Treating Hepatocellular Carcinoma: Medical Oncology Options

Treating Hepatocellular Carcinoma: Medical Oncology Options W. Thomas Purcell, MD, MBA Gastrointestinal Oncology Phase I / Developmental Therapeutics Group Executive Medical Director University of Colorado Cancer Center

CONFLICT OF INTEREST DISCLOSURE 1) Off-label use of chemotherapy will be discussed only in context of clinical research. 2) No speakers bureaus; unpaid advisory boards only. 3) I serve as PI of clinical trials (contracts are with University of Colorado) sponsored by Amgen and Bayer.

LEARNING OBJECTIVES 1. Identify the appropriate patient population and indications for the use of sorafenib in the management of hepatocellular carcinoma 2. Rate toxicities and required dose reductions related to sorafenib treatment 3. Summarize current research trials for new agents in the treatment of hepatocellular carcinoma

Challenges in HCC Clinical Research - Comorbidity from cirrhosis (we are treating 2 diseases!) - Appropriate endpoints in clinical trials: response (RECIST?) vs time to progression vs clinical benefits vs overall survival - Optimal imaging modalities - Identifying promising agents/regimens based on phase II data (due to heterogeneity)

Challenges in HCC Clinical Research: - Lack of interest (comparatively) from Pharma and NCI: difficulty accessing new drugs - HCC famously resistant to chemotherapy - Overexpression of MDR-1 gene/pglycoprotein - Liver failure (poor tolerance and dose reductions) - Drug targets are poorly defined

HPB (Oxford). 2005; 7(1): 35 41.

Understanding Survival Outcomes in Patients With HCC HCC Stage 0 PS 0, Child-Pugh A Stage A-C Okuda 1-2, PS 0-2, Child-Pugh A-B Stage D Okuda 3, PS >2, Child-Pugh C Very early stage (0) Single <2 cm Carcinoma in situ Early stage (A) Single or 3 nodules <3 cm, PS 0 Intermediate stage (B) Multi-nodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) 2010 Natural History Median OS >36 mos Median OS 16 mos Median OS 6 mos (4-8 mos) With Therapy Curative therapies OS >60 mos TACE: OS 20 mos Sorafenib: 10.7 mos* 2013 40% 20% 40% Stage at 2020 60% 20% 20% Diagnosis *Child-Pugh A only. Courtesy of Josep M. Llovet, MD.

Case Study 53yo M patient with HCV receives a course of pegylated interferon, but treatment fails to clear the virus. Subsequent surveillance reveals a 2-cm mass in the right lobe of his liver. His AFP level is 485. The patient undergoes ablation. Four months later, he is found to have another lesion and it is treated with repeat TACE. 4 months later, he has 6 lesions throughout his liver with portal vein invasion: aggregate measure of 12cm. AFP now 2100. What should be the next step? 1. Repeat TACE 2. SIRT 3. Evaluate for transplant 4. Sorafenib

Sorafenib (Nexavar ) ½-life: 25 48 hours Inhibits UGT1A1 and CYP enzymes (sorafenib package insert) - A signal transduction inhibitor that inhibits Raf, VEGFR, RET, KIT, and PDGFR-β Multi-targeted; dirty (vs. selective ) - Phase II study: 137 patients enrolled (Abou-Alfa, JCO, 2006) 3 (2.3%): PR / 8 (5.8%): MR / 46 (33.6%): SD Median OS and TTP: 9.2 m and 4.2 m, respectively - Phase III study, SHARP Trial, met overall survival endpoint (Llovet, NEJM 2008:359(4);378-390)

Phase III Trial of Sorafenib (BAY 43-9006, Nexavar) in First-Line Advanced HCC Randomized phase III trial comparing sorafenib vs placebo for previous untreated HCC: Sorafenib HCC Assessment Randomized Protocol (SHARP) (Llovet, NEJM 2008:359(4);378-390) Unresectable and/or metastatic HCC No prior therapy N=602 Stratified by PS, invasion, geography Arm A: Sorafenib 400 BID Arm B: Placebo Primary endpoint: overall survival, time to symptomatic progression Patients: Median age 65, 87% male, 95% Child s A, >90% PS 0-1 82% BCLC stage C, 70% vasc invasion/extrahepatic spread 29% hepc, 26% EtOH, 19% hepb, 16% unknown

SHARP: Overall Survival (Llovet, NEJM 2008:359(4);378-390)

Treatment-emergent serious adverse events (SAE, %) Safety events Sorafenib (n=297) Placebo (n=302) 52 54 Drug-related adverse events (%) 13 9 Drug-related adverse events (%) All Grade 3/4 All Grade 3/4 Diarrhea 39 8 11 2 Pain (abdomen) 8 2 3 <1 Weight loss 9 2 <1 0 Anorexia 14 <1 3 <1 Nausea 11 <1 8 1 Hand-foot skin reaction 21 8 3 <1 Vomiting 5 1 3 <1 Alopecia 14 0 2 0 Liver dysfunction <1 <1 0 0 Bleeding 7 <1 4 <1/<1 Llovet, ASCO 2007

Sorafenib (BAY 43-9006) Rashes (and many other side effects including HTN) can be severe in some cases; medical oncology or hepatology should be involved in prescribing and managing treatment with sorafenib. Maculopapular rash Hand Foot Syndrome Facial rash http://www.nexavar.com/pdf/final_skin_tox.pdf

Hand-Foot Syndrome: Grading Grade Symptom: Palmar-Plantar Erythrodysesthesia Syndrome 1 Minimal skin changes or dermatitis (eg, erythema) without pain 2 Skin changes (eg, peeling, blisters, bleeding, and edema) with pain, limiting instrumental function 3 Skin changes with pain, limiting self-care function Common Terminology Criteria for Adverse Events, Version 4.0. http://evs.nci.nih.gov/ftp1/ctcae/ctcae_4.03_2010-06-14_quickreference_8.5x11.pdf. Accessed 10/27/11.

Confirmatory Phase III Trial of Sorafenib in First-Line Advanced HCC in Asia (China, South Korea, Taiwan) overall survival HR = 0.68, p=0.014 (6.5 vs 4.2 mos) progression-free survival Sorafenib Placebo Complete response 0 0 Partial response 3% 1% Stable disease 54% 21% Sorafenib Placebo Shorter survival in both arms, but similar benefit magnitude to SHARP. No difference in time to symptomatic progression, QoL questionaires. (Cheng, Lancet Oncol 2009:10;25-34)

What about sorafenib in selected HCC populations (SHARP)? - Patients with elevated transaminases? No difference in adverse events (Greten, ASCO GI 2008) - Child s B patients? Pharmacokinetics, side effects similar; overall survival much lower in Child s B (10.3 vs 4.8 months) (Marrero, ASCO 2011; Abou-Alfa, ASCO GI 2008) - Hepatitis C patients? Same benefit (Bolondi, ASCO GI 2008) - Elderly patients? Similar benefit (Mantovani, ASCO GI 2009) - Poor PS? Similar benefit (Raoul, ASCO 2008) - Does it make economic sense? Similar to other treatments, $62,500/life-year gained (Carr, J Gastroenterol Hepatol 2010)

Efficacy of Sorafenib in Patients with Different Grades of Liver dysfunction N PR (%) SD (%) PD (%) NE (%) Median TTP Median OS (mo) Child-Pugh class A 26-19 58 23 2.2 8.3* Child-Pugh class B 23 4 30 48 17 2.9 4.3 Child-Pugh class C 10-20 60 20 2.8 1.5 Intention to treat 59 2 24 54 20 2.8 6.5 No difference in Time to Progression (TTP differs from PFS, which includes death from any cause). Effect of drug independent? Pinter M, et al. Oncologist 2009;14:70-76 Courtesy of Dr. Alan Venook (UCSF)

CALGB 60301: Guidance on The Use of Sorafenib in Patients With HCC With More Advanced Cirrhosis Courtesy of Dr. Alan Venook (UCSF) Bilirubin 1.5 times the upper limit of normal 1.5-3 times the upper limit of normal Suggested Recommendation* 400 mg PO BID 200 mg PO BID Or 400 mg PO qday > 3 times the upper limit of normal AVOID *Caveat - this trial was conducted in patients with different types of tumors, including HCC. The origin of the underlying cirrhosis is clearly different. This area requires further study. Miller AA, et al. J Clin Oncol. 2009;27(11):1800-1805.

Median OS (Mos) Phase III SHARP Trial: Subgroup Analysis Exploratory Subgroup Analyses Sorafenib Placebo 16 14 12 10 8 6 4 10.7 7.9 HR=0.69 (95% CI, 11.9 8.8 11.9 9.9 HR=0.75 14.0 7.0 10.3 8.0 HR=0.76 13.3 8.8 8.9 5.6 HR=0.71 8.9 6.7 14.5 10.2 HR=0.52 2 0 0.55-0.87; P<0.001) Overall Population (N=602) HR=0.79 Prior Curative Therapy (n=158) Prior TACE (n=176) HR=0.58 HCV (n=178) Alcoholic Cirrhosis (n=159) HR=0.68 ECOG PS 0 (n=325) ECOG PS 1/2 (n=277) HR=0.77 MVI and/or EHS (n=421) No MVI and/or EHS (n=181) EHS=extrahepatic spread; HCV=hepatitis C virus; MVI=macroscopic vascular invasion. Llovet. N Engl J Med. 2008;359:378; Galle. EASL. 2008; Bolondi. ASCO GI. 2008 (abstr 129); Craxi. ASCO. 2008. (abstr 15591); Raoul. ASCO. 2008. (abstr 4587); Sherman. ASCO. 2008 (abstr 4584).

Median OS (Mos) Phase III SHARP Trial: HCV Subgroup Analysis Exploratory Subgroup Analyses Sorafenib Placebo 16 14.0 14 12 10 8 7.0 6 4 2 0 HR=0.58 HCV [3] (n=178) Bolondi. ASCO GI. 2008 (abstr 129).

Hand-foot syndrome AEs: Management Strategies Apply topical therapy for symptomatic relief: creams and lotions Avoid tight footwear Might require dose interruption, reduction, or discontinuation if severe Diarrhea Antidiarrheal agents if severe Fatigue Exercise regimen Consider methylphenidate or dose interruption/reduction if severe Hypertension Start or adjust antihypertensives Monitor blood pressure QT prolongation Monitor for prolonged QT interval in patients with congestive heart failure, bradyarrythmias, drugs known to prolong QT interval, and electrolyte abnormalities Nexavar [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2011; Hull. Int J Palliat Nurs. 2010;16:249; Edmonds. Eur J Oncol Nurs. June 2, 2011 [Epub ahead of print].

AASLD-JNCI Guidelines in HCC: Trial Design Endpoints Survival or time to recurrence (phase III) TTP (phase II) Trial strategy: test in the setting of randomized phase II before moving to phase III HCC classification: BCLC staging system recommended for selection of target population, stratification Assessment of response and TTP: Follow the AASLD-JNCI amendments HCC Subclass (Standard of Care) Testing of Novel Drugs First-line Treatment Second-line Treatment* BCLC 0/A (resection, transplantation, local ablation) Adjuvant: drug vs placebo BCLC B (chemoembolization, TACE) BCLC C (sorafenib) TACE vs TACE + drug TACE vs drug or device Sorafenib vs sorafenib + drug Sorafenib vs drug Drug vs placebo *In case of failure to standard of care. Head-to-head comparisons with standard of care are only justified if phase II data are very promising. AASLD=American Association for the Study of Liver Diseases; BCLC=Barcelona Clinic Liver Cancer; JNCI=Journal of the National Cancer Institute. Lencioni R. Semin Liver Dis. 2010;30:52.

Molecularly Targeted Therapy in HCC Cetuximab VEGF Bevacizumab PDGFR EGFR VEGFR Sunitinib Sorafenib Lanifinib everolimus P P P P P P P P13K AKT mtor STAT HIF-1 HIF-1 P Gefitinib Erlotinib GRB2 P P P P SOS Transcription Factors Ras Raf Mek Sunitinib Sorafenib Brivanib Lanifinib Sorafenib Nucleus Survival/ Apoptosis Angiogenesis Metastases Cell proliferation

CALGB 80802 Phase III Trial: Sorafenib With or Without Doxorubicin in Advanced HCC Patients with locally advanced or metastatic HCC R A N D O M I Z E D Sorafenib bid d1-21 Sorafenib bid d1-21 Doxorubicin IV d1 6 cycles optional Estimated enrollment: 480 Primary outcome: OS Sorafenib bid if no PD Secondary outcomes: TTP, PFS, RECIST tumor response, and toxicity PD=progressive disease; RECIST=Response Evaluation Criteria in Solid Tumors. Clinical Trials.gov website. http://clinicaltrials.gov/ct2/show/nct01015833?term=calgb+80802&rank=1. Accessed 10/07/11.