Imfinzi demonstrates clinical activity in Stage IV, 1st-line non-small cell lung cancer in Phase III MYSTIC trial

The first Phase III data on blood TMB in this setting show an association
between high TMB and overall survival benefit with immunotherapy

13 December 2018

AstraZeneca and MedImmune, its global biologics research and development arm, have presented overall survival (OS) and progression-free survival (PFS) data from the Phase III MYSTIC trial at the European Society for Medical Oncology (ESMO) Immuno-Oncology 2018 Congress in Geneva, Switzerland. The MYSTIC trial evaluated Imfinzi (durvalumab) monotherapy and the combination of Imfinzi plus tremelimumab, an anti-CTLA4 antibody, versus standard-of-care (SoC) platinum-based chemotherapy in previously-untreated patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC).¹

Results show that Imfinzi monotherapy demonstrated clinical activity with an OS hazard ratio (HR) of 0.76 (97.54% CI 0.564-1.019; nominal p=0.036) in the primary analysis population of patients whose tumours express PD-L1 on 25% or more of their cancer cells, but this result did not meet statistical significance. After two years of follow-up, the OS rate for treatment with Imfinzi monotherapy was 38.3% vs. 22.7% with SoC. This difference was observed despite a group of patients in the SoC arm (39.5%) that received subsequent immunotherapy following chemotherapy treatment. The combination of Imfinzi plus tremelimumab did not meet the PFS or OS primary endpoints. A summary of these data are included below.

Summary of primary endpoints

ⁱThe data cut-off date was 4 October 2018 (OS and safety) and 1 June 2017 (PFS).

ⁱⁱStratified by histology.

ⁱⁱⁱConfidence interval adjusted for interim analysis.

^ivCriteria for statistical significance at the final analysis of OS was p-value ≤ 0.0246 for durvalumab vs chemotherapy and p-value ≤ 0.0123 for durvalumab + tremelimumab vs chemotherapy (using Lan DeMets spending function approximating O’Brien Fleming boundary).

Exploratory analysis using a novel biomarker

A prespecified exploratory analysis of blood tumour mutational burden (bTMB) showed that high bTMB, defined as ≥16 mutations per megabase, was associated with better OS in patients treated with Imfinzi monotherapy and the Imfinzi plus tremelimumab combination. In high bTMB patients, combination therapy reduced the risk of death by 38% compared to SoC (HR 0.62, CI 0.451-0.855) and the monotherapy arm had an OS HR of 0.80 compared to SoC (CI 0.588-1.077). These preliminary data included 809 samples representing 72.4% of patients. The analysis used a plasma-based TMB score generated from a minimally-invasive diagnostic test from Guardant Health recently granted breakthrough device designation by the US Food and Drug Administration for patients with NSCLC.² Additional bTMB analyses will be presented at a forthcoming medical meeting.

Hesham Abdullah, Head of Immuno-Oncology, Global Medicines Development, AstraZeneca, said: “We are eager to continue following the science to fully understand the role of both PD-L1 and TMB as biomarkers to help select patients that may benefit from our Immuno-Oncology medicines. We are encouraged to see that Imfinzi monotherapy activity is consistent with the anti-PD1 class in previously-untreated patients with Stage IV non-small cell lung cancer. The apparent association between high blood TMB and response to immunotherapy observed in this exploratory analysis warrants further investigation.”

Naiyer A. Rizvi, MD, principal investigator in the MYSTIC trial said: “It is promising to see that high-TMB patients with metastatic disease, which represents about 40 percent of patients with non-small cell lung cancer, may experience durable survival with combination immunotherapy treatment. These early data underscore the need to better understand the tumour-specific characteristics that will help us unlock the power of immunotherapy and fight cancer. I look forward to our further analyses of the MYSTIC data based on TMB.”

The safety and tolerability profiles for Imfinzi and the Imfinzi plus tremelimumab combination in the MYSTIC trial were consistent with previous experience. Among patients receiving Imfinzi, 40.4% of patients experienced a grade 3 or 4 adverse event (AE) vs. 47.7% with the Imfinzi plus tremelimumab combination and 46.0% with chemotherapy. 5.4% of patients discontinued Imfinzi due to treatment-related AEs vs. 13.2% with the combination and 9.4% on chemotherapy.

Imfinzi is approved for unresectable, Stage III NSCLC in more than 40 countries, including the US, EU and Japan, based on the Phase III PACIFIC trial.^3-8 Imfinzi is currently being tested in a range of Phase III trials for Stage IV NSCLC.^8,9

NOTES TO EDITORS

About MYSTIC

The MYSTIC trial is a randomised, open-label, multi-centre, global Phase III trial of Imfinzi (durvalumab) monotherapy or Imfinzi in combination with tremelimumab versus SoC chemotherapy in the 1st-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type, locally-advanced or metastatic (Stage IV) non-small cell lung cancer.¹

The trial was conducted in 167 centres across 17 countries, including the US, Canada, Europe, Russia, Australia and parts of Asia, including Japan, Korea, Thailand, Vietnam and Taiwan, China. Primary endpoints included progression-free survival (PFS) for the combination, and OS in monotherapy and in combination therapy.¹

About Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour's immune-evading tactics and releasing the inhibition of immune responses.^3,10-13

Imfinzi is approved for unresectable, Stage III NSCLC in more than 40 countries including the US, EU, and Japan based on the Phase III PACIFIC trial.^3-8 Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.^8,9

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, small-cell lung cancer (SCLC), bladder cancer, head and neck cancer and other solid tumours.^8,9

About tremelimumab

Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation and boosting the immune response to cancer.¹⁴ Tremelimumab is being tested in a clinical trial programme in combination with Imfinzi in NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer and blood cancers.^8,9

About Stage IV NSCLC

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths: more than breast, prostate and colorectal cancers combined.¹⁵ Lung cancer is broadly split into NSCLC and SCLC, with 80-85% classified as NSCLC.¹⁶ Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease. Approximately 85% of Stage IV patients are diagnosed after the tumour has spread outside of the lung.¹⁷ For these patients, prognosis is particularly poor, as only 1 in 10 will be alive five years after diagnosis.¹⁸

About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning several stages of disease and lines of therapy.^8,9 We aim to address the unmet needs of patients with EGFR-mutated tumours 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 our approved medicines Iressa and Tagrisso and ongoing FLAURA, ADAURA and LAURA Phase III trials.^8,9,19-21

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a known genetic mutation which represents up to half of all patients with lung cancer.²² Imfinzi, an anti-PDL1 antibody is in development as monotherapy (ADJUVANT BR.31, PACIFIC-2, PACIFIC-5, MYSTIC and PEARL Phase III trials) and in combination with tremelimumab and/or chemotherapy (MYSTIC, NEPTUNE, POSEIDON, ADRIATIC and CASPIAN Phase III trials).^8,9

About AstraZeneca’s approach to immuno-oncology

IO is a therapeutic approach designed to stimulate the body’s immune system to attack tumours.²³ At AstraZeneca and MedImmune, our biologics research and development arm, our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression.^8,9 We believe that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PDL1) as monotherapy and in combination with tremelimumab (anti-CTLA4) in multiple tumour types, stages of disease, and lines of therapy, using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine our IO portfolio with small, targeted molecules from across our Oncology pipeline, and from our research partners, may provide new treatment options across a broad range of tumours.^8,9

About 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 at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.^8,9 In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

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

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of small-molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology; Respiratory; Cardiovascular, Renal & Metabolic Diseases; and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, MD, one of AstraZeneca’s three global R&D centres, with additional sites in Cambridge, UK, and South San Francisco, CA. For more information, please visit www.medimmune.com.

About AstraZeneca

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

 

CONTACTS

References

1.     NIH. U.S. National Library of Medicine. Clinical Trials. AstraZeneca. Phase III Open Label First Line Therapy Study of MEDI 4736 (Durvalumab) With or Without Tremelimumab Versus SOC in Non Small-Cell Lung Cancer (NSCLC). (MYSTIC). NCT02453282. (2018) Available at: https://clinicaltrials.gov/ct2/show/NCT02453282. Accessed December 2018.

2.     Guardant Health. Guardant Health Partners with AstraZeneca to Develop Blood-Based Companion Diagnostic Tests for Tagrisso and Imfinzi. Available at: http://investors.guardanthealth.com/press-releases. Accessed December 2018.

3.     US Food and Drug Administration. IMFINZI™ (durvalumab) Prescribing Information. Available at https://www.azpicentral.com/imfinzi/imfinzi.pdf. Accessed December 2018.

4.     European Medicines Agency. IMFINZI™ (durvalumab) SmPC. Available at https://www.ema.europa.eu/documents/product-information/imfizi-epar-product-information_en.pdf. Accessed December 2018.

5.     AstraZeneca PLC. Imfinzi approved in Japan for unresectable Stage III non-small cell lung cancer. Available at: https://www.astrazeneca.com/media-centre/press-releases/2018/imfinzi-approved-in-japan-for-unresectable-stage-iii-non-small-cell-lung-cancer-02072018.html. Accessed December.

6.     MoneyControl. AstraZeneca gets marketing permission for cancer drug in India. Available at: https://www.moneycontrol.com/news/business/astrazeneca-gets-marketing-permission-for-cancer-drug-in-india-2618931.html. Accessed December 2018.

7.     AstraZeneca PLC. First and Only Immuno-Oncology Treatment, Imfinzi® (durvalumab), for Stage III, Unresectable Non-Small Cell Lung Cancer Now Approved in Canada. Available at: https://www.astrazeneca.ca/en/media/press-releases/2018/first-and-only-immuno-oncology-treatment--imfinzi---durvalumab--.html. Accessed December 2018.

8.     AstraZeneca PLC. Year-to-date and Q3 2018 results. Available at: https://www.astrazeneca.com/content/dam/az/PDF/2018/Q3/Year-To-Date_and_Q3_2018_Results_Presentation.pdf. Accessed December 2018.

9.     AstraZeneca PLC. Clinical trials appendix Q3 2018 results update. Available at https://www.astrazeneca.com/content/dam/az/PDF/2018/Q3/Year-To-Date_and_Q3_2018_Clinical_Trials_appendix.pdf. Accessed December 2018.

10.  Stewart  R, et al. Identification and Characterization of MEDI4736,  an Antagonistic Anti–PD-L1  Monoclonal Antibody. Cancer ImmunolRes; 2015.  Published OnlineFirst May 5, 2015; doi: 10.1158/2326-606.

11.  Patel S P and Kurzrock R. PD-L1 Expression as a Predictive  Biomarker in Cancer  Immunotherapy. MolCancer Ther; 14(4)  April 2015:847-856.

12.  Haile S et al. Tumor Cell Programmed Death Ligand 1-Mediated T Cell Suppression  Is Overcome by Coexpressionof CD80. J Immunol2011; 186: 6822-6829.

13.  Haile S et al. Soluble CD80 Restores T Cell Activation and Overcomes Tumor Cell  Programmed Death Ligand 1-Mediated Immune Suppression. J Immunol2013; 191: 2829-2836.

14.  NIH. National Cancer Institute. NCI Drug Dictionary. Tremelimumab. Available at: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tremelimumab.  Accessed December 2018.

15.  World Health Organization. International Association of Cancer Registries. Globocan 2018 Fact Sheet. Available at: http://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf.  Accessed December 2018.

16.  LUNGevityFoundation. Types of Lung Cancer. https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer.  Accessed December 2018.

17.  Ridge C, et al. Epidemiology of Lung Cancer. Semin Intervent Radiol. 2013;30:93-98.

18.  Global Lung Cancer Coalition. Lung Cancer Facts http://www.lungcancercoalition.org/lung-cancer-facts.html.   Accessed December 2018.

19.  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;2800-12.

20.  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.

21.  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.

22.  Korpanty G, et al. Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1, and KRAS. Frontiers in Oncology. 2014(4).

23.  Dimberu, P.M., & Leonhardt, R.M. (2011).Cancer Immunotherapy Takes a Multi‐Faceted Approach to Kick the Immune System into Gear. The Yale Journal of Biology and Medicine, 84(4),371–380. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238317/.  Accessed December 2018.