0207 1 Luca Mazzarella - precision medicine
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This document discusses major advancements in precision oncology and immuno-oncology, including increasing the number of targeted drugs and biomarkers to expand rational treatment approaches. It also addresses combining therapies like PD1/PD-L1 inhibitors with chemotherapy or novel immune modulators to increase efficacy. As biomarkers proliferate, challenges arise around conducting clinical trials in fragmented populations and relying on liquid biopsies. Ongoing questions center on balancing earlier access to treatments with stronger evidence requirements in regulatory approval.
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0207 1 Luca Mazzarella - precision medicine
- 1. Precision medicine and immuno-oncology Luca Mazzarella, MD PhD European Institute of Oncology, Milan
- 2. An overview of major 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
- 3. Outstanding questions 17/07/2019 3 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
- 4. Published in: Maria Schwaederle; 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
- 5. Two recent examples of biomarkers for exceptionally active drugs: RET and NTRK Larotrectinib
- 6. 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
- 7. Examples of novel complex 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
- 8. Outstanding questions 17/07/2019 8 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 2. How do we increase therapeutic efficacy? • Combinations • PD(L)1 + CTLA4 • Chemotherapy • Novel Immune Modulators • Targeted therapy
- 9. Chemotherapy and CTLA4+PD1 17/07/2019 9 Keynote 189 Gandhi et al NEJM 2018 Checkmate 227 Hellman et al NEJM 2018
- 10. The evolving landscape of Next Generation Immune Modulators (NGIM) 17/07/2019 10 Mazzarella et al Eur J Can 2018
- 11. Outstanding questions 17/07/2019 11 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 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
- 12. Treatment based on liquid biopsy only is effective Aggarwal et al JAMA onc 2019
- 13. Outstanding questions 17/07/2019 13 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 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
- 14. More biomarkers means rarer biomarkers! An extreme example: NTRK 31 out of 11.502 patients positive (0.27%!!!!!) Gatalica et al Mod Path 2018
- 15. The need for a 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
- 16. 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
- 17. Outstanding questions 17/07/2019 17 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 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
- 18. As the size of 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
- 19. Conclusion Oncology is steadily 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 Luca.mazzarella@ieo.it