Tagrisso Becomes First and Only Monotherapy to Achieve Median Overall Survival Beyond Three Years in First-Line EGFR-Mutated Advanced NSCLC

Tagrisso is the only monotherapy for first-line treatment that has achieved a median overall survival of more than 3 years in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations.

In the FLAURA clinical trial: After three years, 28% of patients were still receiving Tagrisso, compared with only 9% for standard therapy with gefitinib or erlotinib.

AstraZeneca today announced detailed overall survival (OS) data from the Phase III FLAURA trial, which evaluated the efficacy of TAGRISSO (osimertinib mesylate tablets) as first-line treatment for adult patients with EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).

Clinical data demonstrated that the trial met its secondary endpoint. Compared with previous standard-of-care treatments for this patient population, namely gefitinib or erlotinib, osimertinib showed both a statistically significant and clinically meaningful improvement in overall survival (HR 0.799 [95% CI, 0.641–0.997]; p=0.0462).

The median overall survival was 38.6 months in the osimertinib group, compared with 31.8 months in the standard-of-care group. At three years, 28% of patients in the osimertinib group were still receiving osimertinib as first-line therapy, versus only 9% in the standard therapy group (gefitinib or erlotinib). Meanwhile, osimertinib reduced the risk of brain metastasis progression by 52% and prolonged brain progression-free survival in patients with brain metastases, demonstrating statistically and clinically significant improvements (HR 0.48 [95% CI, 0.26–0.86]; p=0.014).¹

These results were presented at the Presidential Symposium of ESMO 2019 (European Society for Medical Oncology Annual Congress), held in Barcelona, Spain (Abstract #LBA5_PR).

José Baselga, Executive Vice President of Global Oncology R&D at AstraZeneca, stated, “Osimertinib has set a new benchmark in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC), with a median overall survival exceeding three years. Prior to this, we had never observed such a pronounced survival benefit with any monotherapy in global Phase III clinical trials. These landmark data further confirm the benefits of first-line osimertinib and reinforce its role as the standard first-line therapy for these patients.”

Dr. Suresh S. Ramalingam, principal investigator of the FLAURA clinical trial and a researcher at the Winship Cancer Institute of Emory University in Atlanta, USA, stated: “For patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), the results of the FLAURA clinical trial further support osimertinib as the preferred first-line treatment option. Notably, after three years, 28% of patients remained on osimertinib as their first-line therapy, compared to only 9% for standard therapies such as gefitinib or erlotinib.”

FLAURA Clinical Trial Summary

I. Data cutoff dates were June 25, 2019 (for OS, TFST, and TSST) and June 12, 2017 (for PFS and CNS PFS).

ii. The statistical significance requirement for the p-value of the final OS analysis is <0.0495 (calculated using the O’Brien-Fleming method)

iii NC=Not Calculable NC=Not Calculable

In the FLAURA clinical trial, the safety profile of osimertinib was consistent with data from previous clinical trials. Overall, osimertinib was well tolerated, with an incidence of grade 3 or higher adverse events (AEs) of 42% in patients receiving osimertinib, compared to 47% in the control group. The most commonly reported adverse reactions in patients treated with osimertinib included diarrhea (60%), rash (59%), paronychia (39%), dry skin (38%), stomatitis (29%), fatigue (21%), and decreased appetite (20%). The duration of osimertinib treatment was nearly twice that of standard therapy; however, fewer patients in the osimertinib group experienced grade 3 or higher side effects (42% vs. 47%) or discontinued treatment due to side effects (15% vs. 18%).

In July 2017, the FLAURA clinical trial met its primary endpoint, demonstrating a progression-free survival (PFS) benefit that was both statistically and clinically significant, thereby extending the time patients lived without disease progression.

Currently, osimertinib is approved in 78 countries and regions worldwide, including the United States, Japan, China, and the European Union, for patients with EGFR mutation-positive metastatic non-small cell lung cancer.

Lung cancer is the leading cause of cancer death in both men and women, accounting for approximately one-fifth of all cancer deaths, which exceeds the combined total of breast, prostate, and colorectal cancers.²Lung cancer is typically classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for 80%–85% of cases.³Approximately 10–15% of patients with non-small cell lung cancer (NSCLC) in the United States and Europe are EGFR mutation-positive (EGFRm), whereas the proportion among Asian patients is as high as 30–40%.^4-6These patients are particularly sensitive to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, which block the signaling pathways that drive tumor cell growth. Approximately 25% of patients with EGFR-mutated non-small cell lung cancer (NSCLC) have brain metastases at the time of diagnosis, and this proportion increases to approximately 40% within two years after diagnosis.⁷The presence of brain metastases typically reduces the median survival of patients to less than 8 months.8

Tagrisso (osimertinib mesylate tablets, AZD9291) is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that simultaneously inhibits EGFR sensitizing mutations and the EGFR T790M resistance mutation, demonstrating clinical efficacy against central nervous system metastases. Osimertinib 40 mg and 80 mg once-daily oral tablets have been approved in 78 countries and regions worldwide, including the United States, Japan, China, and the European Union, for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. They have also been approved in more than 85 countries and regions globally, including the United States, Japan, China, and the European Union, for second-line treatment of patients with advanced NSCLC positive for the EGFR T790M mutation. Currently, osimertinib is being evaluated in multiple new clinical trials to explore its efficacy as adjuvant therapy in early-stage lung cancer (ADAURA), in the treatment of locally advanced unresectable lung cancer (LAURA), in combination with chemotherapy (FLAURA2), and in combination with other potential novel agents (SAVANNAH, ORCHARD).

The FLAURA clinical trial was designed to evaluate osimertinib (80 mg orally, twice daily) versus gefitinib (250 mg orally, once daily) or erlotinib (150 mg orally, once daily) in patients with previously untreated, locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. This randomized, double-blind trial was conducted across 29 countries worldwide and enrolled a total of 556 patients.

AstraZeneca has multiple approved drugs or drugs in late-stage clinical development for lung cancer across different stages, treatment phases, and mechanisms of action. We address the unmet treatment needs of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) through our marketed drugs Iressa and Tagrisso, ongoing Phase III clinical trials (ADAURA, LAURA, and FLAURA2), and exploratory combination Phase II clinical trials (SAVANNAH and ORCHARD). Approximately 10%-15% of NSCLC patients in Europe and the United States, and approximately 30%-40% of NSCLC patients in Asia, will benefit from these treatments.4-6

We have a robust pipeline of oncology immunotherapy candidates in late-stage clinical development, specifically targeting lung cancer patients without actionable genetic mutations, who account for approximately half of all lung cancer cases.⁹Imfinzi is an antibody drug targeting PD-L1. It is currently under development as monotherapy or in combination with tremelimumab or chemotherapy for patients with advanced-stage lung cancer (including the Phase III clinical trials POSEIDON, PEARL, and CASPIAN) and early-stage lung cancer (including the six Phase III clinical trials AEGEAN, PACIFIC-2, ADRIATIC, ADJUVANT BR.31, PACIFIC-4, and PACIFIC-5).

AstraZeneca has a long-standing heritage in oncology research. Our rapidly expanding portfolio of novel medicines is transforming patients’ lives and unlocking immense potential for the company’s future growth. With at least six new drugs launched between 2014 and 2020, and a robust pipeline enriched by investigational small molecules and biologics, we are committed to establishing oncology as a key growth driver for AstraZeneca. Our research focuses on tumors in four disease areas: lung, ovarian, breast, and hematologic cancers. In addition to leveraging AstraZeneca’s core capabilities, we actively pursue innovative partnerships and external investments to accelerate the execution of our strategy, such as our investment in Acerta Pharma to advance research in hematologic malignancies.

By leveraging four major scientific platforms—cancer immunotherapy, tumor driver genes and resistance mechanisms, DNA damage repair, and antibody-drug conjugates (ADCs)—and advocating for the development of personalized combination therapies, AstraZeneca aims to redefine cancer treatment and ultimately conquer cancer in the future.

AstraZeneca is an innovation-driven global biopharmaceutical company dedicated to the research, development, manufacturing, and marketing of prescription medicines, with a primary focus on three therapeutic areas: respiratory, inflammatory, and autoimmune diseases; cardiovascular, renal, and metabolic diseases; and oncology. The company also addresses infectious diseases and neuroscience disorders. With operations in more than 100 countries, AstraZeneca’s innovative medicines benefit millions of patients worldwide. For more information, please visit www.astrazeneca.com or follow our official Twitter account @AstraZeneca.

Some of the drug usages mentioned in these studies have not yet been approved for indications in China, and AstraZeneca does not recommend the use of any unapproved drugs. The indications approved for osimertinib in China are: first-line treatment for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. It is also indicated for the treatment of adult patients with locally advanced or metastatic NSCLC who have experienced disease progression during or after prior EGFR tyrosine kinase inhibitor (TKI) therapy and whose tumors test positive for the EGFR T790M mutation.

IMFINZI and tremelimumab have not yet been approved for marketing in China, and AstraZeneca does not recommend the use of any unapproved medicines.

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3. LUNGevity Foundation. Types of Lung Cancer. Available at https://www.lungevity.org/about-lung-cancer/lung-cancer-101/types-of-lung-cancer [Accessed September 2019].

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8. Ali A, et al. Survival of Patients with Non-small-cell Lung Cancer After a Diagnosis of Brain Metastases. Curr Oncol. 2013;20(4):e300-e306 [Accessed September 2019].

9. Pakkala, S, et al. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018;3(15):e120858.