Anticancer Treatment
Conditions
Keywords
Advanced Non-Small Cell Lung Cancer; T790M Mutation Positive
Brief summary
A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene
Detailed description
This is a phase III, open label, randomized study assessing Osimertinib (80 mg, orally, once daily) versus platinum-based doublet chemotherapy (standard of care) in subjects with confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent and whose tumours harbour a T790M mutation within the EGFR Gene. Subjects must be chemotherapy naive and must agree to provide a biopsy for central confirmation of T790 mutation status following confirmed disease progression on their first line EGFR-TKI treatment (e.g. erlotinib, gefitinib or afatinib). Suitable subjects will then be randomized to receive either Osimertinib (80mg orally, once daily) or platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 + carboplatin area under the plasma concentration-time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2) on Day 1 of every 21-day cycle in a 2:1 (Osimertinib: platinum-based doublet chemotherapy) ratio. Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator. The primary objective of the study is to assess the efficacy of Osimertinib compared with platinum-based doublet chemotherapy by assessment of Progression Free Survival (PFS), using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1), as well as asensitivity analysis of Progression Free Survival using Blinded Independent Central Review (BICR).
Interventions
DRUGChemotherapy
Randomization to either Osimertinib or platinum-based doublet-chemotherapy on Day 1 of every 21d cycle in a 2:1 (Osimertinib:platinum-based doublet-chemotherapy) ratio
DRUGCross-over to Osimertinib
Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator. Subjects who stop platinum-based doublet chemotherapy for reasons other than objective disease progression according to RECIST 1.1 will not be eligible to cross-over to Osimertinib.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with histologically or cytologically documented NSCLC. * Locally advanced or metastatic NSCLC * Radiological documentation of disease progression following 1st line EGFR TKI Treatment without any further treatment * Eligible to receive treatment with the selected doublet-chemotherapy * Central confirmation of T790M+ mutation status * World Health Organization (WHO) performance status 0-1 * At least one lesion, not previously irradiated.
Exclusion criteria
* • Prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months prior of starting 1st EGFR TKI treatment * Treatment with more than one prior line of treatment for advanced NSCLC * Treatment with an approved EGFR-TKI (e.g.,erlotinib, gefitinib, afatinib) within 8 days or approximately 5x half-life of the first dose of study treatment * Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment * Previous treatment with Osimertinib, or a 3rd generation EGFR TKI For subjects who cross-over to Osimertinib: * Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review. * At least 14 days since last dose of platinum-based doublet chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Investigator Assessment | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) by Investigator Assessment | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy. |
| Duration of Response (DoR) by Investigator Assessment | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. |
| Disease Control Rate (DCR) by Investigator Assessment | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at \>=6 weeks, prior to any progressive disease (PD). |
| Tumour Shrinkage by Investigator Assessment | RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis). | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response. |
| Secondary: Overall Survival (OS) | From date of randomization until time of final OS analysis, a median follow-up of 43 months | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to First Subsequent Therapy (TFST) | From date of randomisation until time of final OS analysis, a median follow-up of 43 months | Time from randomisation to first subsequent anti-cancer therapy (FST) following randomised treatment discontinuation, or death if no FST administered. Any patient not known to have died nor received any subsequent anti-cancer therapy (ST) was censored at the last time known not to have received ST, ie, the last follow-up visit this was confirmed. |
| Time to Second Subsequent Therapy (TSST) | From date of randomisation until time of final OS analysis, a median follow-up of 43 months | Time from randomisation to second subsequent anti-cancer therapy (SST) following randomised treatment discontinuation, or death if no SST administered. Any patient not known to have died nor received any SST was censored at the last time known not to have received SST, ie, the last follow-up visit this was confirmed. |
Countries
Australia, Canada, China, France, Germany, Hong Kong, Hungary, Italy, Japan, Mexico, Netherlands, Russia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
First patient dosed: 20 August 2014. Data cut off: 15 March 2019. Open for enrolment at 145 study centres, 126 centres in 17 countries randomised patients to treatment. Following the final OS analysis, patients were permitted to continue to receive treatment if, in the investigator's opinion, they were continuing to receive benefit from treatment. The last patient completed the study on the 15 December 2023
Participants by arm
| Arm | Count |
|---|---|
| Osimertinib 80 mg Daily single dose of Osimertinib 80mg | 279 |
| Chemotherapy Platinum-based doublet chemotherapy | 140 |
| Total | 419 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 184 | 88 |
| Overall Study | Eligibility criteria not fulfilled | 0 | 1 |
| Overall Study | Lost to Follow-up | 7 | 1 |
| Overall Study | Other reasons | 1 | 2 |
| Overall Study | Withdrawal by Subject | 27 | 21 |
Baseline characteristics
| Characteristic | Osimertinib 80 mg | Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 61.5 Years STANDARD_DEVIATION 11.64 | 62.0 Years STANDARD_DEVIATION 11.91 | 61.7 Years STANDARD_DEVIATION 11.72 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 182 Participants | 92 Participants | 274 Participants |
| Race/Ethnicity, Customized Black Or African American | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 89 Participants | 45 Participants | 134 Participants |
| Sex: Female, Male Female | 172 Participants | 97 Participants | 269 Participants |
| Sex: Female, Male Male | 107 Participants | 43 Participants | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 188 / 279 | 93 / 136 |
| other Total, other adverse events | 275 / 279 | 134 / 136 |
| serious Total, serious adverse events | 84 / 279 | 36 / 136 |
Outcome results
Primary
Progression Free Survival (PFS) by Investigator Assessment
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib 80mg | Progression Free Survival (PFS) by Investigator Assessment | 10.1 Months |
| Chemotherapy | Progression Free Survival (PFS) by Investigator Assessment | 4.4 Months |
p-value: <0.00195% CI: [0.23, 0.41]Log Rank
Secondary
Disease Control Rate (DCR) by Investigator Assessment
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at \>=6 weeks, prior to any progressive disease (PD).
Time frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib 80mg | Disease Control Rate (DCR) by Investigator Assessment | 93.2 % of participants |
| Chemotherapy | Disease Control Rate (DCR) by Investigator Assessment | 74.3 % of participants |
p-value: <0.00195% CI: [2.64, 8.84]Regression, Logistic
Secondary
Duration of Response (DoR) by Investigator Assessment
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib 80mg | Duration of Response (DoR) by Investigator Assessment | 9.7 months |
| Chemotherapy | Duration of Response (DoR) by Investigator Assessment | 4.1 months |
p-value: <0.00195% CI: [4.04, 9.57]formulae provided in Ellis S et al 2008
Secondary
Objective Response Rate (ORR) by Investigator Assessment
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib 80mg | Objective Response Rate (ORR) by Investigator Assessment | 70.6 % of participants |
| Chemotherapy | Objective Response Rate (ORR) by Investigator Assessment | 31.4 % of participants |
p-value: <0.00195% CI: [3.47, 8.48]Regression, Logistic
Secondary
Secondary: Overall Survival (OS)
Time frame: From date of randomization until time of final OS analysis, a median follow-up of 43 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib 80mg | Secondary: Overall Survival (OS) | 26.8 Months |
| Chemotherapy | Secondary: Overall Survival (OS) | 22.5 Months |
p-value: 0.27795% CI: [0.67, 1.13]Log Rank
Secondary
Tumour Shrinkage by Investigator Assessment
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response.
Time frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Osimertinib 80mg | Tumour Shrinkage by Investigator Assessment | -46.1 % change from baseline | Standard Deviation 29.5 |
| Chemotherapy | Tumour Shrinkage by Investigator Assessment | -24.4 % change from baseline | Standard Deviation 29.27 |
p-value: <0.00195% CI: [-27.71, -15.52]ANCOVA
Other Pre-specified
Time to First Subsequent Therapy (TFST)
Time from randomisation to first subsequent anti-cancer therapy (FST) following randomised treatment discontinuation, or death if no FST administered. Any patient not known to have died nor received any subsequent anti-cancer therapy (ST) was censored at the last time known not to have received ST, ie, the last follow-up visit this was confirmed.
Time frame: From date of randomisation until time of final OS analysis, a median follow-up of 43 months
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib 80mg | Time to First Subsequent Therapy (TFST) | 16.0 Months |
| Chemotherapy | Time to First Subsequent Therapy (TFST) | 6.0 Months |
p-value: <0.00195% CI: [0.16, 0.28]Log Rank
Other Pre-specified
Time to Second Subsequent Therapy (TSST)
Time from randomisation to second subsequent anti-cancer therapy (SST) following randomised treatment discontinuation, or death if no SST administered. Any patient not known to have died nor received any SST was censored at the last time known not to have received SST, ie, the last follow-up visit this was confirmed.
Time frame: From date of randomisation until time of final OS analysis, a median follow-up of 43 months
Population: Full Analysis set (All randomised patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib 80mg | Time to Second Subsequent Therapy (TSST) | 20.0 Months |
| Chemotherapy | Time to Second Subsequent Therapy (TSST) | 19.0 Months |
p-value: <0.00195% CI: [0.69, 1.11]Log Rank