Advanced hepatocellular carcinoma: new therapeutic strategies

1. Advanced hepatocellular carcinoma:new therapeutic strategies Giovanni Brandi University of Bologna

2. BCLC staging system and treatment strategy

3. Depositato presso AIFA in data 28 ottobre 2009; AN n� IT/ONC/2009/10/0306 Depositato presso AIFA in data 28 ottobre 2009; AN n� IT/ONC/2009/10/0306

4. Prognosis of advanced HCC

5. Death causes of HCC patients

6. To treat or not to treat? About two thirds of hepatocellular carcinoma patients will die due to their cancer The other third will die due to liver failure (cirrhosis progression) or other causes Patients with relatively preserved liver function are expected to achieve maximal benefit from HCC treatment Patients with poor liver function are probably managed best with supportive care

7. Chemotherapy is not effective

8. Altered signalling pathways in HCC Many molecular signaling mechanisms have been implicated in hepatocarcinogenesis, including the Ras/Raf/MEK/ERK pathway, the PI3K/Akt/mTor pathway, the wnt/�-catenin pathway, and the JAK/STAT pathway. Constitutive activation (through mutations) of these pathways can initiate hepatocarcinogenesis.1 ADDITIONAL INFORMATION The Ras/Raf/MEK/ERK pathway is activated by an extracellular tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), VEGFR, insulin-like growth factor receptor (IGFR), platelet-derived growth factor receptor (PDGFR), the stem cell growth factor receptor (c-KIT), and the hepatocyte growth factor receptor (MET).1,2 PI3K is associated with growth receptors, and is activated by binding of the ligand.1 Downstream, mTOR regulates the expression of c-myc, cyclin Di, and other genes involved in cell proliferation and angiogenesis. The wnt/�-catenin pathway is illustrated in the far right of the slide1: Wnts are secreted glycoproteins that activate the extracellular receptor frizzled (Fzd). In the quiescent state, glycogen synthase kinase 3� (GSK-3�) is active and phosophorylates �-catenin. This phosphorylation leads to degradation of �-catenin. If the wnt pathway is activated, the protein dishevelled (Dvl) prevents the phosphorylation of �-catenin by GSK-3�. �-catenin accumulates in the cytoplasm, translocates to the nucleus, and acts as a coactivator to stimulate the transcription of genes such as c-myc, c-jun, and cyclin D2, and others. The net result is to activate survival, antiapoptosis, and angiogenesis pathways. Many molecular signaling mechanisms have been implicated in hepatocarcinogenesis, including the Ras/Raf/MEK/ERK pathway, the PI3K/Akt/mTor pathway, the wnt/�-catenin pathway, and the JAK/STAT pathway. Constitutive activation (through mutations) of these pathways can initiate hepatocarcinogenesis.1 ADDITIONAL INFORMATION The Ras/Raf/MEK/ERK pathway is activated by an extracellular tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), VEGFR, insulin-like growth factor receptor (IGFR), platelet-derived growth factor receptor (PDGFR), the stem cell growth factor receptor (c-KIT), and the hepatocyte growth factor receptor (MET).1,2 PI3K is associated with growth receptors, and is activated by binding of the ligand.1 Downstream, mTOR regulates the expression of c-myc, cyclin Di, and other genes involved in cell proliferation and angiogenesis. The wnt/�-catenin pathway is illustrated in the far right of the slide1: Wnts are secreted glycoproteins that activate the extracellular receptor frizzled (Fzd). In the quiescent state, glycogen synthase kinase 3� (GSK-3�) is active and phosophorylates �-catenin. This phosphorylation leads to degradation of �-catenin. If the wnt pathway is activated, the protein dishevelled (Dvl) prevents the phosphorylation of �-catenin by GSK-3�. �-catenin accumulates in the cytoplasm, translocates to the nucleus, and acts as a coactivator to stimulate the transcription of genes such as c-myc, c-jun, and cyclin D2, and others. The net result is to activate survival, antiapoptosis, and angiogenesis pathways.

9. Etiology-dependent molecular alterations in HCC

12. Sorafenib in advanced HCC (I) In patients with good liver function (Child-Pugh class A) sorafenib 400 mg bid significantly reduces risk of progression and improves survival Objective response rate is anyway low (2,3%) Duration of response is only 4 weeks longer in sorafenib vs placebo arm These data have been confirmed by the Asian-Pacific Study

13. Sorafenib in advanced HCC (III)

14. Concerns

16. Large scale evidence of moderate benefitsLarge scale evidence of moderate benefits

19. Sorafenib-related AE

20. Cardiovascular toxicity (I)

21. Cardiovascular toxicity (II) Hypertension grade 3-4 occurs in up to 4% of patients treated with sorafenib, which is also associated to increased vascular stiffness Serious cardiotoxicity is rare, and acute coronary symptoms occur in ~3% of patients After appropriate cardiologic management patients recover and are often still eligible for treatment with sorafenib No test is predictive for cardiotoxicity Thromboembolic events are rare (0.8% G3 events in phase I studies, no grade 3-4 events reported in phase II-III single-agent trials)

22. Neurologic toxicity (?) We have observed severe cognitive impairment in two patients receiving sorafenib for advanced HCC Such event occurs few days after starting treatment, is reversible on drug discontinuation and recurs upon rechallenge Blood tests, neurologic evaluation and brain CT scan excluded other potential organic and toxix-metabolic causes Further studies on animal models are planned

23. Neurologic toxicity (?)

24. Ongoing studies: focus on sorafenib STORM: phase III, international, randomized, double-blind, placebo-controlled trial of sorafenib as adjuvant treatment to prevent HCC recurrence after treatment with curative intent (surgical resection, RFA, PEI) SPACE: phase II, international, randomized, double-blind, placebo-controlled trial of TACE (performed with doxorubicin-loaded DCbeads) plus sorafenib as treatment for intermediate-stage HCC

25. STORM Study will enrol 1100 patients from America, Europe, Asia, Japan The study is recruiting since November, 2008 First results expected in 2012 (RFS) ClinicalTrials.gov ID NCT00692770

26. SPACE The study will enrol 350 intermediate-stage HCC patient from America, Europe, Asia-Pacific region The study is recruiting since March, 2009 First results expected in 2011 ClinicalTrials.gov ID NCT00855218

27. Sunitinib Sunitinib is a small molecule competitive inhibitor of VEGFR1/2/3 and other tyrosine kinases, including PDGFRa/�, KIT, CSF-1R, FLT3, RET A phase II study in advanced HCC patients (canonical schedule) showed modest antitumor activity (ORR 2.9%, SD 50%) associated with changes in tumor vascular permeability Another phase II study confirmed the low ORR (2.7%) with 37% SD lasting at least 3 months Toxicity was pronounced but manageable

28. Sunitinib: phase III study Phase III, randomized, open-label study aimed at enrolling 1200 patient from USA, Europe, Asia The study has been terminated in advance on April 26, 2010 for safety reasons (excess AE in the sunitinib arm) ClinicalTrials.gov ID NCT00699374

29. Erlotinib Erlotinib is a small-molecule inhibitor of tyrosine kinase activity of EGFR Approved by FDA and EMEA for treatment of non-small cell lung cancer and pancreatic cancer A phase II trial in advanced HCC showed modest activity (no objective responses, 43% SD lasting at least 16 weeks) and good tolerability as single agent A phase III study is currently ongoing (SEARCH)

30. SEARCH Phase III, randomized, double-blind, placebo-controlled trial aimed at recruiting 700 patients in Europe, Americas, Asia-Pacific Study started in May 2009 First results expected in 2011 ClinicalTrials.gov ID NCT00901901

31. Bevacizumab Bevacizumab is a monoclonal antibody targeted at VEGF Approved by FDA and EMEA for treatment of colorectal, breast, renal and non-small cell lung cancer A phase II trial in advanced HCC showed significant activity (ORR 13%, 65% of patients progression-free at 6 months) Main grade 3-4 AEs included hypertension, thrombosis and hemorrage (one fatal)

32. Bevacizumab in combinations+ Bevacizumab plus erlotinib is the most promising, achieving ORR 25%, median PFS 9 months, median OS 15.7 months* Bevacizumab plus mTOR inhibitors (sitolimus, temsirolimus, everolimus): phase I/II trials ongoing Bevacizumab plus TACE: a phase II trial stopped early due to toxicity concerns, another completed (results not available) Bevacizumab plus sorafenib: phase I/II trials ongoing

33. Bevacizumab plus erlotinib Phase II, , open-label trial aimed at recruiting 120 American patients Enrollment started randomizedin March 2009 First results expected in 2011 ClinicalTrials.gov ID NCT00881751

34. Bevacizumab plus erlotinib Left: 11C-acetate PET/TC shows hypercaptation in D8 and L2 vertebrae (HCC bone metastases) Center: complete metabolic response after B+E Right: MRI confirms complete response

35. Everolimus (RAD001) Everolimus is an orally administred mTOR inhibitor Approved by FDA and EMEA for renal cell carcinoma resistant to anti-VEGF therapy mTOR signaling is pivotal in HCC pathogenesis, favouring angiogenesis and cell survival Everolimus reduced tumor growth and increaded survival in a xenograft HCC model Various phase I/II clinical trials ongoing (also in combination) A phase III clinical trial planned (EVOLVE-1) in patients pretreated with sorafenib

36. EVOLVE-1 in pretreated pts Phase III, randomized, double-blind, placebo-controlled trial aimed at recruiting 531 patients The study should start in 2010 First results expected in 2012-2013 ClinicalTrials.gov ID NCT01035229

37. Sorafenib plus everolimus International phase I/II trial, aimed at recruiting Americans, Europeans and Asians Study started in December 2008 First results expected in 2011 ClinicalTrials.gov ID NCT00828594

38. AMG 386 AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2 In a phase I trial on patients with advanced solid tumors showed some clinical activity (one PR, four SD lasting more than 16 weeks) Its toxicity profile appears good (MTD not reached) and different from that of VEGF axis-targeted drugs Most common AEs: fatigue and peripheral edema

39. AMG 386 plus sorafenib This phase II trial will enrol 30 patients from USA, Europe and Australia Study started in August 2009 First results expected in 2011 ClinicalTrials.gov ID NCT00872014

40. Brivanib Brivanib alaninate is an ester prodrug of brivanib, an investigational inhibitor of tyrosine kinase activity of VEGFR2 and FGFR Both have been involved in growth and neovascularization of HCC In preclinical HCC models brivanib significantly reduced tumor growth and microvascular density In an open-label, phase II study on HCC patients brivanib appeared to have some activity

41. Brivanib as second-line therapy This phase III, randomized, double.blind, placebo-controlled trial aims at recruiting 340 patients from America, Europe and Asia Study started in February 2009 First results expected in 2011 ClinicalTrials.gov ID NCT00825955

42. Brivanib as first-line therapy This phase III, randomized, open-label trial aims at recruiting 1050 patients in America, Europe, Asia and Australia Study started in May 2009 First results expected in 2013 ClinicalTrials.gov ID NCT00858871

43. Adjuvant brivanib after TACE This randomized, phase III trial aims at recruiting 870 patients from America, Europe, Asia and Australia Study sarted in August 2009 First results expected in 2012 ClinicalTrials.gov ID NCT00908752

44. Regorafenib (BAY 73-4506) Regorafenib is an inhibitor of various receptor tyrosine kinases (VEGFR, KIT, RET, FGFR, PDGFR) and serine/threonine kinases (Raf, p38 MAPK) In phase I studies in patients with advanced solid tumors it has been associated wit a 73% DCR Common adverse events are thrombocytopenia, hand-foot skin reaction, mucositis, diarrhea, fatigue, hypertension No published data on HCC patients

45. Regorafenib in pretreated HCC patients This uncontrolled phase II trial will enrol 36 European and Korean patients Study started in September 2009 First results expected in 2010 ClinicalTrials.gov ID NCT01003015

46. Ramucirumab (IMC-1121B) Ramucirumab is a human recombinant monoclonal antibody (class IgG1) which binds extracellular domain of VEGFR2, preventing activation by its lignad Two phase I studies on patients with advanced solid tumors demonstrate clinical activity (~30% DCR) Common AEs include fatigue, anorexia, nausea, vomiting, diarrhea, hypertension A phase II trial on HCC patients is ongoing (no published results)

47. Ramucirumab phase III study in pretreated HCC pts This phase III, international, randomized, double-blind, placebo-controlled trial will enrol 544 patients The study will be conducted in approximately 200 sites in North America, Europe, and East Asia and should start in 2010 EudraCT No. 2010-019318-26 IND No. BB-IND 11856

48. Pegylated arginine deaminase HCC is auxotrofic for arginine, a nonessential amino acid, and arginine deprivation induces cell death Arginine deaminase is a mycoplasmic enzyme which converts arginine into citrulline, decreasing serum arginine level In a phase II trial, two different doses of the drug (80 and 160 units qw) achieved a DCR of 63.1% (1 CR, 1 PR, 46 SD, 16 PD), with median OS 11.4 months Treatment is tolerated reasonably well ( 19% G3) The drug is immunogenic and loses efficacy in about six months

49. Is chemotherapy era over? (I) Hepatic artery infusion (HAI) of cytotoxics increases exposition of HCC cells to the drug while minimizing AEs We conducted a phase I trial of prolonged irinotecan HAI for 5d every 21 d MTD 27.5 mg/m2/d Median TTP 14.0 months for dose levels >17.5 mg/m2/d, median OS 17 months Common toxicity are anemia, leukopenia, thrompocytopenia, diarrhea, nausea, vomiting, (no G4 events, two G3 events at 27.5 mg/m2/d) Management of hepatic artery catheter can be cumbersome

50. HAI efficacy

51. Is chemotherapy era over? (II) Metronomic chemotherapy (i.e. frequent or continuous administration of low-dose cytotoxics) has antiangiogenic effect with very good tolerability Metronomic capecitabine, 500 mg bid in our single-institution casistic (61 patients) achieved a CR, 7 PR and 30 SD (DCR 66.7%) Median TTP 7.45 months, median OS 12.94 months Minimal toxicity (3 drug-related G3 AEs)

52. Durable Complete response to metronomic capecitabine In A and B, hepatic artery angiography and liver CT scan showing multinodular HCC In C, liver CT scan after three monts of treatment, demonstrating complete response After more than 3,5 years the patient is still in CR

53. Conclusions Sorafenib is the only approved treatment for advanced HCC patients Studies are now evaluating safety and efficacy in the adjuvant setting: After treatment with curative intent After TACE Many targeted agents with antiangiogenic and/or antiproliferative effect are in various phases of clinical development, alone or in combination While conventional chemotherapy is not effective, optimized schedules and new treatment modalities warrant further evaluation