Non-Small Cell Lung Cancer
Conditions
Keywords
Locally, Advanced, Metastatic, Carcinoma, Non-Small Cell Lung Cancer, Osimertinib, Tagrisso
Brief summary
The reason for the study is to find out if an experimental combination of an oral medication called osimertinib (TAGRISSO®) when used in combination with chemotherapy is more effective than giving osimertinib alone for the treatment of locally advanced or metastatic non-small cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA) which, if known, can help physicians decide the best treatment for their patients. One type of mutation can occur in the gene that produces a protein on the surface of cells called the Epidermal Growth Factor Receptor (EGFR). Osimertinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets Epidermal Growth Factor Receptor (EGFR) mutations. Unfortunately, despite the benefit observed for patients treated with osimertinib, the vast majority of cancers are expected to develop resistance to the drug over time. The exact reasons why resistance develops are not fully understood but based upon clinical research it is hoped that combining osimertinib with another type of anti-cancer therapy known as chemotherapy will delay the onset of resistance and the worsening of a patient's cancer. In total the study aims to enroll approximately 586 patients, consisting of approximately 30 patients who will participate in a safety run-in component of the trial, and approximately 556 who will receive osimertinib alone or osimertinib in combination with chemotherapy in the main trial. In the main part of the trial there is a one in two chance of receiving osimertinib alone, and the treatment is decided at random by a computer. The study involves a Screening Period, Treatment Period, and Follow up Period. Whilst receiving study medication, it is expected patients will attend, on average, approximately 15 visits over the first 12 months and then approximately 4 visits per year afterwards. Each visit will last about 2 to 6 hours depending on the arrangement of medical assessments by the study centre.
Interventions
DRUGOsimertinib
Drug: Osimertinib (Oral) Other Names: AZD9291
Drug: Pemetrexed (500 mg/m2) plus carboplatin (AUC5) on Day 1 of 21day cycles (every 3 weeks) for 4 cycles, followed by Osimertinib daily with pemetrexed maintenance (500 mg/m2) every 3 weeks.
Drug: Pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) on Day 1 of 21day cycles (every 3 weeks) for 4 cycles, followed by Osimertinib daily with pemetrexed maintenance (500 mg/m2) every 3 weeks.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel Assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to 110 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, at least 18 years of age; patients from Japan at least 20 years of age. 2. Pathologically confirmed non-squamous Non-Small Cell Lung Cancer (NSCLC). NSCLC of mixed histology is allowed. 3. Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic Non-Small Cell Lung Cancer (NSCLC) (clinical stage IVA or IVB) or recurrent Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. 4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M. 5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. 6. WHO PS of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks. 7. Life expectancy \>12 weeks at Day 1. 8. Willing to use contraception as appropriate during the study and for a period of time after discontinuing study treatment.
Exclusion criteria
1. Spinal cord compression; and unstable brain metastases, with stable brain metastases who have completed definitive therapy, are not on steroids, and have a stable neurological status for at least 2 weeks after completion of the definitive therapy and steroids can be enrolled. Patients with asymptomatic brain metastases can be eligible for inclusion if in the opinion of the Investigator immediate definitive treatment is not indicated 2. Past medical history of Interstitial Lung Disease (ILD), drug-induced Interstitial Lung Disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active Interstitial Lung Disease. 3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including Hep. B, Hep. C and HIV. Screening for chronic conditions is not required. Active infection will include any patients receiving treatment for infection. 4. QT prolongation or any clinically important abnormalities in rhythm. 5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: * Absolute neutrophil count below the lower limit of normal (\<LLN) * Platelet count below the LLN * Hemoglobin \<90 g/L. The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted. * ALT \>2.5 x the upper limit of normal (ULN) if no demonstrable liver metastases or \>5 x ULN in the presence of liver metastases * AST \>2.5 x ULN if no demonstrable liver metastases or \>5 x ULN in the presence of liver metastases * Total bilirubin \>1.5 x ULN if no liver metastases or \>3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases * Creatinine clearance \<60 mL/min calculated by Cockcroft and Gault equation or 24 hour urine collection (refer to Appendix I for appropriate calculation) 6. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib. 7. Prior treatment with any systemic anti-cancer therapy for advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiation including chemotherapy, biologic therapy, immunotherapy, or any investigational drug. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents), or definitive radiation/chemoradiation with or without regimens including immunotherapy, biologic therapies, investigational agents are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease. 8. Prior treatment with an Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). 9. Major surgery within 4 weeks of the first dose of investigational product (IP). Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery are permitted. 10. Radiotherapy treatment to more than 30% of the bone marrow or( with a wide field of radiation within 4 weeks of the first dose of investigational product (IP). 11. History of hypersensitivity to active or inactive excipients of investigational product (IP) or drugs with a similar chemical structure or class to investigational product (IP).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | From first dose date to 28 days following last dose, up to 45 months | Adverse events were summarized by maximum reported Common Terminology Criteria for Adverse Event (CTCAE) grade, version 5.0. Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 (Severe or medically significant but not immediately life-threatening): hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 (Life-threatening consequences): urgent intervention indicated. Grade 5: Death related to AE. Includes adverse events with onset date on or after the date of first dose and up to and including 28 days following discontinuation of treatment but prior to the start of a new anti-cancer therapy. |
| Progression-free Survival (PFS) (Randomized Component) | Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.3 months) | Progression-free survival (PFS) using Investigator assessment as defined by RECIST 1.1. Median progression free survival (months) calculated using the Kaplan-Meier method. Progression-free survival (PFS) is defined as the time from 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 anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The primary efficacy analysis of the investigator-assessed progression-free survival will be performed when approximately 278 PFS events and at least 16 months of follow-up after Last subject in, has occurred in the 556 randomized patients. |
| Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component) | Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.2 months). | Sensitivity analysis for progression-free survival (PFS) by blinded independent central review (BICR) using Investigator assessment as defined by RECIST 1.1. Median progression free survival (months) calculated using the Kaplan-Meier method. Progression-free survival (PFS) is defined as the time from 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 anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The primary efficacy analysis of the investigator-assessed progression-free survival will be performed when approximately 278 PFS events and at least 16 months of follow-up after Last subject in, has occurred in the 556 randomized patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only) | Up to 45 months | Depth of Response (percent change from Baseline in tumor diameter) is defined as the relative percent change in the sum of the longest diameters of RECIST 1.1 target lesions (TL) at the nadir in the absence of new lesions or progression of non-target lesions (NTL) compared to baseline. The best percentage change in TL size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. Tumor assessments of the chest and abdomen (including the entire liver and both adrenal glands) were performed using RECIST 1.1 by the investigator on images from CT (preferred) or MRI with IV contrast. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component. |
| Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only) | Up to 45 months | Disease control rate is defined as the percentage of subjects who have a best overall response of Complete response (CR) or Partial response (PR) or Stable disease (SD) by RECIST 1.1 as assessed by the Investigator. For participants with a best overall response of SD, a RECIST assessment of SD must have been observed at least 6 weeks minus 1 week (at least 35 study days) following the first dose. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component. |
| Overall Survival (OS) (Randomized Component) | Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months) | Overall survival is defined as the time from the date of randomization until death due to any cause. Subjects not known to have died at the time of analysis are censored at the last recorded date on which the subject was known to be alive. Median overall Survival calculated using the Kaplan-Meier method. |
| Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component) | Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months) | Landmark Overall Survival at 1, 2, and 3 years looks at the percent of patients alive at 1, 2 and 3 year time points. Overall survival at 36 months not included to data cut off prior to 36-month timepoint. Overall survival percentage calculated using the Kaplan-Meier method. |
| Objective Response Rate (ORR) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Objective Response Rate (ORR) (per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of Complete Response or Partial Response. Data obtained up until progression, or the last evaluable assessment in the absence of progression, was included in the assessment of Objective Response Rate. The investigator-assessed ORR was summarized with a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local). |
| Duration of Response (DoR) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | The duration of response is 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 should coincide with the date of progression or death from any cause used for the progression-free survival endpoint. The time of the initial response is defined as the latest of the dates contributing towards the first response of Partial response or Complete response. Median values of the duration of response, along with two-sided 95% CI in each treatment group were computed using the Kaplan-Meier method. |
| Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Depth of Response (percent change from Baseline in tumor diameter) is defined as the relative percent change in the sum of the longest diameters of RECIST 1.1 target lesions (TL) at the nadir in the absence of new lesions or progression of non-target lesions (NTL) compared to baseline. The best percentage change in TL size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. Tumor assessments of the chest and abdomen (including the entire liver and both adrenal glands) were performed using RECIST 1.1 by the investigator on images from CT (preferred) or MRI with IV contrast. |
| Disease Control Rate (DCR) by Investigator (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by the Investigator. For participants with a best overall response of SD, a RECIST assessment of SD must have been observed at least 6 weeks minus 1 week (at least 35 study days) following the randomization. The adjusted disease control rate was calculated using a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local). |
| Progression Free Survival 2 (PFS2) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Progression Free Survival 2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary Progression Free Survival (PFS), or death in absence of a first or second progression. The second progression event must have occurred after subsequent treatment administered after the initial progression free survival event. Any participant that was lost to follow-up, withdrew consent or discontinued for other reasons at the time of the analysis were censored at the last evaluable progression assessment. Median second progression free survival (months) calculated using the Kaplan-Meier method. |
| Time to First Subsequent Therapy (TFST) or Death (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Time to first subsequent therapy (TFST) or death is defined as the time from the date of randomization to the earlier of the date of anti- cancer therapy start date following IP discontinuation or death. Any patient not known to have had a subsequent therapy or not known to have died at the time of the analysis were censored at the last known time to have not received subsequent therapy; i.e., the last follow-up visit where this was confirmed. Median time to first subsequent therapy or death calculated using the Kaplan-Meier method. |
| Time to Second Subsequent Therapy (TSST) or Death (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Time to second subsequent therapy (TSST) or death is defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following IP discontinuation or death. Any patient not known to have died at the time of the analysis and not known to have had a second subsequent therapy will be censored at the last known time to have not received second subsequent therapy, i.e., the last follow-up visit where this was confirmed. If a patient terminated the study for reason other than death before second subsequent therapy, these patients will be censored at the earliest of their last known to be alive and termination dates. Median time to second subsequent therapy or death calculated using the Kaplan-Meier method. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | QLQ-C30 has 30 questions and scores range from 0-100 after a linear transformation. Questions are combined to produce symptom scales, individual symptom items, functional scales, and global health status (GHS)/quality of life (QoL). Positive change from baseline scores on the GHS/QoL and functioning scales indicate improvement on health status/function, and negative change scores on symptom scales/items represent less symptom severity/improvement on symptom status. The score values calculated by averaging across patients overall mean across all visits. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (random effect), treatment, visit (fixed effect & repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction. |
| Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | The EORTC QLQ-C30 consists of 30 questions that are combined to produce 3 symptom scales (fatigue, pain, and nausea/vomiting), 5 individual symptom items (dyspnea, insomnia, appetite loss, constipation, and diarrhea), 5 functional scales (physical, role, cognitive, emotional, and social), and a global measure of health status/QoL. Scores range from 0-100 after a linear transformation. Time to deterioration (TTD) is defined as the time from randomization until the date of the first clinically meaningful worsening (a change in the score from baseline of ≥10) that is confirmed at a subsequent assessment or death in the absence of a clinically meaningful symptom, function, or global health status/QoL worsening, regardless of whether the patient withdraws from study treatment or receives another anticancer therapy prior to symptom, function or GHS/QoL deterioration. The median TTD was calculated using the Kaplan-Meier method. |
| Overall Survival (OS) (Safety Run-In Treatment Arms Only) | Up to 45 months (maximum follow up 44.6 months) | Overall survival is defined as the time from the date of first dose until death due to any causes. Subjects not known to have died at the time of analysis are censored at the last recorded date on which the subject was known to be alive. Median overall survival calculated using the Kaplan-Meier method. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component. |
| Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. Time to deterioration (TTD) is defined as the time from randomization until the date of the first clinically meaningful worsening (a change in the score from baseline of ≥10) that is confirmed at a subsequent assessment or death in the absence of a clinically meaningful symptom, function, or global health status/QoL worsening, regardless of whether the patient withdraws from study treatment or receives another anticancer therapy prior to symptom, function or GHS/QoL deterioration. The median TTD was calculated using the Kaplan-Meier method. |
| Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component) | Screening/Baseline | Comparing the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results in participants with EXON 19 Deletion, excluding invalid results. Since this endpoint uses pre-randomization data to compare results from a central vs. local lab, randomized component treatment arms were combined for analysis. |
| Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component) | Screening/Baseline | Comparing the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results in participants with L858R, excluding invalid results. Since this endpoint uses pre-randomization data to compare results from a central vs. local lab, randomized component treatment arms were combined for analysis. |
| Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | PFS is defined as the time from randomization until an event. An event is defined as the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from study treatment or receives another anti-cancer therapy prior to progression. Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term. |
| Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | PFS is defined as the time from randomization until an event. An event is defined as the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from study treatment or receives another anti-cancer therapy prior to progression. Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term. |
| Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106. | An analysis will be performed to assess whether the plasma concentration of osimertinib is affected when given with or without chemotherapy. Samples were collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples were collected pre-dose and 1-, 2-, 4-, and 6-hours post-dose. |
| Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106. | An analysis will be performed to assess whether the plasma concentration of metabolite AZ5104 is affected when given with or without chemotherapy. Samples were collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples were collected pre-dose and 1-, 2-, 4-, and 6-hours post-dose. |
| Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Cmin,ss is the minimum plasma concentration of Osimertinib at steady state. Cmax,ss is the maximum plasma concentration of Osimertinib at steady state. |
| Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | Cmin,ss is the minimum plasma concentration of AZ5104 at steady state. Cmax,ss is the maximum plasma concentration of AZ5104 at steady state. |
| Mean AUCss of Osimertinib (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | AUCss is the area under the plasma concentration-time curve over a doing interval at a stead state. |
| Mean AUCss of AZ5104 (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | AUCss is the area under the plasma concentration-time curve over a doing interval at a stead state. |
| Mean CLss/F of Osimertinib (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | CLss/F is the apparent plasma clearance at steady state. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Up to approximately 33 months after the first patient is randomized. | EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. While the QLQ-LC13 includes more scales, only the Coughing, Pain in chest, and Dyspnea subscale scores were analyzed for this endpoint. Negative change from baseline scores indicates less symptom severity, and thus improvement on health status. The score values calculated by averaging across patients overall mean across all visits. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (as a random effect), treatment, visit (as fixed effect and repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction. |
| Duration of Response (DoR) (Safety Run-In Treatment Arms Only) | Up to 45 months | Duration of response (DoR) is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression (i.e. date of progression free survival event or censoring - date of first response + 1). The end of response should coincide with the date of progression or death from any cause used for the progression free survival endpoint. The time of the initial response is defined as the latest of the dates contributing towards the first visit that was Complete response or Partial response that was subsequently confirmed. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component. |
| Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only) | Up to 45 months | Confirmed objective response rate (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of subjects with at least 1 visit response of Completed Response (CR) or Partial Response (PR), where each CR or PR must be subsequently confirmed at least 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. Confidence Interval is calculated using the exact Clopper-Pearson method. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component. |
Countries
Argentina, Australia, Brazil, Canada, Chile, China, Czechia, France, India, Japan, Peru, Philippines, Russia, Slovakia, South Africa, South Korea, Taiwan, Thailand, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
A total of 587 participants were enrolled in the study, 30 in the SRI and 557 in the Randomization component of the study. 6 participants were randomized to the Randomization component but did not receive any study treatment (2 Screen Failures, 2 Subject Decision, and 2 Deaths).
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed Osimertinib (AZD9291) 80 mg once daily (QD) with Carboplatin (AUC of 5 mg/mL/min \[AUC5\]) and Pemetrexed (500 mg/m2), both administered every 3 weeks (Q3W) for 4 cycles, followed by Osimertinib 80 mg once daily plus Pemetrexed maintenance (500 mg/m2) Q3W | 15 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed Osimertinib (AZD9291) 80 mg once daily (QD) with Cisplatin (75 mg/m2) and Pemetrexed (500 mg/m2), both administered every 3 weeks (Q3W) for 4 cycles, followed by Osimertinib 80 mg once daily plus Pemetrexed maintenance (500 mg/m2) Q3W | 15 |
| Randomized: AZD9291 + Chemo Osimertinib (AZD9291) 80 mg in combination with pemetrexed (500 mg/m2) plus either cisplatin (75 mg/m2) or carboplatin (AUC5) on Day 1 of 21-day cycles for 4 cycles, followed by Osimertinib (AZD9291) 80 mg QD with Pemetrexed maintenance (500 mg/m2) Q3W | 279 |
| Randomized: AZD9291 Osimertinib (AZD9291) 80mg QD. | 278 |
| Total | 587 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 6 | 3 | 70 | 77 |
| Overall Study | Ongoing Study at Data Cut Off (03APR2023) | 7 | 10 | 197 | 191 |
| Overall Study | Screen Failure | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 11 | 9 |
Baseline characteristics
| Characteristic | Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Randomized: AZD9291 + Chemo | Randomized: AZD9291 | Total |
|---|---|---|---|---|---|
| Age, Continuous Age (Years) | 62.4 Years STANDARD_DEVIATION 12.82 | 60.4 Years STANDARD_DEVIATION 8.36 | 61.0 Years STANDARD_DEVIATION 10.03 | 60.7 Years STANDARD_DEVIATION 10.57 | 60.9 Years STANDARD_DEVIATION 10.3 |
| Age, Customized Age Group <50 | 4 Participants | 2 Participants | 38 Participants | 44 Participants | 88 Participants |
| Age, Customized Age Group >=50-<65 | 5 Participants | 7 Participants | 136 Participants | 122 Participants | 270 Participants |
| Age, Customized Age Group >=65-<75 | 3 Participants | 6 Participants | 82 Participants | 88 Participants | 179 Participants |
| Age, Customized Age Group >=75 | 3 Participants | 0 Participants | 23 Participants | 24 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 0 Participants | 0 Participants | 39 Participants | 29 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 15 Participants | 15 Participants | 239 Participants | 248 Participants | 517 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnic Population Asian, not specified | 9 Participants | 7 Participants | 108 Participants | 107 Participants | 231 Participants |
| Race/Ethnicity, Customized Ethnic Population Chinese | 4 Participants | 2 Participants | 71 Participants | 69 Participants | 146 Participants |
| Race/Ethnicity, Customized Ethnic Population Missing | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnic Population Other ethnic population (Non-Asian) | 2 Participants | 6 Participants | 99 Participants | 100 Participants | 207 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 11 Participants | 6 Participants | 17 Participants |
| Race/Ethnicity, Customized Race Asian | 13 Participants | 9 Participants | 179 Participants | 176 Participants | 377 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 13 Participants | 10 Participants | 23 Participants |
| Race/Ethnicity, Customized Race White | 2 Participants | 6 Participants | 74 Participants | 83 Participants | 165 Participants |
| Sex: Female, Male Sex Female | 9 Participants | 10 Participants | 173 Participants | 169 Participants | 361 Participants |
| Sex: Female, Male Sex Male | 6 Participants | 5 Participants | 106 Participants | 109 Participants | 226 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 15 | 3 / 15 | 71 / 279 | 78 / 278 |
| other Total, other adverse events | 15 / 15 | 14 / 15 | 273 / 276 | 258 / 275 |
| serious Total, serious adverse events | 5 / 15 | 6 / 15 | 104 / 276 | 53 / 275 |
Outcome results
Primary
Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only)
Adverse events were summarized by maximum reported Common Terminology Criteria for Adverse Event (CTCAE) grade, version 5.0. Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 (Severe or medically significant but not immediately life-threatening): hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 (Life-threatening consequences): urgent intervention indicated. Grade 5: Death related to AE. Includes adverse events with onset date on or after the date of first dose and up to and including 28 days following discontinuation of treatment but prior to the start of a new anti-cancer therapy.
Time frame: From first dose date to 28 days following last dose, up to 45 months
Population: Participants from the Safety Analysis Set, which includes all participants in the Safety Run-In Treatment Arms who received at least 1 dose of study treatment (osimertinib, cisplatin, carboplatin, or pemetrexed).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 1 | 1 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 2 | 9 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 3 | 3 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 4 | 0 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 5 | 2 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | No Adverse Events Reported | 0 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 5 | 0 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 1 | 0 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 4 | 2 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 2 | 4 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | No Adverse Events Reported | 1 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Adverse Events Graded by Common Terminology Criteria for Adverse Event v5 (Safety Run-In Treatment Arms Only) | Grade 3 | 8 Participants |
Primary
Progression-free Survival (PFS) (Randomized Component)
Progression-free survival (PFS) using Investigator assessment as defined by RECIST 1.1. Median progression free survival (months) calculated using the Kaplan-Meier method. Progression-free survival (PFS) is defined as the time from 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 anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The primary efficacy analysis of the investigator-assessed progression-free survival will be performed when approximately 278 PFS events and at least 16 months of follow-up after Last subject in, has occurred in the 556 randomized patients.
Time frame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.3 months)
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Progression-free Survival (PFS) (Randomized Component) | 25.5 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Progression-free Survival (PFS) (Randomized Component) | 16.7 Months |
Comparison: The analysis was performed using a log rank test stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: <0.000195% CI: [0.49, 0.79]Log Rank
Primary
Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component)
Sensitivity analysis for progression-free survival (PFS) by blinded independent central review (BICR) using Investigator assessment as defined by RECIST 1.1. Median progression free survival (months) calculated using the Kaplan-Meier method. Progression-free survival (PFS) is defined as the time from 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 anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. The primary efficacy analysis of the investigator-assessed progression-free survival will be performed when approximately 278 PFS events and at least 16 months of follow-up after Last subject in, has occurred in the 556 randomized patients.
Time frame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 33.2 months).
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component) | 29.4 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Sensitivity Analysis for Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment (Randomized Component) | 19.9 Months |
Comparison: The analysis was performed using a log rank test stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.000295% CI: [0.48, 0.8]Log Rank
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)
QLQ-C30 has 30 questions and scores range from 0-100 after a linear transformation. Questions are combined to produce symptom scales, individual symptom items, functional scales, and global health status (GHS)/quality of life (QoL). Positive change from baseline scores on the GHS/QoL and functioning scales indicate improvement on health status/function, and negative change scores on symptom scales/items represent less symptom severity/improvement on symptom status. The score values calculated by averaging across patients overall mean across all visits. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (random effect), treatment, visit (fixed effect & repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Functional Scale: Physical Functioning Score (Change from Baseline) | 2.37 Scores on a Scale |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Symptom Scale: Fatigue Score (Change from Baseline) | -0.03 Scores on a Scale |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Individual Symptom Item: Appetite Loss Score (Change from Baseline) | 2.87 Scores on a Scale |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Global Health Status/Quality of Life Score (Change from Baseline) | 3.32 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Symptom Scale: Fatigue Score (Change from Baseline) | -6.31 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Global Health Status/Quality of Life Score (Change from Baseline) | 7.38 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Functional Scale: Physical Functioning Score (Change from Baseline) | 6.74 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Individual Symptom Item: Appetite Loss Score (Change from Baseline) | -4.58 Scores on a Scale |
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component)
EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. While the QLQ-LC13 includes more scales, only the Coughing, Pain in chest, and Dyspnea subscale scores were analyzed for this endpoint. Negative change from baseline scores indicates less symptom severity, and thus improvement on health status. The score values calculated by averaging across patients overall mean across all visits. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (as a random effect), treatment, visit (as fixed effect and repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Coughing Score (Change from Baseline) | -13.23 Scores on a Scale |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Pain in Chest Score (Change from Baseline) | -6.33 Scores on a Scale |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Dyspnea Score (Change from Baseline) | -3.09 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Coughing Score (Change from Baseline) | -11.19 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Pain in Chest Score (Change from Baseline) | -6.61 Scores on a Scale |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Dyspnea Score (Change from Baseline) | -5.67 Scores on a Scale |
Secondary
Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component)
Comparing the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results in participants with EXON 19 Deletion, excluding invalid results. Since this endpoint uses pre-randomization data to compare results from a central vs. local lab, randomized component treatment arms were combined for analysis.
Time frame: Screening/Baseline
Population: Participants with a valid local and central test result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component) | Local Laboratory Test = Negative, Cobas Central Test = Negative | 98 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component) | Local Laboratory Test = Negative, Cobas Central Test = Positive | 0 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component) | Local Laboratory Test = Positive, Cobas Central Test = Negative | 2 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: Exon 19 Deletion (Randomized Component) | Local Laboratory Test = Positive, Cobas Central Test = Positive | 154 Participants |
Secondary
Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component)
Comparing the local EGFR mutation test result used for patient selection with the retrospective central cobas® EGFR Mutation Test v2 results in participants with L858R, excluding invalid results. Since this endpoint uses pre-randomization data to compare results from a central vs. local lab, randomized component treatment arms were combined for analysis.
Time frame: Screening/Baseline
Population: Participants with a valid local and central test result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component) | Local Laboratory Test = Negative, Cobas Central Test = Negative | 145 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component) | Local Laboratory Test = Negative, Cobas Central Test = Positive | 0 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component) | Local Laboratory Test = Positive, Cobas Central Test = Positive | 96 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Concordance of Epidermal Growth Factor Receptor (EGFR) Mutation Status Between the Local EGFR Mutation Test and the Central Cobas® EGFR Mutation Test v2 Results: L858R (Randomized Component) | Local Laboratory Test = Positive, Cobas Central Test = Negative | 6 Participants |
Secondary
Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component)
Depth of Response (percent change from Baseline in tumor diameter) is defined as the relative percent change in the sum of the longest diameters of RECIST 1.1 target lesions (TL) at the nadir in the absence of new lesions or progression of non-target lesions (NTL) compared to baseline. The best percentage change in TL size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. Tumor assessments of the chest and abdomen (including the entire liver and both adrenal glands) were performed using RECIST 1.1 by the investigator on images from CT (preferred) or MRI with IV contrast.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component) | -50.77 Percent change from baseline |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Depth of Response (Percent Change From Baseline in Tumor Diameter) (Randomized Component) | -47.41 Percent change from baseline |
Comparison: The analysis was performed using analysis of covariance with baseline tumor size and time from baseline scan to randomization as covariates and with factors race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.106795% CI: [-7.44, 0.72]ANCOVA
Secondary
Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only)
Depth of Response (percent change from Baseline in tumor diameter) is defined as the relative percent change in the sum of the longest diameters of RECIST 1.1 target lesions (TL) at the nadir in the absence of new lesions or progression of non-target lesions (NTL) compared to baseline. The best percentage change in TL size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. Tumor assessments of the chest and abdomen (including the entire liver and both adrenal glands) were performed using RECIST 1.1 by the investigator on images from CT (preferred) or MRI with IV contrast. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.
Time frame: Up to 45 months
Population: Safety Analysis Set, includes all participants in the Safety Run-In Treatment Arms who received at least 1 dose of study treatment (osimertinib, cisplatin, carboplatin, or pemetrexed).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Depth of Response (Percent Change From Baseline in Tumor Diameter) (Safety Run-In Treatment Arms Only) | -57.72 Percent change from baseline | Standard Deviation 22.09 |
Secondary
Disease Control Rate (DCR) by Investigator (Randomized Component)
Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by the Investigator. For participants with a best overall response of SD, a RECIST assessment of SD must have been observed at least 6 weeks minus 1 week (at least 35 study days) following the randomization. The adjusted disease control rate was calculated using a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Disease Control Rate (DCR) by Investigator (Randomized Component) | 96.22 Percent of Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Disease Control Rate (DCR) by Investigator (Randomized Component) | 95.02 Percent of Participants |
Comparison: The analysis was performed using a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.448395% CI: [0.63, 2.81]Regression, Logistic
Secondary
Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only)
Disease control rate is defined as the percentage of subjects who have a best overall response of Complete response (CR) or Partial response (PR) or Stable disease (SD) by RECIST 1.1 as assessed by the Investigator. For participants with a best overall response of SD, a RECIST assessment of SD must have been observed at least 6 weeks minus 1 week (at least 35 study days) following the first dose. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.
Time frame: Up to 45 months
Population: Safety Analysis Set, includes all participants in the Safety Run-In Treatment Arms who received at least 1 dose of study treatment (osimertinib, cisplatin, carboplatin, or pemetrexed).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only) | Complete Response (CR) | 3 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only) | Partial Response (PR) | 23 Participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Disease Control Rate (DCR) by Investigator (Safety Run-In Treatment Arms Only) | Stable Disease (SD) | 4 Participants |
Comparison: A 95% CI was calculated on the percentage of participants with a Response or Stable Disease using the exact (Clopper-Pearson) method.95% CI: [88.43, 100]Clopper-Pearson
Secondary
Duration of Response (DoR) (Randomized Component)
The duration of response is 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 should coincide with the date of progression or death from any cause used for the progression-free survival endpoint. The time of the initial response is defined as the latest of the dates contributing towards the first response of Partial response or Complete response. Median values of the duration of response, along with two-sided 95% CI in each treatment group were computed using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Participants from the Full Analysis Set, which includes all randomized participants, that had a response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Duration of Response (DoR) (Randomized Component) | 24.0 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Duration of Response (DoR) (Randomized Component) | 15.3 Months |
Secondary
Duration of Response (DoR) (Safety Run-In Treatment Arms Only)
Duration of response (DoR) is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of disease progression (i.e. date of progression free survival event or censoring - date of first response + 1). The end of response should coincide with the date of progression or death from any cause used for the progression free survival endpoint. The time of the initial response is defined as the latest of the dates contributing towards the first visit that was Complete response or Partial response that was subsequently confirmed. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.
Time frame: Up to 45 months
Population: Participants from the Safety Analysis Set, which includes all participants in the Safety Run-In Treatment Arms who received at least 1 dose of study treatment (osimertinib, cisplatin, carboplatin, or pemetrexed), that had a confirmed response.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Duration of Response (DoR) (Safety Run-In Treatment Arms Only) | 27.5 Months | Standard Deviation 13.48 |
Secondary
Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component)
Landmark Overall Survival at 1, 2, and 3 years looks at the percent of patients alive at 1, 2 and 3 year time points. Overall survival at 36 months not included to data cut off prior to 36-month timepoint. Overall survival percentage calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component) | Overall survival at 12 months (%) | 88.8 percent of participants |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component) | Overall survival at 24 months (%) | 78.9 percent of participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component) | Overall survival at 12 months (%) | 92.0 percent of participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Landmark Overall Survival (LOS) at 1, 2, and 3 Years (Randomized Component) | Overall survival at 24 months (%) | 73.0 percent of participants |
Secondary
Mean AUCss of AZ5104 (Randomized Component)
AUCss is the area under the plasma concentration-time curve over a doing interval at a stead state.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean AUCss of AZ5104 (Randomized Component) | 1277 h*nmol/L | Geometric Coefficient of Variation 54.72 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean AUCss of AZ5104 (Randomized Component) | 1177 h*nmol/L | Geometric Coefficient of Variation 47.11 |
Secondary
Mean AUCss of Osimertinib (Randomized Component)
AUCss is the area under the plasma concentration-time curve over a doing interval at a stead state.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean AUCss of Osimertinib (Randomized Component) | 11840 h*nmol/L | Geometric Coefficient of Variation 45.45 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean AUCss of Osimertinib (Randomized Component) | 11790 h*nmol/L | Geometric Coefficient of Variation 37.37 |
Secondary
Mean CLss/F of Osimertinib (Randomized Component)
CLss/F is the apparent plasma clearance at steady state.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean CLss/F of Osimertinib (Randomized Component) | 13.52 L/h | Geometric Coefficient of Variation 45.45 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean CLss/F of Osimertinib (Randomized Component) | 13.58 L/h | Geometric Coefficient of Variation 37.37 |
Secondary
Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component)
Cmin,ss is the minimum plasma concentration of AZ5104 at steady state. Cmax,ss is the maximum plasma concentration of AZ5104 at steady state.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component) | Cmin,ss | 45.34 nmol/L | Geometric Coefficient of Variation 59.51 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component) | Cmax,ss | 59.07 nmol/L | Geometric Coefficient of Variation 59.8 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component) | Cmin,ss | 42.70 nmol/L | Geometric Coefficient of Variation 49.42 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of AZ5104 (Randomized Component) | Cmax,ss | 55.59 nmol/L | Geometric Coefficient of Variation 46.26 |
Secondary
Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component)
Cmin,ss is the minimum plasma concentration of Osimertinib at steady state. Cmax,ss is the maximum plasma concentration of Osimertinib at steady state.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component) | Cmin,ss | 392.5 nmol/L | Geometric Coefficient of Variation 50.45 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component) | Cmax,ss | 587.5 nmol/L | Geometric Coefficient of Variation 46.37 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component) | Cmin,ss | 397.2 nmol/L | Geometric Coefficient of Variation 40.39 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Mean Cmin,ss and Mean Cmax,ss of Osimertinib (Randomized Component) | Cmax,ss | 593.4 nmol/L | Geometric Coefficient of Variation 37.26 |
Secondary
Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component)
The EORTC QLQ-C30 consists of 30 questions that are combined to produce 3 symptom scales (fatigue, pain, and nausea/vomiting), 5 individual symptom items (dyspnea, insomnia, appetite loss, constipation, and diarrhea), 5 functional scales (physical, role, cognitive, emotional, and social), and a global measure of health status/QoL. Scores range from 0-100 after a linear transformation. Time to deterioration (TTD) is defined as the time from randomization until the date of the first clinically meaningful worsening (a change in the score from baseline of ≥10) that is confirmed at a subsequent assessment or death in the absence of a clinically meaningful symptom, function, or global health status/QoL worsening, regardless of whether the patient withdraws from study treatment or receives another anticancer therapy prior to symptom, function or GHS/QoL deterioration. The median TTD was calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Insomnia Symptom Item (months) | NA Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Role Functioning Scale (months) | 13.1 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Fatigue Symptom Scale (months) | 5.9 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Pain Symptom Scale (months) | 28.0 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Appetite Loss Symptom Item (months) | 10.1 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Constipation Symptom Item (months) | 21.7 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Diarrhea Symptom Item (months) | 7.8 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Global Health Status/Quality of Life (months) | 25.8 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Cognitive Functioning Scale (months) | 15.7 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Emotional Functioning Scale (months) | 29.6 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Social Functioning Scale (months) | 19.3 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Nausea/Vomiting Symptom Scale (months) | 20.5 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Dyspnea Symptom Item (months) | NA Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Physical Functioning Scale (months) | 25.5 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Dyspnea Symptom Item (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Physical Functioning Scale (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Diarrhea Symptom Item (months) | 7.7 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Role Functioning Scale (months) | 21.9 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Social Functioning Scale (months) | 28.4 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Emotional Functioning Scale (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Fatigue Symptom Scale (months) | 20.0 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Global Health Status/Quality of Life (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Pain Symptom Scale (months) | 24.6 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Insomnia Symptom Item (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Nausea/Vomiting Symptom Scale (months) | 30.5 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Appetite Loss Symptom Item (months) | 28.4 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Cognitive Functioning Scale (months) | 20.0 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Median Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) (Randomized Component) | Median TTD for Constipation Symptom Item (months) | NA Months |
Secondary
Objective Response Rate (ORR) (Randomized Component)
Objective Response Rate (ORR) (per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of Complete Response or Partial Response. Data obtained up until progression, or the last evaluable assessment in the absence of progression, was included in the assessment of Objective Response Rate. The investigator-assessed ORR was summarized with a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Objective Response Rate (ORR) (Randomized Component) | 84.40 Percent of Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Objective Response Rate (ORR) (Randomized Component) | 77.10 Percent of Participants |
Comparison: The analysis was performed using a logistic regression stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.026195% CI: [1.06, 2.44]Regression, Logistic
Secondary
Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only)
Confirmed objective response rate (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of subjects with at least 1 visit response of Completed Response (CR) or Partial Response (PR), where each CR or PR must be subsequently confirmed at least 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. Confidence Interval is calculated using the exact Clopper-Pearson method. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.
Time frame: Up to 45 months
Population: Safety Analysis Set, includes all participants in the Safety Run-In Treatment Arms who received at least 1 dose of study treatment (osimertinib, cisplatin, carboplatin, or pemetrexed).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Objective Response Rate (ORR) (Safety Run-In Treatment Arms Only) | 86.7 Percent of Participants |
Secondary
Overall Survival (OS) (Randomized Component)
Overall survival is defined as the time from the date of randomization until death due to any cause. Subjects not known to have died at the time of analysis are censored at the last recorded date on which the subject was known to be alive. Median overall Survival calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized (maximum follow up of 34.1 months)
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Overall Survival (OS) (Randomized Component) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Overall Survival (OS) (Randomized Component) | NA Months |
Comparison: The analysis was performed using a log rank test stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.523895% CI: [0.65, 1.24]Log Rank
Secondary
Overall Survival (OS) (Safety Run-In Treatment Arms Only)
Overall survival is defined as the time from the date of first dose until death due to any causes. Subjects not known to have died at the time of analysis are censored at the last recorded date on which the subject was known to be alive. Median overall survival calculated using the Kaplan-Meier method. Per the protocol, the safety run-in treatment arms were combined and analyzed regardless of chemotherapy received for consistency with the randomized component.
Time frame: Up to 45 months (maximum follow up 44.6 months)
Population: Safety Analysis Set, includes all participants in the Safety Run-In Treatment Arms who received at least 1 dose of study treatment (osimertinib, cisplatin, carboplatin, or pemetrexed).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Overall Survival (OS) (Safety Run-In Treatment Arms Only) | NA Months |
Secondary
Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component)
An analysis will be performed to assess whether the plasma concentration of metabolite AZ5104 is affected when given with or without chemotherapy. Samples were collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples were collected pre-dose and 1-, 2-, 4-, and 6-hours post-dose.
Time frame: Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 22, 1-hour post-dose | 49.56 nM | Geometric Coefficient of Variation 81.57 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 4-hour post-dose | 52.44 nM | Geometric Coefficient of Variation 67.61 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 1-hour post-dose | 46.48 nM | Geometric Coefficient of Variation 80 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 6-hour post-dose | 53.04 nM | Geometric Coefficient of Variation 65.94 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, pre-dose | 47.77 nM | Geometric Coefficient of Variation 80.8 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 106, pre-dose | 47.33 nM | Geometric Coefficient of Variation 64.86 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 2-hour post-dose | 49.19 nM | Geometric Coefficient of Variation 71.52 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 106, 1-hour post-dose | 47.17 nM | Geometric Coefficient of Variation 65.49 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 22, pre-dose | 51.74 nM | Geometric Coefficient of Variation 82.11 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 106, 1-hour post-dose | 41.30 nM | Geometric Coefficient of Variation 57.6 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 22, pre-dose | 52.42 nM | Geometric Coefficient of Variation 56.28 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 22, 1-hour post-dose | 52.78 nM | Geometric Coefficient of Variation 56.56 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, pre-dose | 43.89 nM | Geometric Coefficient of Variation 61.54 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 1-hour post-dose | 44.89 nM | Geometric Coefficient of Variation 60.66 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 2-hour post-dose | 47.14 nM | Geometric Coefficient of Variation 56.2 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 4-hour post-dose | 50.92 nM | Geometric Coefficient of Variation 54.33 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 43, 6-hour post-dose | 50.89 nM | Geometric Coefficient of Variation 53.01 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Metabolite AZ5104 When Osimertinib is Given With or Without Chemotherapy (Randomized Component) | Day 106, pre-dose | 41.09 nM | Geometric Coefficient of Variation 57.71 |
Secondary
Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component)
An analysis will be performed to assess whether the plasma concentration of osimertinib is affected when given with or without chemotherapy. Samples were collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples were collected pre-dose and 1-, 2-, 4-, and 6-hours post-dose.
Time frame: Pre-dose and 1-hour post-dose on Day 22; pre-dose, 1-, 2-, 4-, and 6-hours post-dose on Day 43; pre-dose and 1-hour post-dose on Day 106.
Population: Pharmacokinetic Analysis Set, includes all randomized participants that received at least 1 dose of study treatment, have at least 1 measurable PK concentration and no missing doses 7 days prior to the PK sample, without any protocol deviation that affects PK, supported by the relevant date and time of this sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 22, 1-hour post-dose | 430.1 nM | Geometric Coefficient of Variation 77.16 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 4-hours post-dose | 525.8 nM | Geometric Coefficient of Variation 55.41 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 1-hour post-dose | 401.6 nM | Geometric Coefficient of Variation 69.97 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 6-hours post-dose | 544.3 nM | Geometric Coefficient of Variation 53.51 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, pre-dose | 401.0 nM | Geometric Coefficient of Variation 71.08 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 106, pre-dose | 393.7 nM | Geometric Coefficient of Variation 59.73 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 2-hours post-dose | 457.0 nM | Geometric Coefficient of Variation 60.85 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 106, 1-hour post-dose | 407.6 nM | Geometric Coefficient of Variation 60.12 |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 22, pre-dose | 430.6 nM | Geometric Coefficient of Variation 81.81 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 106, 1-hour post-dose | 380.3 nM | Geometric Coefficient of Variation 54.56 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 22, pre-dose | 470.1 nM | Geometric Coefficient of Variation 46.33 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 22, 1-hour post-dose | 486.8 nM | Geometric Coefficient of Variation 46.23 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, pre-dose | 404.1 nM | Geometric Coefficient of Variation 53.67 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 1-hour post-dose | 425.4 nM | Geometric Coefficient of Variation 54.48 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 2-hours post-dose | 475.4 nM | Geometric Coefficient of Variation 52.81 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 4-hours post-dose | 546.8 nM | Geometric Coefficient of Variation 46.75 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 43, 6-hours post-dose | 549.8 nM | Geometric Coefficient of Variation 45.28 |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Plasma Concentration of Osimertinib When Given With or Without Chemotherapy (Randomized Component) | Day 106, pre-dose | 372.0 nM | Geometric Coefficient of Variation 53.87 |
Secondary
Progression Free Survival 2 (PFS2) (Randomized Component)
Progression Free Survival 2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary Progression Free Survival (PFS), or death in absence of a first or second progression. The second progression event must have occurred after subsequent treatment administered after the initial progression free survival event. Any participant that was lost to follow-up, withdrew consent or discontinued for other reasons at the time of the analysis were censored at the last evaluable progression assessment. Median second progression free survival (months) calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Progression Free Survival 2 (PFS2) (Randomized Component) | 30.6 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Progression Free Survival 2 (PFS2) (Randomized Component) | 27.8 Months |
Comparison: The analysis was performed using a log rank test stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.013295% CI: [0.52, 0.93]Log Rank
Secondary
Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component)
PFS is defined as the time from randomization until an event. An event is defined as the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from study treatment or receives another anti-cancer therapy prior to progression. Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Subgroup of Full Analysis Set, includes all randomized participants with Exon 19 Deletion EGFR mutation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component) | 65 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: Exon 19 Deletion - Participants With an Event (Randomized Component) | 94 Participants |
Comparison: Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term.95% CI: [0.44, 0.83]Cox proportional hazards model
Secondary
Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component)
PFS is defined as the time from randomization until an event. An event is defined as the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the subject withdraws from study treatment or receives another anti-cancer therapy prior to progression. Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Subgroup of Full Analysis Set, includes all randomized participants with L858R EGFR mutation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component) | 55 Participants |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Progression-free Survival (PFS) by Investigator by Plasma Epidermal Growth Factor Receptor Mutation Status: L858R - Participants With an Event (Randomized Component) | 70 Participants |
Comparison: Subgroup analysis was performed using a Cox proportional hazards model including treatment, subgroup and a treatment-by subgroup interaction term.95% CI: [0.44, 0.9]
Secondary
Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component)
EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. Time to deterioration (TTD) is defined as the time from randomization until the date of the first clinically meaningful worsening (a change in the score from baseline of ≥10) that is confirmed at a subsequent assessment or death in the absence of a clinically meaningful symptom, function, or global health status/QoL worsening, regardless of whether the patient withdraws from study treatment or receives another anticancer therapy prior to symptom, function or GHS/QoL deterioration. The median TTD was calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, all randomized participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Dysphagia Subscale (months) | 25.6 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Pain in Chest Subscale (months) | NA Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Haemoptysis Subscale (months) | NA Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Sore mouth Subscale (months) | 4.3 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Peripheral neuropathy Subscale (months) | 11.3 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Pain in arm or shoulder Subscale (months) | 25.2 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Alopecia Subscale (months) | 3.4 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Dyspnea Subscale (months) | 9.0 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Pain in other parts Subscale (months) | 23.0 Months |
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Coughing Subscale (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Pain in other parts Subscale (months) | 21.3 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Coughing Subscale (months) | 24.7 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Haemoptysis Subscale (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Dysphagia Subscale (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Pain in arm or shoulder Subscale (months) | 23.8 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Dyspnea Subscale (months) | 19.4 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Pain in Chest Subscale (months) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Peripheral neuropathy Subscale (months) | 15.1 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Alopecia Subscale (months) | 8.9 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 Items (EORTC QLQ-LC13) (Randomized Component) | Median TTD for Sore mouth Subscale (months) | 5.8 Months |
Secondary
Time to First Subsequent Therapy (TFST) or Death (Randomized Component)
Time to first subsequent therapy (TFST) or death is defined as the time from the date of randomization to the earlier of the date of anti- cancer therapy start date following IP discontinuation or death. Any patient not known to have had a subsequent therapy or not known to have died at the time of the analysis were censored at the last known time to have not received subsequent therapy; i.e., the last follow-up visit where this was confirmed. Median time to first subsequent therapy or death calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to First Subsequent Therapy (TFST) or Death (Randomized Component) | 30.7 Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to First Subsequent Therapy (TFST) or Death (Randomized Component) | 25.4 Months |
Comparison: The analysis was performed using a log rank test stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.015995% CI: [0.56, 0.94]Log Rank
Secondary
Time to Second Subsequent Therapy (TSST) or Death (Randomized Component)
Time to second subsequent therapy (TSST) or death is defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following IP discontinuation or death. Any patient not known to have died at the time of the analysis and not known to have had a second subsequent therapy will be censored at the last known time to have not received second subsequent therapy, i.e., the last follow-up visit where this was confirmed. If a patient terminated the study for reason other than death before second subsequent therapy, these patients will be censored at the earliest of their last known to be alive and termination dates. Median time to second subsequent therapy or death calculated using the Kaplan-Meier method.
Time frame: Up to approximately 33 months after the first patient is randomized.
Population: Full Analysis Set, includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In: AZD9291 + Carboplatin + Pemetrexed | Time to Second Subsequent Therapy (TSST) or Death (Randomized Component) | NA Months |
| Safety Run-In: AZD9291 + Cisplatin + Pemetrexed | Time to Second Subsequent Therapy (TSST) or Death (Randomized Component) | 33.2 Months |
Comparison: The analysis was performed using a log rank test stratified by race (Chinese/Asian vs. Non-Chinese/Asian vs. Non-Asian), WHO performance status (0 vs. 1), and method used for tissue testing (central vs. local).p-value: 0.015795% CI: [0.51, 0.93]Log Rank