / Vomiting

QLQ-C30 Pain

QLQ-C30 Appetite Loss

QLQ-C30 Constipation

QLQ-C30 Diarrhea

QLQ-C30 Dyspnea

QLQ-C30 Insomnia

The global FAS included all patients randomized prior to the end of global recruitment. For QLQ-C30 function scales and global health status/HRQoL, only patients with baseline scores ≥10 (and with data available) were included in the analysis. For QLQ-C30 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.

Time to Deterioration of Health-Related Quality of Life (HRQoL) and Patient Reported Outcome (PRO) Symptoms, Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) in the Global Cohort

QLQ-LC13 Coughing

QLQ-LC13 Dyspnea

QLQ-LC13 Hemoptysis

QLQ-LC13 Pain in Arm or Shoulder

QLQ-LC13 Pain in Chest

QLQ-LC13 Pain in Other Parts

The global FAS included all patients randomized prior to the end of global recruitment. For QLQ-L13 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.

Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) in the Global Cohort

EORTC QLQ-LC13 Cough

EORTC QLQ-LC13 Dyspnea

EORTC QLQ-LC13 Chest pain

EORTC QLQ-C30 Fatigue

EORTC QLQ-C30 Appetite loss

The global FAS included all patients randomized prior to the end of global recruitment. For each symptom scale, only patients with data available were included in the analysis.

Change From Baseline in Primary PRO Symptoms as Assessed by EORTC QLQ in the Global Cohort; D + T + EP Compared With EP

Change From Baseline in Primary Symptoms, Assessed Using EORTC QLQ-C30 and EORTC QLQ-LC13 in the Global Cohort; D + EP Compared With EP

D + T + EP vs D + EP. HR \<1 favors D + T + EP to be associated with a longer OS than D + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

OS in the China Cohort; D + T + EP Compared With D + EP

D + EP vs EP. HR \<1 favors D + EP to be associated with a longer PFS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

D + T + EP vs EP. HR \<1 favors D + T + EP to be associated with a longer PFS than EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

D + T + EP vs D + EP. HR \<1 favors D + T + EP to be associated with a longer PFS than D + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

PFS in the China Cohort

D + EP vs EP. An odds ratio \>1 favors D + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

D + T + EP vs EP. An odds ratio \>1 favors D + T + EP. The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory.

ORR in the China Cohort

APF6 in the China Cohort

APF12 in the China Cohort

OS18 in the China Cohort

The China PK analysis set included all patients in the China cohort who received at least 1 dose of IP, per the protocol for whom any post-dose PK data were available. PK for durvalumab was performed for the D + T + EP and D + EP groups only.

PK of Durvalumab; Peak and Trough Serum Concentrations in the China Cohort

The China PK analysis set included all patients in the China cohort who received at least 1 dose of IP, per the protocol for whom any post-dose PK data were available. PK for tremelimumab was performed for the D + T + EP group only.

PK of Tremelimumab; Peak and Trough Serum Concentrations in the China Cohort

The China ADA evaluable patients included those in the China safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for durvalumab was performed for the D + T + EP and D + EP groups only. The denominator was durvalumab ADA evaluable patients.

Number of Patients With ADA Response to Durvalumab in the China Cohort

The China ADA evaluable patients included those in the China safety analysis set who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA result. ADA for tremelimumab was performed for the D + T + EP group only. The denominator was tremelimumab ADA evaluable patients.

Number of Patients With ADA Response to Tremelimumab in the China Cohort

The China FAS included all randomized patients in the China cohort. For QLQ-C30 function scales and global health status/HRQoL, only patients with baseline scores ≥10 (and with data available) were included in the analysis. For QLQ-C30 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of AZD2811 + Durvalumab in ES-SCLC	NCT04745689	Small-Cell Lung...	Durvalumab AZD2811 Carboplatin Cisplatin Etoposide	18 Years - 130 Years	AstraZeneca
Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer (CASPIAN)	NCT03043872	Small Cell Lung...	Durvalumab Tremelimumab Carboplatin Cisplatin Etoposide	18 Years - 130 Years	AstraZeneca
Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer (CASPIAN)	NCT03043872	Small Cell Lung...	Durvalumab Tremelimumab Carboplatin Cisplatin Etoposide	18 Years - 130 Years	AstraZeneca
Study of AZD2811 + Durvalumab in ES-SCLC	NCT04745689	Small-Cell Lung...	Durvalumab AZD2811 Carboplatin Cisplatin Etoposide	18 Years - 130 Years	AstraZeneca

Spots Global Cancer Trial Database for oat cell carcinoma of lung