Trial did not meet primary endpoint of improving overall survival in challenging to treat mesothelioma patients with no currently approved treatment options in the second-line setting
Tremelimumab remains key component of Immuno-Oncology combination strategy across multiple tumour types
AstraZeneca and MedImmune, its global biologics research and development arm, today announced that DETERMINE,the Phase IIb clinical trial of 10 mg/kg tremelimumab monotherapy in second or third-line treatment of unresectable malignant mesothelioma,did not meet its primary endpoint of overall survival.
Robert Iannone, Senior Vice President, Head of Immuno-Oncology, Global Medicines Development at AstraZeneca, said:“We are disappointed that tremelimumab monotherapy did not demonstrate a survival benefit in this patient population with no approved medicines beyond first-line treatment. However,we remain confident in tremelimumab’s clinical activity in combination, as shown in our recently published Study 006 trial of tremelimumab and durvalumab in non-small cell lung cancer.”
In addition to investigation as monotherapy for patients with mesothelioma, tremelimumab is being studied in combination with AstraZeneca’s anti-PD-L1 investigational immunotherapy durvalumab in multiple tumour types,including non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck,bladder,pancreatic, gastric and liver cancers.Preclinical data have suggestedthat targeting both PD-L1and CTLA-4mayhave additive orsynergisticeffects.1 Inthe recently published Study006, combination treatment with durvalumab and tremelimumab demonstrated antitumour activity in patients with locally advanced or metastatic NSCLC,irrespective of PD-L1 status. 2
TheCompanywill completeafull evaluation ofthefinalDETERMINEdata,which will be submitted for presentation at an upcoming medical meeting in 2016.
1 Stewart et al.Preclinicalmodeling ofimmune checkpointblockade(P2012).JImmunol2013: 190(1Meeting
2 AntoniaS,et al.SafetyandantitumouractivityinaPhase1b studyofcombinedcheckpoint blockade with anti- PD-L1(durvalumab) and anti-CTLA-4(tremelimumab) innon-smallcelllungcancer.TheLancetOncology. Available at http://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00544-6.pdf.Accessed February 2016.
3 DelgermaaVetal.Globalmesothelioma deathsreportedtotheWorldHealthOrganizationbetween 1994and
4 DriscollTet al.The globalburden ofdiseaseduetooccupationalcarcinogens.AmJ IndMed.2005
Mesotheliomaisarareand deadly formofcancerthataffectstheliningof the lungs or abdomen.Thereisahigh unmetmedical needfor mesothelioma treatments, withmedian overall survival 9 to12 monthsafterinitial diagnosis.3Thediseasecausesapproximately 43,000 deaths peryearglobally.4In 2015, tremelimumabwas grantedOrphan Drug Designation bythe U.S. Food and Drug Administration.
DETERMINE (NCT01843374) is a randomised, double-blind,placebo-controlled Phase IIb global trial with 571 patients across multiple countries. The trial evaluated the safety and efficacy of tremelimumab versus placebo in the treatment of unresectable pleural or peritoneal malignant mesothelioma.
Tremelimumab is an investigational,selective human antibody directed against cytotoxicT- lymphocyte-associated protein 4(CTLA-4). By blocking the activity of CTLA-4, tremelimumab “releases the brakes”on T cell activation and boosts the immune response against cancer cells.Tremelimumabisbeinginvestigated inan extensive clinical trial programme,asmonotherapyorincombinationwith durvalumab,in NSCLC,bladder,head and neck,gastric,pancreatic,HCC andblood cancers. In2015, the U.S. Food and Drug
AdministrationgrantedtremelimumabFastTrackDesignation andOrphanDrug Designation as apotentialtreatment formalignant mesothelioma,an aggressive,rareform ofcancer that affectstheliningof the lungsand abdomen.
Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1(PD-L1).PD-L1 expression enables tumours to evade detection from the immunesystem through binding to PD-1on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 onT cells,countering the tumour's immune- evading tactics. Durvalumabis being developed alongside other immunotherapies to activate the patient's immune system to attack the cancer. Durvalumabis being investigated in an extensive clinical trial programme, as monotherapy or in combination with tremelimumab,in NSCLC,bladder,head and neck, gastric,pancreatic, HCC and blood cancers. In 2015,durvalumab received Fast Track Designation for the treatment of patients with PD-L1–positive metastatic SCCHN,and in 2016,durvalumab was granted Break through Designation by the U.S. Food and Drug Administrationas a potential treatment form etastaticurothelial bladder cancer.
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 6 new medicines to be launched between 2014 and 2020 and abroad pipeline of small molecules and biologics in development,we are committed to advance New Oncology as one of AstraZeneca’s six Growth Platforms focused on lung, ovarian,breast and blood cancers. Inaddition to our corecapabilities,we activelypursue innovative partnerships andinvestmentsthat acceleratethe deliveryofourstrategy,asillustratedby ourinvestmentin AcertaPharmain haematology.
Byharnessing thepowerof fourscientificplatforms--immuno-oncology, thegenetic drivers ofcancerand resistance,DNA damagerepairand antibodydrug conjugates--andby championing thedevelopment ofpersonalised combinations, AstraZenecahasthe vision to redefine cancer treatmentandone dayeliminate cancerasacause ofdeath.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery,development and commercialisation of prescription medicines,primarily for the treatment of cardiovascular, metabolic, respiratory,inflammation, autoimmune,oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.Formoreinformation, please visit: www.astrazeneca.com.
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