Collaboration to focus on newly launched global Phase III MERMAID-1 trial for patients with resected, early-stage non-small cell lung cancer
AstraZeneca will collaborate with ArcherDX, a genomic analysis company focused on precision oncology, to use personalised cancer monitoring to detect minimal residual disease (MRD) in patients with early-stage non-small cell lung cancer (NSCLC).
ArcherDX’s personalised assay will be used in AstraZeneca’s recently launched Phase III MERMAID-1 trial to evaluate the effect of adjuvant treatment with Imfinzi (durvalumab) plus chemotherapy versus chemotherapy alone on disease-free survival (DFS). The trial is in patients with completely resected, Stage II and III NSCLC who show evidence of MRD suggesting a high risk of relapse.
MRD describes a very small number of otherwise undetectable cancer cells that shed circulating tumour DNA (ctDNA) in the blood. Monitoring for the presence of MRD using ctDNA may provide valuable information on how well a treatment is working, inform prognosis, and detect if a patient’s cancer has returned. Ultimately, MRD detection may enable physicians to intervene earlier and tailor the best treatment options for individual cancer patients.
Charles Swanton, MD, PhD, Professor at UCL and the Francis Crick Institute, Chief Clinician at Cancer Research UK, leader of Tracking Cancer Evolution through Therapy (Rx) (TRACERx) and international coordinating investigator in the MERMAID-1 trial, said: “MERMAID-1 is a novel randomised trial using ctDNA to identify patients at high risk of recurrence after surgery who may benefit from intervention with immunotherapy. We hope this approach will lead to better patient outcomes by intensifying treatment for patients most likely to relapse, while avoiding additional chemotherapy after surgery when not needed.”
José Baselga, Executive Vice President of Oncology R&D, said: “While detecting and monitoring for minimal residual disease has proven challenging in solid tumours, the MERMAID-1 trial and this partnership stand to break new ground in lung cancer. This innovative endeavour is reflective of our strategy to improve cancer outcomes by treating patients as early as possible. It is in this early setting that the chance of cure is higher and identifying personalised, effective treatments could increase survival and improve quality of life.”
Jason Myers, Chief Executive Officer and co-founder of ArcherDX, said: “While there has been progress in improving adoption of precision oncology for patients with late-stage cancers, there is a pressing need to accelerate access to precision oncology for all patients diagnosed with cancer regardless of the stage or location of the care setting. AstraZeneca shares this critical mission, and we are pleased to partner with them in the development of biomarker-driven therapies and the expansion of personalised cancer monitoring for all patients.”
Under the terms of the agreement, ArcherDX will perform whole exome sequencing of NSCLC patient samples and generate highly sensitive, personalised ctDNA assays to test for MRD that remains after a patient’s successful surgery. The ongoing development of these assays is informed by the TRACERx study, funded by Cancer Research UK and led by UCL and the Francis Crick Institute.
Imfinzi is being tested in an extensive development programme in lung cancer with several ongoing Phase III trials in earlier stages of NSCLC in potentially curative settings.
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 (SCLC), with 80-85% classified as NSCLC.2 Approximately 39% of patients with NSCLC present with localised or regional lung cancer, where surgery (complete resection) may be an option.3 Among Stage II-III patients who undergo surgery, up to 60% eventually develop recurrence.4
MERMAID-1
MERMAID-1 is a randomised, multi-centre, double-blind, placebo-controlled Phase III trial evaluating adjuvant Imfinzi in combination with chemotherapy versus standard-of-care chemotherapy in approximately 330 patients diagnosed with resectable (Stage II-III) NSCLC who have undergone complete resection of the primary tumour. The primary endpoint is DFS for patients who show evidence of MRD, which will be tested using a highly sensitive, personalised ctDNA assay based on whole exome sequencing of patient samples.
Collaboration between AstraZeneca and ArcherDX
ArcherDX’s personalised cancer monitoring (PCM) technology is intended to detect MRD in early-stage cancer patients following surgery, and it has received a Breakthrough Device Designation from the US Food and Drug Administration. ArcherDX plans to leverage the PCM assays to develop companion diagnostics for AstraZeneca’s selected medicines, and together, the companies plan to seek regulatory approval if clinical trials are completed successfully. The assays are currently for investigational use only.
PCM, TRACERx and Cancer Research UK
TRACERx (Tracking Cancer Evolution through therapy (Rx)), which informs the ongoing development of the ArcherDX PCM assay, is the single biggest investment in lung cancer research by Cancer Research UK. Taking place over nine years, the translational research programme is the first study to look at the evolution of cancer in real time and immense detail. Researchers follow patients with lung cancer all the way from diagnosis through to either disease relapse or cure after surgery, tracking and analysing how their cancer develops. TRACERx is led by University College London and the Francis Crick Institute via the Cancer Research UK Lung Cancer Centre of Excellence and also supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre and the Rosetrees Trust.
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.
Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. Imfinzi is approved for the 1st-line treatment of extensive-stage SCLC in combination with SoC chemotherapy in the US and Singapore. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.
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, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumours.
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 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 the approved medicines Iressa (gefitinib) and Tagrisso, and its ongoing Phase III trials LAURA, and FLAURA2.5-7
AstraZeneca is committed to addressing tumour 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. Enhertu (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 programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.8 Imfinzi, 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. Imfinzi is also in development in the Phase II combination trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline.
AstraZeneca in Immuno-Oncology
Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.
The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant 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 the IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.
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 focused 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 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.
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References
1. World Health Organization. International Agency for Research on Cancer. Globocan Worldwide Fact Sheet 2018. Available at http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.
2. LUNGevity Foundation. Types of Lung Cancer. Available at https://www.lungevity.org/about-lung-cancer/lung-cancer-101/types-of-lung-cancer.
3. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Lung and Bronchus Cancer. Available at https://seer.cancer.gov/statfacts/html/lungb.html.
4. Wakelee HA, Dahlberg SE, Keller SM, Tester WJ, Gandara DR, Graziano SL, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2017;18:1610-23.
5. 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.
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.
7. 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.
8. Pakkala, S, et al. Personalized Therapy for Lung Cancer: Striking a Moving Target. JCI Insight. 2018;3(15):e120858.
