Aktuelles zur medikamento sen Therapie in der metastasierten Situation

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1 Johannes Ettl Interdisziplinäres i Brustzentrum t und Frauenklinik ik rechts der Isar, Technische Universität München Aktuelles zur medikamento sen Therapie in der metastasierten Situation

2 Überlebenszeit b nach Auftreten t von Metastasen t HRpos/neg Adapted from Hölzel et al, J Cancer Res Clin Oncol Apr 20. doi: /s

3 Überlebenszeit b nach Auftreten t von Metastasen t HRpos/neg Adapted from Hölzel et al, J Cancer Res Clin Oncol Apr 20. doi: /s

4 Veränderung des Metastasierungsmusters

5 HR+/HER2 häufigster Subtyp beim HR-pos MammaCa HR+ HR 80,5% 19,5% Hölzel et al, J Cancer Res Clin Oncol Apr 20. doi: /s

6 Entwicklung der Erstlinientherapie beim HRpos MBC TAM ~6 months 1 5 AI months 6 8 FULV 16.6 months 6 AI + CDK4/6 inhibitor months Median TTP/PFS (months) 1. Mouridsen H, et al. J Clin Oncol 2001;19: ; ; 2. Mouridsen H, et al. J Clin Oncol 2003;21:2101 9; ; 3. Bonneterre J, et al. Cancer 2001;92: ; 4. Nabholtz JM, et al. J Clin Oncol 2000;18: ; 5. Paridaens RJ, et al. J Clin Oncol 2008;26: ; 6. Robertson JF, et al. Lancet 2016;388: ; 7. Finn RS, et al. N Engl J Med 2016;375: ; 8. Ribociclib EU SmPC, August 2017; 9. Hortobagyi G, et al. N Engl J Med 2016;375:

7 Entwicklung der endokrinen Zweitlinientherapie beim HRpos MBC AI 3.2 months 1 FULV months 2 4 AI + mtor inhibitor 7.8 months 1 FULV+ PI3K inhibitor 6.9 months 5 FULV + CDK4/6 inhibitor months 2,3, Median TTP/PFS (months) 1. Yardley DA, et al. Adv Ther 2013;30:870 84; 2. Palbociclib EU SmPC, May 2017; 3. Turner NC, et al. SABCS 2016 (Abstract t P ); 4. Di Leo A, et al. J Clin Oncol 2010;28: ; 5. Baselga J, et al. Lancet Oncol 2017;18:904 16; 6. Sledge GW, et al. J Clin Oncol 2017:35;25:

8 CDK4/6 Inhibitoren Substanz Firma Dosierungs Schema Zulassungsstatus Nebenwirkungen CDK4/6 in vitro IC 50 (nm) Palbociclib Pfizer 3/4 Wochen III; FDA/EMA Neutropenia/Myelotoxizitä CDK4 (cyclind1): 11 (PD ) t CDK6 (cyclind2): 15 Ibrance Ribociclib (LEE011) Kisqali Novartis 3/4 Wochen III; FDA/EMA Neutropenie/Myelotoxiziät LFTs QTc CDK4 (cyclind1): 10 CDK6 (cyclind2): 40 Abemaciclib (LY285219) Verzenio Eli Lilly Kontinuierlich III; FDA Diarrhoe Neutropenie/Myelotoxizität Kreatinin i CDK4 (cyclind1): 2 CDK6 (cyclind1): 10 Finn RS et al., Breast Cancer Res Feb 9;18(1):17

9 Wirkmechanismus der CDK4/6 Inhibitoren Aktiver CDK4/6 Cyclin D Signalweg 1,2 = Proliferation 1 Lundberg AS, Weinberg RA. Mol Cell Biol. 1998; 18(2): ; 2 Harbour JW, et al. Cell.1999; 98(6):

10 Wirkmechanismus der CDK4/6 Inhibitoren Inhibierter CDK4/6-Cyclin D Signalweg 1,2 = Zellproliferation gehemmt Palbociclib, Ribociclib, Abemaciclib 1 Lundberg AS, Weinberg RA. Mol Cell Biol. 1998; 18(2): ; 2 Harbour JW, et al. Cell.1999; 98(6):

11 Schwere-/febrile Neutropenien unter CDK4/6- Inhibitoren Neutropenie Neutropenie febrile Grad III Grad IV Neutropenie Palbociclib Paloma 2 56% 10% 1,8 % Paloma ao a3 55% 10% <1% Ribociclib Monaleesa 2 49,7% 9,6% 1,5% Abemaciclib Monarch 2 23,6% 2,9% 1%

12 Pathomechanismus h der CDK4/6- induzierten Neutropenie Mechanismus Palbociclib induzierte Neutropenie Zellzyklus Arrest, aber kein Absterben von proliferierenden Neutrophile Vorstufen Chemotherapie induzierte Neutropenie DNA Schaden und Apoptose von proliferierenden Neutrophilen Vorstufen Reversibilität Schnelle Erholung Verzögerte Erholung Hu W, et al. Clin Cancer Res 2016

13 Benefit der CDK4/6 Inhibitoren

14 Benefit der CDK4/6 Inhibitoren

15 Internationale Leitlinien: Endokrine Therapie als Standard of Care für Pat. mit HR+/HER2 mbc Endocrine therapy should be recommended as initial treatment for patients with HR-positive mbc, except for patients with immediately lifethreatening disease or for those experiencing rapid visceral recurrence during adjuvant endocrine therapy. 1 ET is the preferred option for HR-positive mbc even in the presence of visceral disease, unless there is visceral crisis or concern or proof of endocrine resistance 2 Women with recurrent or metastatic disease characterised by tumours that are ER- and/ or PR-positive are appropriate candidates for initial endocrine therapy 3 Endocrine-based therapy represents the first choice for metastatic breast cancer with positive (or unknown) hormone receptor (HR) status 4 1. Rugo H, et al. J Clin Oncol 2016 Sep 1;34(25): ; 2. Cardoso F, et al. Annals of Oncology 2017;28:16 33; 3. NCCN Guidelines: Breast Cancer. Version 2:2016; 4. Guidelines of the AGO breast committee. Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer online.de/fileadmin/downloads/leitlinien/mamma/ /ago_englisch/pdf_gesamtdatei_englisch/updated%20guidelines_2017.pdf. Accessed October 2017.

16 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% HR+ metastatic t ti breast cancer cohort 65% 63% 35% 37% 91% 9% Multiple Visceral Bone Endocrine therapy Chemotherapy Lobbezoo DJ, et al. Ann Oncol 2016; 27:

17 PFS/OAS in Abhängigkeit i von der Erstlinientherapie i i Progres ssion free surv vival (%) P< Patients t with initial iti chemotherapy, median PFS 5.3 months (95% CI: ) Patients with initial endocrine chemotherapy, median PFS 13.3 months (95% CI: ) Months Survival (%) P< Patients with initial chemotherapy, h median OS 16.1 months (95% CI: ) Patients with initial endocrine chemotherapy, median OS 36.9 months (95% CI: ) Months Lobbezoo DJ, et al. Ann Oncol 2016; 27:

18 Internationale Leitlinien: Endokrine Therapie als Standard of Care für Pat. mit HR+/HER2 mbc Endocrine therapy should be recommended as initial treatment for patients with HR-positive mbc, except for patients with immediately lifethreatening disease or for those experiencing rapid visceral recurrence during adjuvant endocrine therapy. 1 ET is the preferred option for HR-positive mbc even in the presence of visceral disease, unless there is visceral crisis or concern or proof of endocrine resistance 2 Women with recurrent or metastatic disease characterised by tumours that are ER- and/ or PR-positive are appropriate candidates for initial endocrine therapy 3 Endocrine-based therapy represents the first choice for metastatic breast cancer with positive (or unknown) hormone receptor (HR) status 4 1. Rugo H, et al. J Clin Oncol 2016 Sep 1;34(25): ; 2. Cardoso F, et al. Annals of Oncology 2017;28:16 33; 3. NCCN Guidelines: Breast Cancer. Version 2:2016; 4. Guidelines of the AGO breast committee. Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer online.de/fileadmin/downloads/leitlinien/mamma/ /ago_englisch/pdf_gesamtdatei_englisch/updated%20guidelines_2017.pdf. Accessed October 2017.

19 ...UND WAS KOMMT NACH CDK4/6??? 17. AUFLAGE