T790M Plasma Testing Methodology Comparison and Clinical Validation

Phase 3

Completed

Conditions: Lung Cancer

Interventions: Procedure: T790M+ Testing
Procedure: Baseline Visit Blood & Urine Testing
Procedure: Baseline ECG
Procedure: Visual Slit-Lamp Testing
Drug: AZD9291 Dosing
Procedure: Plasma AZD9291 testing

Registration Number: NCT02997501

Lead Sponsor: AstraZeneca

Brief Summary: The aim of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Detailed Description: Objective: The primary objective of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Study number of patients planned: Approximately 250 patients will be recruited in China.

Study Design: This is an open-label, multi-center testing and treatment study.

Target patient population: 250 locally advanced or metastatic EGFR mutation positive NSCLC patients with progression on a previous EGFR-TKI will be recruited.

Investigational product (IP), dosage, and mode of administration: AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitizing 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. All AEs/SAEs would be reported in ASTRIS main study and would not be reported repeatedly in current study.

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 a maximum period of 18 months after the last patient is enrolled. Contingencies will be made to ensure continued drug supply for patients who are still deriving benefit from AZD9291 at that time.

Study measures: Data collected will include patient demographics, smoking history, information needed to determine patient eligibility (including medical history, past and current disease characteristics, and tumor EGFR mutations status, T790M and sensitizing mutations status results and type of test performed), AZD9291 exposure, investigator-reported efficacy (including tumor response and disease progression), overall survival (OS).

Statistical methods: The concordance of T790M resistance mutation testing between the Cobas test and each of other platforms will be calculated. The sensitivity, specificity, PPV and NPV of each testing platform (Super-ARMS, digital PCR, and NGS) will be calculated with the Cobas test as the reference. The Kappa coefficient will be calculated to measure the agreement of T790M mutation testing between the Cobas test and each of other platforms. Descriptive statistics will be provided for all variables, as appropriate. Continuous variables will be summarized by the number of observations, mean, standard deviation, median, interquartile range (Q1, Q3), minimum, and maximum. Categorical variables will be summarized by frequency counts and percentages for each category. The 95% confidence interval (CI) will be calculated as appropriate. PFS and OS, respectively, will be summarized using Kaplan-Meier estimates of the median time to event (progression and death) and quartiles together with their 95% confidence intervals.The chi-square test will be used to compare the sensitivity, specificity, and concordance between any of the two platforms using Cobas as reference testing in an exploratory manner.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 256

Inclusion Criteria

Provision of informed consent prior to any study specific procedures.
Adults (according to China regulations for age of majority)
Histological or cytological confirmed locally advanced NSCLC (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy.
Patients who have progressed following prior therapy with an EGFR-TKI agent.

Exclusion Criteria

Patients who disagree to participate this study.
Patients whose medical objection was recorded to use the existing data from medical practice for scientific research.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
AZD9291	Plasma AZD9291 testing	Single arm of AZD9291, starting dose of 80mg
AZD9291	AZD9291 Dosing	Single arm of AZD9291, starting dose of 80mg
AZD9291	Visual Slit-Lamp Testing	Single arm of AZD9291, starting dose of 80mg
AZD9291	T790M+ Testing	Single arm of AZD9291, starting dose of 80mg
AZD9291	Baseline Visit Blood & Urine Testing	Single arm of AZD9291, starting dose of 80mg
AZD9291	Baseline ECG	Single arm of AZD9291, starting dose of 80mg

Primary Outcome Measures

Name	Time	Method
Concordance	Up to 6 months	To evaluate concordance of T790M plasma mutation testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS.
PFS Using Investigator Assessments According to RECIST v1.1	The time from first dose of AZD9291 in this study until the date of disease progression as recorded in CRF or death (by any cause in the absence of progression), assessed up to 18 months	To assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR- TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms. PFS was defined using Response Evaluation Criteria In Solid Tumors version 1.1(RECIST v1.1).

Secondary Outcome Measures

Name	Time	Method
Testing Sensitivity, Specificity, PPV, NPV	Up to 6 months.	To evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of Super-ARMS/digital PCR/NGS by using Cobas as the reference.
Overall Response Rate (ORR)	From first patient first CT scan for RECIST assessment, till the last patient last CT scan, up to 22 months.	To assess the efficacy of AZD9291 monotherapy by assessment of ORR in adult patients who have received prior EGFR-TKI therapy and are EGFR T790M mutation positive detected by any one of the four plasma testing platforms. ORR is defined as the percentage of patients with measurable disease with at least 1 visit response of CR or PR. Data obtained until progression or last evaluable assessment in the absence of progression will be included in the assessment of ORR.
75% OS Duration	From first patient signed the consent to study completion, up to 22 months.	To assess the efficacy of AZD9291 monotherapy by assessment of overall survival (OS) in adult patients who have received prior EGFR-TKI therapy and are EGFR T790M mutation positive detected by any one of the four plasma testing platforms. 75% OS duration was calculated.