TAGRISSO Demonstrated Unprecedented Patient Benefit in the Adjuvant Treatment of EGFR-Mutated Lung Cancer

Detailed results from the Phase III ADAURA trial showed AstraZeneca’s TAGRISSO® (osimertinib) demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in the adjuvant treatment of patients with early-stage (Stage IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection with curative intent.

Results will be presented during the plenary session of the American Society of Clinical Oncology ASCO20 Virtual Scientific Program on May 31, 2020 (abstract #LBA5).

In the primary endpoint of DFS in patients with Stage II and IIIA disease, adjuvant (after surgery) treatment with TAGRISSOreduced the risk of disease recurrence or death by 83% (based on a hazard ratio [HR] of 0.17; 95% confidence interval [CI] 0.12, 0.23; p<0.0001). DFS results in the overall trial population, Stage IB through IIIA, a key secondary endpoint, demonstrated a reduction in the risk of disease recurrence or death of 79% (based on a HR of 0.21; 95% CI 0.16, 0.28; p<0.0001).

At two years, 89% of all patients in the trial treated with TAGRISSO remained alive and disease free versus 53% on placebo. Consistent DFS results were seen across all subgroups, including patients treated with surgery followed by chemotherapy and those who received surgery only, as well as in Asian and non-Asian patients.

Roy S. Herbst, MD, PhD, chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT and principal investigator in the Phase III ADAURA trial, said: “These data are transformative for patients with early-stage EGFR-mutated non-small cell lung cancer who face high rates of recurrence even after successful surgery and subsequent treatment with adjuvant chemotherapy. TAGRISSOwill provide a much-needed new treatment option that has the potential to change the practice of medicine and improve outcomes for patients in this setting.”

José Baselga, Executive Vice President, Oncology R&D, said: “The momentous results of the Phase III ADAURA trial for TAGRISSOdemonstrate for the first time in a global trial that an EGFR inhibitor can change the course of early-stage EGFR-mutated lung cancer and provide hope for a cure. We are discussing these outstanding data with regulatory authorities and look forward to bringing the benefits of TAGRISSOto patients with early-stage disease.”

In April 2020, an Independent Data Monitoring Committee recommended the Phase III ADAURA trial to be unblinded two years early based on its determination of overwhelming efficacy. At the time of data cut-off, overall survival (OS) data were not mature. The trial will continue to assess OS as a secondary endpoint.

Summary of ADAURA results

iThe data cut-off date for DFS was January 17, 2020.

The safety and tolerability of TAGRISSOin this trialwas consistent with previous trials in the metastatic setting. Adverse events at Grade 3 or higher from all causes occurred in 10% of patients in the TAGRISSOarm versus 3% in the placebo arm as assessed by the investigator.

TAGRISSOis approved for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC in the US, Japan, China, the EU and many other countries around the world.

Several presentations featured during the ASCO20 Virtual Scientific Program will showcase AstraZeneca’s leadership in lung cancer across early- and late-stage disease and reinforce the Company’s biomarker-driven approach.

TAGRISSO IMPORTANT SAFETY INFORMATION

• There are no contraindications for TAGRISSO

• Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed

• Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 1142 TAGRISSO-treated patients in clinical trials, 0.9% were found to have a QTc >500 msec, and 3.6% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia

• Cardiomyopathy occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment.Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO

• Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist

• Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanently discontinue if confirmed

• Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose

• Most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and decreased appetite

INDICATIONS

• TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
• TAGRISSO is indicated for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy

Please see complete Prescribing Information, including Patient Information.

NOTES TO EDITORS

About 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, with 80%-85% classified as NSCLC.2 A significant portion of patients with resectable NSCLC eventually develop recurrence despite surgery (complete resection).3,4 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.5-7 These patients are particularly sensitive to treatment with EGFR-tyrosine kinase inhibitors (TKIs) which block the cell-signaling pathways that drive the growth of tumor cells.8 Approximately 25-30% of patients with NSCLC present with resectable disease at diagnosis.9-11

About ADAURA

ADAURA is a randomized, double-blinded, global, placebo-controlled Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II, and IIIA EGFRm NSCLC with complete tumor resection and adjuvant chemotherapy as an option. In the experimental arm, patients were treated with TAGRISSO 80 mg once-daily oral tablets for three years or until disease recurrence. The trial enrolled in more than 200 centers across more than 20 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint is DFS in Stage II and IIIA patients and a key secondary endpoint is DFS in Stage IB, II and IIIA patients. The data readout was originally anticipated in 2022. The trial will continue to assess OS as a secondary endpoint.

About TAGRISSO

TAGRISSO® (osimertinib) is a third-generation, irreversible EGFR-TKI with clinical activity against CNS metastases. TAGRISSO 40 mg and 80 mg once-daily oral tablets have received approval in the US, Japan, China, the EU and many countries around the world for 1st-line EGFRm advanced NSCLC. TAGRISSO is also being developed in the Stage III, unresectable setting (LAURA), in combination with chemotherapy (FLAURA2) and in combination with potential new medicines to address resistance to EGFR-TKIs (SAVANNAH, ORCHARD).

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action. AstraZeneca aims to address the unmet needs of patients with EGFRm tumors as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines gefitinib and TAGRISSO, and its ongoing Phase III trials LAURA and FLAURA2.5-7

AstraZeneca is committed to addressing tumor mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD, which test TAGRISSO in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Trastuzumab deruxtecan, a HER2-directed antibody drug conjugate, is in development for metastatic non-squamous HER2-overexpressing or HER2-mutated NSCLC, including trials in combination with other anticancer treatments.

An extensive, late-stage, Immuno-Oncology program focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.12Durvalumab, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially curative settings (Phase III trials MERMAID-1, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Durvalumab is also in development in the Phase II trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including trastuzumab deruxtecan.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focusing on lung, ovarian, breast and blood cancers. In addition to AstraZeneca's main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms - Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

REFERENCES

1. World Health Organization. International Agency for Research on Cancer. Globocan Worldwide Fact Sheet 2018. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed: May 2020.

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5. Szumera-Cieckiewicz 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;2800-12.

6. 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.

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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.

9. Cagle PT, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Arch Pathol Lab Med. 2013;137:1191–1198.

10. Datta D, et al. Preoperative Evaluation of Patients Undergoing Lung Resection Surgery. Chest. 2003;123: 2096–2103.

11. Le Chevalier T. Adjuvant chemotherapy for resectable non-small-cell lung cancer: where is it going? Ann Oncol. 2010;21:196–8.

12. Pakkala, S, et al. Personalized Therapy for Lung Cancer: Striking a Moving Target. JCI Insight. 2018;3(15):e120858.

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