Πόσο μπορούν να εμπιστευθούν οι ασθενείς την ανοσοθεραπεία & την στοχευμένη θεραπεία στον καρκίνο της ουροδόχου κύστης και στον καρκίνο των νεφρών; ΑΡΙΣΤΟΤΕΛΗΣ ΜΠΑΜΙΑΣ ΚΑΘΗΓΗΤΗΣ ΘΕΡΑΠΕΥΤΙΚΗΣ ΟΓΚΟΛΟΓΙΑΣ ΕΘΝΙΚΟ & ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ
< ΑΠΟΛΥΤΑ > Σε εξειδικευμένα κέντρα
ΠΟΙΑ Η ΔΙΑΦΟΡΑ ΜΕΤΑΞΥ ΑΝΟΣΟΘΕΡΑΠΕΙΑς ΚΑΙ ΣΤΟΧΕΥΜΕΝΗΣ ΘΕΡΑΠΕΙΑΣ; Η ανοσοθεραπεία είναι μορφή στοχευμένης θεραπείας
Αρχή στοχευμένης θεραπείας pvhl HIF1α HIF2α VEGF Organ-specific metastasis 1-3 Angiogenesis 3,4 Endothelial stabilization 3,4 Autocrine growth stimulation 5 Figure adapted with permission from: Targeting the Signal Transduction Pathway. Feb 16, 2006. http://www.medscape.org/viewarticle/523548_3. Accessed March 29, 2016. 1. Zagzag D et al. Cancer Res. 2005;65(14):6178-88. 2. Patrussi L and Baldari CT. Curr Med Chem. 2011;18(4):497-512. VHL, von Hippel-Lindau; PDGF, platelet-derived growth factor; HIF-1α, Hypoxia-inducible factor 1-3. Milella M et al. J Cancer. 2011;2:369-373. alpha; TGF-α, transforming growth factor alpha 4. Heng DYC and Bukowski RM. Current Cancer Drug Targets. 2008;8:676-682. 5. Pfaffenroth EC et al. Exp Opin Biol Ther. 2008;8:779-790.
VEGF Signaling Pathway Inhibitors: Approved and Investigational Agents Bevacizumab VEGF Sorafenib Sunitinib Pazopanib Axitinib Tivozanib VEGF VEGFr EC Akt PI3K P P P P Raf MEK Sorafenib Vascular permeability EC survival MAPK Erk EC migration EC proliferation EC, endothelial cell; Erk, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogenactivated protein/extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B Modified with permission from: Garcia JA, Rini BI. CA Cancer J Clin. 2007;57:112-125.
Median survival (months) Evolution in the first-line treatment of mrcc Median survival before and after the introduction of targeted agents (TKIs) 1 11 30 18 32* 25 20 13 22 15 6 15* 10 3 6 5 0 Before PFS After Before OS After *With targeted agents as first-line mrcc therapy primarily in favourable/intermediate risk patients 1. Coppin et al. Cochrane Database Syst Rev 2005; 2. Gore et al. Lancet 2010; 3. Motzer et al. N Engl J Med 2007; 4. Escudier et al. Lancet 2007; 5. Rini et al. J Clin Oncol 2008; 6. Motzer et al. N Engl J Med 2013; 7. Motzer et al. J Clin Oncol 2009; 8. Escudier et al. J Clin Oncol 2010; 9. Rini et al. J Clin Oncol 2010; 10. Michel et al. ASCO GU 2014; 11. Motzer et al. ASCO 2013.
Immunotherapy for RCC: targeting the PD-1/PD-L1 Pathway PD-1 receptor (T lymphocytes) + PD-L1 ligand (tumor cells) Blocking PD-1/PD-L1 signaling can enhance the immune response Suppression of immune response to tumor PD-1, programmed cell-death protein 1; PD-L1, programmed death-ligand 1;PD-L2, programmed deathligand 2. Ortega RMM, Drabkin HA. Exp Opin Biol Ther. 2015;15:1049-60.
Immunosuppressive tumor microenvironment MHC + tumor antigen TCR Tumor cell Death or Dendritic cell PD-L1 Nivolumab PD-1 Inhibited T cell PD-L2 Nivolumab PD-1 A. Amin, ASCO 2014 PD-L1 expression provides immune escape mechanism PD-1 expression on TILs impairs T cell function PD-1, programmed death-1; PD-L1, programmed death ligand-1. Gabrilovich D, et al. Nat Med. 1996;2:1096-103; Gabrilovich D, et al. Nat Rev Immunol. 2009;9:162-74; Bronte V, et al. J Immunother. 2001;24:431-46; Finke JH, et al. Clin Cancer Res. 2008;14:6674-82; Ko JS, et al. Clin Cancer Res. 2009;15:2148-57; Thompson RH, et al. Clin Cancer Res. 2007;13:1757-61; Thompson RH, et al. Proc Natl Acad Sci U S A. 2004;101:17174-9.
Overall Survival (Probability) Overall survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median OS, months (95% CI) Nivolumab 25.0 (21.8 NE) Everolimus 19.6 (17.6 23.1) HR (98.5% CI): 0.73 (0.57 0.93) P = 0.0018 Everolimus Nivolumab 0.0 0 3 6 9 12 15 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 Everolimus 411 366 324 287 265 241 187 115 61 20 2 0 Minimum follow-up was 14 months. NE, not estimable.
ΕΙΝΑΙ ΚΑΙ ΟΙ ΔΥΟ ΠΡΟΣΕΓΓΙΣΕΙς ΚΑΤΑΛΛΗΛΕς ΓΙΑ ΑΣΘΕΝΕΙς ΜΕ ΟΥΡΟ-ΓΕΝΝΗΤΙΚΟ ΚΑΡΚΙΝΟ; Καρκίνος νεφρού και ουροθηλίου
Εγκεκριμένες στοχευμένες θεραπείες στον καρκίνο νεφρού VEGF/VEGFR targeting mtor inhibitors Checkpoint inhibitors Sorafenib Sunitinib Bevacizumab Pazopanib Axitinib Cabozantinib Lenvatinib Everolimus Temsirolimus Nivolumab mab, monoclonal antibody; mtor, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. 1. Sanchez-Gastaldo A, et al. Cancer Treat Rev. 2017;60:77-89.
Εξέλιξη συστηματικής θεραπέιας στον ουροθηλιακό καρκίνο Docetaxel Gemcitabine + cisplatin Standard MVAC 1989 Accelerated MVAC Paclitaxel Vinflunine 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2016 Cisplatin FDA 1978 Gemcitabine EMA Vinflunine EMA Sternberg CN, Yagoda A, et al. Cancer 1989;64:2448-2458. McCaffrey JA, et al. J Clin Oncol 1997;15:1853-1857. von der Maase H, et al. J Clin Oncol 2005;23:4602-4608. Sternberg CN, et al. J Clin Oncol 2001;19:2638-2646. Vaughn DJ, et al. J Clin Oncol 2002;20:937-940. Bellmunt J, et al. J Clin Oncol 2009;27:4454-4461. Rosenberg JE, et al. Lancet. 2016;387:1909-1920. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. http://www.ema.europa.eu/ema/
Η συστηματική θεραπεία του ουροθηλιακού καρκίνου σήμερα Docetaxel Gemcitabine + cisplatin Pembrolizumab FDA, EMA Standard MVAC 1989 Accelerated MVAC Paclitaxel Vinflunine Nivolumab FDA, EMA 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 Cisplatin FDA 1978 Gemcitabine EMA Vinflunine EMA Sternberg CN, Yagoda A, et al. Cancer 1989;64:2448-2458. McCaffrey JA, et al. J Clin Oncol 1997;15:1853-1857. von der Maase H, et al. J Clin Oncol 2005;23:4602-4608. Sternberg CN, et al. J Clin Oncol 2001;19:2638-2646. Vaughn DJ, et al. J Clin Oncol 2002;20:937-940. Bellmunt J, et al. J Clin Oncol 2009;27:4454-4461. Rosenberg JE, et al. Lancet. 2016;387:1909-1920. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. http://www.ema.europa.eu/ema/ Durvalumab FDA Avelumab FDA Atezolizumab FDA Slide credit: clinicaloptions.com
ΜΠΟΡΕΙ ΠΡΕΠΕΙ Η ΑΝΟΣΟΘΕΡΑΠΕΙΑ ΝΑ ΑΝΤΙΚΑΤΑΣΤΗΣΕΙ Ή ΝΑ ΧΡΗΣΙΜΟΠΟΙΗΘΕΙ ΠΑΡΑΛΛΗΛΑ ΜΕ ΤΗΝ ΧΗΜΕΙΟΘΕΡΑΠΕΙΑ ΣΤΟΝ ΟΥΡΟ-ΓΕΝΝΗΤΙΚΟ ΚΑΡΚΙΝΟ; Σε επιλεγμένες ομάδες ασθενών
Θεραπεία βασισμένη στην πλατινα
DANUBE
Θεραπεία βασισμένη στην πλατινα
Unmet medical needs of chemotherapy in urothelial cancer Increase efficacy of perioperative systemic therapy Increase disease-free/cure rate of cisplatin-eligible patients in advanced disease More effective therapies for cisplatin-ineligible patients More effective therapies for relapsed disease
Overall survival Events, n HR (95% CI) p Pembro 155 0.73 (0.59-0.91) 0.0022 Chemo 179 Median (95% CI) Data cutoff date: Sep 7, 2016.
ΜΠΟΡΟΥΝ ΟΛΟΙ ΑΣΘΕΝΕΙς ΝΑ ΛΑΒΟΥΝ ΑΝΟΣΟΘΕΡΑΠΕΊΑ Ή ΕΞΑΤΟΜΙΚΕΥΜΕΝΗ ΘΕΡΑΠΕΙΑ; Η συντριπτική πλειοψηφία ΣΕ ΕΞΕΙΔΙΚΕΥΜΕΝΑ ΚΕΝΤΡΑ ΠΡΕΠΕΙ ΟΛΟΙ ΑΣΘΕΝΕΙς ΝΑ ΛΑΒΟΥΝ ΑΝΟΣΟΘΕΡΑΠΕΊΑ Ή ΕΞΑΤΟΜΙΚΕΥΜΕΝΗ ΘΕΡΑΠΕΙΑ; Εντός των ενδείξεων η σε κλινικές μελέτες ΣΕ ΕΞΕΙΔΙΚΕΥΜΕΝΑ ΚΕΝΤΡΑ
ΓΙΑ ΠΟΣΟ ΧΡΟΝΟ ΜΠΟΡΕΙ ΝΑ ΛΑΜΒΑΝΕΙ ΑΝΟΣΟΘΕΡΑΠΕΊΑ Ή ΣΤΟΧΕΥΜΕΝΗ ΘΕΡΑΠΕΙΑ Ο ΑΣΘΕΝΉς; Για όσο καιρό ωφελείται και δεν έχει σοβαρές παρενέργειες Στόχος: διακοπή της θεραπείας με διατήρηση οφέλους
Atezolizumab (MPDL3280A): Duration of Treatment and Response in UBC Pts with UBC and CR or PR as best response 1 yr Treatment duration (IC2/3) Treatment duration (IC0/1) First CR/PR First PD Treatment discontinuation* Ongoing response* 0 100 200 300 400 500 600 Days *Discontinuation and ongoing response status markers have no timing implication; 4 pts discontinued treatment after cycle 16 prior to 1 year per original protocol. Responses plotted are investigator assessed and have not all been confirmed by the data cutoff (12/2014). Petrylak DP, et al. ASCO 2015. Abstract 4501. Slide credit: clinicaloptions.com
ΤΙ ΣΥΜΠΤΩΜΑΤΑ ΜΠΟΡΕΙ ΝΑ ΑΝΑΜΕΝΕΙ Ό ΑΣΘΕΝΗς ΣΕ ΑΝΟΣΟΘΕΡΑΠΕΙΑ Ή ΣΤΟΧΕΥΜΕΝΗ ΘΕΡΑΠΕΙΑ;
Παρενέργειες εξατομικευμένης θεραπείας Hair color change Weight decreased Serum ALT increased Alopecia Upper abdominal pain Serum AST increased Fatigue Rash Pain in extremity Constipation Taste Alteration LDH increased Serum creatinine increased Peripheral edema Hand-foot syndrome Dyspepsia Pyrexia Leukopenia Hypothyroidism Epistaxis Serum TSH increased Mucositis Neutropenia Anemia Thrombocytopenia Favors pazopanib Favors sunitinib
Παρενέργειες ανοσοθεραπείας Nivolumab N=406 Everolimus N=397 Any grade Grade 3 Grade 4 * Any grade Grade 3 Grade 4 Treatment-related AEs, % 79 18 1 88 33 4 Fatigue 33 2 0 34 3 0 Nausea 14 <1 0 17 1 0 Pruritus 14 0 0 10 0 0 Diarrhea 12 1 0 21 1 0 Decreased appetite 12 <1 0 21 1 0 Rash 10 <1 0 20 1 0 Cough 9 0 0 19 0 0 Anemia 8 2 0 24 8 <1 Dyspnea 7 1 0 13 <1 0 Edema peripheral 4 0 0 14 <1 0 Pneumonitis 4 1 <1 15 3 0 Mucosal inflammation 3 0 0 19 3 0 Dysgeusia 3 0 0 13 0 0 Hyperglycemia 2 1 <1 12 3 <1 Stomatitis 2 0 0 29 4 0 Hypertriglyceridemia 1 0 0 16 4 1 Epistaxis 1 0 0 10 0 0 Adapted from Sharma et al, 2015, ESMO. No deaths from study-drug toxicity were reported in the nivolumab group, and two death were reported in the everolimus group ( 1 from septic shock and 1 from bowel ischemia) Based on data cut-off of June 2015. * Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1). Grade 4 AEs not listed in table: increased blood triglycerides (2), acute kidney injury (1), sepsis (1), chronic obstructive pulmonary disorder (1), increased blood cholesterol (1), neutropenia (1), pneumonia (1). See speaker notes for references and abbreviations.
ΣΕ ΠΟΣΟ ΧΡΟΝΟ ΜΠΟΡΕΙ ΝΑ ΑΝΑΜΕΝΕΙ ΘΕΤΙΚΗ ΕΚΒΑΣΗ Ο ΑΣΘΕΝΗς;
Atezolizumab (MPDL3280A): Duration of Treatment and Response in UBC Pts with UBC and CR or PR as best response 1 yr Treatment duration (IC2/3) Treatment duration (IC0/1) First CR/PR First PD Treatment discontinuation* Ongoing response* 0 100 200 300 400 500 600 Days *Discontinuation and ongoing response status markers have no timing implication; 4 pts discontinued treatment after cycle 16 prior to 1 year per original protocol. Responses plotted are investigator assessed and have not all been confirmed by the data cutoff (12/2014). Petrylak DP, et al. ASCO 2015. Abstract 4501. Slide credit: clinicaloptions.com
ΕΧΕΙ ΤΟ ΧΡΌΝΟ Ο ΓΙΑΤΡΌς ΝΑ ΕΝΗΜΕΡΏΣΕΙ ΠΛΉΡΩς ΤΟΝ ΑΣΘΕΝΗ; Οφείλει να τον βρει
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