0207 1 Luca Mazzarella - precision medicine

0207 1 Luca Mazzarella - precision medicine

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  Precision medicine and immuno-oncology LucaMazzarella, MD PhD European Institute of Oncology, Milan
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  An overview ofmajor advancements in oncology. Non-Small Cell Lung Cancer (NSCLC) 17/07/2019 2 Actionable mutation High PD-L1 Diagnosis Treatment Targeted therapy Immuno- therapy No molecular characteriz ation Chemo- therapy Wu et al Lancet Onc 2014 Garon JCO 2019 Lux-Lung 6 Keynote 001
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  Outstanding questions 17/07/2019 3 Biomarker- positive DiagnosisTreatment Rational therapy No molecular characteriz ation Non- rational therapy 1. How do we expand the population that can be treated rationally? • Increase the number of targeted drugs
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  Published in: MariaSchwaederle; Melissa Zhao; J. Jack Lee; Alexander M. Eggermont; Richard L. Schilsky; John Mendelsohn; Vladimir Lazar; Razelle Kurzrock; JCO 2015, 33, 3817-3825. DOI: 10.1200/JCO.2015.61.5997 Copyright © 2015 American Society of Clinical Oncology Targeting therapy improves efficacy Benefit for patients Benefit for drug development
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  Two recent examplesof biomarkers for exceptionally active drugs: RET and NTRK Larotrectinib
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  17/07/2019 6 Biomarker- positive Diagnosis Treatment Rational therapy No molecular characteriz ation Non- rational therapy 1.How do we expand the population that can be treated rationally? • Increase the number of targeted drugs • Increase the number of biomarkers Outstanding questions
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  Examples of novelcomplex biomarkers: Tumor Mutational Burden (TMB), MisMatch Repair Deficiency (dMMR) and Homologous Recombination Deficiency (HRD) 17/07/2019 7 Mirza et al NEJM 2016Peters S AACR 2018 Le et al NEJM 2015
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  Outstanding questions 17/07/2019 8 Biomarker- positive DiagnosisTreatment Rational therapy No molecular characteriz ation Non- rational therapy 1. How do we expand the population that can be treated rationally? • Increase the number of targeted drugs • Increase the number of biomarkers 2. How do we increase therapeutic efficacy? • Combinations • PD(L)1 + CTLA4 • Chemotherapy • Novel Immune Modulators • Targeted therapy
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  Chemotherapy and CTLA4+PD1 17/07/20199 Keynote 189 Gandhi et al NEJM 2018 Checkmate 227 Hellman et al NEJM 2018
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  The evolving landscapeof Next Generation Immune Modulators (NGIM) 17/07/2019 10 Mazzarella et al Eur J Can 2018
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  Outstanding questions 17/07/2019 11 Biomarker- positive DiagnosisTreatment Rational therapy No molecular characteriz ation Non- rational therapy 1. How do we expand the population that can be treated rationally? • Increase the number of targeted drugs • Increase the number of biomarkers 2. How do we increase therapeutic efficacy? • Combinations • PD(L)1 + CTLA4 • Chemotherapy • Novel Immune Modulators • Targeted therapy 3. How do we deal with all these biomarkers? • Decrease the need for biopsy by using circulating biomarkers
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  Treatment based onliquid biopsy only is effective Aggarwal et al JAMA onc 2019
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  Outstanding questions 17/07/2019 13 Biomarker- positive DiagnosisTreatment Rational therapy No molecular characteriz ation Non- rational therapy 1. How do we expand the population that can be treated rationally? • Increase the number of targeted drugs • Increase the number of biomarkers 2. How do we increase therapeutic efficacy? • Combinations • PD(L)1 + CTLA4 • Chemotherapy • Novel Immune Modulators • Targeted therapy 3. How do we deal with all these biomarkers? • Decrease the need for biopsy by using circulating biomarkers • Build a statistical and regulatory consensus for trials on hyperfragmented population
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  More biomarkers meansrarer biomarkers! An extreme example: NTRK 31 out of 11.502 patients positive (0.27%!!!!!) Gatalica et al Mod Path 2018
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  The need fora new clinical trial framework  Difficult to conduct randomized controlled trials with hyperfragmented population  Larger phase 1-2 trials than phase 3  Emphasis on early biomarker implementation  Novel trial designs (basket, umbrella, platform, adaptive)  Include real world data  Regulatory approval should be granted even without RCTs  However this should be regulated and explicit criteria for trial conduct should be identified 7/17/2019 15
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  Access vs evidence.A hamletic tradeoff 7/17/2019 16 Outcome parameters and safety are not different between breakthrough (BT) and non-breakthrough (nBT)-approved drugs Expectedly, BT drugs were approved 2 years earlier than nBT How should we interpret these data? • No justification for granting BT approval since clinical benefit is equal to nBT (authors’perspective) Or • No justification for NOT granting BT approval to nBT drugs, since clinical benefit is equal (my perspective) In general, what do we prefer: earlier access or stronger evidence? Hwang et al JCO 2018
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  Outstanding questions 17/07/2019 17 Biomarker- positive DiagnosisTreatment Rational therapy No molecular characteriz ation Non- rational therapy 1. How do we expand the population that can be treated rationally? • Increase the number of targeted drugs • Increase the number of biomarkers 2. How do we increase therapeutic efficacy? • Combinations • PD(L)1 + CTLA4 • Chemotherapy • Novel Immune Modulators • Targeted therapy 3. How do we deal with all these biomarkers? • Decrease the need for biopsy by using circulating biomarkers • Build a statistical and regulatory consensus for trials on hyperfragmented population • Educate patients, doctors and all stakeholders on pros and cons of genetic/clinical data sharing
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  As the sizeof the sequenced genome increases, so does the chance for incidental findings or variants of unknown significance 17/07/2019 0 500 1000 1500 2000 2500 3000 3500 LS OM PS FO G360 FbTMB GO estimated genomic space (Kb) Gandara et al Nat Med 2018 Liquid biopsy panels are getting bigger
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  Conclusion  Oncology issteadily becoming • histology-agnostic • biomarker-avid • data-intensive  This is causing a radical change in the way: • diagnosis is obtained • clinical research is conducted • patients are engaged  We need to educate ourselves to this new world • Devise adequate statistical tools • Create an adequately regulated but sufficiently flexible regulatory environment • Engage in public debates over the utility of genetic and clinical data exchange • Provide adequate educational tools to all stakeholders Thank you for your attention [email protected]