1 | Citeline © 2014 All rights reserved. Top Five Asian Cancers -‐ Trends in Clinical Development Rachel Meighan-‐Mantha, PhD Principal Analyst, Oncology 2 | Citeline © 2014 All rights reserved. Predicted Incidence of Top Five Asian Cancers 2500000 2012 2015 2020 2025 2030 2035 By 2035, incidence of these cancers will increase by rates of 51-‐97%. 2000000 1500000 1000000 500000 0 Lung Stomach Breast Colorectal Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed in April 2014. 3 | Citeline © 2014 All rights reserved. Liver Predicted Mortality of Top Five Asian Cancers 2000000 2012 2015 2020 2025 2030 2035 By 2035, mortality of these cancers will increase by rates of 63-‐101%. 1500000 1000000 500000 0 Lung Stomach Breast Colorectal Liver Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed in April 2014. 4 | Citeline © 2014 All rights reserved. Summary • • • • • Basic Questions Primary Drugs and Mechanisms of Action Primary Endpoints and Trial Outcomes Biomarkers Correlations, Trends and Opportunities 5 | Citeline © 2014 All rights reserved. Basic QuesPons 6 | Citeline © 2014 All rights reserved. Where are clinical trials taking place in Asia? Source: Citeline’s Trialtrove®, data accessed April 2014 and XLCubed.com 7 | Citeline © 2014 All rights reserved. Where are clinical trials taking place in Asia? Trials recruiPng the most paPents are in Japan, China and South Korea. By Status 0 500 1000 1500 2000 2500 By Phase 3000 0 China China Hong Kong Hong Kong India India Japan Japan Malaysia Malaysia Philippines Philippines Singapore Singapore South Korea Only later stage trials take place in Thailand, Phillippines and Malaysia. 1000 2000 3000 South Korea Taiwan Taiwan Thailand Thailand Planned Open Temporarily Closed Closed Terminated Completed Source: Citeline’s Trialtrove®, data accessed April 2014 8 | Citeline © 2014 All rights reserved. I I/II II II/III III Source: Citeline’s Trialtrove®, data accessed April 2014 III/IV IV Where are clinical trials taking place in Asia? By Patient Segment 0 1000 2000 By Sponsor Type 3000 0 China China Hong Kong Hong Kong India India Japan Japan Malaysia Malaysia Philippines Philippines Singapore South Korea Taiwan Thailand Trials with all paPent segments occur in the top 10 countries. First Line Second Line Neoadjuvant Adjuvant Maintenance Source: Citeline’s Trialtrove®, data accessed April 2014 9 | Citeline © 2014 All rights reserved. 2000 3000 Non-‐Industry sponsors more trials than Industry in Japan, China and South Korea. Singapore South Korea Taiwan Thailand Industry 1000 Joint Non-‐Industry Source: Citeline’s Trialtrove®, data accessed April 2014 What sponsor types are conducPng trials? By Disease By Start Year 2500 Non-‐Industry 2000 400 Industry Joint Joint Industry Non-‐Industry 300 Non-‐Industry sponsorship has rapidly outpaced Industry and Joint sponorship since the late 1990s. 1500 200 1000 100 500 0 0 Lung Gastric Breast Colorectal Source: Citeline’s Trialtrove®, data accessed April 2014 10 | Citeline © 2014 All rights reserved. Liver Source: Citeline’s Trialtrove®, data accessed April 2014 What sponsor types are conducPng trials? By Phase By Status 4000 Non-‐Industry 4000 Joint Joint Industry 3000 Non-‐Industry alone sponsors 84% of phase II trials. Joint sponsorship occurs most frequently in phase II and III trials . 2000 1000 3000 2000 1000 0 0 I I/II II II/III III Source: Citeline’s Trialtrove®, data accessed April 2014 11 | Citeline © 2014 All rights reserved. IV Non-‐industry Other Source: Citeline’s Trialtrove®, data accessed April 2014 Industry Top 10 Industry sponsors conduct trials in many different countries. Industry Top 10 Non-‐ Industry sponsors conduct trials usually in just one country. Non-Industry Where are they conducPng these trials? Source: Citeline’s Trialtrove®, data accessed April 2014 12 | Citeline © 2014 All rights reserved. What trials have they conducted recently? Source: Citeline’s Trialtrove®, data accessed April 2014 13 | Citeline © 2014 All rights reserved. Primary Drugs and Mechanisms of AcPon 14 | Citeline © 2014 All rights reserved. What approved drugs are in clinical trials? Top 10 approved primary drugs in at 3 of the 5 cancers Cisplatin TS-1 Fluorouracil Paclitaxel Oxaliplatin Docetaxel Capecitabine Gemcitabine 15 | Citeline © 2014 All rights reserved. What pipeline drugs are in clinical trials? Lung Gastric Breast Colorectal Liver apatinib apatinib apatinib apatinib buparlisib neratinib buparlisib neratinib orantinib pexastimogene devacirepvec dacomitinib ramucirumab neratinib orantinib ceritinib dovitinib orantinib dalotuzumab doxorubicin, Celsion PEG-arginase, BioCancer onartuzumab poziotinib BYL-719 cediranib peretinoin nintedanib paclitaxel, NanoCap dalotuzumab binimetinib tyroserleutide nivolumab rilotumumab olaparib encorafenib refametinib necitumumab tesetaxel LEE-011 fruquintinib golvatinib palbociclib Novaferon LJM-716 ridaforolimus Source: Citeline’s Trialtrove® and Pharmaprojects®, data accessed April 2014 16 | Citeline © 2014 All rights reserved. What are the mechanisms-‐of-‐acPon of these pipeline drugs? Lung Gastric Breast Colorectal Liver RET/VEGFR-2 tyrosine RET/VEGFR-2 tyrosine kinase inhibitor kinase inhibitor Pan-EGFR/ErbB tyrosine PI3 kinase inhibitor kinase inhibitor PI3 kinase inhibitor Pan-EGFR (ErbB) Pan-EGFR (ErbB) tyrosine kinase inhibitor VEGFR-2 antagonist tyrosine kinase inhibitor ALK tyrosine kinase FGFR1/3 tyrosine VEGFR2/PDGFR/FGFR inhibitor kinase inhibitor tyrosine kinase inhibitor Pan-EGFR (ErbB) MET (HGFR) antagonist tyrosine kinase inhibitor PI3 kinase inhibitor Multi tyrosine kinase inhibitor Taxane IGF1R antagonist RET/VEGFR-2 tyrosine kinase inhibitor Pan-EGFR/ErbB tyrosine kinase inhibitor VEGFR2/PDGFR/FGFR tyrosine kinase inhibitor VEGFR2/PDGFR/FGFR tyrosine kinase inhibitor IGF1R antagonist Pan-VEGFR tyrosine kinase inhibitor Arginase stimulant MEK inhibitor ICAM-1 inhibitor PD-1 antagonist MET/HGFR antagonist PARP inhibitor MEK inhibitor EGFR antagonist Taxane MET/VEGFR-2 tyrosine kinase inhibitor HER3 (ErbB3) antagonist CDK4/6 inhibitor B-RAF kinase inhibitor Pan-VEGFR tyrosine kinase inhibitor CDK4/6 inhibitor Immunostimulant RET/VEGFR-2 tyrosine kinase inhibitor mTOR kinase inhibitor Source: Citeline’s Trialtrove® and Pharmaprojects®, data accessed April 2014 17 | Citeline © 2014 All rights reserved. GM-CSF oncolytic virus DNA topoisomerase II inhibitor Retinoid What is their stage of clinical development in Asia? poziotinib chidamide tivantinib tivantinib bavituximab dovitinib luminespib ombrabulin pembrolizumab nivolumab orantinib dovitinib apatinib tesataxel dacomitinib lenvatinib dacomitinib apatinib paclitaxel, buparlisib ramucirumab rilotumumab NanoCap alectinib motesanib onartuzumab onartuzumab dovitinib olaparib dovitinib necitumumab paclitaxel, peretinoin orantinib NanoCap Competitive ramucirumab buparlisib Landscape orantinib palbociclib refametinib tyroserleutide apatinib ramucirumab tivantinib dalotuzumab neratinib lenvatinib LEE-011 BYL-719 doxorubicin, ramucirumab pexastimogene Celsion bavituximab cediranib motesanib tivantinib fruquintinib Source: Citeline’s Trialtrove® and Pharmaprojects®, data accessed April 2014 18 | Citeline © 2014 All rights reserved. orantinib dalotuzumab apatinib Novaferon Primary Endpoints and Trial Outcomes 19 | Citeline © 2014 All rights reserved. What are the primary endpoints? Lung and Gastric: PFS and OS > DFS and TTP Breast and Colorectal: PFS and DFS > OS and TTP Liver: OS > PFS, DFS and TTP By Disease 1200 Progression Free Survival Disease Free Survival 1000 Time to Progression Overall Survival 800 Response/Efficacy 400 Progression Free Survival Disease Free Survival 350 Time to Progression 300 Overall Survival Treatment Comple[on Feasibility 250 Safety/Toxicity 600 200 Treatment Comple[on Feasibility 400 Other 150 Other 100 200 50 0 0 Lung Gastric Breast Colorectal Source: Citeline’s Trialtrove®, data accessed April 2014 20 | Citeline © 2014 All rights reserved. Liver Lung Gastric Breast Colorectal Liver What are the primary endpoints? Joint sponsorship is most likely to occur in trials with DFS and OS as primary endpoints. By Sponsor Type 0% 20% 40% 60% 80% 100% Progression Free Survival 50 Industry 45 Joint 40 Non-‐Industry 35 Disease Free Survival 30 Time to Progression 25 Overall Survival 20 Response/Efficacy 15 10 Safety/Toxicity 5 Treatment Comple[on Industry Joint Non-‐Industry Source: Citeline’s Trialtrove®, data accessed April 2014 21 | Citeline © 2014 All rights reserved. Source: Citeline’s Trialtrove®, data accessed April 2014 Other Feasibility Treatment Comple[on Safety/Toxicity Other Response/ Efficacy Feasibility Overall Survival Progression Free Survival Disease Free Survival Time to Progression 0 What are the trial outcomes? Industry conducts the most trials with either clear posiPve or clear By Sponsor Type negaPve outcomes. By Disease 0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100% Completed, Nega[ve outcome Lung Completed, Outcome indeterminate Completed, Outcome unknown Gastric Completed, Posi[ve outcome Breast Terminated, Business decision Colorectal Terminated, Early posi[ve outcome Terminated, Lack of efficacy Liver Terminated, Lack of funding Completed, Nega[ve outcome Completed, Outcome indeterminate Completed, Outcome unknown Completed, Posi[ve outcome Terminated, Business decision Terminated, Early posi[ve outcome Terminated, Lack of efficacy Terminated, Lack of funding Terminated, Other Terminated, Planned but never ini[ated Terminated, Poor enrollment Terminated, Safety/adverse effects Terminated, Unknown Source: Citeline’s Trialtrove®, data accessed April 2014 22 | Citeline © 2014 All rights reserved. Terminated, Other Terminated, Planned but never ini[ated Terminated, Poor enrollment Terminated, Safety/adverse effects Terminated, Unknown Industry Joint Non-‐Industry Source: Citeline’s Trialtrove®, data accessed April 2014 What are the trial outcomes? By Primary Endpoint 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Progression Free Survival Disease Free Survival Time to Progression Overall Survival Response/Efficacy Safety/Toxicity Treatment Comple[on Feasibility Other Completed, Nega[ve outcome Completed, Outcome indeterminate Completed, Outcome unknown Completed, Posi[ve outcome Terminated, Business decision Terminated, Early posi[ve outcome Terminated, Lack of efficacy Terminated, Lack of funding Terminated, Other Terminated, Planned but never ini[ated Terminated, Poor enrollment Terminated, Safety/adverse effects Terminated, Unknown Source: Citeline’s Trialtrove®, data accessed April 2014 23 | Citeline © 2014 All rights reserved. Biomarkers 24 | Citeline © 2014 All rights reserved. How are bio-‐ and pharmacogenomic markers Lung and Breast trials being incorporated? are most likely to By Disease and Patient Segment 0 200 400 600 800 incorporate Bio/PGX markers. Liver trials are least likely. 1000 1200 1400 Lung Gastric Biomarker/Efficacy Breast Biomarker/Toxicity Colorectal Liver PGX -‐ Biomarker Iden[fica[on/Evalua[on PGX -‐ Pa[ent Preselec[on/ Stra[fica[on First Line Second Line Neoadjuvant Adjuvant Maintenance Source: Citeline’s Trialtrove®, data accessed April 2014 25 | Citeline © 2014 All rights reserved. First and Second Line trials are most likely to incorporate Bio/PGX markers. How are bio-‐ and pharmacogenomic markers being incorporated? By Primary Endpoint 0 Progression Free Survival Disease Free Survival Time to Progression Overall Survival Response/Efficacy 200 400 600 800 1000 1200 1400 2X trials with PFS vs. DFS and OS as primary endpoints incorporated Bio/PGX markers and 3-‐4X of these trials preselected and straPfied paPents based on PGX markers. Safety/Toxicity Biomarker/Efficacy Treatment Comple[on Feasibility Other Source: Citeline’s Trialtrove®, data accessed April 2014 26 | Citeline © 2014 All rights reserved. Biomarker/Toxicity PGX -‐ Biomarker Iden[fica[on/ Evalua[on PGX -‐ Pa[ent Preselec[on/ Stra[fica[on How are bio and pharmacogenomic markers being incorporated? By Trial Outcome Terminated, Unknown Biomarker/Efficacy Terminated, Safety/adverse effects Biomarker/Toxicity Over 2X m ore completed PGX -‐ Biomarker Iden[fica[on/trials Evalua[on with posiPve outcomes PGX -‐ Pa[ent Preselec[on/ Stra[fica[on incorporated Bio/PGX markers than completed trials with negaPve outcomes. Terminated, Poor enrollment Terminated, Planned but never ini[ated Terminated, Other Terminated, Lack of funding Terminated, Lack of efficacy Terminated, Early posi[ve outcome Terminated, Business decision Completed, Posi[ve outcome Completed, Outcome unknown Completed, Outcome indeterminate Completed, Nega[ve outcome 0 Source: Citeline’s Trialtrove®, data accessed April 2014 27 | Citeline © 2014 All rights reserved. 50 100 150 200 250 CorrelaPons to PosiPve Outcomes • Use of pharmacogenomic biomarkers for identification or correlation of efficacy • Use of pharmacogenomic biomarkers to select or stratify patients • PFS > OS > DFS > TTP • Investigator-initiated trials (data not shown) 28 | Citeline © 2014 All rights reserved. Trends Historically, clinical trials in lung, breast, gastric, colorectal and liver cancers have been conducted almost exclusively in just 10 Asian countries (China, Hong Kong, India, Japan, Malaysia, Philippines, Singapore, South Korea, Taiwan and Thailand). 29 | Citeline © 2014 All rights reserved. Since the late 1990s, non-‐industry sponsors have drama[cally increased their sponsorship of clinical trials, while industry sponsorship has increased at a much slower rate. Since ~2007, industry and joint sponsorship has been rela[vely flat. Trials started in colorectal, gastric and liver cancers since 2010 have been limited to just a few of the top 10 industry sponsors in contrast to breast and lung cancers, while non-‐industry sponsors are conduc[ng trials across all of the top 5 cancers. OpportuniPes • Clinical development in gastric, colorectal and liver cancers • Oncology clinical trials conducted in less historically popular Asian countries (Indonesia, Kazakhstan and Vietnam) • Increase overall industry sponsorship • Increase joint sponsorship between industry and nonindustry for global trials • Drugs that are not tyrosine kinase inhibitors (especially VEGFR and ErbB/HER) • Increase the rate of positive outcomes with PFS and OS as primary endpoints for later stage trials • Increase the rate of positive outcomes with targeted patient populations and the incorporation of pharmacogenomic biomarkers 30 | Citeline © 2014 All rights reserved.
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