T790M Plasma Testing Methodology Comparison and Clinical Validation

Study Overview
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Brief Summary
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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
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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. 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), and safety (including serious adverse events [SAEs], adverse events [AEs]). 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.

Official Title
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Detect EGFR T790M Mutation in ctDNA of Chinese Advanced/Metastatic NSCLC Patients by Cobas, Super-ARMS, Digital PCR and NGS and Evaluate Clinical Outcomes of T790M Mutation Positive Patients Who Had AZD9291 Monotherapy

Conditions
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Lung Cancer

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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD9291<br>Single arm of AZD9291, starting dose of 80mg | Procedure: T790M+ Testing<br>* The patient will need to have T790M+ testing<br>Procedure: Baseline Visit Blood & Urine Testing<br>* Blood count and standard chemistry testing to ensure patient meets inclusion/exclusion criteria<br>Procedure: Baseline ECG<br>* ECG to ensure absence of any cardiac abnormality<br>Procedure: Visual Slit-Lamp Testing<br>* Slit-lamp testing performed to ensure patients do not have any eye abnormalities or symptoms<br>Drug: AZD9291 Dosing<br>* Patients to be provided with AZD9291 every 6 weeks (+/- 7 days)<br>Procedure: Plasma AZD9291 testing<br>* The patient will need to have plasma AZD9291 testing before treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance of T790M mutation plasma testing between Cobas test and Super-ARMS platform | To evaluate concordance of T790M mutation plasma testing between the Cobas test and Super-ARMS platform. | Within 1- 28 days after enrollment and before study treatment | 
| Progression Free Survival (PFS) using investigator assessments according to RECIST v1.1 | 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: Cobas/Super-ARMS/ digital PCR/NGS. | From first dose intake to Progression of disease (PD), up to 3 years | 
| Concordance of T790M mutation plasma testing between Cobas test and digital PCR platform | To evaluate concordance of T790M mutation plasma testing between the Cobas test and digital PCR platform. | Within 1- 28 days after enrollment and before study treatment | 
| Concordance of T790M mutation plasma testing between Cobas test and NGS platform | To evaluate concordance of T790M mutation plasma testing between the Cobas test and NGS platform. | Within 1- 28 days after enrollment and before study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Testing sensitivity | To evaluate the sensitivity of Super-ARMS/digital PCR/NGS by using Cobas as the reference. | Within 1- 28 days after enrollment and before study treatment | 
| Objective Response Rate (ORR) | To assess the efficacy of AZD9291 monotherapy by assessment of ORR 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: Cobas/Super-ARMS/ digital PCR/NGS. | From first dose intake to end of study, up to 3 years | 
| Overall Survival (OS) | To assess the efficacy of AZD9291 monotherapy by assessment of OS 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: Cobas/Super-ARMS/ digital PCR/NGS. | From first dose intake to end of study, up to 3 years | 
| Testing specificity | To evaluate the specificity of Super-ARMS/digital PCR/NGS by using Cobas as the reference. | Within 1- 28 days after enrollment and before study treatment | 
| Testing positive predictive value (PPV) | To evaluate PPV of Super-ARMS/digital PCR/NGS by using Cobas as the reference. | Within 1- 28 days after enrollment and before study treatment | 
| Testing negative predictive value (NPV) | To evaluate the NPV of Super-ARMS/digital PCR/NGS by using Cobas as the reference. | Within 1- 28 days after enrollment and before study treatment |