Hepatocellular Carcinoma: An Oncologist s Perspective. March 6, 2015 Bruce Lin, M.D.

Transcription

1 Hepatocellular Carcinoma: An Oncologist s Perspective March 6, 2015 Bruce Lin, M.D.

2 Learning Objectives Treatment for advanced HCC Limitation of traditional chemotherapy in HCC Signaling pathways of hepatocarcinogenesis Targeted therapies in advanced HCC Clinical trials for advanced HCC at Virginia Mason

3 Hepatocellular Carcinoma Worldwide incidence over 600,000 cases per year Estimated 26,190 in the United States Third leading cause of cancer death worldwide Treatment most effective in early stages 50% diagnosed at advanced stages

4 Chemotherapy Not Routinely Used HCC relatively chemotherapy refractory High expression of drug resistance genes p-glycoprotein (MDR1), glutathione-s-transferase, heat shock proteins, p53 mutations Chemotherapy not well tolerated by patients with significant hepatic dysfunction Survival often not determined by response to treatment, but by the degree of hepatic dysfunction Clinical trials for single-agent chemotherapy showed response rates of 0-20% Usage often limited by elevated toxicity Studies often in diverse populations Asian studies younger, well-compensated cirrhosis, hepatitis B or C North American/Europe older (> 60 y/o), alcoholic cirrhosis, co-morbid illnesses

5 Wagman et al., Liver, Gallbladder, and Biliary Tract Cancers: Cancer Management: Online Edition, March 2013

6 Signaling Pathways of Hepatocarcinogenesis Spangenberg, H. C. et al. (2009) Targeted therapy for hepatocellular carcinoma Nat Rev Gastroenterol Hepatol doi: /nrgastro

7 Targeted Therapies Agents against tyrosine kinase receptors or ligands Wei et al., Clinical Medicine Insights: Oncology 2013:7

8 Agents against targets in signaling pathways Wei et al., Clinical Medicine Insights: Oncology 2013:7

9 Wei et al., Clinical Medicine Insights: Oncology 2013:7

10 Chua et al., International Journal of Hepatology, 2011:348297

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14 Hand-foot Syndrome Lipworth et al., Oncology 2009; 77:

15 Limitations of Sorafenib Data Child-Pugh class A only Retrospective series by Pinter et al. evaluating sorafenib in 59 patients Median OS 8.3 months in CP class A, 4.3 months in CP class B, 1.5 months in CP class C Phase 3 study for CP class B patients ongoing in Italy Median OS much shorter in a similar Asian study 6.5 months in sorafenib group vs. 4.2 months in placebo group 12% with Hep B and 30% with Hep C in SHARP study, 73% with Hep B and 8.4% with Hep C in Asian study More patients with more advanced disease or poorer performance status in Asian study Possible pharmacogenetic differences between Asian and Western populations

16 Challengers of Sorafenib Kelley and Venook, Making Progress in Therapeutics for Advanced HCC, 2013 ASCO Education Book

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18 Kelley and Venook, Making Progress in Therapeutics for Advanced HCC, 2013 ASCO Education Book Immune modulation Nivolumab (anti-pd-1 Ab) Phase I NCT

19 Clinical Trials at VM Randomized phase III study of Regorafenib in patients with HCC after Sorafenib Regorafenib oral multi-kinase inhibitor, inhibits VEGFRs 2 and 3, Ret, Kit, PDGRF, and Raf kinases FDA approved for third line advanced GIST treatment and third line metastatic colorectal cancer

20 Upcoming Clinical Trial Phase 3 Randomized, Open-Label Study Comparing Pexa-Vec (Vaccinia GM-CSF / Thymidine Kinase- Deactivated Virus) Followed by Sorafenib Versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) Without Prior Systemic Therapy

21 JX-594 (Pexa-Vec) oncolytic virus Vaccinia poxvirus with addition of GM-CSF gene and deletion of thymidine kinase gene Only replicate in cells with high levels of thymidine kinase such as cancer cells GM-CSF may help initiate anti-tumor immune response Administered by intra-tumoral injections 30-patient randomized dose-finding phase 2 trial showed median survival of 14.1 months

22 References 1. NCCN Guidelines, Hepatocellular Carcinoma, Kelley and Venook, Making Progress in Therapeutics for Advanced HCC, 2013 ASCO Education Book 3. Wei et al., Targeted Therapies in the Treatment of Advanced Hepatocellular Carcinoma, Clinical Medicine Insights: Oncology 2013:7 4. Spangenberg, H. C. et al. (2009) Targeted therapy for hepatocellular carcinoma, Nat Rev Gastroenterol Hepatol doi: /nrgastro Wagman et al., Liver, Gallbladder, and Biliary Tract Cancers: Cancer Management: Online Edition, March Chua et al., Targeted Therapy in Hepatocellualr Carcinoma, International Journal of Hepatology, 2011: Llovet, et al., Sorafenib in Advanced Hepatocellular Carcinoma, NEJM 2008; Lipworth et al., Hand-Foot Syndrome:Focus on Sorafenib and Sunitinib; Oncology 2009; 77: