Results from the FLAURA2 Phase III trial showed AstraZeneca's Tagrisso (osimertinib) with the addition of chemotherapy provided a clinically meaningful and consistent benefit in subsequent outcomes after disease progression in patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Tagrisso with the addition of chemotherapy also demonstrated a favourable trend toward overall survival (OS) improvement at two years of follow up. These results were presented today at the 2024 European Lung Cancer Congress (ELCC) in Prague, Czech Republic (abstract #4O).

This follows primary endpoint data (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) presented at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) and published in The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2306434), which showed Tagrisso with the addition of chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS). In February 2024, Tagrisso with the addition of chemotherapy was approved in the US (https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-plus-chemo-approved-in-us-for-lung-cancer.html) following a 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) based on these results.

At 41% data maturity, the OS interim results showed a favourable trend with the Tagrisso plus chemotherapy arm (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.57-0.97), with consistent results across prespecified subgroups, including sex, race, type of EGFR mutation, age at time of diagnosis, smoking history, performance status and central nervous system (CNS) metastases status at baseline. The OS data were not statistically significant at this interim analysis and will continue to be assessed as a key secondary endpoint at final analysis.

Tagrisso with the addition of chemotherapy also showed a consistent benefit across prespecified post-progression endpoints of time to first subsequent treatment (TFST; HR 0.73; 95% CI 0.56-0.94), time to progression on 2nd-line therapy (PFS2; HR 0.70; 95% CI 0.52-0.93) and time to second subsequent treatment (TSST; HR 0.69; 95% CI 0.51-0.93).

Pasi A. Jänne, MD, PhD, medical oncologist at Dana-Farber Cancer Institute and principal investigator for the trial, said: "The improvement in post-progression outcomes with chemotherapy added to standard-of-care osimertinib is encouraging for patients with advanced EGFR-mutated lung cancer, particularly the encouraging trend toward overall survival. These results further validate the importance of this additional treatment option, especially for those patients whose cancer has spread to the brain, those with L858R mutations, or other cause for poorer prognosis."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "FLAURA2 reinforces Tagrisso as the backbone therapy in EGFRm non-small cell lung cancer either as monotherapy or in combination with chemotherapy, delivering the longest reported progression-free survival benefit in the 1st-line advanced setting. We're excited to see a favourable trend toward overall survival and look forward to seeing this data mature over time."

Summary of key post-progression results: FLAURA2

[][][][][][][][][][][][][][][]
Tagrisso plus Tagrisso monotherapy(n=278)
chemotherapy(n=279)
TFST[i]
Median TFST, in 30.7 (27.3, NC[ii]) 25.4 (22.8, NC[ii])
months (95% CI)
Hazard ratio 0.73 (0.56-0.94)
(95% CI)
PFS2[i]
Median PFS2, in 30.6 (29.0-NC[ii]) 27.8 (26.0-NC[ii])
months (95% CI)
Hazard ratio 0.70 (0.52-0.93)
(95% CI)
TSST[i]
Median TSST, in NR[iii] (NC[ii] 33.2 (28.2-NC[ii])
months (95% CI) -NC[ii])
Hazard ratio 0.69 (0.51-0.93)
(95% CI)
Second interim
OS[i]
Median OS, in NR[iii] (38.0 36.7 (33.2-NC[ii])
months (95% CI) -NC[ii])
Hazard ratio 0.75 (0.57-0.97)
(95% CI)
i The data cut
-off date was 3
April 2023
*except second
interim OS,
which was 8
January 2024
ii NC: Not
calculable
iii NR: Not
reached

Additional safety analyses from the FLAURA2 trial were also presented at ELCC (abstract #10P). Results showed adverse event onset frequency and severity were highest following initial chemotherapy added to Tagrisso and reduced over time during the maintenance period.

An analysis of patient-reported outcomes from the FLAURA2 trial was also presented at ELCC (abstract #9P). Results showed a trend toward improved health-related quality of life (HRQoL) and a trend toward improvement in several symptoms following chemotherapy added to Tagrisso. Symptoms included dyspnoea (shortness of breath or breathlessness), chest pain and cough. Any decline in HRQoL from adding chemotherapy to Tagrisso was not clinically meaningful and was temporary, resolving after chemotherapy was completed.

Tagrisso is also approved as monotherapy in more than 100 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. Regulatory applications are under review in several countries based on the FLAURA2 Phase III results.

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. Each of these Phase III trials serves to reinforce the proven benefit of Tagrisso in the early-stage 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] 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. The majority of all NSCLC patients are diagnosed with advanced disease.[1-3]

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.[4-6] 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.[7]

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 with the addition of 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 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 more than 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 of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes 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), locally advanced stages in the LAURA Phase III trial (https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-improved-pfs-in-stage-iii-lung-cancer.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) and FLAURA2 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).

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

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. World Health Organisation. 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 March 2024. 
2. LUNGevity Foundation. Types of Lung Cancer. Available at: https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed March 2024.   
3. 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.
4. 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.
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;29:2121-2127.
6. 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.
7. 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.