November is Lung Cancer Awareness Month – a time to raise the profile of a disease that is diagnosed in nearly two million people each year and kills almost 1.6 million.1 Responding to the urgent need for effective treatment for lung cancer, AstraZeneca is making rapid progress in the development of innovative, targeted and immuno-oncology (IO)-based therapies – used singly and in combination.
Lung cancer is not one disease, it’s many. Non-small cell lung cancer (NSCLC) accounts for 80-85% of cases2 but, within this large group, several different genetic alterations have been identified which may help guide treatment. In fact, over half of all cases of NSCLC are now associated with known genetic alterations,3 including mutations in EGFR (epidermal growth factor receptor) and KRAS (Kirsten rat sarcoma viral oncogene homolog), and ALK (anaplastic lymphoma kinase) rearrangements.
One of the largest molecular groups is defined by activating mutations in EGFR which occur in approximately 15% of patients with NSCLC in Europe4 and in the US,5 and 30-40% in Asia.6
Blocking tumour cell signalling
Tumours with EGFR mutations (EGFRm) depend on EGFR signaling for growth and survival and are often sensitive to treatment with EGFR tyrosine kinase inhibitors (TKIs) which block the cell signalling pathways.7-9 At AstraZeneca we developed gefitinib, the first EGFRTKI that targets NSCLC tumours with EGFRm, and this and similar agents are now widely used in the treatment of patients with this type of lung cancer.
Unfortunately, tumours with EGFRm almost always develop resistance to treatment, leading to disease progression. In approximately two-thirds of patients treated with approved EGFR-TKIs, this resistance arises when there is substitution in EGFR of the “gatekeeper” amino acid 790 to methionine.10 This mutation, known as T790M, is understood to reduce the ability of reversible EGFR inhibitors to bind to the tyrosine kinase domain of EGFR.11
At AstraZeneca, our strategy to overcome this mechanism of resistance has been to develop irreversible EGFR inhibitors that target both the sensitising EGFRm and the T790M resistance mutation. Following promising results from clinical trials, the first of these agents, AZD9291, is undergoing priority review for marketing authorisation by the US Food and Drug Administration and accelerated assessment by the European Medicines Agency.
Harnessing the immune system
In addition to treatments that target NSCLC mutations such as EGFRm T790M, there are novel therapies that activate the body’s own immune system to fight cancer. AstraZeneca is developing IO compounds that help restore the immune system’s ability to recognise and attack cancer cells. Cancer cells are known to be able to “hijack” naturally-occurring immune checkpoints, such as programmed death 1 (PD-1) receptor, that normally shut down the immune response after it has dealt with a recognised threat, such as the presence of cancer cells.12 One of the mechanisms by which tumours can avoid detection by the body’s immune system is by expressing programmed death ligand 1 (PD-L1) that binds to and disrupts the normal checkpoint activities of PD-1.13,14 Blockade of PD-L1 may help overcome these immunosuppressive effects and restore immune activity against tumours.
Novel PD-L1 blocking compounds, such as the human monoclonal antibody, durvalumab, are in development at AstraZeneca, for use as monotherapy and in combination with other agents in our oncology portfolio.
Combinations are key
AstraZeneca has put combination therapy at the heart of its oncology strategy. By targeting multiple mechanisms in the complex process by which cells become cancerous and elude the body’s defences, combinations of novel anti-cancer compounds have the potential to achieve targeted, durable responses. Under investigation are combinations of IO compounds that are active at multiple immune checkpoints, such as PD-1 and cytotoxic T lymphocyte antigen-4 (CTLA-4), combinations of IO compounds, such as PD-L1 inhibitors and small molecules such as EGFR TKIs, and combinations of small molecules that target multiple genetic mutations such as EGFR, ALK and KRAS. Studies are also investigating potential chemotherapy-sparing IO combinations in broader populations of patients with PD-L1 unselected, EGFR/ALK wild-type advanced or metastatic NSCLC.
In reflecting on the year since AstraZeneca marked Lung Cancer Awareness Month 2014, I am encouraged by the progress we’ve made across all areas of our lung cancer research programme. But we recognise that there is still a long way to go before we can offer effective options for every lung cancer patient.
The goals of Lung Cancer Awareness Month 2015 are mirrored in our goals. We understand the importance of raising awareness about lung cancer and encouraging more people to seek help at the first sign of symptoms, when their disease is most treatable. This month, let’s turn the spotlight on lung cancer, and offer our support to all those who have been affected by it in the past, or are currently on that difficult journey. Together, we can make a difference, we can conquer lung cancer!
Felip E, Vilar E. The expanding role of systemic treatment in non-small cell lung cancer neo-adjuvant therapy. Ann Oncol. 2006;17(Suppl 10):x108-12.
Savas P, et al. Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer. J Thorac Dis 2013;5(Suppl.5):S579-S592.
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
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: 2121-7.
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.
Sharma SV, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169-181.
Mok TS, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med. 2009;361:947–957.
Rosell R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet Oncology. 2012;13:239–46.
Yu H, et al, Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers. Clin Cancer Res. 2013:19:8 2240-2247.
Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046-61.
Topalian SL et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54.
Khleif S, et al. MEDI4736, an anti-PD-L1 antibody with modified Fc domain: Preclinical evaluation and early clinical results from a phase 1 study in patients with advanced solid tumors. Eur J Cancer 2013;49(Suppl.2):S161 (abstract 802).
Lutzky J, et al. A phase 1 study of MEDI4736, an anti-PD-L1 antibody, in patients with advanced solid tumors. Presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA; 30 May – 3 June 2014. Abstract available at: http://abstracts.asco.org/144/AbstView_144_133649.html. Data cited is included in final data presentation on 3 June 2014: Developmental Therapeutics – Immunotherapy; Oral Abstract Session