A Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib

Study Overview
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Brief Summary
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A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR mutation-positive locally advanced or metastatic NSCLC treated with osimertinib.

Detailed Description
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Study design This is a phase II, open-label, single-arm tissue and plasma acquisition study assessing the efficacy, safety and underlying resistance mechanisms of osimertinib (80 mg orally, once daily) as first-line treatment in patients with locally advanced or metastatic EGFR mutation positive non-small cell lung cancer who are EGFR tyrosine kinase inhibitor treatment-naïve and eligible for first-line treatment. Participants with EGFR mutation-positive non-small cell lung cancer will be required to consent to 2 mandatory tumour biopsies to be considered for enrolment in this study. The first biopsy will be done prior to initiating treatment with osimertinib and the second biopsy will be obtained any time between Investigator assessed, Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1)-defined progression and before the start of any new anticancer treatment. A third optional biopsy may be taken during the course of treatment at the Investigator's discretion if the patient consents and if clinically feasible. Tumour tissue and plasma samples will be collected and examined for genetic and non genetic aberrations that may be important in determining response and resistance to the treatment that participants will receive as a part of their cancer care. Patients should continue on osimertinib until progression or until other treatment discontinuation criteria are met. However, if patients continue to show clinical benefit to treatment as judged by the Investigator, patients may continue to receive osimertinib beyond RECIST 1.1-defined progression. Therefore, there is no maximum duration of treatment. Tumour assessments will be performed at baseline and then every 8 weeks from study enrolment until 3.5 years, and then every 10 weeks until RECIST 1.1-defined. Patients will be followed up for a period of 28 days following discontinuation of osimertinib. Target patient population Male and female patients aged 18 years and over with locally advanced or metastatic pathologically confirmed adenocarcinoma of the lung, not amenable to curative surgery or radiotherapy. Patients will have a tumour that harbours one of the EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor sensitivity, either alone or in combination with other EGFR mutations (EGFR mutation status determined by a local laboratory). Patients must be EGFR tyrosine kinase inhibitor treatment-naïve and eligible to receive first line treatment with osimertinib. Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer with a significant selectivity margin over wild type EGFR. Osimertinib (80 mg orally, once daily) will be administered. Doses may be reduced to 40 mg if needed.

Official Title
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A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib

Conditions
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EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior Patients aged 18 years or older Patients with histological confirmation of locally advanced or metastatic NSCLC Patients with M1 stage according to the Tumor, Node and Metastasis Classification of Malignant Tumours (TNM) Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be associated with EGFR TKI sensitivity Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the primary tumour or metastatic tumour tissue WHO performance status 0-1 Life expectancy ≥12 weeks Capacity to swallow Patients able to complete study and within geographical proximity allowing for adequate follow up Resolution of all acute toxic effects of previous anticancer therapy Female patients must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of childbearing potential Male patients must be willing to use barrier contraception Exclusion Criteria: Locally advanced lung cancer candidate for curative treatment through radical surgery and/or radio(chemo)therapy Patients diagnosed with another lung cancer subtype Patients with an EGFR exon 20 insertion Patients with just one measurable or evaluable tumour lesion that has been resected or irradiated prior to their enrolment in the study Second active neoplasia Treatment with an investigational drug within five half-lives of the compound Participation in another clinical study with an investigational product (IP) during the last 3 weeks before the first day of study treatment Patients who have received prior immunotherapies Patients who have received prior EGFR treatments for lung cancer Patients who have received prior treatment with an EGFR TKI including in the adjuvant setting Patients who have received previous treatment for metastatic or stage IV disease Prior treatment with cytotoxic chemotherapy for advanced NSCLC Patients with a history of cancer that has been completely treated, with no evidence of malignant disease currently cannot be enrolled in the study if their chemotherapy was completed less than 6 months prior and/or have received a bone marrow transplant less than 2 years before the first day of study treatment Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses or active infection (eg, patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HIV), or active uncontrolled Hepatitis B virus (HBV) infection. Patients who have had a surgical procedure unrelated to the study within 14 days or major surgery within 1 month prior to the administration of the study drug Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis Any of the following cardiac criteria: Mean resting QT interval corrected for heart rate (QTc) more than 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, hypomagnesaemia, hypocalcaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval Spinal cord compression, symptomatic and unstable brain metastases except for those patients who have completed definitive therapy, and have had a stable neurological status for at least 2 weeks after completion of definitive therapy. 20.Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib 21.Inadequate bone marrow reserve or organ function 22.Female patients who are breastfeeding 23.Patients currently receiving medications or herbal supplements known to be potent inducers of cytochrome (CYP) 3A4. 24.Patient unwilling to undergo a biopsy at the time of disease progression 25.History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib 26.Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements 27.Involvement in the planning and/or conduct of the study 28.Previous enrolment in the present study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Osimertinib<br>An oral, potent, selective, irreversible inhibitor of both EGFR-tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer | Drug: Osimertinib<br>* Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR-tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer with a significant selectivity margin over wild type EGFR.<br>* Other names: TAGRISSO, AZD9291;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a given tumour genetic and proteomic marker at the point of disease progression as defined by the Investigator | To characterize the frequency of genetic and proteomic markers at disease progression regardless of their prevalence. | Tumour Genetic and Proteomic markers will be assessed from tissue samples collected prior to initiation of treatment and at the time of disease progression for max 4.2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is defined as the time from first dose of osimertinib until the date of Investigator assessed RECIST 1.1-defined progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression. | At baseline and every 8 weeks from enrolment until 3.5 years and every 10 weeks until disease progression or death or end of study for max 4.2 years | 
| Objective Response Rate (ORR) | ORR is defined as the number (%) of patients with at least one visit response of complete response or partial response that is confirmed at least 4 weeks later. | At baseline and every 8 weeks from enrolment until 3.5 years and every 10 weeks until disease progression or death or end of study for max 4.2 years | 
| Duration of Response (DoR) | DoR is defined as the time from the date of first documented response, (that is subsequently confirmed) until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint. | From time of first documented response until date of documented progression or death in the absence of disease progression or end of study up to max 4.2 years | 
| Time toTreatment Discontinuation or Death (TTD) | TTD is defined as the time from the date of first dose of osimertinib to the earliest of treatment discontinuation or death. | At every visit from enrolment to end of treatment or death or end of study for max 4.2 years | 
| Time to first subsequent therapy or Death (TFST) | TFST is defined as the time from the date of first dose of osimertinib to the earlier of the date of anticancer therapy start date following study treatment discontinuation, or death. | At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years | 
| Disease Control Rate | Percentage of patients who have a best overall response, complete response, partial response or stable disease. | At baseline and every 8 weeks from enrolment until 3.5 years and every 10 weeks until disease progression or death or end of study for max 4.2 years | 
| PFS in patient subgroups defined by molecular profile | PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA). | At baseline and every 8 weeks from enrolment until 3.5 years and every 10 weeks until disease progression or death or end of study for max 4.2 years | 
| ORR in patient subgroups defined by molecular profile | ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. | At baseline and every 8 weeks from enrolment until 3.5 years and every 10 weeks until disease progression or death or end of study for max 4.2 years | 
| TTD in patient subgroups defined by molecular profile | TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. | At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years | 
| Tumour shrinkage/depth of response in patient subgroups defined by molecular profile | Tumour shrinkage is defined as the best change from baseline in the sum of diameters of target lesions. Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. | At baseline and every 8 weeks from enrolment until 3.5 years and every 10 weeks until disease progression or death or end of study for max 4.2 years | 
| Proportion of patients with pre-specified characteristics will be summarised by molecular profile | The patient characteristics will include: gender (male/female), age (<65yrs/>65yrs), race (Asian/non Asian), and WHO Performance Status (0/1). These will be summarized by subgroups defined by molecular profile, including but not limited to: EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. | At baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, NSCLC, Lung Cancer, Biopsy, Molecular Profiling