Study of Durvalumab + Tremelimumab With Chemotherapy or Durvalumab With Chemotherapy or Chemotherapy Alone for Patients With Lung Cancer (POSEIDON).
- Conditions
- Non Small Cell Lung Cancer NSCLC
- Interventions
- Registration Number
- NCT03164616
- Lead Sponsor
- AstraZeneca
- Brief Summary
This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of durvalumab + tremelimumab combination therapy + Standard of care (SoC) chemotherapy or durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone as first line treatment in patients with metastatic non small-cell lung cancer (NSCLC) with tumors that lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions.
- Detailed Description
Adult patients with a histologically or cytologically documented metastatic NSCLC, with tumors that lack activating EGFR mutations and ALK fusions, are eligible for enrollment. Patients will be randomized in a 1:1:1 ratio to receive treatment with durvalumab + tremelimumab combination therapy + SoC chemotherapy, durvalumab monotherapy + SoC chemotherapy, or SoC chemotherapy alone. Tumor evaluation scans will be performed until objective disease progression as efficacy assessment. All patients will be followed for survival until the end of the study. An independent data monitoring committee (IDMC) composed of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 1186
For inclusion in the study, patients should fulfill the following criteria:
- Aged at least 18 years.
- Histologically or cytologically documented Stage IV NSCLC.
- Confirmed tumor PD-L1 status prior to randomization.
- Patients must have tumors that lack activating EGFR mutations and ALK fusions.
- No prior chemotherapy or any other systemic therapy for metastatic NSCLC.
- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- No prior exposure to immunemediated therapy, excluding therapeutic anticancer vaccines.
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
- Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant.
- Active or prior documented autoimmune or inflammatory disorders.
- Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids.
- Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment Arm 1 Pemetrexed + carboplatin durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 1 Pemetrexed + cisplatin durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 2 Pemetrexed + cisplatin durvalumab monotherapy + SoC chemotherapy Treatment Arm 3 Pemetrexed + carboplatin SoC chemotherapy alone Treatment Arm 2 Abraxane + carboplatin durvalumab monotherapy + SoC chemotherapy Treatment Arm 1 Tremelimumab durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 1 Durvalumab durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 1 Gemcitabine + carboplatin durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 2 Gemcitabine + carboplatin durvalumab monotherapy + SoC chemotherapy Treatment Arm 2 Pemetrexed + carboplatin durvalumab monotherapy + SoC chemotherapy Treatment Arm 3 Abraxane + carboplatin SoC chemotherapy alone Treatment Arm 3 Pemetrexed + cisplatin SoC chemotherapy alone Treatment Arm 1 Abraxane + carboplatin durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 3 Gemcitabine + carboplatin SoC chemotherapy alone Treatment Arm 2 Gemcitabine + cisplatin durvalumab monotherapy + SoC chemotherapy Treatment Arm 3 Gemcitabine + cisplatin SoC chemotherapy alone Treatment Arm 1 Gemcitabine + cisplatin durvalumab + tremelimumab combination therapy + SoC chemotherapy Treatment Arm 2 Durvalumab durvalumab monotherapy + SoC chemotherapy
- Primary Outcome Measures
Name Time Method Progression-Free Survival (PFS); D + SoC Compared With SoC Alone Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). PFS (per RECIST version 1.1 \[RECIST 1.1\] using Blinded Independent Central Review \[BICR\] 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. Median PFS was calculated using the Kaplan-Meier technique. The final analysis of PFS in the global cohort was pre-specified after approximately 497 BICR PFS events occurred across the D + SoC and SoC alone treatment arms (75% maturity).
Overall Survival (OS); D + SoC Compared With SoC Alone From baseline until death due to any cause. Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). 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. The final analysis of OS in the global cohort was pre-specified after approximately 532 OS events occurred across the D + SoC and SoC alone treatment arms (80% maturity).
- Secondary Outcome Measures
Name Time Method Objective Response Rate (ORR) Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). ORR (per RECIST 1.1 using BICR assessments) was defined as the percentage of patients with at least one visit response of complete response (CR) or partial response (PR). Results are presented for the pre-specified ORR analysis using unconfirmed responses based on BICR.
PK of Tremelimumab; Peak and Trough Serum Concentrations Samples were collected post-dose on Day 1 (Week 0), pre-dose on Weeks 3 and 12 and at follow-up (3 months after the last valid dose). Assessed at the global cohort DCO of 12 March 2021. 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.
Number of Patients With ADA Response to Tremelimumab Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of study treatment (ie, tremelimumab). Blood samples were collected at pre-specified timepoints and number of patients who developed detectable ADAs against tremelimumab was determined. ADA prevalence is defined as percentage of patients with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as either treatment-induced ADA or treatment-boosted ADA. ADA incidence is percentage of patients who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted by ≥4-fold during the study period. Persistently positive is defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks (112 days) between the first and last positive, or an ADA positive result at the last available assessment. Transiently positive is 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.
PFS; T + D + SoC Compared With SoC Alone and T + D + SoC Compared With D + SoC Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months. PFS (per RECIST 1.1 using BICR 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. Median PFS was calculated using the Kaplan-Meier technique.
OS; T + D + SoC Compared With SoC Alone and T + D + SoC Compared With D + SoC From baseline until death due to any cause. Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). 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.
Best Objective Response (BoR) Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). The BoR was calculated based on the overall visit responses from each RECIST 1.1 assessment. BOR was defined as the best response a patient had following randomization, but prior to starting any subsequent cancer therapy and up to and including RECIST 1.1 progression or the last evaluable assessment in the absence of RECIST 1.1 progression, as determined by BICR. Categorization of BoR was based on RECIST using the following 'response' categories: CR and PR and the following 'non-response' categories: stable disease (SD) ≥6 weeks, progression (ie, PD) and not evaluable (NE). Results are presented for number (%) of patients in each specified category.
Time to Deterioration of Global Health Status / 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) At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever came first). Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). 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 was defined as time from randomization until the date of first clinically meaningful deterioration that was confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations Samples were collected post-dose on Day 1 (Week 0), pre-dose on Weeks 3 and 12 and at follow-up (3 months after the last valid dose). Assessed at the global cohort DCO of 12 March 2021. 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.
Duration of Response (DoR) Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). DoR (per RECIST 1.1 using BICR assessments) was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. The end of response coincided with the date of progression or death from any cause used for the RECIST 1.1 PFS endpoint. The time of the initial response was defined as the latest of the dates contributing towards the first visit of PR or CR. Results are presented for the pre-specified DoR analysis using unconfirmed responses based on BICR.
Time From Randomization to Second Progression (PFS2) Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). PFS2 was defined as the time from the date of randomization to the earliest of the progression event (subsequent to that used for the primary variable PFS) or death. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could involve any of: objective radiological imaging, symptomatic progression or death.
Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of study treatment (ie, durvalumab). Blood samples were collected at pre-specified timepoints and number of patients who developed detectable ADAs against durvalumab was determined. ADA prevalence is defined as percentage of patients with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as either treatment-induced ADA or treatment-boosted ADA. ADA incidence is percentage of patients who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted by ≥4-fold during the study period. Persistently positive is defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks (112 days) between the first and last positive, or an ADA positive result at the last available assessment. Transiently positive is 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.
Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever came first). Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). 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 treatment-related symptoms 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 was defined as time from randomization until the date of first clinically meaningful deterioration that was confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
Trial Locations
- Locations (1)
Research Site
🇻🇳Ho Chi Minh, Vietnam