T790M Plasma Testing Methodology Comparison and Clinical Validation (ADELOS)

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

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.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Procedure: Baseline Visit Blood & Urine Testing; Procedure: Baseline ECG; Procedure: Visual Slit-Lamp Testing; Drug: AZD9291 Dosing; Procedure: T790M+ Testing; Procedure: Plasma AZD9291 testing

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.

• Study Type: Interventional
• Enrollment (Actual): 256
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Changchun, China, 130012
    • Research Site
  • Chengdu, China, 610041
    • Research Site
  • Guangzhou, China, 510080
    • Research Site
  • Wuhan, China, 430079
    • Research Site
  • Wuhan, China, 430022
    • Research Site
  • Wuhan, China, 430030
    • Research Site
  • Xi'an, China, 710038
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: AZD9291; Single arm of AZD9291, starting dose of 80mg

Procedure: Baseline Visit Blood & Urine Testing; Blood count and standard chemistry testing to ensure patient meets inclusion/exclusion criteria; Procedure: Baseline ECG; ECG to ensure absence of any cardiac abnormality; Procedure: Visual Slit-Lamp Testing; Slit-lamp testing performed to ensure patients do not have any eye abnormalities or symptoms; Drug: AZD9291 Dosing; Patients to be provided with AZD9291 every 6 weeks (+/- 7 days); Procedure: T790M+ Testing; The patient will need to have T790M+ testing; Procedure: Plasma AZD9291 testing; The patient will need to have plasma AZD9291 testing before treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concordance	To evaluate concordance of T790M plasma mutation testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS.	Up to 6 months
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. PFS was defined using Response Evaluation Criteria In Solid Tumors version 1.1(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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Testing Sensitivity, Specificity, PPV, NPV	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.	Up to 6 months.
Overall Response Rate (ORR)	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.	From first patient first CT scan for RECIST assessment, till the last patient last CT scan, up to 22 months.
75% OS Duration	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.	From first patient signed the consent to study completion, up to 22 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with each EGFR mutation (C797S and T790M etc.) at different time point.	To dynamically monitor EGFR mutations by NGS and digital PCR in ctDNA of patients receiving AZD9291 treatment.	every 6 weeks during treatment, up to 3 years
Changes of distribution of resistance related genes at PD compared with baseline.	To explore the mechanisms of acquired resistance in patients who received AZD9291 treatment by NGS testing of tissue and/or blood samples from the collection at PD versus baseline.	every 6 weeks during treatment, up to 3 years
Key genetic and proteomic markers including, but not limited to, EGFR mutations	To describe the genomic profile of long-term survivors, especially to find out potential genomic prognosis and/or predictive factors for AZD9291 long-term efficacy as compared to rapid PD patients.	every 6 weeks during treatment, up to 3 years
Testing concordance	To evaluate concordance of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.	Within 1- 28 days after enrollment and before study treatment
Testing sensitivity	To evaluate sensitivity of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.	Within 1- 28 days after enrollment and before study treatment
Testing specificity	To evaluate specificity of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.	Within 1- 28 days after enrollment and before study treatment
Testing positive predictive value (PPV)	To evaluate PPV of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.	Within 1- 28 days after enrollment and before study treatment
Testing negative predictive value (NPV)	To evaluate NPV of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.	Within 1- 28 days after enrollment and before study treatment
Objective Response Rate (ORR)	To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.	From first dose intake to end of study, up to 3 years
Progression Free Survival (PFS)	To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.	From first dose intake to end of study, up to 3 years
Overall Survival (OS)	To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.	From first dose intake to end of study, up to 3 years

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: TigerMed
• Investigators: Principal Investigator: Yilong WU, Guangdong General Hospita; Principal Investigator: Zhiyong LIANG, Peking Union Medical College Hospital

Publications and helpful links

Helpful Links

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Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2016
• Primary Completion (Actual): October 24, 2018
• Study Completion (Actual): October 24, 2018

Study Registration Dates

• First Submitted: December 9, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimated): December 20, 2016

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Osimertinib
• Other Study ID Numbers: D5160C00042

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No