NSCLC
Conditions
Keywords
AZD9291, Osimertinib, Gefitinib, NSCLC, liquid biopsy, ctDNA
Brief summary
The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.
Detailed description
Primary objective To evaluate the best strategy for delivering Osimertinib (AZD9291) in NSCLC patients with EGFR mutation. The objective is assessed by Progression Free Survival rate at 18 months (PFSR-OSI-18). Secondary objectives * To evaluate PFS while receiving osimertinib measured from randomization by RECIST criteria 1.1. * To evaluate PFS measured from switching to osimertinib by RECIST criteria 1.1. * To determine the proportion of patients receiving osimertinib based on the determination of cfDNA T790M mutation positive. * To evaluate PFS-2. * To evaluate Overall Response Rate (ORR) to osimertinib. * To evaluate the Treatment duration. * To evaluate Time to progression (TTP) on osimertinib (measured from switching to osimertinib). * To evaluate Overall Survival (OS). * To evaluate brain progression free survival (BPFS). * Safety.
Interventions
DRUGOsimertinib
Osimertinib 60 or 40 mg daily until progression
DRUGGefitinib
Gefitinib 250mg daily until progression
Sponsors
European Organisation for Research and Treatment of Cancer - EORTC
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: Registration: * Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory; * Stage IV NSCLC; * Blood sample available for cfDNA EGFR T790M central testing; * Age ≥18 years; * EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI; * Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration; * Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations Randomization: * Report of adequacy sample for cfDNA EGFR T790M test by central laboratory; * Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization; * Patients with brain metastases are allowed provided they are stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before randomization; Baseline tumor assessment scans are done within 21 days before randomization; * Evaluable disease as defined below; * At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis of ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements. * WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks; * Adequate bone marrow, renal, hepatic and liver function within 21 days from randomization and defined as follows: * Absolute neutrophil count ≥1.5 x 109/L; * Platelet count ≥100 x 109/L; * Haemoglobin ≥9 g/dL; * Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases; * Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases; * Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; * Serum creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation); * No significant comorbidity that according to the investigator would hamper the participation on the trial; * Female patients should be using adequate contraceptive measures, should not be breastfeeding, until 12 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: * Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. * Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution. * Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation. * Male patients should be willing to use barrier contraception, i.e., condoms o Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the study should they wish to father children, and not to donate sperm until 6 months after discontinuation of study treatment." (as per Investigator Brochure, IB) * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. Exclusion: * Treatment with any of the following: * Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug; * Prior treatment with an EGFR-TKI; * Major surgery (excluding placement of vascular access) within 4 weeks before randomization; * Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks before randomization * Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4; * Other anti-cancer therapies and alternative medications such as homeopathic treatment, etc; * Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known; * Leptomeningeal carcinomatosis; spinal cord compression; * Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 2 at the time of randomization; * Patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer or localised and presumed cured prostatic cancer) within 2 years before randomization and are not receiving specific treatment for these malignancies at baseline assessment; * 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 jeopardise compliance with the protocol; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Active infection will include any patients receiving intravenous treatment for infection; active hepatitis B infection will, at a minimum, include all patients who are Hepatitis B surface antigen positive (HbsAg positive) based on serology assessment. Screening for chronic conditions is not required; * 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 or Gefitinib; * Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) \>470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval \>250 msec or history of episodes of bradycardia (\<50 BPM); * 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. * Abnormal cardiac function: LVEF \< 50% (assessed by MUGA or ECHO) * Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS Rate at 18 Months | 18 months after randomization | The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not experience an event for PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI). Specifically, it relates to progression of disease according to RECIST 1.1 or death after switching to osimertinib in arms "Gefitinib till + blood test/progression then Osimertinib" and "Gefitinib till progression then Osimertinib". It is formally assessed in these two arms, whilst only provided as a reference for the "Osimertinib till progression" arm, in which progression of disease or death is measured from baseline considering that patients start with osimertinib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS While Receiving Osimertinib by RECIST Criteria 1.1 | From randomization till the date of progression on osimertinib or death, an average of 2 years. | For patients in arm "Osimertinib till progression", progression Free Survival "while receiving osimertinib" (PFS-OSI) is defined as the time interval between the date of randomization and the date of disease progression according to the RECIST 1.1 or death whichever comes first. For patients in arm "Gefitinib till + blood test/progression than Osimertinib" and "Gefitinib till progression than Osimertinib "switching to osimertinib, PFS-OSI is defined as the time interval between the date of randomization and the date of disease progression or death "after switching to osimertinib" whichever comes first. For patients in those two arms who do not start osimertinib for any reason, PFS-OSI is defined as the time interval between the date of randomization and the date of first disease progression according to the RECIST 1.1 or death whichever comes first. The median will be calculated using the Kaplan-Meier method. |
| Proportion of Patients Receiving Osimertinib Based on the Determination of cfDNA T790M Mutation Positive | From randomization till the date of positive cfDNA T790M status or death, on average 2 years. | The proportion of patients receiving osimertinib based on the determination of cfDNA T790M is the number of patients receiving at least 1 dose of osimertinib based on the determination of cfDNA T790M (positive mutation). This endpoint is only defined and applicable for the "Gefitinib till + blood test/progression than Osimertinib" arm. The 95% confidence intervals will be calculated using the exact binomial method. |
| Time to Progression on Osimertinib | From randomization till the date of progression on osimertinib or death, on average 2 years. | Time to progression on osimertinib is defined as the time interval between the date receiving osimertinib and the date of disease progression. Death is not counted as an event. If the event has not been observed or if the patient dies before the analysis cut-off date, then the patient is censored at the date of the last disease assessment or the date of death prior the cut-off date. Patients not receiving osimertinib are excluded for this endpoint. The nature of this endpoint is different in Arm "Osimertinib till progression" (first line progression) compared to the other two arms (second line progression). |
| Overall Response Rate (ORR) to Osimertinib | Time from randomization until end of osimeritinib treatment, or death, on average 2 years. | Overall response rate (ORR) to osimertinib is defined as the proportion of patients achieving complete response (CR) or partial response (PR) during osimertinib treatment. The analysis of overall response rate (ORR) on osimertinib was performed on the per-protocol population. Patients not receiving Osimertinib will not be included in the osimertinib analysis. |
| Treatment Duration | From randomization till the date of end of protocol treatment | treatment duration is measured from randomization till the last day of treatment administration. For patients in arm "Osimertinib till progression" this corresponds to the whole osimertinib treatment duration, and for patients in the other two arms, to the whole gefitinib and osimertinib treatment duration. Patients for whom no end of treatment form has been collected, are known be alive and have not started any off protocol treatment prior to clinical cut off date will be considered as still on treatment and censored in this analysis. |
| Overall Survival (OS) | From randomization till the date of death | Overall survival (OS) is defined as the time interval between the date of randomization and the date of death from any cause. Patients still alive at the analysis cut-off date are censored at the last date known to be alive (before the cut-off date). The median will be calculated using the Kaplan-Meier method. |
| Brain Progression Free Survival (BPFS) | From randomization till the date of progression in the brain | Brain progression free survival is defined as the time interval between the randomization and the date of brain progression (progression within target lesions in the brain, unequivocal progression in non-target lesions in the brain, or appearance of new lesions in the brain) or death whichever comes first. CT scan will be used to evaluate new or recurrence progression in the brain. If the event has not been observed or if the patient dies or has PD that hampered further assessment/evaluation of brain progression, then the patient is censored at the date of the last follow up examination. The medians have been estimated using the Kaplan-Meier method. |
| PFS-2 | From randomization till the date of second progression on second line treatment | In the "Osimertinib till progression" arm, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or death, irrespective of treatment(s) received. In the other two arms, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or death after switching to osimertinib, the first PD being PD by RECIST 1.1 or by positive cfDNA T790M status. For patients unable to start osimertinib, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 on any subsequent off protocol anticancer treatment line. If no PFS-2 event has been observed prior to the analysis cut-off date, then the patient is censored at the date of the last disease assessment before the cut-off date. |
Countries
Belgium, France, Jordan, Poland, Slovenia, Spain
Contacts
PRINCIPAL_INVESTIGATORRafal Dziadziuszko, MD PhD
Mecical University of Gdansk, Poland
Participant flow
Recruitment details
After registration was completed, eligible patients were randomized within 4 weeks.
Pre-assignment details
The patients were first registered (step 1) to the trial by authorized sites. The site immediately sent the blood samples for circulating free DNA EGFR T790M (cfDNA T790M) testing to the central lab. Once the sample was assessed (step 2), the site was notified whether they could proceed to patient randomization. Patients were then randomized (step 3) after verification of all eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Osimertinib Till Progression Osimertinib until PD according to RECIST 1.1
Osimertinib: Osimertinib 60 or 40 mg daily until progression | 53 |
| Gefitinib Till + Blood Test/Progression Than Osimertinib Gefitinib until emergence of positive T790M status (cfDNA T790M positive progression) followed by Osimertinib until second PD according to RECIST 1.1
Osimertinib: Osimertinib 60 or 40 mg daily until progression
Gefitinib: Gefitinib 250mg daily until progression | 52 |
| Gefitinib Till Progression Than Osimertinib Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1
Osimertinib: Osimertinib 60 or 40 mg daily until progression
Gefitinib: Gefitinib 250mg daily until progression | 51 |
| Total | 156 |
Baseline characteristics
| Characteristic | Osimertinib Till Progression | Gefitinib Till + Blood Test/Progression Than Osimertinib | Gefitinib Till Progression Than Osimertinib | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 32 Participants | 20 Participants | 84 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 20 Participants | 31 Participants | 72 Participants |
| Age, Continuous | 68 years | 69 years | 61 years | 66 years |
| EGFR mutation Del19 | 35 Participants | 33 Participants | 33 Participants | 101 Participants |
| EGFR mutation L858R | 18 Participants | 19 Participants | 18 Participants | 55 Participants |
| Presence of brain metastases No | 43 Participants | 36 Participants | 37 Participants | 116 Participants |
| Presence of brain metastases Yes | 10 Participants | 16 Participants | 14 Participants | 40 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 5 Participants | 5 Participants | 16 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 6 Participants | 15 Participants |
| Race (NIH/OMB) White | 40 Participants | 42 Participants | 38 Participants | 120 Participants |
| Region of Enrollment Belgium | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 22 participants | 20 participants | 21 participants | 63 participants |
| Region of Enrollment Jordan | 5 participants | 3 participants | 7 participants | 15 participants |
| Region of Enrollment Poland | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Slovenia | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Spain | 25 participants | 28 participants | 21 participants | 74 participants |
| Sex: Female, Male Female | 30 Participants | 39 Participants | 33 Participants | 102 Participants |
| Sex: Female, Male Male | 23 Participants | 13 Participants | 18 Participants | 54 Participants |
| WHO Performance Status 0 | 21 Participants | 23 Participants | 26 Participants | 70 Participants |
| WHO Performance Status 1 | 30 Participants | 28 Participants | 22 Participants | 80 Participants |
| WHO Performance Status 2 | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 19 / 53 | 20 / 52 | 18 / 51 |
| other Total, other adverse events | 52 / 53 | 51 / 52 | 50 / 51 |
| serious Total, serious adverse events | 9 / 53 | 6 / 52 | 13 / 51 |
Outcome results
Primary
PFS Rate at 18 Months
The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not experience an event for PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI). Specifically, it relates to progression of disease according to RECIST 1.1 or death after switching to osimertinib in arms Gefitinib till + blood test/progression then Osimertinib and Gefitinib till progression then Osimertinib. It is formally assessed in these two arms, whilst only provided as a reference for the Osimertinib till progression arm, in which progression of disease or death is measured from baseline considering that patients start with osimertinib.
Time frame: 18 months after randomization
Population: Per-protocol population defined as patients who have started their study treatment and satisfying all eligibility criteria as per medical review
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib Till Progression | PFS Rate at 18 Months | 51.1 Percentage of participants |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | PFS Rate at 18 Months | 67.2 Percentage of participants |
| Gefitinib Till Progression Than Osimertinib | PFS Rate at 18 Months | 53.5 Percentage of participants |
Comparison: Each arm will be assessed individually against a historical control with a single proportion test. The test is designed to reject a PFS rate at 18 months of 40% (null hypothesis) at the 0.08 significance level. Under the alternative hypothesis of a PFS rate at 18 months of 60%, 49 patients are required to reach a power of 84%.84% CI: [56.4, 75.9]
Comparison: Each arm will be assessed individually against a historical control with a single proportion test. The test is designed to reject a PFS rate at 18 months of 40% (null hypothesis) at the 0.08 significance level. Under the alternative hypothesis of a PFS rate at 18 months of 60%, 49 patients are required to reach a power of 84%.84% CI: [42.3, 63.5]
Secondary
Brain Progression Free Survival (BPFS)
Brain progression free survival is defined as the time interval between the randomization and the date of brain progression (progression within target lesions in the brain, unequivocal progression in non-target lesions in the brain, or appearance of new lesions in the brain) or death whichever comes first. CT scan will be used to evaluate new or recurrence progression in the brain. If the event has not been observed or if the patient dies or has PD that hampered further assessment/evaluation of brain progression, then the patient is censored at the date of the last follow up examination. The medians have been estimated using the Kaplan-Meier method.
Time frame: From randomization till the date of progression in the brain
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib Till Progression | Brain Progression Free Survival (BPFS) | 34.30 Months |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | Brain Progression Free Survival (BPFS) | 24.44 Months |
| Gefitinib Till Progression Than Osimertinib | Brain Progression Free Survival (BPFS) | 21.39 Months |
Secondary
Overall Response Rate (ORR) to Osimertinib
Overall response rate (ORR) to osimertinib is defined as the proportion of patients achieving complete response (CR) or partial response (PR) during osimertinib treatment. The analysis of overall response rate (ORR) on osimertinib was performed on the per-protocol population. Patients not receiving Osimertinib will not be included in the osimertinib analysis.
Time frame: Time from randomization until end of osimeritinib treatment, or death, on average 2 years.
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review. Patients not receiving Osimertinib will not be included in the osimertinib analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib Till Progression | Overall Response Rate (ORR) to Osimertinib | 0.889 proportion of patients |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | Overall Response Rate (ORR) to Osimertinib | 0.656 proportion of patients |
| Gefitinib Till Progression Than Osimertinib | Overall Response Rate (ORR) to Osimertinib | 0.588 proportion of patients |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the time interval between the date of randomization and the date of death from any cause. Patients still alive at the analysis cut-off date are censored at the last date known to be alive (before the cut-off date). The median will be calculated using the Kaplan-Meier method.
Time frame: From randomization till the date of death
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib Till Progression | Overall Survival (OS) | NA Months |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | Overall Survival (OS) | NA Months |
| Gefitinib Till Progression Than Osimertinib | Overall Survival (OS) | 42.84 Months |
Secondary
PFS-2
In the Osimertinib till progression arm, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or death, irrespective of treatment(s) received. In the other two arms, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or death after switching to osimertinib, the first PD being PD by RECIST 1.1 or by positive cfDNA T790M status. For patients unable to start osimertinib, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 on any subsequent off protocol anticancer treatment line. If no PFS-2 event has been observed prior to the analysis cut-off date, then the patient is censored at the date of the last disease assessment before the cut-off date.
Time frame: From randomization till the date of second progression on second line treatment
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib Till Progression | PFS-2 | 25.76 Months |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | PFS-2 | 21.98 Months |
| Gefitinib Till Progression Than Osimertinib | PFS-2 | 20.27 Months |
Secondary
PFS While Receiving Osimertinib by RECIST Criteria 1.1
For patients in arm Osimertinib till progression, progression Free Survival while receiving osimertinib (PFS-OSI) is defined as the time interval between the date of randomization and the date of disease progression according to the RECIST 1.1 or death whichever comes first. For patients in arm Gefitinib till + blood test/progression than Osimertinib and Gefitinib till progression than Osimertinib switching to osimertinib, PFS-OSI is defined as the time interval between the date of randomization and the date of disease progression or death after switching to osimertinib whichever comes first. For patients in those two arms who do not start osimertinib for any reason, PFS-OSI is defined as the time interval between the date of randomization and the date of first disease progression according to the RECIST 1.1 or death whichever comes first. The median will be calculated using the Kaplan-Meier method.
Time frame: From randomization till the date of progression on osimertinib or death, an average of 2 years.
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib Till Progression | PFS While Receiving Osimertinib by RECIST Criteria 1.1 | 19.48 months |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | PFS While Receiving Osimertinib by RECIST Criteria 1.1 | 21.98 months |
| Gefitinib Till Progression Than Osimertinib | PFS While Receiving Osimertinib by RECIST Criteria 1.1 | 20.17 months |
Secondary
Proportion of Patients Receiving Osimertinib Based on the Determination of cfDNA T790M Mutation Positive
The proportion of patients receiving osimertinib based on the determination of cfDNA T790M is the number of patients receiving at least 1 dose of osimertinib based on the determination of cfDNA T790M (positive mutation). This endpoint is only defined and applicable for the Gefitinib till + blood test/progression than Osimertinib arm. The 95% confidence intervals will be calculated using the exact binomial method.
Time frame: From randomization till the date of positive cfDNA T790M status or death, on average 2 years.
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib Till Progression | Proportion of Patients Receiving Osimertinib Based on the Determination of cfDNA T790M Mutation Positive | 0.170 proportion of participants |
Secondary
Time to Progression on Osimertinib
Time to progression on osimertinib is defined as the time interval between the date receiving osimertinib and the date of disease progression. Death is not counted as an event. If the event has not been observed or if the patient dies before the analysis cut-off date, then the patient is censored at the date of the last disease assessment or the date of death prior the cut-off date. Patients not receiving osimertinib are excluded for this endpoint. The nature of this endpoint is different in Arm Osimertinib till progression (first line progression) compared to the other two arms (second line progression).
Time frame: From randomization till the date of progression on osimertinib or death, on average 2 years.
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review. Only patients who started osimertinib are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib Till Progression | Time to Progression on Osimertinib | 19.48 Time in months |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | Time to Progression on Osimertinib | 10.81 Time in months |
| Gefitinib Till Progression Than Osimertinib | Time to Progression on Osimertinib | 7.39 Time in months |
Secondary
Treatment Duration
treatment duration is measured from randomization till the last day of treatment administration. For patients in arm Osimertinib till progression this corresponds to the whole osimertinib treatment duration, and for patients in the other two arms, to the whole gefitinib and osimertinib treatment duration. Patients for whom no end of treatment form has been collected, are known be alive and have not started any off protocol treatment prior to clinical cut off date will be considered as still on treatment and censored in this analysis.
Time frame: From randomization till the date of end of protocol treatment
Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib Till Progression | Treatment Duration | 24.4 Months |
| Gefitinib Till + Blood Test/Progression Than Osimertinib | Treatment Duration | 21.6 Months |
| Gefitinib Till Progression Than Osimertinib | Treatment Duration | 16.2 Months |