Hepatozelluläres Karzinom und Cholangiokarzinom was kommt nach Sorafenib? Stefan Kubicka

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1 Hepatozelluläres Karzinom und Cholangiokarzinom was kommt nach Sorafenib? Stefan Kubicka

2 SHARP 1 versus Asia-Pacific-Study 2 SHARP S:299/P:303 Asia-Pacific S:150/P:76 End point HR p-value HR p-value OS 10.7 / 7.9 < / TTSP TTP 5.5 / 2.8 < / 1.4 < RR 2 % / 1 % 3 % / 1.3% 1 Llovet JM et al. NEJM 2008; 2 Cheng et al. Lancet Oncology 2009

3 Molecular Pathogenesis and Targeted Therapy of Hepatocellular Carcinoma Zender L, Kubicka S; Onkologie 2008 Autor Protokoll N RR PFS/TTP MS Anti-EGFR O Dwyer 06 Gefitinib 31 3,2 2,3 NA NA Ramanathan 06 Lapatinib 37 5% 2,3 NA 6,2 Philip 05 Erlotinib 38 9 % 3,2 32% 13 Grünwald 07 Cetuximab ,0 22,2% NA Louafi 07 GemOx+Cetux 37 24% 4,5 40% 9,2 Antiangiogenese Kanai 06 TSU % NA NA NA Schwatz 06 Bevacizumab 30 10% 6,5 NA NA Malka 07 Bevacizumab 24 12,5 3,5 17% NA Zhu 06 GemOx-Beva 33 20% 5,3 48% 9,6 Sun 07 CapOx+Beva 30 13,3 4,5 45% 10,6 Multikinase-I Abou-Alfa 04 Sorafenib 137 5% 5,6 37% 9,5 Llovet 07 Sorafenib 299* 2,3 5,5 NA 10,7 Zhu 07 Sunitinib 26 3,8 4,1 35% 11,6 Faiver 07 Sunitinib 37 2,7 5,2 35% 11,2 Multi-target Ansatz Thomas 07 Erlotinib+Beva 29 20,6 8,8 NA 19

4 Sunitinib in advanced HCC US 1 EU/AS 2 Swiss 3 (n=34) (n=37) (n=45) 37,5 mg 50mg 37,5mg RR 1 (3) 1 (3) 1 (2) DCR 16 (52) 14 (38) 19 (42) OS TTP PFS Zhu AX et al. ASCO 08; 2 Faivre SJ et al. ASCO 07, 3 Koeberle et al. ASCO 09

5 Toxizität in HCC Studien: Sorafenib / Sunitinib Sorafenib (n=299) Sunitinib (n=34) Drug related adverse events (%) All Grade 3/4 All Grade 3/4 Diarrhea 39 8/- 47 -/- Anorexia 14 <1/- 38 6/- Nausea 11 <1/- 44 6/- Hand-foot skin reaction 21 8/- 15 6/- Vomiting 5 1/- 21 3/- Bleeding 7 <1/- 6 6/- Fatigue 22 3/ Leukopenia 85 18/- Neutropenia Thromocytopenia 65 6/6

6 Phase II Trial of the Combination of Bevacizumab and Erlotinib in Patients who have advanced hepatocellular carcinoma. Thomas MB et al., JCO 2009

7 Phase II Trial of the Combination of Bevacizumab and Erlotinib in Patients who have advanced hepatocellular carcinoma. Thomas MB et al., JCO 2009 * n=51 3 (5.9) 20 (39.2) 23 (45.1) * Hsu et al., #4585, ASCO 09

8 Toxizität in HCC Studien Bev+Erlotinib 1 Bevacizumab 2 n=40 n=46 Drug related adverse events (%) All Grade 3/4 All Grade 3/4 Diarrhea 60 10/- - - Anorexia / Nausea / Vomiting 35 -/ Bleeding (nose) 72,5 -/ Bleeding (rectum) 17,5 2,5/- Bleeding (oesophagus) / Hypertension 20 15/ Proteinuria 12,5 2.5/ Thomas MB et al., JCO 2009 ; 2 Siegel AB et al, JCO 2008

9 Stadien - adaptierte Therapie des HCC PST 0, PST 0-2 PST 2 Child A, Child A-B SIRT Child C Okuda 1 Okuda 1-2 Okuda 3 very early stage early stage intermediate advanced terminal Single<2cm single 5cm or >3 nodules portal invasion stage D Carcinoma in situ 3 nodules 3cm single >5cm N1 / M1 Normal portal pressure Liver function : CHE >3, Normal Bilirubin Radiation Yes No Associated disease No Yes Child A Child B/C Resection LTX RFA/PEI Chemoembo Sorafenib Symptomatic treatment or new agents

10 Auswahl aktueller HCC Studien Therapie Linie Phase Sorafenib in Child B 1st II Bevacizumab + RAD001 1st II AMG 386 1st II Sunitinib / Sorafenib 1st III Bev+Erlotinib / Sorafenib 1st III Sorafenib+Erlotinib / Sorafenib 1st III Brivanib / BSC 2nd III Sorafenib Adjuvant (Resek) III Rapamune / CNI Adjuvant (LTX) III

11 weitere offene Fragen der HCC-Therapie Therapie für Child B/C -? - Sorafenib +/- X-nib u/o Y-mab -? - Bev/Erlotinib besser als Sorafenib? - 2 nd -line Optionen (Brivanib, etc ) - Bei N0 oder M0 Systemtherapie mit TACE -? - Adjuvante Therapie nach RFA/Resektion-? - Sorafenib + LTX = > Milan -?

12 Gemcitabine-based versus fluoropyrimidine-based chemotherapy with or without platinum in unresectable biliary tract cancer: a retrospective study Mi-Jung Kim et al. BMC 2008.

13 Gemcitabine-based versus fluoropyrimidine-based chemotherapy with or without platinum in unresectable biliary tract cancer: a retrospective study Mi-Jung Kim et al. BMC 2008.

14 ABC-02 Randimisierte Phase III Studie zur Gemcitabine Monotherapie versus Kombinationschemotherapie beim Cholangio- und Gallenblasenkarzinom Gem 1000 Gem 1000 p-value Cispl 25 D1, 8, 15 D1, 8 N OS , Valle J et al., #4503, ASCO 2009

15 Zielgerichtete Therapie von Cholangiokarzinomen Therapie Target RR Kommentar Autor Erlotinib EGFR 7% 6-mo PFS 17% Philip Cetuximab EGFR Case report Paule / Sprinzl Lapatinib EGFR 0 % 17 patients Ramanathan HER-2/NEU Sorafenib VEGF 6% Ongoing phase II El-Khoueiry PDGFR B-Raf Bevacizumab VEGF 29 % Ongoing phase II Clark + GemOx Hezel and Zhu, 2008

16 Randimisierte Phase II Studie zur Untersuchung von GEMOX versus GEMOX+Cetuximab beim Cholangio- und Gallenblasenkarzinom Statistical Ineffective if 4 month-pfs is <40% Hypothesis Effective if 4 month-pfs is 60 % No Ras or B-Raf entry criteria GEMOX GEMOX+ Cetuximab N mo PFS 50 % 61 % Median PFS 5 mo 7 mo Malka et al. # 4520, ASCO 2009

17 Therapie von Cholangiokarzinomen Resektabel Nicht resektabel OP Chemotherapie? Radiochemotherapie? Molekulare Therapie? Ikterus Cholangitis ERC-Stent o. PTC-Stent PDT Palliative Chemotherapie 1 st line: Gemcitabine*/Cisplatin*??? 2 nd line:??? ggf. Xel*/MMC*, oder Iri* + Cetux* * off label use