Moscow summit 2020 : seeking for the cure of primary and secondary liver malignancies.
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Thanks to Prof. Chavdar Pavlov, MD, PhD, MScD - Department Head of Therapy, Head of the Centre for Evidence-Based Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia for helping organizing this event in Moscow.
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Moscow summit 2020 : seeking for the cure of primary and secondary liver malignancies.
- 1. Medical management of advanced hepatocellular carcinoma Professor Eric Raymond MD, PhD Chair of Medical Oncology @ Groupe Hospitalier Paris Saint-Joseph France eraymond@hpsj.fr Seeking for the Cure of Primary & Secondary Liver Malignancies France meets Russia in Moscow January 24-25, 2020 Conference venue: 125284, Botkinskaya Hospital, Green hall 2nd Botkin passage 5, Moscow, Russia
- 2. France meets Russia at the Botkine University Hospital in Moscow
- 3. Barcelona staging for hepatocellular carcinoma Medical therapies Palliative care
- 4. Indications of systemic medical treatments • Major indications – Extrahepatic spread and/or diffuse intrahepatic evolution refractory / non amenable to local therapies localization – Portal vein thrombosis – Evolution within 6 months or after two courses of chemoembolization • Other indications – Rapid alteration of the general performance status (WHO > 0 – CHILD A-B6) – Rapid kinetics with new lesion within less than 6 months – High grade tumors – High level and kinetics of AFP
- 5. Cellular & Molecular Components of the Hepatocellular Carcinoma Microenvironment Endothelial cells Pericytes VEGFR-PDGFR T cells (CD4-Treg) CD4:PD1-CTLA4-CD28 Treg: CD73-CD39 Dendritic cells PDL1-PD1-MSH II-CD80/86 Tumor associated macrophages CXCR4-TGFβR Tumor cells TGFβR-MET-PDL1 Fibroblasts FGFR TGFβ HGF FGF19 IL8 IL10 SDF1/CXCL12
- 6. Characteristics of Hepatocellular Carcinoma Microenvironment • Likely to vary according to the type of tumor carcinogenesis that may also affect liver functions and patient conditions – Alcohol – Viral hepatitis B/C induced inflammation – NASH – Others • Likely to be influenced by angiogenesis & focal hypoxia – Tumor angiogenesis being genuine or induced by antiangiogenic drugs – Induction of epithelial to mesenchymal differentiation – Induction of lactic acid metabolism – Facilitate the occurrences of various oncogenic mutations • Associated with local immunosuppression – Inhibition of T-cell functions (PD1/PDL1, CTLA4)
- 7. Angiogenesis as a major target for hepatocellular carcinoma Targeted agents in Hepatocellular Carcinoma
- 8. Learning experience with Sorafenib in Advanced hepatocellular carcinoma 2005 2006 2007 2008 2009 2010 2011 2012 5 10 15 Medianoveralsurvival ofsorafenib(month) Lag times of accrual SHARP SUNITINIB GIDEON BRISK ASIAN-PACIFIC SUNITINIB BRISK Placebo SHARP Placebo ASIAN-PACIFIC Non-Asian patients Asian patients Faivre S, de Gramont A, Raymond E. Target Oncol. 2016
- 9. Differences in target engagement of targeted therapies in hepatocellular carcinoma First line Second line Drugs Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab Targets VEGFR2 Yes Yes Yes Yes Yes FGFR No FEGFR 1-4 FGFR1 No No C-met No No No Yes No Other targets VEGFR3 PDGFR KIT B-raf, C-raf VEGFR 1-3 PDGFR KIT RET VEGFR 1-3 PDGFR KIT RET Raf-1 B-Raf TIE-2 AXL KIT RET None
- 10. Main results of clinical trials with targeted therapies in hepatocellular carcinoma First line Second line (post sorafenib) Drugs Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab Results Control Placebo Sorafenib Placebo Placebo Placebo Trials SHARP REFLECT RESORCE CELESTIAL REACH 1/2 OS (months) 10.7 vs 7.9 13.6 vs 12.3 10.6 vs 7.8 10.2 vs 8.0 8.1 vs 5.0 HR 0.69 0.92(non inferiority) 0.63 0.76 0.69 RR 2% vs 1% 24% vs 9% 11% vs 4% 4% vs 0.4% 5.4% vs 0.9% Safety (grade 3-4) Hand foot syndrome 11% 3% 13% 17% 0% HTA 14% 23% 15% 16% 12.7% Diarrhea 8% 4% 4% 10% 1%
- 11. Efficacy – Safety – Vulnerability The 3 major components for the selection of targeted therapies Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab First line Second line
- 12. A proposed algorithm of selection for targeted therapies in hepatocellular carcinoma Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab Cabozantinib Regorafenib Standard Option Option OptionOption Standard 1st line 2nd line 3nd line
- 13. Non antiangiogenic targeted agents in hepatocellular carcinoma Novel targeted agents in Hepatocellular Carcinoma Tumor associated macrophages CXCR4-TGFβR Tumor cells TGFβR-MET-PDL1 Fibroblasts FGFR TGFβ HGF FGF19 IL8 IL10 SDF1/CXCL12
- 14. Novel selective targeted agents based on activated pathways • MET inhibitors (tepotinib, …) • FGFR4-FGF19 inhibitors (BLU554, …) • TGF-beta receptor inhibitors (galunicertib, …)
- 15. Checkpoint inhibition in Hepatocellular Carcinoma The challenge of immunotherapy T cells (CD4-Treg) CD4:PD1-CTLA4-CD28 Treg: CD73-CD39 Dendritic cells PDL1-PD1-MSH II-CD80/86 Tumor cells TGFβR-MET-PDL1
- 16. Around 30% of HCCs belong to the "immune class," with high levels of immune cell infiltration Clin Cancer Res; 25(7) April 1, 2019
- 17. Rational for checkpoint inhibitors in hepatocellular carcinoma 1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454 MHC PD-L1 PD-1 PD-1 T-cell receptor PD-L2 T cell NFκB Other PI3K Tumor cell IFNγ IFNγR Shp-2 Checkpoint inhibitors (monoclonal antibodies) Immune infiltration Local immunosuppression 30%
- 18. Rational for combining antiangiogenic and checkpoint inhibitors Bevacizumab Decreases the activity of immunosuppressive cells (MDSCs and Tregs) Bevacizumab Normalises the tumour vasculature, increasing T-cell infiltration Atezolizumab Restores anti-cancer immunity with activity further enhanced through VEGF-mediated immunomodulatory effects Bevacizumab Promotes DC maturation Atezolizumab Promotes T-cell activation 1. Chen DS, et al. Immunity.2013;39(1):1-10. 2. Hegde PS, et al. SeminCancer Biol.2018;52(2):117-124. 3. WallinJJ, et al. Nat Commun.2016;7:12624. 4. GoelS, et al. PhysiolRev.2011;91(3):1071-1121. 5. MotzGT, et al. Nat Med. 2014;20(6):607-615. 6. Hodi FS, et al. Cancer Immunol Res.2014;2(7):632-642. 7. GabrilovichDI, et al. Nat Rev Immunol.2009;9(3):162-174. 8. Roland CL, et al. PLoSOne.2009;4(11):e7669. 9. FacciabeneA, et al.Nature. 2011;475(7355):226-230. 10. VoronT, et al. J ExpMed.2015;212(2):139-148.11. GabrilovichDI, et al. Nat Med.1996;2(10):1096-1103. 12. OyamaT, et al. J Immunol. 1998;160(3):1224-1232.
- 19. • 58-year-old white male with HCV-infected HCC, ECOG 0, Child-Pugh A5 • Progressed on sorafenib CA209-040: Durable Partial Response to Nivolumab Week 12 Week 48Baseline Arterial Venous + + + + + + + + + + Anthony B. El-Khoueiry et al. ASCO 2015
- 20. Immunotherapy has demonstrated activity in phase I-II trials leading to accelerated FDA approvals Activity reported across subgroups regardless PD1/PDL1 expression Median OS: around 14 months irrespective of prior sorafenib treatment AE> grade 3: 1% - Well tolerated First line Second line
- 21. Adjuvant First line Second line Overall Survival (OS) Early stages Advanced stages SURGERY/ABLATION Ongoing phase III of immunotherapy in HCC according to disease setting CheckMate-9DX (nivolumab versus placebo) CheckMate-459 (nivolumab versus sorafenib) KEYNOTE-240 (pembrolizumab versus placebo) NCT03412773 (tislelizumab versus sorafenib) HIMALAYA (durvalumab+/tremelimumab versus sorafenib) Relapse-free survival (RFS) Negative phase III trials IMbrave150 study Bevacizumab + atezolizumab versus sorafenib Positive phase III trials
- 22. The combination of atezolizumab + bevacizumab sets the first line for advanced hepatocellular carcinoma Grade 3-4 adverse events (AEs) occurred in 57% of people receiving Tecentriq and Avastin and 55% of people receiving sorafenib
- 23. Evidence-based options for therapy in advanced hepatocellular carcinoma based on Imbrave Data Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab CabozantinibRegorafenib New Standard Option OptionOption Option Option 1st line 2nd line 3nd line Bavacizumab + atezolizumab Pembrolizumab + lenvatinib NivolumabSorafenib OptionOption OptionOptionNo data IMbrave data are profoundly challenging the standard of care and future trials in advanced hepatocellular carcinoma
- 24. Conclusions • Various components of tumor microenvironment could be used as targets to control tumor growth in hepatocellular carcinoma • Inhibition of tumor angiogenesis, microenvironment signaling and local immunosuppression appear as promising options for tumor growth control • Combination therapies normalizing the microenvironment offer promise for optimal control of hepatocellular carcinogenesis
- 25. Thanks for you attention and welcome to the PAMM winter meeting in Stockholm, Sweden in 2020 Seeking for the Cure of Primary & Secondary Liver Malignancies France meets Russia in Moscow January 24-25, 2020 Conference venue: 125284, Botkinskaya Hospital, Green hall 2nd Botkin passage 5, Moscow, Russia