Results from a prespecified exploratory analysis of the FLAURA2 Phase III trial showed AstraZeneca's Tagrisso (osimertinib) with the addition of chemotherapy demonstrated a 42% improvement in central nervous system (CNS) progression-free survival (PFS), compared to Tagrisso alone for patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) and brain metastases at baseline, representing 40% of patients in the trial, as assessed by blinded independent central review (BICR).

These results were presented today in an oral presentation at the European Society for Medical Oncology (ESMO) Congress in Madrid, Spain (abstract #LBA68).

In this group of patients, Tagrisso with the addition of chemotherapy reduced the risk of CNS disease progression or death by 42% compared to Tagrisso alone (based on a hazard ratio [HR] of 0.58; 95% confidence interval [CI] 0.33-1.01) as assessed by BICR. With two years of follow-up, 74% of patients treated with Tagrisso plus chemotherapy had not experienced CNS disease progression or death versus 54% of patients treated with Tagrisso monotherapy. Results also showed a higher proportion of patients demonstrated CNS complete response (CR) with Tagrisso plus chemotherapy (59%) versus Tagrisso alone (43%).

David Planchard, MD, PhD, thoracic oncologist at Gustave Roussy Institute of Oncology and principal investigator for the trial, said: "Osimertinib has a proven ability to cross the blood-brain barrier and improve outcomes for patients with lung cancer and central nervous system metastases, who often face a poorer prognosis than patients whose disease has not spread to the brain. In FLAURA2, the addition of chemotherapy to osimertinib led to a complete response and the disappearance of these tumours in the brain, in more than half of these patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "In this trial, patients with brain metastases at baseline saw a meaningful benefit with the FLAURA2 regimen, offering hope for patients whose cancer has spread to the brain. These data build on the recent positive progression-free survival results from FLAURA2, further reinforcing Tagrisso as the backbone therapy in EGFR-mutated non-small cell lung cancer."

The safety profile of Tagrisso with the addition of chemotherapy was generally manageable and consistent with the established profiles of the individual medicines. Adverse event (AEs) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Tagrisso discontinuation rates were low in both arms of the trial (11% for the Tagrisso plus chemotherapy arm and 6% for the monotherapy arm).

In the Tagrisso plus chemotherapy arm, patients remained on Tagrisso for a median duration of 22.3 months, while patients had a median exposure to platinum-based chemotherapy of 2.8 months and a median exposure to pemetrexed of 8.3 months.

Summary of results: FLAURA2 CNS efficacy[i]
 

[][]
Tagrisso plus Tagrisso monotherapy(n=104)
chemotherapy(n=118)
PFS HR (95% CI) 0.58 (0.33-1.01)
Median PFS (months; 95% 30.2 (28.4-NC[ii]) 27.6 (22.1-NC)
CI)
CNS objective response 86 (73) 72 (69)
rate, n (%)
CR, n (%) 70 (59) 45 (43)
Median CNS duration of NR[iii] (23.8-NC) 26.2 (19.4-NC)
response (in months; 95%
CI)
i The data cut-off date
was 3 April, 2023. 
ii NC, non-calculable
iii NR, not reached

Earlier this month, Tagrisso with the addition of chemotherapy was granted Priority Review (https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemotherapy-granted-priority-review-us-patients-egfr-mutated-advanced-lung-cancer.html) by the Food and Drug Administration (FDA) for the 1st-line treatment of adult patients with locally advanced or metastatic EGFRm NSCLC based on positive PFS data from the FLAURA2 Phase III trial recently presented (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) at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer. In August 2023, Tagrisso with the addition of chemotherapy also received Breakthrough Therapy Designation from the FDA in this setting.

Notes

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.[1 ]Lung cancer is broadly split into NSCLC and small cell lung cancer.[2] The majority of all NSCLC patients are diagnosed with advanced disease.[3]

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.[4]

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 with Tagrisso 80mg once daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5) every three weeks for four cycles, followed by Tagrisso with 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 overall survival (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 700,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. These 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 (IB, II and IIIA) EGFRm NSCLC, where Tagrisso recently demonstrated a statistically significant and clinically meaningful OS benefit.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve survival in both early-stage disease in the ADAURA Phase III trial  (https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-demonstrated-strong-overall-survival-benefit-in-the-adaura-phase-iii-trial.html)and late-stage disease in the FLAURA Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2019/tagrisso-significantly-improves-overall-survival-in-the-phase-iii-flaura-trial-for-1st-line-egfr-mutated-non-small-cell-lung-cancer-09082019.html). 

AstraZeneca also has several ongoing Phase III trials focused on earlier stages of lung cancer, including a trial in the Stage IA2-IA3 adjuvant resectable setting (ADAURA2), in the neoadjuvant setting (NeoADAURA), and in the Stage III locally advanced unresectable setting (LAURA).

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 operates in over 100 countries and its innovative medicines are 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

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References

1. 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 October 2023.
2. LUNGevity Foundation. Types of Lung Cancer. Available at https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed October 2023.  
3. Cancer.Net. Lung Cancer - Non-Small Cell: Statistics. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics. Accessed October 2023. 
4. 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.