Non Small Cell Lung Cancer (Stage III)
Conditions
Keywords
Phase III, Osimertinib, Non Small Cell Lung Cancer (Stage III), Unresectable NSCLC, EGFR, chemoradiation therapy
Brief summary
A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer
Detailed description
This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable EGFR mutation-positive NSCLC, including the most common EGFR sensitising mutations (Ex19Del and L858R), either alone or in combination with other EGFR mutations. Chemoradiation may have been given either given concurrently or sequentially. Patients whose disease has not progressed following chemoradiation will be randomised within 6 weeks of completion of chemoradiation to receive osimertinib or placebo in a 2:1 ratio, and treatment will be continued until disease progression, unacceptable toxicity or other discontinuation criteria are met. After progression, patients can be unblinded and may receive open-label osimertinib. After the final OS analysis, the study blind will be broken and patients still receiving open-label osimertinib will be supplied with open-label osimertinib by AstraZeneca for as long as their treating physician considers they are deriving clinical benefit.
Interventions
DRUGOsimertinib 80mg/40mg
The initial dose of Osimertinib 80mg once daily can be reduced to 40mg once daily. Treatment can continue until disease progression, unacceptable toxicity or other discontinuation criteria are met.
DRUGPlacebo Osimertinib 80mg/40mg
The initial dose of Placebo Osimertinib 80mg once daily can be reduced to 40mg once daily. Treatment can continue until disease progression, unacceptable toxicity or other discontinuation criteria are met
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female aged at least 18 years. 2. Patients with histologically documented NSCLC of predominantly non-squamous Pathology who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer \[IASLC\] Staging Manual in Thoracic Oncology). 3. The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) or FoundationOne® test in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing (cobas® v2 only). 4. Patients must have received either concurrent chemoradiation or sequential chemoradiation including at least 2 cycles of platinum based chemotherapy and a total dose of radiation of 60 Gy ±10% (54 to 66 Gy). 5. Chemoradiation must be completed ≤6 weeks prior to randomization. 6. Patients must not have had disease progression during or following definitive platinum-based, chemoradiation therapy. 7. World Health Organization (WHO) performance status of 0 or 1. 8. Life expectancy \>12 weeks at Day 1. 9. Female patients who are not abstinent (in line with the preferred and usual lifestyle choice) must be using adequate contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-childbearing potential.
Exclusion criteria
1. Mixed small cell and non-small cell lung cancer histology 2. History of interstitial lung disease (ILD) prior to chemoradiation 3. Symptomatic pneumonitis following chemoradiation 4. Any unresolved toxicity Common Terminology Criteria for Adverse Events (CTCAE) \> Grade 2 from the prior chemoradiation therapy 5. Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) \>470 msec, obtained from 3 ECGs * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG * Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes 6. Inadequate bone marrow reserve or organ function 7. History of other malignancies, except: adequately treated non-melanoma skin cancer or lentigo maligna , curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for \> 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy. 8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). 9. 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 10. Prior treatment with any prior chemotherapy, radiation therapy, immunotherapy or investigational agents for NSCLC outside of that received in the definitive setting for Stage III disease (chemotherapy and radiotherapy in SCRT and CCRT regimens is allowed for treatment of Stage III disease). 11. Prior treatment with EGFR-TKI therapy 12. Major surgery as defined by the investigator within 4 weeks of the first dose of study drug. 13. Patients currently receiving (unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior to receiving the first dose of study drug). 14. Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on BICR assessment according to RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Number of PFS events (PFS is time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on BICR assessment according to RECIST v1.1) |
| Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Number of PFS events (PFS is time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on blinded independent central review (BICR) assessment according to RECIST v1.1) |
| Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from randomisation until the date of CNS disease progression or death (by any cause in the absence of CNS progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on CNS BICR assessment according to RECIST v1.1 |
| Overall Survival (Count) | Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months | Number of patients with Overall Survival (OS), the time from the date of randomisation until date of death by any cause |
| Overall Survival (Duration) | Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months | Time from the date of randomisation until death by any cause |
| Objective Response Rate by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Percentage of evaluable patients with at least one BICR assessed visit response of complete response (CR) or partial response (PR). CR defined as disappearance of all target lesions (TL) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm. PR defined as \>= 30% decrease in the sum of diameters of target lesions (compared to baseline sum of diameters). Responses include both confirmed and unconfirmed BICR responses |
| Duration of Response, Unconfirmed by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Date of PFS event - date of first unconfirmed response + 1 day (and expressed in months) for unconfirmed responses only |
| Disease Control Rate by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Percentage of patients who have a best overall response of complete response (CR), partial response (PR) or stable disease (SD) as assessed by BICR |
| Tumour Shrinkage by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Depth of response (or tumour shrinkage or change in tumour size) was assessed using BICR responses in target lesions. The best change in tumour size is the largest decrease from baseline or the smallest increase from baseline in the absence of a reduction |
| Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Proportion with depth of response (or tumour shrinkage or change in tumour size) |
| Time to Death or Distant Metastases by Blinded Independent Central Review (BICR) | Time from randomisation to the date of distant metastases or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from the date of randomisation until the first date of distant metastases or date of death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is detected on a scan that is anywhere other than lung or regional lymph node according to RECIST v1.1 or proven by biopsy |
| Time to Study Treatment Discontinuation | Time from randomisation to the earlier of the date of study treatment discontinuation or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from randomisation to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death (i.e. date of study treatment discontinuation/death or censoring - date of randomisation + 1 day, expressed in months) |
| Time to First Subsequent Treatment | Time from randomisation to the start of first subsequent anti-cancer therapy or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from the date of randomisation to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death |
| Time to Second Subsequent Treatment | Time from randomisation to the start of second subsequent anti-cancer therapy or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from the date of randomisation to the earlier of the second subsequent anti-cancer therapy start date following study drug discontinuation or death |
| Second Progression-free Survival (PFS2) | Every 8 weeks for first 48 weeks, then every 12 weeks. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months | Time from randomisation to the earliest progression event following first objective disease progression, subsequent to the first subsequent therapy, or death. |
Countries
Argentina, Brazil, China, Hungary, India, Japan, Malaysia, Mexico, Peru, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United States, Vietnam
Contacts
PRINCIPAL_INVESTIGATORSuresh S Ramalingam, MD
Emory University School of Medicine, Atlanta, U.S.
PRINCIPAL_INVESTIGATORShun Lu, MD
Shanghai Chest Hospital, Shanghai, China
Participant flow
Pre-assignment details
Patients assigned to osimertinib may continue to receive osimertinib if, in the opinion of their treating physician, they are continuing to derive clinical benefit. Patients receiving placebo may receive open-label osimertinib, in accordance with local clinical practice and the judgement of their treating physician. For all patients, post-progression treatment with AZ-supply osimertinib may continue as long as the treating physician considers the patient to be deriving clinical benefit
Participants by arm
| Arm | Count |
|---|---|
| Osimertinib 80mg once daily tablet | 143 |
| Placebo Matching Placebo | 73 |
| Total | 216 |
Baseline characteristics
| Characteristic | Placebo | Total | Osimertinib |
|---|---|---|---|
| Age, Continuous | 64 Years | 62.5 Years | 62 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 13 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 203 Participants | 132 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 62 Participants | 178 Participants | 116 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) White | 10 Participants | 30 Participants | 20 Participants |
| Sex: Female, Male Female | 42 Participants | 132 Participants | 90 Participants |
| Sex: Female, Male Male | 31 Participants | 84 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 143 | 15 / 73 |
| other Total, other adverse events | 129 / 143 | 54 / 73 |
| serious Total, serious adverse events | 55 / 143 | 11 / 73 |
Outcome results
Primary
Progression-free Survival (PFS) by Blinded Independent Central Review (BICR)
Time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on BICR assessment according to RECIST v1.1
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) | 39.13 Months |
| Placebo | Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) | 5.55 Months |
p-value: <0.00195% CI: [0.1, 0.24]Log Rank
Secondary
Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR)
Time from randomisation until the date of CNS disease progression or death (by any cause in the absence of CNS progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on CNS BICR assessment according to RECIST v1.1
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) | NA Months |
| Placebo | Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) | 14.88 Months |
p-value: <0.00195% CI: [0.09, 0.32]Log Rank
Secondary
Disease Control Rate by Blinded Independent Central Review (BICR)
Percentage of patients who have a best overall response of complete response (CR), partial response (PR) or stable disease (SD) as assessed by BICR
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib | Disease Control Rate by Blinded Independent Central Review (BICR) | 88.8 % of participants |
| Placebo | Disease Control Rate by Blinded Independent Central Review (BICR) | 79.5 % of participants |
p-value: 0.06995% CI: [0.94, 4.47]Regression, Logistic
Secondary
Duration of Response, Unconfirmed by Blinded Independent Central Review (BICR)
Date of PFS event - date of first unconfirmed response + 1 day (and expressed in months) for unconfirmed responses only
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Duration of Response, Unconfirmed by Blinded Independent Central Review (BICR) | 36.9 Months |
| Placebo | Duration of Response, Unconfirmed by Blinded Independent Central Review (BICR) | 6.5 Months |
Secondary
Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation
Number of PFS events (PFS is time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on BICR assessment according to RECIST v1.1)
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osimertinib | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | Ex19Del positive | 26 Participants |
| Osimertinib | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | L858R positive | 31 Participants |
| Osimertinib | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | Missing | 0 Participants |
| Placebo | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | Ex19Del positive | 39 Participants |
| Placebo | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | L858R positive | 24 Participants |
| Placebo | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation | Missing | 0 Participants |
Comparison: PFS in Ex19Del positive patients95% CI: [0.1, 0.29]Cox proportional hazard model
Comparison: PFS in L858R positive patients95% CI: [0.19, 0.56]Cox proportional hazard model
Secondary
Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA
Number of PFS events (PFS is time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on blinded independent central review (BICR) assessment according to RECIST v1.1)
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osimertinib | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | EGFR mutation-unknown | 11 Participants |
| Osimertinib | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | EGFR mutation-positive | 4 Participants |
| Osimertinib | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | EGFR mutation-negative | 42 Participants |
| Placebo | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | EGFR mutation-negative | 51 Participants |
| Placebo | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | EGFR mutation-unknown | 8 Participants |
| Placebo | Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA | EGFR mutation-positive | 4 Participants |
Comparison: Negative at screening95% CI: [0.15, 0.34]Cox proportional hazard model
Secondary
Objective Response Rate by Blinded Independent Central Review (BICR)
Percentage of evaluable patients with at least one BICR assessed visit response of complete response (CR) or partial response (PR). CR defined as disappearance of all target lesions (TL) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm. PR defined as \>= 30% decrease in the sum of diameters of target lesions (compared to baseline sum of diameters). Responses include both confirmed and unconfirmed BICR responses
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib | Objective Response Rate by Blinded Independent Central Review (BICR) | 57.3 % of participants |
| Placebo | Objective Response Rate by Blinded Independent Central Review (BICR) | 32.9 % of participants |
p-value: <0.00195% CI: [1.54, 5.08]Regression, Logistic
Secondary
Overall Survival (Count)
Number of patients with Overall Survival (OS), the time from the date of randomisation until date of death by any cause
Time frame: Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osimertinib | Overall Survival (Count) | Died | 28 Participants |
| Osimertinib | Overall Survival (Count) | Censored (includes participants still in survival follow up and terminated prior to death) | 115 Participants |
| Placebo | Overall Survival (Count) | Died | 15 Participants |
| Placebo | Overall Survival (Count) | Censored (includes participants still in survival follow up and terminated prior to death) | 58 Participants |
Secondary
Overall Survival (Duration)
Time from the date of randomisation until death by any cause
Time frame: Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Overall Survival (Duration) | 53.95 Months |
| Placebo | Overall Survival (Duration) | NA Months |
p-value: 0.5395% CI: [0.42, 1.56]Log Rank
Secondary
Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR)
Proportion with depth of response (or tumour shrinkage or change in tumour size)
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osimertinib | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction | 0.92 Proportion of participants |
| Osimertinib | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction > 30% | 0.65 Proportion of participants |
| Osimertinib | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction > 75% | 0.18 Proportion of participants |
| Osimertinib | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction > 50% | 0.43 Proportion of participants |
| Placebo | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction > 50% | 0.11 Proportion of participants |
| Placebo | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction | 0.83 Proportion of participants |
| Placebo | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction > 75% | 0.09 Proportion of participants |
| Placebo | Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR) | Proportion with reduction > 30% | 0.40 Proportion of participants |
Secondary
Second Progression-free Survival (PFS2)
Time from randomisation to the earliest progression event following first objective disease progression, subsequent to the first subsequent therapy, or death.
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Second Progression-free Survival (PFS2) | 48.20 Months |
| Placebo | Second Progression-free Survival (PFS2) | 47.38 Months |
p-value: 0.08895% CI: [0.35, 1.08]Log Rank
Secondary
Time to Death or Distant Metastases by Blinded Independent Central Review (BICR)
Time from the date of randomisation until the first date of distant metastases or date of death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is detected on a scan that is anywhere other than lung or regional lymph node according to RECIST v1.1 or proven by biopsy
Time frame: Time from randomisation to the date of distant metastases or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Time to Death or Distant Metastases by Blinded Independent Central Review (BICR) | NA Months |
| Placebo | Time to Death or Distant Metastases by Blinded Independent Central Review (BICR) | 13.04 Months |
p-value: <0.00195% CI: [0.11, 0.38]Log Rank
Secondary
Time to First Subsequent Treatment
Time from the date of randomisation to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death
Time frame: Time from randomisation to the start of first subsequent anti-cancer therapy or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Time to First Subsequent Treatment | 43.83 Months |
| Placebo | Time to First Subsequent Treatment | 9.46 Months |
p-value: <0.00195% CI: [0.08, 0.21]Log Rank
Secondary
Time to Second Subsequent Treatment
Time from the date of randomisation to the earlier of the second subsequent anti-cancer therapy start date following study drug discontinuation or death
Time frame: Time from randomisation to the start of second subsequent anti-cancer therapy or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Time to Second Subsequent Treatment | NA Months |
| Placebo | Time to Second Subsequent Treatment | 47.38 Months |
p-value: 0.02295% CI: [0.28, 0.91]Log Rank
Secondary
Time to Study Treatment Discontinuation
Time from randomisation to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death (i.e. date of study treatment discontinuation/death or censoring - date of randomisation + 1 day, expressed in months)
Time frame: Time from randomisation to the earlier of the date of study treatment discontinuation or death. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Time to Study Treatment Discontinuation | 40.28 Months |
| Placebo | Time to Study Treatment Discontinuation | 8.31 Months |
p-value: <0.00195% CI: [0.14, 0.32]Log Rank
Secondary
Tumour Shrinkage by Blinded Independent Central Review (BICR)
Depth of response (or tumour shrinkage or change in tumour size) was assessed using BICR responses in target lesions. The best change in tumour size is the largest decrease from baseline or the smallest increase from baseline in the absence of a reduction
Time frame: Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Tumour Shrinkage by Blinded Independent Central Review (BICR) | -43.3 % change from baseline |
| Placebo | Tumour Shrinkage by Blinded Independent Central Review (BICR) | -21.9 % change from baseline |