AstraZeneca and Chi-Med’s Savolitinib Shows Encouraging Clinical Activity in 2nd-Line EGFR Mutation-positive Lung Cancer with MET-amplification
AstraZeneca and its partner Chi-Med today presented preliminary safety and clinical activity of savolitinib when given in combination with either Tagrisso (osimertinib) or Iressa (gefitinib) in two Phase Ib trials conducted in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) with MET-amplification who had progressed following 1st-line treatment with an EGFR inhibitor.1,2 In both trials, the addition of savolitinib (600mg, once daily), an investigational selective inhibitor of c-MET (mesenchymal epithelial transition factor) receptor tyrosine kinase, to osimertinib (80mg, once daily) or gefitinib (250mg, once daily) demonstrated preliminary anti-tumour activity. The data were shared in two oral presentations at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan, 15-18 October 2017.
Dr. Myung-Ju Ahn, Department of Haematology & Oncology, Samsung Medical Centre, Seoul, South Korea, said: “Secondary resistance mechanisms often emerge during treatment with mutation-targeted medicines, leading to disease progression. The data presented at WCLC demonstrate the potential of utilising savolitinib in cMET-driven lung cancers to address resistance challenges.”
Susan Galbraith, Head of Oncology, AstraZeneca Research and Early Development, said: “We are committed to developing innovative medicines to overcome the key drivers of cancer mechanisms of resistance and are strategically focused on developing effective combinations. The latest results for savolitinib in combination with osimertinib and gefitinib support our approach in collaboration with Chi-Med.”
Preliminary results for savolitinib in combination with osimertinib1
Early data on safety and anti-tumour activity for savolitinib (600mg, once daily) plus osimertinib (80mg, once daily) in the Phase Ib TATTON trial in patients with EGFR mutation-positive (EGFRm) advanced NSCLC with MET-amplification were presented. In 66 patients treated with savolitinib plus osimertinib, the most common all-causality adverse events (AEs) of any grade were nausea (44%), vomiting (35%), fatigue (30%), and decreased appetite (30%), and were consistent with the known safety profiles of both therapies.
Preliminary data showed partial response according to RECIST 1.1 criteria in 28% of patients previously treated with third-generation T790M-directed EGFR tyrosine kinase inhibitors (TKIs), including osimertinib(n=25). In patients who had progressed after prior treatment with a first- or second-generation EGFR inhibitor, 53% of T790M-negative patients (n=15) had a partial response, while 57% of T790M-positive patients (n=7) had a partial response.
Preliminary data for savolitinib in combination with gefitinib2
Data from a Phase Ib trial assessing savolitinib (600mg, once daily) plus gefitinib (250mg, once daily) in patients in China with EGFRm advanced NSCLC with MET-amplification who progressed following EGFR-TKI therapy were also reported. The most common AEs independent of causality in 51 patients were vomiting (39%), increased ALT (37%), increased AST (35%), nausea (35%), and rash (35%), and were consistent with the known safety profiles of both therapies.
Preliminary results showed that 31% of patients achieved a partial response according to RECIST 1.1 criteria, of which 52% of T790M-negative patients (n=23) and 9% of T790M-positive patients (n=23) had a partial response.
Christian Hogg, Chief Executive Officer of Chi-Med, said: “MET-amplification impacts a meaningful proportion of patients with EGFRm NSCLC who experience disease progression following treatment with a tyrosine kinase inhibitor in the first- or second-line setting. Among patients with this difficult-to-treat resistance mechanism, there is a clear unmet medical need.”3-6
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NOTES TO EDITORS
Savolitinib (AZD6094/HMPL-504) is a potential first-in-class selective inhibitor of c-MET (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumours. It was developed as a potent and highly selective oral inhibitor.
Savolitinib was discovered by Chi-Med and is being developed in collaboration with AstraZeneca. Savolitinib is currently being studied in multiple tumour types worldwide including kidney, lung, and gastric cancers, both as a monotherapy or in combination with other targeted and immunotherapy agents.
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR-T790M resistance mutations, with clinical activity against central nervous system (CNS) metastases. Osimertinib 40mg and 80mg once-daily oral tablets have been approved in more than 50 countries, including the US, EU, Japan and China, for patients with EGFR T790M mutation-positive advanced NSCLC. Osimertinib is also being investigated in the adjuvant setting and in combination with other treatments.
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-quarter of all cancer deaths, more than breast, prostate and colorectal cancers combined. Approximately 10-15% of patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. These patients are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to EGFR-TKI treatment, leading to disease progression. Approximately half of patients develop resistance to approved EGFR-TKIs such as gefitinib and erlotinib due to the resistance mutation, EGFR T790M. Osimertinib also targets this secondary mutation that leads to disease progression. There is also a need for medicines with improved CNS efficacy, since approximately 25% of patients with EGFR-mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.
About AstraZeneca in Lung Cancer
AstraZeneca is committed to developing medicines to help every patient with lung cancer. We have two approved medicines and a growing pipeline that targets genetic changes in tumour cells and boosts the power of the immune response against cancer. Our unrelenting pursuit of science aims to deliver more breakthrough therapies with the goal of extending and improving the lives of patients across all stages of disease and lines of therapy.
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 New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. 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.
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 main therapy areas – Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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.
Hutchison China MediTech, known as Chi-Med, is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China. Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings.
For more information, please visit www.chi-med.com.
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1 Ahn M-J, et al. TATTON Phase Ib Expansion Cohort: Osimertinib Plus Savolitinib for Patients with EGFR-mutant MET-amplified NSCLC After Progression on Prior EGFR-TKI. Abstract #8985. To be presented at the World Lung Cancer Congress (WCLC) 2017, Yokohama, Japan, 15-18 October 2017.
2 Yang J-J, et al. A Phase Ib Trial of Savolitinib Plus Gefitinib for Patients with EGFR-mutant MET-amplified Advanced NSCLC. Abstract #8995. To be presented at the World Lung Cancer Congress (WCLC) 2017, Yokohama, Japan, 15-18 October 2017.
3 Stewart EL, et al. Known and Putative Mechanisms of Resistance to EGFR Targeted Therapies in NSCLC Patients with EGFR Mutations—a Review. Transl Lung Cancer Res. 2015:4(1):67–81.
4 Engelman et al. MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling. Science 2007;316:1039-1043.
5 Bean et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007;104:20932–20937.
6 Sequist et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Science Transitional Medicine 2011; 3(75):75ra26.