TAGRISSO Extended Disease-Free Survival Regardless of Prior Adjuvant Chemotherapy in Early-Stage EGFR-Mutated Lung Cancer

Rhea-AI Summary

AstraZeneca's TAGRISSO® (osimertinib) has demonstrated significant disease-free survival (DFS) benefits in the ADAURA Phase III trial for patients with EGFR-mutated non-small cell lung cancer (NSCLC). TAGRISSO reduced the risk of disease recurrence or death by 84% in patients previously treated with chemotherapy and by 77% in those untreated. The trial also showed consistent DFS benefits across disease stages. Following its recent US approval for adjuvant treatment, AstraZeneca aims to expand TAGRISSO's availability globally.

Positive

• TAGRISSO reduced disease recurrence risk by 84% in patients with prior adjuvant chemotherapy and 77% without it.
• Large DFS benefits consistent across various disease stages.
• TAGRISSO recently approved in the US for adjuvant treatment, enhancing its market position.

Negative

• Adverse events of Grade 3 or higher occurred in 20% of TAGRISSO-treated patients compared to 13% in placebo.

Results from an exploratory analysis of the positive ADAURA Phase III trial showed AstraZeneca’s TAGRISSO^® (osimertinib) extended disease-free survival (DFS) in patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) regardless of prior adjuvant chemotherapy treatment or stage of disease, building on the unprecedented primary DFS results for TAGRISSO in the adjuvant setting announced last year. Results from ADAURA were presented during the 2020 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (IASLC) and featured in the Press Program.

In this exploratory analysis of the overall trial population, adjuvant TAGRISSO reduced the risk of disease recurrence or death by 84% in patients who had been treated with prior adjuvant chemotherapy (based on a hazard ratio [HR] of 0.16, 95% confidence interval [CI] 0.10-0.26) and by 77% in patients who had not (HR 0.23; 95% CI 0.13-0.40). DFS benefits were similar across each stage of disease.

In addition, a separate exploratory post-hoc analysis of patient-reported outcomes in ADAURA showed that patients treated with TAGRISSO maintained their quality of life, with no clinically meaningful differences in physical or mental health measures in the TAGRISSO and placebo arms.

Yi-Long Wu, MD, FACS, Tenured Professor of the Lung Cancer Institute at Guangdong Provincial People's Hospital and Academy of Medical Sciences in Guangzhou, China, and a principal investigator in the ADAURA Phase III trial, said: “The overwhelming disease-free survival benefit in patients in ADAURA already supported the role of TAGRISSO as a pioneering therapy in the adjuvant treatment of EGFR-mutated non-small cell lung cancer. This latest analysis shows the magnitude of that benefit is consistent with or without prior adjuvant chemotherapy, and regardless of disease stage, reinforcing the critical role of TAGRISSO in this setting.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “These new data show that TAGRISSO provides transformative benefits independent of prior chemotherapy treatment, preventing lung cancer from returning while allowing patients to sustain their quality of life. Following the recent approval of TAGRISSO in the US in the adjuvant setting, we continue to work urgently with regulatory authorities globally to bring this new standard of care to patients with early-stage lung cancer.”

Exploratory DFS analysis with and without chemotherapy (CTx)
OSI: TAGRISSO; PBO: placebo

Stage IB

Stage II

Stage IIIA

Stage IB-IIIA

OSI

PBO

OSI

PBO

OSI

PBO

OSI

PBO

With CTx

n=28

n=30

n=81

n=85

n=94

n=92

n=203

n=207

DFS events patients (%)

4 (14)

11 (37)

6 (7)

36 (42)

12 (13)

56 (61)

22 (11)

103 (50)

DFS HR (95% CI)

NC (NC, NC)

0.15 (0.06, 0.32)

0.13 (0.06, 0.23)

0.16 (0.10, 0.26)

Without CTx

n=78

n=76

n=37

n=33

n=21

n=27

n=136

n=136

DFS events patients (%)

7 (9)

18 (24)

5 (14)

16 (48)

3 (14)

22 (81)

15 (11)

56 (41)

DFS HR (95% CI)

0.38 (0.15, 0.88)

0.20 (0.07, 0.52)

0.10 (0.02, 0.29)

0.23 (0.13, 0.40)

In the ADAURA Phase III trial, chemotherapy use was balanced across the two treatment arms, with 60% of patients receiving prior adjuvant chemotherapy. In line with uptake observed in prior studies and clinical practice, younger patients (<70 years) and those with more advanced disease were more likely to have prior adjuvant chemotherapy.^1,2 Treatment with chemotherapy did not vary according to a patient’s performance status.

The safety and tolerability of TAGRISSO was consistent with previous trials in the metastatic EGFRm NSCLC setting. Adverse events at Grade 3 or higher from all causes occurred in 20% of patients in the TAGRISSO arm versus 13% in the placebo arm as assessed by investigators.

Primary results of ADAURA, which were published in The New England Journal of Medicine in September 2020, showed adjuvant treatment with TAGRISSO reduced the risk of disease recurrence or death by 83% (HR 0.17; 95% CI 0.12-0.23; p<0.0001) among patients with Stage II and IIIA EGFRm NSCLC and, as shown in a prespecified exploratory analysis, demonstrated a clinically meaningful improvement in central nervous system (CNS) DFS compared to placebo.

Additional TAGRISSO highlights at WCLC

In addition to these ADAURA analyses, several other presentations and posters for TAGRISSO across lung cancer settings and in novel combinations were featured during WCLC, including:

• Results from the ODIN BM Phase I trial, which support the efficacy and uniform brain penetration of TAGRISSO in patients with CNS metastases as reported in previous clinical trials. This trial used a micro dose of intravenous TAGRISSO detectable on PET scans, which showed rapid, high and widespread brain exposure of TAGRISSO in both the healthy tissue and CNS metastases of four patients with EGFRm NSCLC. Results also showed that TAGRISSO markedly reduced CNS metastases in patients following three to four weeks of daily oral treatment
• Final results from two expansion cohorts of the TATTON Phase Ib trial, which support the potential of TAGRISSO plus savolitinib, a selective inhibitor of mesenchymal epithelial transition (c-MET) factor receptor tyrosine kinase, to overcome MET-based resistance in patients with NSCLC whose disease has progressed on prior EGFR-tyrosine kinase inhibitor (TKI) treatment. The safety profile of TAGRISSO plus savolitinib was consistent with previous reports. The combination is currently being tested in the ongoing SAVANNAH and ORCHARD Phase II trials
• The design of a Phase I study exploring TAGRISSO in combination with patritumab deruxtecan (U3-1402) in patients with locally advanced or metastatic EGFRm NSCLC who progressed during or after prior treatment with TAGRISSO alone³
• The design of the NeoADAURA Phase III trial testing the benefit of treating patients with resectable Stage II-IIIB NSCLC with neoadjuvant TAGRISSO as monotherapy or in combination with a choice of standard platinum-based chemotherapies versus chemotherapy with placebo. Patient recruitment for this trial is ongoing

TAGRISSO was recently approved in the US for the adjuvant treatment of adult patients with early-stage EGFRm NSCLC after tumor resection with curative intent based on the ADAURA Phase III trial. This indication is under priority review in China and regulatory review in the EU; additional global submission discussions are ongoing. TAGRISSO is also approved for the 1st-line treatment of patients with metastatic EGFRm NSCLC and for the treatment of metastatic EGFR T790M mutation-positive NSCLC in the US, Japan, China, the EU and many other countries around the world.

TAGRISSO Important Safety Information

• There are no contraindications for TAGRISSO

• Interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of the 1479 TAGRISSO-treated patients; 0.3% 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 1479 TAGRISSO-treated patients in clinical trials, 0.8% were found to have a QTc >500 msec, and 3.1% 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 3% of the 1479 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 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. 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 1479 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

• Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity

• 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 (≥20%) adverse reactions, including laboratory abnormalities, were leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough

INDICATIONS

• TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with 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 first-line treatment of adult 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 adult 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

For additional information, please see the complete Prescribing Information, including Patient Information.

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.⁴ Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.⁵ The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.^6-8

For those with resectable tumors, the majority of patients eventually develop recurrence despite complete tumor resection and adjuvant chemotherapy.⁹ Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.^10,11

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.^12-14 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.¹⁵

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, IIIA EGFRm NSCLC following complete tumor resection and adjuvant chemotherapy as indicated. Patients were treated with TAGRISSO 80 mg once-daily oral tablets or placebo 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 was DFS in Stage II and IIIA patients and a key secondary endpoint was DFS in Stage IB, II and IIIA patients. The data readout was originally anticipated in 2022. The trial will continue to assess overall survival.

About TAGRISSO

TAGRISSO^® (osimertinib) is a third-generation, irreversible EGFR-TKI with clinical activity against central nervous system 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 metastatic NSCLC and EGFR T790M mutation-positive metastatic NSCLC.

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 with the approved medicines gefitinib and TAGRISSO, and its ongoing LAURA, NeoADAURA, and FLAURA2 Phase III trials.

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.

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 seven 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 focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms - Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies - 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.

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. For more information, please visit https://www.astrazeneca-us.com/ and follow us on Twitter @AstraZenecaUS.

References

1. Chouaid C, et al. Adjuvant treatment patterns and outcomes in patients with stage IB-IIIA non-small cell lung cancer in France, Germany, and the United Kingdom based on the LuCaBIS burden of illness study. Lung Cancer. 2018;124:310-316.
2. Buck PO, et al. Treatment Patterns and Health Resource Utilization Among Patients Diagnosed With Early Stage Resected Non-Small Cell Lung Cancer at US Community Oncology Practices. Clin Lung Cancer. 2015;16:486-495.
3. Trial collaboration with Daiichi Sankyo which maintains exclusive rights to patritumab deruxtecan.
4. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed January 2021.
5. LUNGevity Foundation. Types of Lung Cancer. https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer. Accessed January 2021.
6. Cagle P, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Arch Pathol Lab Med. 2013;137:1191-1198.
7. Le Chevalier T, et al. Adjuvant Chemotherapy for Resectable Non-Small-Cell Lung Cancer: Where is it Going? Ann Oncol. 2010;21:196-198.
8. Datta D, et al. Preoperative Evaluation of Patients Undergoing Lung Resection Surgery. Chest. 2003;123:2096-2103.
9. Pignon JP, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559.
10. Sethi S, et al. Incidental Nodule Management – Should There Be a Formal Process? J Thorac Onc. 2016:8;S494-S497.
11. LUNGevity Foundation. Screening and Early Detection. https://lungevity.org/for-patients-caregivers/lung-cancer-101/screening-early-detection. Accessed January 2021.
12. 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.
13. 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;2:2121-2127.
14. 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.
15. 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.

US-49454 Last Updated 1/21

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FAQ

What were the results of the ADAURA Phase III trial for AZN's TAGRISSO?

The ADAURA trial showed that TAGRISSO significantly extended disease-free survival, reducing the risk of recurrence by 84% in patients with prior chemotherapy and 77% without.

When was TAGRISSO approved in the US for adjuvant treatment?

TAGRISSO received US approval for adjuvant treatment in early 2020 following the ADAURA trial results.

How does TAGRISSO affect quality of life in patients?

Patients treated with TAGRISSO maintained their quality of life with no significant differences in physical or mental health compared to placebo.

What is the safety profile of TAGRISSO based on recent trials?

Safety data indicated Grade 3 or higher adverse events occurred in 20% of TAGRISSO patients, consistent with prior studies.