Tagrisso (Osimertinib) Plus Chemotherapy Approved in the U.S. for First-Line Treatment of EGFR-Mutated Advanced NSCLC Based on FLAURA2 Trial

This approval is based onFLAURA2Study: Compared with the first-line standard treatment, Tagrisso combined with chemotherapy can extend the median survival time by nearly9Months

ShanghaiFebruary 22, 2024PR Newswire -- AstraZeneca's Tagrisso (osimertinib) in combination with chemotherapy has been approved in the United States for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC).

This approval by the U.S. Food and Drug Administration (FDA) under Priority Review was based on the results of the FLAURA2 Phase III study published in The New England Journal of Medicine. Compared with the global standard first-line treatment regimen of osimertinib monotherapy, the combination of osimertinib and chemotherapy reduced the risk of disease progression or death by 38% (Hazard Ratio [HR]: 0.62; 95% Confidence Interval [CI] 0.49-0.79; p<0.0001). The investigator-assessed results showed that the combination of osimertinib and chemotherapy extended the median progression-free survival (PFS) to 25.5 months for patients, which was 8.8 months longer than the median PFS of 16.7 months achieved with osimertinib monotherapy.

This is consistent with the PFS results assessed by the Blinded Independent Central Review (BICR): the combination of osimertinib and chemotherapy extended the median Progression-Free Survival (PFS) to 29.4 months, compared to osimertinib monotherapy (median PFS of 19.9 months), prolonging the median PFS by 9.5 months (HR: 0.62; 95% CI 0.48-0.80; p=0.0002).

In the United States, more than 200,000 people are diagnosed with lung cancer each year, of which 80%-85% are non-small cell lung cancer, the most common type of lung cancer.^[1-3]About 70% of non-small cell lung cancer cases are already at an advanced stage at the time of diagnosis.^[4]In addition, about 15% of non-small cell lung cancer patients in the United States have EGFR mutations.^[5]。

Pasi A. Jänne, MD, PhD, a medical oncology expert at Dana-Farber Cancer Institute and the principal investigator of the FLAURA2 study, stated: "This approval is based on the unprecedented results of the FLAURA2 study, which brings crucial new treatment options for patients with advanced EGFR mutations. Now, with these two highly effective osimertinib-based treatment regimens, physicians can better tailor treatments to individual needs, ensuring optimal outcomes for every patient."

Dave Fredrickson, Executive Vice President of AstraZeneca Global and Head of Oncology Business, stated: "This crucial treatment option can delay disease progression for nearly nine months, setting a new standard in first-line treatment for advanced lung cancer and delivering the longest progression-free survival benefit to date. This approval further solidifies osimertinib's foundational role in treating EGFR-mutated lung cancer, whether used as monotherapy or in combination with chemotherapy. This is particularly important for patients with poor prognoses, including those with brain metastases and L858R mutations."

Laurie Ambrose, President and CEO of the GO2 Foundation for Lung Cancer, stated: "I am thrilled to see this ongoing progress, which will provide more personalized treatment options for our community. Our shared vision is to deliver the right care to the right patient at the right time, ensuring better survival benefits for our community members."

Exploratory analysis pre-specified for patients with baseline brain metastases in the FLAURA2 study showed that, compared to osimertinib monotherapy, the combination of osimertinib and chemotherapy reduced the risk of central nervous system (CNS) disease progression or death by 42% (HR 0.58; 95% CI 0.33–1.01), as assessed by BICR. After two years of follow-up, 74% of patients receiving osimertinib plus chemotherapy had no intracranial progression, compared to 54% of those on osimertinib monotherapy.

Although the overall survival (OS) data were not yet mature (41% maturity) at the time of the second interim analysis, no trend toward harm was observed (HR 0.75; 95% CI 0.57-0.97). The study will continue to evaluate OS as a key secondary endpoint.

The safety of osimertinib in combination with chemotherapy is generally manageable and consistent with the known safety profiles of each drug. The incidence of adverse events (AEs) was higher in the osimertinib plus chemotherapy group, which was attributed to chemotherapy-induced AEs. The discontinuation rate of osimertinib due to AEs was low in both trial groups (11% for osimertinib plus chemotherapy and 6% for osimertinib monotherapy).

In December 2023, based on the FLAURA2 study, osimertinib in combination with chemotherapy was included as a "Category 1 recommendation - Other Recommended Regimens" in the NCCN Clinical Practice Guidelines® (NCCN Guidelines®) for the treatment of patients with non-small cell lung cancer harboring EGFR Exon 19 Del/Exon 21 L858R mutations.^[6]。

The US registration application document is currently under review in the Orbis project, which aims to provide regulatory agencies with a collaborative framework for the common submission and approval of oncology drugs. As part of the project, osimertinib in combination with chemotherapy is also under review by regulatory authorities in Australia, Canada, and Switzerland. Meanwhile, registration applications based on the FLAURA2 study results are also being reviewed in several other countries.

Osimertinib has been approved as a monotherapy in more than 100 countries, including the United States, the European Union, China, and Japan, for the first-line treatment of patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer, the treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive non-small cell lung cancer, and the adjuvant treatment of patients with early-stage EGFR-mutated non-small cell lung cancer.

AstraZeneca remains committed to the promise of "dedicating efforts to treat lung cancer patients as early as possible." As part of this commitment, the NeoADAURA Phase III clinical trial, which evaluates the efficacy of osimertinib as a neoadjuvant therapy, is expected to yield results later this year. Additionally, the ADAURA2 Phase III clinical trial, assessing the efficacy of osimertinib in the adjuvant treatment of early-stage resectable patients, is currently ongoing.

Notes

About Lung Cancer

Lung cancer is the leading cause of cancer death in men and women, accounting for approximately one-fifth of all cancer deaths.^[7]. Lung cancer is divided into non-small cell lung cancer and small cell lung cancer.^[2]Most non-small cell lung cancers are already at an advanced stage when diagnosed.^[4]。

Non-small cell lung cancer patients with EGFR mutations are sensitive to the treatment of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), which can block the cellular signaling pathways that drive tumor cell growth.^[8]。

AboutFLAURA2Research

FLAURA2 is a randomized, controlled, open-label, global multicenter Phase III trial for first-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFR-mutated non-small cell lung cancer. Patients in the experimental group received osimertinib 80mg once-daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)), administered every three weeks for four cycles, followed by maintenance therapy with osimertinib combined with pemetrexed every three weeks.

The study enrolled a total of 557 patients across more than 150 centers globally, including over 20 countries such as the United States, Europe, South America, and Asia. This analysis focuses on the primary endpoint, PFS. The study is still ongoing, with further evaluation of the secondary endpoint OS to follow.

About Osimertinib

Osimertinib is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with confirmed clinical efficacy in non-small cell lung cancer patients, including those with central nervous system metastases. Osimertinib (40mg and 80mg once-daily oral tablets) has been used globally in nearly 800,000 patients for various approved indications. AstraZeneca continues to explore osimertinib for treating EGFR-mutated non-small cell lung cancer patients at different stages of the disease.

A substantial body of evidence supports the use of osimertinib in non-small cell lung cancer with EGFR mutations, and it is the only targeted therapy that can simultaneously improve clinical outcomes for both early-stage (ADAURA Phase III clinical trial) and advanced-stage (FLAURA and FLAURA2 Phase III clinical trials) non-small cell lung cancer patients.

AstraZeneca is also exploring osimertinib in combination with savolitinib (an oral, potent and highly selective MET-TKI) as well as other potential new drugs through the SAVANNAH and ORCHARD Phase II studies, and the SAFFRON Phase III study, to investigate methods to address mechanisms of tumor resistance.

Research on AstraZeneca in the Field of Lung Cancer

AstraZeneca is committed to improving the cure rate for lung cancer patients through early diagnosis and treatment, while advancing related science to enhance treatment outcomes for drug-resistant and late-stage patients. By defining new therapeutic targets and evaluating innovative therapies, AstraZeneca is dedicated to ensuring that the most appropriate drugs are used for patients who can achieve maximum benefit.

The Company’s comprehensive portfolio includes leading lung cancer medicines and next-wave innovative medicines, including osimertinib and gefitinib (Iressa); durvalumab (Imfinzi) and tremelimumab; trastuzumab deruxtecan (Enhertu) and datopotamab deruxtecan co-developed with Daiichi Sankyo; savolitinib (Orpathys) co-developed with Hutchmed, as well as a pipeline of novel drugs and combinations across various mechanisms of action.

AstraZeneca is a founding member of the global Lung Ambition Alliance, a worldwide coalition dedicated to accelerating innovation and providing meaningful improvements for lung cancer patients, including treatments and beyond.

About AstraZeneca's Research in the Oncology Field

AstraZeneca is leading a revolution in the field of oncology, committed to providing a diversified range of cancer treatment options. Through scientific exploration of the complexities in oncology, the company discovers, develops, and delivers life-changing medicines to patients.

AstraZeneca’s oncology business focuses on the most challenging cancer diseases. Through continuous innovation, AstraZeneca has built a leading, diversified portfolio and pipeline across the industry, constantly driving changes in medical practice and transforming patient experiences.

AstraZeneca’s vision aims to redefine cancer treatment with the hope of ending cancer as a cause of death in the future.

Disclaimer: This article involves products or indications not approved in China. AstraZeneca does not recommend any unapproved drugs./Indications for use.

References References

1. ASCO. Lung Cancer - Non-Small Cell: Introduction. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/types-treatment. Accessed February 2024.

2. LUNGevity Foundation. Types of Lung Cancer. Available at: https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed February 2024.    

3. American Cancer Society. What Is Lung Cancer? Available at: https://www.cancer.org/cancer/lung-cancer/about/what-is.html#:~:text=About%2080%25%20to%2085%25%20of,(outlook)%20are%20often%20similar. Accessed February 2024.    

4. Cagle PT, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Archives Pathology Lab Med. 2013;137:1191-1198.  

5. Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27. 

6. NCCN, National Comprehensive Cancer Network® (NCCN®). Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer Version 1.2024.© National Comprehensive Cancer Network, Inc. [2024]. All rights reserved. Accessed [February 14, 2024]. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

7. World Health Organisation. International Agency for Research on Cancer. Lung Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed February 2024.

8. Cross DA, et al. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov. 2014;4(9):1046-1061.