Lung Cancer
Conditions
Keywords
NSCLC, EGFRm, T790M
Brief summary
The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.
Detailed description
Objective: The primary objective of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. Study site(s) and number of patients planned: Approximately 1500 patients will be recruited in Europe. The recruitment will be increased beyond that as the study will expand in other regions of the world (America, Asia). Study Design This will be an open-label, single-arm, multinational, multicenter, real world treatment study. Target patient population: Adult patients (fulfilling the definition of age of majority per local regulations) with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC with confirmed T790M mutation, who have received prior EGFR-TKI therapy. Investigational product (IP), dosage, and mode of administration: AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitising and resistance mutations in NSCLC with a significant selectivity margin over wild-type EGFR. AZD9291 will be administered orally as one 80 mg tablet once a day. Duration of IP administration: Patients may continue to receive AZD9291 as long as they continue to show clinical benefit, as judged by the investigator, and in the absence of discontinuation criteria). The study will be closed in each participating country as soon as possible following national reimbursement of AZD9291 in that country (up to a max of 90 days post reimbursement). Enrolment will be closed within 6 months after market license approval in that country or at national reimbursement, whichever is sooner. Patients withdrawing from the treatment prior to national reimbursement will be followed up as part of this study. Patients on treatment will receive commercial supply until documented disease progression as per investigator assessment. In the event that national reimbursement should not be granted following a reasonable time after market license approval in the country, the study will be closed in a maximum period of 18 months after the last patient is enrolled in that country. If applicable, timelines for conversion to commercial drug will be agreed with local bodies which may include regulatory agencies, ethics committees, and institutions. Patient will be followed until death or lost to follow-up. Study measures: Data collected will include patient demographics, information needed to determine patient eligibility (including medical history, past and current disease characteristics, and tumor EGFR mutational status), AZD9291 exposure, investigator-reported efficacy (including tumor response and disease progression), overall survival (OS), and safety (including serious adverse events \[SAEs\], adverse events leading to dose modification, and adverse events of special interest \[interstitial lung disease/pneumonitis-like events, and QTc prolongation events\]). Statistical methods: All data will be presented for the overall full analysis/evaluable set, and also by cohorts defined by number and type of previous treatment lines for the advanced disease. Descriptive statistics will be used for all variables, as appropriate. Continuous variables will be summarised by the number of observations, mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarised by frequency counts and percentages for each category. OS and PFS will be summarized using Kaplan-Meier estimates of the median time to death or censoring and quartiles together with their 95% confidence intervals.
Interventions
PROCEDURET790M+ Testing
If a previous lab report is unavailable, the patient will need to have T790M+ testing.
PROCEDUREBaseline Visit Blood & Urine Testing
Blood count and standard chemistry testing to ensure patient meets inclusion/exclusion criteria
PROCEDUREBaseline ECG
ECG to ensure absence of any cardiac abnormality
PROCEDUREVisual Slit-Lamp Testing
Slit-lamp testing performed to ensure patients do not have any eye abnormalities or symptoms
DRUGAZD9291 Dosing
Patients to be provided with AZD9291 every 6 weeks (+/- 7 days)
Sponsors
Parexel
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Adults (according to each country regulations for age of majority) 3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation 4. Prior therapy with an EGFR-TKI. Patients may have also received additional lines of treatment 5. World Health Organization (WHO) performance status 0-2 6. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, biochemistry in blood and urine at baseline (please refer to IB for guidance) 7. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion criterion #6 8. Female patients of childbearing potential must be using adequate contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to start of dosing. Otherwise, they must have evidence of nonchildbearing potential 9. Male patients must be willing to use barrier contraception, i.e., condoms
Exclusion criteria
1. Previous (within 6 months) or current treatment with AZD9291 2. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of AZD9291) any treatment known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, active infection including hepatitis B, hepatitis C, and human immunodeficiency virus, or significantly impaired bone marrow reserve or organ function, including hepatic and renal impairment, which in the investigator's opinion would significantly alter the risk/benefit balance. 4. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids to manage CNS symptoms within the 2 weeks prior to start AZD9291 administration; 5. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD 6. Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTcF) \> 470 ms using Fredericia's formula : 2. 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) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 7. Any unresolved toxicity from prior therapy CTCAE \> grade 3 at the time of starting treatment 8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of first dose of Osimertinib until the date of death (due to any cause) or last participant contact [up to 43 months] | OS was defined as the time, in months from the date of first dose of Osimertinib until death due to any cause, or at last documented contact with participant status alive (in this study any participants alive at study discontinuation, or lost to follow-up was considered being censored at study discontinuation date or at the last known date participant was alive). OS was summarized using a Kaplan-Meier (KM) estimate of the median time to death or censoring together with their 95% confidence intervals. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From screening to progression follow-up [every 6 weeks +/- 1 week] relative to the date of enrolment until the end of study [up to 43 months] | Safety assessment of Osimertinib was analyzed by evaluating AEs and SAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months] | PFS was defined as the time, in months from first dose of AZD9291/ost/study drug/ study treatment until the date of disease progression or death in the absence of progression. Participants who had not progressed or died at study discontinuation were censored at the time of the latest date of disease assessment. PFS was summarized using KM estimates of the median time to progression or death with their 95% confidence intervals. |
| Time to Treatment Discontinuation (TTD) | From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months] | TTD or death was assessed as a supportive summary to PFS and defined as the time from the date of the first dose of osimertinib in the study until the date of osimertinib discontinuation or death, regardless of the reason for discontinuation. TTD was summarized using KM estimates of the median times to progression or death or treatment discontinuation. |
| Response Rate (RR) | From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months] | RR was defined as the number (%) of participants with a best response (by Investigator assessment) of 'responding', regardless of the method of evaluation, and was based on a subset of the full analysis set consisting of subjects with at least one documented response assessment. RR was summarised together with the 95% CI. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Denmark, Ireland, Italy, Saudi Arabia, South Korea, Spain, Sweden, Taiwan, United Kingdom
Participant flow
Recruitment details
Participants who met all the inclusion and none of the exclusion criteria received treatment in a total of 209 centres in 16 countries. The study started on 18 September 2015 and primary completion date was 18 April 2019.
Pre-assignment details
During the screening period (28 days), eligible participants signed the informed consent. All the study assessments were performed as per the schedule of assessment. Out of 3017 patients enrolled with treatment dose assigned, 3 died (due to disease progression) prior to starting treatment.
Participants by arm
| Arm | Count |
|---|---|
| Osimertinib All participants received oral 80 mg tablet once a day (the dose could be reduced to 40 mg for management of osimertinib-related toxicities) | 3,014 |
| Total | 3,014 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1,361 |
| Overall Study | Eligibility Criteria not Fulfilled | 2 |
| Overall Study | Lost to Follow-up | 98 |
| Overall Study | Other | 43 |
| Overall Study | Withdrawal by Subject | 124 |
Baseline characteristics
| Characteristic | Osimertinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1216 Participants |
| Age, Categorical Between 18 and 65 years | 1798 Participants |
| Age, Continuous | 61.7 Years STANDARD_DEVIATION 10.91 |
| Country Argentina | 30 Participants |
| Country Australia | 31 Participants |
| Country Austria | 46 Participants |
| Country Belgium | 31 Participants |
| Country Brazil | 88 Participants |
| Country Canada | 99 Participants |
| Country China | 1350 Participants |
| Country Denmark | 6 Participants |
| Country Ireland | 10 Participants |
| Country Italy | 510 Participants |
| Country Saudi Arabia | 3 Participants |
| Country South Korea | 466 Participants |
| Country Spain | 131 Participants |
| Country Sweden | 7 Participants |
| Country Taiwan | 188 Participants |
| Country United Kingdom | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2085 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 897 Participants |
| Sex: Female, Male Female | 1927 Participants |
| Sex: Female, Male Male | 1087 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1,361 / 3,014 |
| other Total, other adverse events | 380 / 3,014 |
| serious Total, serious adverse events | 657 / 3,014 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Safety assessment of Osimertinib was analyzed by evaluating AEs and SAEs.
Time frame: From screening to progression follow-up [every 6 weeks +/- 1 week] relative to the date of enrolment until the end of study [up to 43 months]
Population: The full analysis set included all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AESI causally related to Osimertinib | 89 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 657 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE of special interest (AESI) or SAE | 923 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AESI or SAE a causally related to Osimertinib | 338 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE leading to dose modification | 414 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE leading to discontinuation | 191 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AESI | 113 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE causally related to Osimertinib | 95 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE leading to death | 152 Participants |
| Osimertinib | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE leading to death causally related to Osimertinib | 19 Participants |
Primary
Overall Survival (OS)
OS was defined as the time, in months from the date of first dose of Osimertinib until death due to any cause, or at last documented contact with participant status alive (in this study any participants alive at study discontinuation, or lost to follow-up was considered being censored at study discontinuation date or at the last known date participant was alive). OS was summarized using a Kaplan-Meier (KM) estimate of the median time to death or censoring together with their 95% confidence intervals.
Time frame: From the date of first dose of Osimertinib until the date of death (due to any cause) or last participant contact [up to 43 months]
Population: The full analysis set included all participants who received at least one dose of study treatment. No statistical tests were performed, the statistical analyses were descriptive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Overall Survival (OS) | 22.8 Months |
Secondary
Progression Free Survival
PFS was defined as the time, in months from first dose of AZD9291/ost/study drug/ study treatment until the date of disease progression or death in the absence of progression. Participants who had not progressed or died at study discontinuation were censored at the time of the latest date of disease assessment. PFS was summarized using KM estimates of the median time to progression or death with their 95% confidence intervals.
Time frame: From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months]
Population: The full analysis set included all participants who received at least one dose of study treatment. No statistical tests were performed, the statistical analyses were descriptive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Progression Free Survival | 11.1 Months |
Secondary
Response Rate (RR)
RR was defined as the number (%) of participants with a best response (by Investigator assessment) of 'responding', regardless of the method of evaluation, and was based on a subset of the full analysis set consisting of subjects with at least one documented response assessment. RR was summarised together with the 95% CI.
Time frame: From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months]
Population: The full analysis set included all participants who received at least one dose of study treatment. No statistical tests were performed, the statistical analyses were descriptive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib | Response Rate (RR) | 57.3 Percentage of participants |
Secondary
Time to Treatment Discontinuation (TTD)
TTD or death was assessed as a supportive summary to PFS and defined as the time from the date of the first dose of osimertinib in the study until the date of osimertinib discontinuation or death, regardless of the reason for discontinuation. TTD was summarized using KM estimates of the median times to progression or death or treatment discontinuation.
Time frame: From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months]
Population: The full analysis set included all participants who received at least one dose of study treatment. No statistical tests were performed, the statistical analyses were descriptive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Time to Treatment Discontinuation (TTD) | 13.5 Months |