Resistance & Activating Mutations Diagnosed Among NSCLC Community Dwelling EGFR Mutation Positive Patients

An Open-Label, Non-randomized, Prospective Biomarker Study to Assess Analytic Concordance Between Non-invasive Testing and Tissue Testing for EGFR T790M Mutation Detection in Patients With Non-small Cell Lung Cancer

The study is being done to determine if non-invasive testing (urine and plasma testing) is as effective as tissue testing in identifying epidermal growth factor receptor (EGFR) T790M mutation status. EGFR is a type of protein found on the surface of cells in the body. When this protein is mutated and becomes too active, it can lead to cancer growth. T790M is a mutation that develops in response to treatment of the EGFR mutation.

Participating patients will have tumor tissue (via cobas test), as well as 2 plasma samples (via cobas and Guardant360 tests) and 1 urine sample (via Trovera test), tested for EGFR T790M mutation status. If the results of the cobas tissue and/or plasma test show that a patient is T790M positive, they will be treated according to standard of care, which may include treatment with osimertinib. Osimertinib is approved for use in the United States for the treatment of EGFR T790M mutation-positive non-small cell lung cancer (NSCLC).

RADIANCE is an open-label, prospective biomarker study to assess analytic concordance between non-invasive testing (plasma and urine) and tissue testing for the EGFR T790M mutation. All patients will have tumor tissue (via cobas test) as well as 2 plasma samples (via cobas and Guardant360) and 1 urine sample (via Trovera) tested for the EGFR T790M mutation (Part 1). Patients who are confirmed T790M negative based on both cobas biomarker tests (tissue and plasma) will have completed the study. Patients who demonstrate T790M+ on cobas tissue and/or cobas plasma testing may choose to undergo treatment with osimertinib in consultation with their healthcare provider (no investigational product will be provided for this study) and will continue to Part 2. In case of insufficient samples for biomarker testing or invalid results from any of the 4 testing modalities, another sample may be acquired from the patient, if feasible, including the patient's decision to undergo a second biopsy. Failure of a patient to undergo a tissue, plasma, or urine sample collection for biomarker testing will result in their withdrawal from the study. If 1 or more samples are insufficient for testing or 1 or more of the test results are invalid, the patient may still qualify for the clinical outcomes part of the study (Part 2) as long as cobas tissue and/or cobas plasma test is T790M+ and the patient receives at least one dose of osimertinib.

During Part 2 Follow-Up Visits will occur according to standard of care, but at least every 12 weeks for the first 12 months of treatment. A Final Study Visit will occur at 18 months (Week 72 +/- 14 days) or upon early withdrawal.

Statistical methods Sample size: The sample size is such to provide enough statistical precision for the primary endpoint. A sample size of 400 patients with evaluable biomarker test results for analytic concordance has been selected in order to achieve a precision of no more than ±5% around the estimated concordance rate. If a 15% inflation factor is applied (~70 patients) to this sample size to take into account those patients who may not be evaluable for concordance estimates, a total of approximately 470 patients will be enrolled.

The Full Analysis Sets will include the following:

Part 1: All patients in the study with cobas tissue, Guardant360 plasma, and Trovera urine test results.

Part 2: Patients who demonstrate T790M+ cobas tissue and/or cobas plasma testing and were treated with at least 1 dose of osimertinib (i.e., all patients in Part 2).

Safety analysis sets: The safety analysis sets will include the following:

Part 1: All patients in the study from the time of informed consent until completion of Part 1.

Part 2: Patients who demonstrate T790M+ cobas tissue and/or cobas plasms testing and were treated with at least 1 dose of osimertinib (i.e., all patients in Part 2).

The analyses of the data collected within this study will be descriptive only, with no formal statistical testing. Continuous variables will be summarized by the number of observations, mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by frequency counts and percentages for each category. A Statistical Analysis Plan will be prepared and finalized prior to the first interim analysis, which will occur upon completion of the diagnostic analytic validity part of the study (Part 1). The concordance rate between non-invasive testing and cobas tissue testing will be presented as the point estimate together with the exact 95% confidence interval (CI) estimated using the Clopper-Pearson method. The ORR will be presented as the point estimate together with the exact 95% CI according to the Clopper-Pearson method. The duration of response (DoR) and progression-free survival (PFS) will be presented for all patients in Part 2, summarized using the Kaplan-Meier (K-M) method with associated K-M curves. The median DoR and PFS will be presented, as well as the rates at clinically relevant time points, together with the associated 95% CIs.

Inclusion Criteria:

• Provision of informed consent prior to any study-specific procedures
• Females and males >/= 18 years
• Primary diagnosis of NSCLC with evidence of disease progression during or following treatment with an EGFR tyrosine kinase inhibitor (diagnosis of NSCLC that is confirmed by cytology is acceptable)
• Willing to undergo tumor biopsy (e.g., excision, core biopsy, or endoscopic biopsy), preferably of a progressing lesion, and provide blood and urine for biomarker testing
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study
• Prior treatment with osimertinib or another T790M directed therapy
• Current participation in another clinical study with an investigational product or patients who plan to receive any treatment that is not FDA-approved for EGFR mutation positive NSCLC at any time during the course of this study
• Use of any chemotherapeutic agent within 1 week of tissue, plasma, and urine sample collection
• For women - currently pregnant or plan to become pregnant during the course of the study: pre-menopausal women of childbearing potential must have a urine or serum pregnancy test performed during the screening/enrollment period and prior to initiating anti-cancer treatment
• Judgment by the investigator that the patient should not participate in the study due to the patient being unlikely to comply with study procedures, restrictions, and requirements, such as in the case of severe or uncontrolled systemic disease.