OSIREAL - Osimertinib RWE on EGFRm NSCLC in Spain

Study Overview
=================
Brief Summary
-----------------
Lung cancer (LC) is the tumor responsible for the highest mortality worldwide. Lung adenocarcinoma is the major subtype of lung cancer and represents the deadliest human cancer, affecting current-, ex-, and even non-smokers. Osimertinib is indicated as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations in the EGFR, for the treatment of adult patients with EGFR T790M mutation-positive locally advanced or metastatic NSCLC, and for the adjuvant treatment of adult patients with NSCLC stages IB-IIIA after complete resection of the tumor that has activating mutations of the EGFR. The FLAURA trial showed that treatment with osimertinib significantly prolongs PFS and improves overall survival (OS) compared to standard EGFR tyrosine kinase inhibitors. The results of the ADAURA study showed a reduction in the risk of recurrence or death by 83% in stages II to IIIA, and in 80% in stages IB-IIIA. Additionally, osimertinib demonstrated a highly statistically significant improvement in DFS and HRQoL was maintained. To date, there are real-world data on osimertinib use in pretreated patients with stages IIIB-IV NSCLC EGFRm/T790M in Spain, obtained from the OSIREX study. However, there are no real-world data on osimertinib either in first-line treatment in locally advanced or metastatic EGFRm NSCLC nor as adjuvant treatment, in early stages of cancer, regarding effectiveness, adherence, treatment exposure and quality of life (QoL), among others, and in particular for the use of osimertinib in subpopulations less represented in pivotal trials as elderly or patients with uncommon EGFR mutations. Furthermore, the duration of treatmenti in real life is also a gap, as it appears to be longer than in clinical trials, which means that there are patients who are treated beyond progression, Therefore, this observational ambispective study based on real-world data aims to provide data on osimertinib use as adjuvant treatment in adult patients diagnosed with stages IB-IIIA EGFRm NSCLC and in first line treatment in patients with locally advanced or metastatic EGFRm NSCLC, in Spain, indications currently marketed in Spain. Specifically, the study will focus on patient characteristics, adherence, treatment exposure, administration, survival, QoL, effectiveness and safety providing insights into osimertinib use in daily practice for patients with EGFRm NSCLC, where there are current evidence gaps.

Detailed Description
-----------------
Cancer continues to be one of the leading causes of morbidity and mortality in the world. It is estimated that in the year 2020, approximately 18.1 million new cases of cancer in the world, and that this figure will increase in the next two decades to 27 million. The most frequently diagnosed tumors in the world in 2020 were those of the breast, lung (which occupies the second position), colon and rectum, prostate and stomach, all of them with more than one million cases. Also, in Spain, cancer is one of the main causes of morbidity and mortality. It is estimated that in 2020 there were 113,054 deaths from cancer in Spain. The number of cancers diagnosed in Spain in 2022 is estimated to reach 280,100 cases according to REDECAN calculations, which represents a slight increase compared to previous years. Lung cancer (LC) is the tumor responsible for the highest mortality worldwide. After prostate cancer, it is the second most common cancer in men and, after breast cancer, in women. Lung adenocarcinoma is the major subtype of lung cancer and represents the deadliest human cancer, affecting current-, ex-, and even non-smokers. The most frequently diagnosed cancers in Spain in 2023 will be those of the colon and rectum, breast, lung, prostate, and urinary bladder. Lung cancer is a very common cancer in Spain, however, due to its high mortality, its prevalence at five years is relatively low. Approximately 30% of patients with non-small cell lung cancer (NSCLC) have early-stage disease that is treated with surgery. A high percentage of these patients relapse and die, so patients receive postoperative adjuvant systemic chemotherapy to increase their survival. However, the benefits of this strategy are modest. NSCLC is often associated with druggable molecular alterations that drive lung carcinogenesis. EGFR tyrosine kinase inhibitors (TKIs) have been included in treatment paradigms with the aim of improving the outcome of adjuvant therapy in patients with completely resected, EGFR mutation-positive (EGFRm+) disease. The standard of care for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitizing mutations is treatment with a first-generation or second-generation EGFR-TKI such as gefitinib, erlotinib, or afatinib. Treatment with EGFR-TKIs in this patient population has extended progression-free survival relative to chemotherapy as initial therapy. Osimertinib is indicated as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR), for the treatment of adult patients with EGFR T790M mutation-positive locally advanced or metastatic NSCLC, and for the adjuvant treatment of adult patients with NSCLC stages IB-IIIA after complete resection of the tumor that has activating mutations of the EGFR (exon 19 deletion or exon 21 substitution (L858R)). The FLAURA trial showeds that treatment with osimertinib significantly prolongs progression-free survival (PFS) compared to EGFR TKI comparator (median 18.9 months and 10.2 months, respectively, HR=0.46, 95% CI: 0.37, 0.57; P<0.0001) (5) and improves overall survival (OS) (HR=0.799 [95.05% CI: 0.641, 0.997]) compared to standard EGFR tyrosine kinase inhibitors (TKIs), in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). A greater proportion of patients treated with osimertinib were alive at 12, 18, 24 and 36 months (89%, 81%, 74% and 54% respectively) compared to patients treated with EGFR TKI comparator (83%, 71%, 59% and 44% respectively). The results of the ADAURA trial showed that adjuvant treatment with osimertinib reduced the risk of recurrence or death by 83% in stages II to IIIA, and in 80% in stages IB-IIIA, compared with placebo, in patients with NSCLC with completely resected stage IB to IIIA disease and confirmed EGFR mutation. Additionally, osimertinib demonstrated a highly statistically significant improvement in disease free survival (DFS) and HRQoL was maintained. A DFS benefit favouring osimertinib over placebo was seen across all prespecified subgroups, including those based on disease stage, EGFR sensitizing mutation, ethnicity and receipt of adjuvant chemotherapy. Furthermore, the DFS benefit with osimertinib was similar in patients who had or had not received chemotherapy.

Official Title
-----------------
An Ambispective, Non-interventional, Multiple Cohort Study to Assess the Management of Osimertinib Treatment in Patients With EGFRm Non-small Cell Lung Cancer Under Real-world Conditions in Spain

Conditions
-----------------
Non-small Cell Lung Cancer

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female or male patients, treated with osimertinib Age ≥ 18 years at starts of osimertinib treatment (i.e., index date). Patients histologically diagnosed with EGFRm NSCLC (before index date): Patients with first-line treatment with EGFRm locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy (Cohort 1). Patients with stage IB-IIIA after complete tumor resection (Cohort 2). Provision of informed consent (for alive patients). Deceased patients who met the selection criteria when they started treatment with osimertinib could also be included in the study. Exclusion Criteria: Osimertinib treatment administration in a clinical trial setting.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1<br>Patients diagnosed with locally advanced or metastatic NSCLC with activating EGFR mutations that received first line treatment with osimertinib (FLAURA regimen). | |
| Cohort 2<br>Patients with stage IB-IIIA NSCLC after complete tumour resection that has activating mutations in the EGFR (deletion of exon 19 or substitution of exon 21 [L858R]) that received adjuvant treatment with osimertinib (ADAURA regimen). | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effectiveness of osimertinib in terms of median OS in patients with locally advanced or metastatic EGFRm NSCLC (Cohort 1). | Overall survival (OS) measured as median time from start of osimertinib treatment to death and rates at months 6, 12 and 18 (cohort 1), and 2, 3, 4 and 5 years (both cohorts) after starting osimertinib. | From start of osimertinib treatment to death, assesed up to 6 years | 
| To evaluate the effectiveness of osimertinib in terms of 4-year rwDFS rate in patients with stages IB-IIIA EGFRm NSCLC (Cohort 2). | Real World Disease Free Survival (rwDFS) defined as the time from start of osimertinib until the date of disease recurrence or death from any cause in the absence of disease recurrence. The primary measure of interest is the 4-year real world disease-free survival rate and corresponding 95% confidence interval. - 4-year real world disease-free survival rate for Cohort 2. (i.e., percentage of patients with clinical or radiological recurrence 4 years after the start of osimertinib treatment, as evaluated by the treating physician according to standard clinical practice). | 4 years after the start of osimertinib | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effectiveness of osimertinib in terms of rwPFS in patients with locally advanced or metastatic EGFRm NSCLC (Cohort 1) and in terms of rwDFS rates and OS in patients with stages IB-IIIA EGFRm NSCLC (Cohort 2) treated with Osimertinib. | Real World Progression-Free Survival (rwPFS) defined as the time from start of osimertinib treatment to clinical/radiological progression or death from any cause, in the basence of progression, as evaluated by the treating physician according to standard clinical practice. The primary measure of interest is the median and corresponding 95% confidence interval. | From start of osimertinib to clinical/radiological progression or death from any cause, whichever came first, assesed up to 6 years | 
| To describe changes in osimertinib treatment administration for EGFRm NSCLC. | Frecuency of dose changes, measured as interrumptions and reductions and their reasons | During osimertinib treatment, assesed up to 6 years in cohort 1 and up to 3 years in cohort 2. | 
| To describe healthcare resource use (HCRU) during the osimertinib treatment for EGFRm NSCLC in real life. | Healthcare resources used in relation to EGFRm NSCLC and its treatment assessed by the mean number of hospitalizations (and their duration) and outpatient, pharmacy and emergency unit visits related to EGFRm NSCLC and specific tests/procedures performed. | During osimertinib treatment, assesed up to 6 years in cohort 1 and up to 3 years in cohort 2. | 
| To describe therapies received before and after osimertinib treatment progression or relapse | Therapies received during adjuvant and neoadjuvant: active drug, dose, mode of administration, duration, interruption. Surgery: type, outcome (R0-R1) Number and type of other treatments received during osimertinib administration. Number and types of therapies received after osimertinib treatment progression or relapse | Before and after osimertinib treatment, assesed up to 6 years in cohort 1 and up to 3 years in cohort 2. | 
| To describe the safety profile of osimertinib in a real-world setting. | Events of clinical interest (ECIs) (start and end date, causality, impact on treatment (i.e., requires dose reduction or interruption), adverse events that lead to osimertinib dose changes, interruptions, or permanent discontinuation, and AEs that are considered serious (including fatal events). | During osimertinib treatment, assesed up to 6 years in cohort 1 and up to 3 years in cohort 2 | 
| To describe duration of osimertinib treatment in real life for EGFRm NSCLC | Median duration of treatment measured as time from start of osimertinib treatment to discontinuation of treatment or death and discontinuation rates at 6 montly intervarls | During osimertinib treatment, assesed upt to 6 years in cohort 1, and up to 3 years in cohort 2 |