AstraZeneca's Tagrisso (osimertinib) with the addition of pemetrexed and platinum-based chemotherapyhas been approved in the European Union (EU) for the 1st-line treatment of adult patients with advanced epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose tumours have exon 19 deletions or exon 21 (L858R) mutations.

The approval by the European Commission follows the positive opinion (https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-plus-chemo-recommended-for-approval-in-eu.html) of the Committee for Medicinal Products for Human Use and is based on results from the FLAURA2 (https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemotherapy-extended-median-progression-free-survival-by-nearly-9-months-in-egfr-mutated-advanced-lung-cancer-in-flaura2-phase-iii-trial.html) Phase III trial published inThe New England Journal of Medicine (https://www.nejm.org/).

In the trial, Tagrissowith the addition of chemotherapy reduced the risk of disease progression or death by 38% by investigator assessment compared toTagrissomonotherapy, which is the 1st-line global standard of care (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). Median progression-free survival (PFS) was 25.5 months for patients treated with Tagrisso plus chemotherapy, an 8.8-month improvement versus Tagrisso monotherapy (16.7 months).

PFS results from blinded independent central review (BICR) were consistent with the results by investigator assessment, showing 29.4 months median PFS with Tagrisso plus chemotherapy, a 9.5-month improvement over Tagrisso monotherapy (19.9 months) (HR 0.62; 95% CI 0.48-0.80; nominal p=0.0002).

Results from a prespecified exploratory analysis of patients in the FLAURA2 trial with brain metastases at baseline showedTagrissoplus chemotherapy reduced the risk of central nervous system (CNS) disease progression or death by 42% compared toTagrissomonotherapy (HR 0.58; 95% CI 0.33-1.01) as assessed by BICR. With two years of follow up, 74% of patients treated withTagrissoplus chemotherapy had not experienced CNS disease progression or death versus 54% of patients treated withTagrissomonotherapy.

While the overall survival (OS) results remained immature at the second interim analysis (41% maturity), a trend towards an OS benefit was observed with Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.75; 95% CI 0.57-0.97), as presented (https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-the-addition-chemotherapy-showed-favourable-trend-overall-survival-egfr-mutated-advanced-lung-cancer-further-follow-flaura2-phase-iii-trial.html) at the 2024 European Lung Cancer Congress. The trial continues to assess OS as a key secondary endpoint.  

David Planchard, MD, PhD, Thoracic Oncologist at Gustave Roussy Institute of Oncology and principal investigator for the trial, said: "Today's news marks a significant advance for patients with EGFR-mutated lung cancer in Europe, providing a new 1st-line treatment option with osimertinib now in combination with chemotherapy. The FLAURA2 results build on the established efficacy of osimertinib monotherapy, showing a meaningful nine-month improvement in progression-free survival and offering physicians the option to tailor treatment to a patient's specific needs."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "This approval reinforces Tagrisso as the backbone therapy in EGFR-mutated lung cancer either as monotherapy or in combination with chemotherapy. This is especially important for those with more aggressive disease, including patients whose cancer has spread to the brain and those with L858R mutations."

The safety profile ofTagrissoplus chemotherapy was consistent with the established profiles of the individual medicines. Adverse event (AE) rates were higher in theTagrissoplus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Discontinuation rates of Tagrisso due to AEs were 11% forTagrisso plus chemotherapy and 6% for monotherapy.

Tagrisso is approved as monotherapy in more than 110 countries including in the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFRm NSCLC. Tagrisso with the addition of chemotherapy is also approved in the US, China, Japan and several other countries for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC.Tagrisso is also currently under review with global regulatory authorities for patients with unresectable, Stage III EGFRm NSCLC based on the LAURA Phase III trial.

Lung cancer

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.5 Lung cancer is broadly split into NSCLC and small cell lung cancer.3 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.3,5-6

In Europe, more than 450,000 people are diagnosed with lung cancer each year.1 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.7-9 Additionally, the majority of patients with NSCLC are diagnosed with advanced disease.4 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.10

FLAURA2

FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated withTagrisso80mg once-daily oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed byTagrissowith pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against CNS metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use ofTagrissoin EGFRm NSCLC.Tagrissois the only targeted therapy to improve patient outcomes in early-stage disease in theADAURA Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-achieved-unprecedented-survival-in-early-stage-egfr-mutated-lung-cancer-with-88-of-patients-alive-at-five-years-in-adaura-phase-iii-trial.html), locally advanced stages in theLAURA Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-reduced-the-risk-of-disease-progression-or-death-by-84-percent-in-patients-with-unresectable-stage-iii-egfr-mutated-lung-cancer-vs-placebo.html)and late-stage disease in theFLAURA Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2019/tagrisso-is-the-only-1st-line-treatment-for-egfr-mutated-non-small-cell-lung-cancer-to-deliver-a-median-overall-survival-of-more-than-three-years.html)andFLAURA2 Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemotherapy-extended-median-progression-free-survival-by-nearly-9-months-in-egfr-mutated-advanced-lung-cancer-in-flaura2-phase-iii-trial.html).

As part of AstraZeneca's ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial.

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.

AstraZeneca in lung cancer

AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company's comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca's innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow the Company on social media @AstraZeneca (https://www.linkedin.com/company/astrazeneca).

Contacts

For details on how to contact the Investor Relations Team, please click here (https://www.astrazeneca.com/investor-relations.html#Contacts). For Media contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html).

References

1. Ferlay J, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018;103:356-387.
2. Sanden SV, et al. Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis. Targeted Onc. 2022;17:153-166.
3. LUNGevity Foundation. Types of Lung Cancer. Available at: https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed July 2024.
4. González M, et al. Overall survival for early and locally advanced non-small-cell lung cancer from one institution: 2000-2017. Clin Transl Oncol 23. 2021;1325-1333
5. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf. Accessed July 2024.   
6. Cheema PK, et al. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42
7. 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.
8. Szumera-Ciećkiewicz A, et al.EGFR Mutation Testing on Cytological and Histological Samples in Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence.Int J Clin Exp Pathol. 2013;6:2800-2812.
9. Ellison G, et al. EGFR Mutation Testing in Lung Cancer: a Review of Available Methods and Their Use for Analysis of Tumour Tissue and Cytology Samples. J Clin Pathol. 2013;66:79-89.
10. 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.