Welcome to Master Class for Oncologists. Miami, FL. December 19, The following relationships exist related to this presentation: Session 2

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1 Session 2 Welcome to Master Class for Oncologists 8:15 AM 9:00 AM Miami, FL December 19, 2009 Alan P. Venook, MD Professor of Clinical Medicine University of California San Francisco Medical School Chief, Gastrointestinal Oncology University of California, San Francisco Cancer Center Presenter Disclosure Information The following relationships exist related to this presentation: Dr Venook receives research grants from Genentech and Bayer-Onyx. A 58 yo male undergoes a pylorus-preserving Whipple (pancreaticoduodenectomy) for a localized pancreatic head mass. Pathology findings include a 3.2 cm moderately differentiated adenocarcinoma with 2/11 involved lymph nodes. Surgical margins are negative. The patient comes to see you 5 weeks later, with an uneventful postoperative recovery, and asks what further therapy should be given. Data from phase III trials support the use of which of the following adjuvant therapies 1. Radiation with concurrent fluorouracil (5-FU) 2. Gemcitabine 3. 5-FU/radiation with additional gemcitabine pre- and post-xrt 4. All of the above PANCREATIC CANCER: STAGING AND PROGNOSIS UNRESOLVED ISSUES IN THE ADJUVANT TREATMENT OF PANCREATIC CANCER Stage classification % at diagnosis 5-year survival Localized 8 20% Locally advanced/ unresectable Metastatic 31 8% 61 2% What are the respective roles of chemotherapy and radiation Are both necessary How should they be sequenced (or does this matter) What agents should be used and how can we be more judicious in our selection Should any/all therapy be delivered in the preoperative setting Does everyone require treatment 1

2 GASTROINTESTINAL TUMOR STUDY GROUP ADDRESSING THE ROLE OF ADJUVANT 5-FU BASED CHEMORADIATION IN PANCREATIC CANCER EVOLUTION OF ADJUVANT THERAPY FOR PANCREATIC CANCER OVER THE PAST DECADE Median survival: 20 vs 11 months (P = 0.03) Study ESPAC-1 (N = 289) Comments Called into question the role of adjuvant chemoxrt Suboptimal delivery of XRT (split course, 4000 cgy) 5-FU, not gemcitabine, used 2 yr survival 43 vs. 18% (4000 cgy XRT in splitcourse with concurrent 5-FU, followed by weekly 5-FU x 2 years) Note: based on 43 patients only, accrued over 8 years. Study terminated prematurely before reaching original accrual goal. CONKO-001 (N = 368) RTOG 9704 (N = 451) - Established 6 month course of gemcitabine as standard of care - Did not address question of XRT - Did not definitively resolve question of gemcitabine vs 5-FU - More grade 4 heme toxicity with gemcitabine - Did not address question of XRT Kalser MH, et al. Arch Surg. 1985;120: EUROPEAN STUDY GROUP FOR PANCREATIC CANCER (Neoptomelos, NEJM 2004) CONKO-001 TRIAL N = x 2 factorial design pooled analysis Median survival, chemo vs no chemo: 20.1 vs 15.5 months Median survival, chemoxrt vs no chemoxrt: 15.9 vs 17.9 months Authors conclusions: chemotherapy produces survival benefit s/p pancreatic ca resection; whereas chemoradiation has deleterious effect Observation (69) Chemotherapy (75) ChemoXRT (73) ChemoXRT chemotherapy (72) - Chemotherapy regimen: 5FU/LV monthly x 6 - Chemoradiation regimen: 4000 cgy XRT (split course) with concurrent 5-FU 71% node (+) 81% R0 resection 73% node (+) 85% R0 resection - Median DFS: 13.4 vs 6.9 months (P < 0.001) - Median OS: 22.8 vs 20.2 months (P = 0.005) - 3-year survival: 36.5 vs 19.5% Oettle H, et al. JAMA. 2007;297: Neuhaus P, et al. ASCO 2008 (LBA #4504). RTOG 9704: 5-FU VS. GEMCITABINE BEFORE AND AFTER 5-FU-BASED CHEMORADIATION WHAT PROGRESS HAVE WE REALLY MADE IN RESECTABLE PANCREATIC CANCER ALL PATIENTS: No difference in overall or disease-free survival between 2 groups Summary of U.S./European phase III adjuvant trials for pancreatic adenocarcinoma over past 3 decades PANCREATIC HEAD TUMORS ONLY (n = 388): Median surv 20.5 vs 16.9 mos, 3-yr surv 31% vs 22% in favor of gem-containing arm Regine WF, et al. JAMA. 2008;299: Regine WF, et al. JAMA. 2008;299:

3 ESPAC-3 TRIAL (Neoptolemos, ASCO 2009, LBA 4505) RTOG 9704: ANALYSIS OF hent1h AS A PREDICTOR OF POSTSURGICAL OUTCOMES WITH ADJUVANT GEMCITABINE VS 5-FU 5 THERAPY Resected pancreatic adenocarcinoma (R0/R1 resection) DFS OS Observation Gemcitabine 1,000 mg/m 2 Days 1,8, and 15 q28 days x 6 months (N = 537) Stratification by: - resection margin - country 5-FU 425 mg/m 2 Folinic acid 20 mg/m 2 Daily iv bolus, dd 1-5 q28 days x 6 months (N = 551) Median PFS 14.3 months 14.1 months Median OS 23.6 months 23.0 months hent1 expression (equilibrative nucleoside transporter) in in patients patients receiving receiving adjuvant adjuvant gemcitabine 5-FU in RTOG in RTOG Farrell JJ, et al. Gastroenterology. 2009;136: SHOULD NEOADJUVANT THERAPY BE CONSIDERED FOR OPERABLE DISEASE THEORETICAL ADVANTAGES OVER POSTOPERATIVE TREATMENT Improved rate of obtaining negative surgical margins Do not need to worry about prolonged postoperative recovery before administering treatment In older postop studies, ~20-25% of patients intended for adjuvant therapy do not end up receiving it Patients who manifest with distant metastases on restaging studies are spared the morbidity associated with surgery Allows testing of novel agents for on-target tumor effects MD Anderson experience: approximately 2/3rds of patients make it to surgery with a 2-4 months course of preop chemoxrt; of these, median surv = months (Evans DB. J Clin Oncol. 2008;26: Varadhachary GR. J Clin Oncol. 2008;26: ) MAJOR CONCERN: delay of only potentially curative option (surgery) A 58 yo male undergoes a pylorus-preserving Whipple (pancreaticoduodenectomy) for a localized pancreatic head mass. Pathology findings include a 3.2 cm moderately differentiated adenocarcinoma with 2/11 involved lymph nodes. Surgical margins are negative. The patient comes to see you 5 weeks later, with an uneventful postoperative recovery, and asks what further therapy should be given. Data from phase III trials support the use of which of the following adjuvant therapies 1. Radiation with concurrent fluorouracil (5-FU) 2. Gemcitabine 3. 5-FU/radiation with additional gemcitabine pre- and post-xrt 4. All of the above TREATMENT OF METASTATIC DISEASE: ARE WE STUCK ON GEMCITABINE A 62 yo male is diagnosed with pancreatic adenocarcinoma with multiple hepatic metastases. He has a ECOG performance status of zero. The most appropriate treatment for him would consist of: 1. Gemcitabine alone 2. Gemcitabine plus erlotinib 3. Gemcitabine plus a platinum analog 4. Gemcitabine plus capecitabine 5. There is no single standard of care but gemcitabine serves as the mainstay of treatment Gemcitabine approved in 1997 for first-line therapy of advanced PDAC Median survival (vs bolus 5-FU): 5.65 vs 4.41 mos. (P = ) 1-yr survival: 18% vs 2% Clinical benefit: 23.8% vs 4.8% RR: 5.4% vs 0% Burris HA. J Clin Oncol. 1997;15:

4 OPTIMIZATION OF PHARMACOKINETICS: ADMINISTRATION OF GEMCITABINE AT FIXED DOSE RATE INFUSION ECOG 6201: A RANDOMIZED PHASE III STUDY Gem 2200 mg/m standard 30 min infusion RR 4.1% 11.6% Median survival 5.0 months 8.0 months TTP 1.8 months 2.2 months 1-yr survival 7.3% 23.8% Grade 3/4 neutropenia 27.3% 48.8% Grade 3/4 10.2% 37.2% thrombocytopenia LFT abnormalities 4.4% 14.6% Gem 1500 mg/m 10 mg/m 2 /min (FDR) GEM 4.9 ( ) 17% FDR GEM 6.0 ( ) 21% GEMOX 5.9 ( ) 21% FDR GEM vs GEM: hazard ratio: 0.83 (95%CI, ); stratified log rank P = 0.05 GEMOX vs GEM: hazard ratio: 0.88 (95%CI, ); stratified log rank P = 0.16 P = 0.2 Tempero M, et al. J Clin Oncol. 2003;21: Poplin, ASCO 2006 Gem FDR gem GemOx WHAT ABOUT COMBINATION THERAPY: GEMCITABINE/PLATINUM DOUBLETS FOR ADVANCED PANCREATIC CANCER (PHASE III STUDIES) OTHER GEMCITABINE-BASED DOUBLETS: PHASE III TRIALS OF GEM-CAP VS GEMCITABINE GEM-CAP Gemcitabine Statistically significant Treatment Progression-free Median survival survival Gruppo Oncologia Gemcitabine 8 weeks 5 months dell Italia Meridionale Study Combined Gemcitabine/cisplatin analysis: 20 weeks (p=0.048) 7.5 months (P = 0.48) (n = 107) German Multicentre gemcitabine/platinum Study Gemcitabine 3.1 results months in 6.0 months (n = 190) Gemcitabine/cisplatin 5.3months (p=0.053) significant improvement in 7.5 months (P = 0.15) GERCOR/GISCAD Gemcitabine 3.7 months 7.1 months Intergroup Study overall (n=313) survival (HR 0.85, P = 0.01) Gemcitabine/oxaliplatin 5.8 months (p=0.04) 9.0 months (P = 0.13) ECOG 6201 (n=833) Heinemann Gemcitabine et al, BMC Cancer N/A months * Third arm = FDR gem Gemcitabine/oxaliplatin N/A 5.9 months Viret et al (n=83) Gemcitabine 2.5 months 6.7 months Gemcitabine/cisplatin 2.2 months (p=ns) 8.0 months (P = 0.73) Cunningham, Eur J Cancer. 2005;3(suppl):4 (abstr PS11). N Med survival 7.4 months 6 months P = Herrmann R, et al. J Clin Oncol. 2007;25: (SAKK study) N Med survival 8.4 months 7.2 months P = (SAKK study, post hoc analysis on pts with KPS ) N Med survival P = TO DATE, NO PUBLISHED PHASE III STUDY HAS SHOWN A SURVIVAL BENEFIT OF COMBINATION CYTOTOXIC THERAPY COMPARED WITH GEMCITABINE ALONE PERFORMANCE STATUS IS CRITICAL IN SELECTING TREATMENT FOR ADVANCED PANCREATIC CANCER Gemcitabine + : Platinum analogs (cisplatin, oxaliplatin) Meta-analysis indicates significant survival benefit of gemcitabine + platinum analog (HR 0.85) Fluoropyrimidines (5-FU, capecitabine, S-1) Meta-analysis indicates significant survival benefit of gemcitabine + fluoropyrimidine (HR 0.90) Camptothecins Meta-analysis of randomized trials confirms that performance status is critical factor in determining who is more likely to benefit from combination chemotherapy. ECOG PS 0-1/ Karnofsky PS % ECOG PS 2/ Karnofsky PS 60-80% Benefit from combination therapy Yes (HR, 0.76, P < 0.001) No (HR, 1.08, P = 0.40) Heinemann V, et al. BMC Cancer. 2008;8:82. 4

5 PA.3: ERLOTINIB BECOMES THE FIRST TARGETED AGENT APPROVED FOR USE IN PANCREATIC CANCER PHASE III STUDY OF GEMCITABINE + ERLOTINIB IN ADVANCED PANCREATIC CANCER (NCIC PA.3) EGFR overexpression seen in 42-90% of human pancreatic adenocarcinomas Correlates with: Poor patient prognosis and more aggressive disease Reduced sensitivity to chemotherapy In preclinical models, EGFR inhibitors enhanced gemcitabine activity PA.3: SURVIVAL RESULTS WHY HAS ERLOTINIB NOT CAUGHT ON MORE IN PANCREATIC CANCER Despite the statistically significant difference in overall survival, a median absolute improvement of 0.33 months may not be: Clinically meaningful Cost-effective Better results with other gemcitabine-based cytotoxic doublets Moore MJ, et al. J Clin Oncol. 2007;25: Copyright American Society of Clinical Oncology PFS: 3.75 vs 3.55 months (P = 0.004) RR: 8.6 vs 8.0% (P = NS) Why should a tumor characterized by almost ubiquitous K-ras mutational activation be responsive to an EGFR inhibitor THE DISAPPOINTMENT OF TARGETED AGENTS IN PANCREATIC CANCER: SURVIVAL IN PHASE III TRIALS POSSIBLE REASONS FOR PANCREATIC TUMOR RESISTANCE TO TARGETED AGENTS Drug X Mechanism Sample size Marimastat Matrix metalloproteinase inhibitor R Farnesyl transferase inhibitor Gem alone Gem + drug X months 5.4 months months 6.0 months Erlotinib Oral TKI, EGFR months 6.4 months Bevacizumab mab, VEGF months 5.8 months Cetuximab mab, EGFR months 6.4 months Complexity and redundancy of signaling: single targeted agent less likely to be effective Surrounding desmoplasia: role of supporting connective tissue elements Pancreatic cancer stem cells: highly tumorigenic, can generate phenotypic diversity within the tumor; may be resistant to standard therapies 5

6 WHAT ABOUT LOCALLY ADVANCED PANCREATIC CANCER: OUTSTANDING QUESTIONS SUMMARY OF EARLY STUDIES IN LOCALLY ADVANCED PANCREATIC CANCER Need to treat differently than metastatic disease To radiate or not to radiate Up-front vs delayed radiation How often is downstaging successfully accomplished RADIATION FIRST, CHEMO LATER Importance of obtaining optimal local control Better palliation of symptoms Better likelihood of cytoreduction to downstage a patient for potential surgery CHEMO FIRST, RADIATION LATER Greatest imperative is to eradicate micrometastatic disease Limits XRT to subgroup of patients whose tumors do not spread and are wellcontrolled with a period of up-front systemic therapy (series suggest 25-35% dropout rate with this strategy) Study N Results GITSG 1981 GITSG 1988 ECOG XRT alone (6000 cgy): median surv = 23 weeks XRT (4000 cgy) + bolus 5-FU: median surv = 42 weeks XRT (6000 cgy) + bolus 5-FU: median surv = 40 weeks 5-FU/XRT (4000 cgy) followed by SMF: median surv = 42 weeks SMF alone (streptozocin/mmc/5- FU): median surv = 32 weeks 5-FU/XRT (4000 cgy) followed by 5-FU: median survival = 8.3 mos 5-FU alone: median surv = 8.2 mos Take Home Message chemoxrt superior to XRT (chemoxrt chemo) superior to chemotherapy (chemoxrt chemo) equivalent to chemotherapy RECENT PHASE III STUDIES FOR LOCALLY ADVANCED PANCREATIC CANCER: FFCD-SFRO vs ECOG 4201 CAN NON-GEMCITABINE BASED REGIMENS BE USED FOR FRONT-LINE THERAPY Induction regimen Maintenance chemotherapy Median OS compared with chemo alone FFCD/SFRO Cisplatin/5-FU cgy XRT (6 weeks) Gemcitabine until progression 8.6 vs 13.9 months, in favor of chemo alone ECOG Gemcitabine cgy XRT (6 weeks) Gemcitabine x 5 cycles 11.0 vs 9.2 months, in favor of induction chemoxrt 1-year survival 32% vs 53% 50% vs 32% Did ECOG study use a more effective radiosensitizing regimen Was the induction regimen prescribed by FFCD/SFRO overly intensive delayed administration and total amount of subsequent systemic therapy Further exploration of delayed chemoradiation is required. CapOx/FOLFOX Showed comparable efficacy to gemcitabine-based combination regimens in randomized phase II German trial (Boeck S, et al. Ann Oncol. 2008;19: ) Has emerged as standard of care in second-line setting (CONKO-003) (Pelzer U. ASCO Abstract 4508.) Docetaxel/irinotecan Encouraging phase II data (Burtness B, et al. Cancer J. 2007;13: ) Basis of randomized phase II trial through ECOG (+/- cetuximab) (Burtness B. ASCO Abstract 4642.) PROGRESS IN PANCREATIC CANCER: NEW AGENTS TO WATCH FOR nab-paclitaxel (Abraxane) Phase I results of gem/abraxane: RR, 40%, median OS > 10 mos (von Hoff DD. ASCO Abstract 4525.) May be particularly effective in SPARC-positive tumors through albumin binding Cationic liposomal paclitaxel (EndoTag) Inhibitors of other signaling pathways: Hedgehog TGF-beta Raf/MEK/ERK and other Ras effector pathways Potential role of PARP inhibitors for BRCA1/2-associated pancreatic cancers A 62 yo male is diagnosed with pancreatic adenocarcinoma with multiple hepatic metastases. He has a ECOG performance status of zero. The most appropriate treatment for him would consist of: 1. Gemcitabine alone 2. Gemcitabine plus erlotinib 3. Gemcitabine plus a platinum analog 4. Gemcitabine plus capecitabine 5. There is no single standard of care but gemcitabine serves as the mainstay of treatment 6

7 CHALLENGES OF HCC Clinical course affected by various factors: Underlying etiology (HBV, HCV, alcohol, etc.) Hepatic function Cirrhosis complicates outcome assessment Competing causes of death (HCC and liver dysfunction) Altered pk Difficult to image cirrhotic liver CHILD-PUGH SCORE OF LIVER CIRRHOSIS HEPATOCELLULAR CARCINOMA: CANCER LIVER ITALIAN PROGRAM (CLIP) STAGING Parameter Points Albumin (g/dl) > < 2.8 Bilirubin (mg/dl) < > 3 Ascites Absent Slight Moderate Encephalopathy None I - II III - IV PT (INR) < > 2.3 Childs- Pugh Tumor AFP (ng/dl) A B C Single, < 50% Multi, < 50% < 400 > 400 Massive, > 50% Score A B C Portal vein thrombus No Yes Points Pugh RNH, et al. British Journal of Surgery. 1973;60: Range: 0-6 CLIP, Hepatology, 1998 MANAGEMENT OF HEPATOCELLULAR CARCINOMA: RESULTS WITH RESECTION MANAGEMENT OF HEPATOCELLULAR CARCINOMA: RESULTS WITH ORTHOTOPIC LIVER TRANSPLANT Only 20-25% of patients resectable - Decompensated liver disease / vascular invasion - Multi-focal tumors / metastases Ablation techniques increase candidates - Less loss of hepatic parenchyma - Minimally invasive techniques Benefit to adjuvant therapies Historically < 20% survival with HCC Mazzaferro criteria : - If solitary, no tumor > 5 cm - If multiple, no more than 3 tumors, none > 3 cm - No metastases - 4-year survival after OLT of 83% (= benign) Yao (UCSF) criteria - If solitary, tumor 6.5 cm - If multifocal, 3 tumors, none > 4.5 cm - Total tumor diameter 8 cm - 1-yr survival = 90% ; 5-yr survival = 75% OLT vs resection Mazzaferro V, et al. N Engl J Med. 1996;334: Yao FY, et al. Hepatology. 2001;33:

8 MANAGEMENT OF HEPATOCELLULAR CARCINOMA: LOCOREGIONAL THERAPIES MANAGEMENT OF HCC: DOES LOCOREGIONAL CONTROL IMPROVE SURVIVAL Numerous techniques to kill tumor: Ablation Percutaneous ethanol Radiofrequency waves Cryotherapy High-intensity focused ultrasound Embolization / chemoembolization Internal radiotherapy (TheraSpheres, SIR-Spheres) Conformal radiation 791 excluded! (common reasons: very early or very advanced HCC, vasc invasion, ESLD) SURVIVAL ADVANTAGE FOR TACE COMPARED TO CONSERVATIVE RX 2-yr surv 63 vs 27% (P = 0.009) Llovet JM, et al. Lancet. 2002;359: MANAGEMENT OF HEPATOCELLULAR CARCINOMA: DOES CHEMOTHERAPY WORK Single agent / combo response rates 5-10% Doxorubicin standard Capecitabine Cisplatin / IFN / dox / 5-FU (PIAF): 20-25% objective response rate Some pathological complete responses in phase II study (Leung TW, et al. Clin Cancer Res. 1999;5: ) Subsequent phase III study demonstrated NO improvement in overall survival compared to doxorubicin alone (Yeo W, et al. J Natl Cancer Inst. 2005;97: ) has been shown to improve survival in all populations of patients with hepatocellular carcinoma except which of the following 1. Patients with hepatitis C viral disease 2. Patients with hepatitis B viral disease 3. Patients with multifocal HCC 4. Patients with any degree of liver dysfunction 5. Patients with cirrhosis that is no worse than Child-Pugh A SORAFENIB TARGETS BOTH TARGET CELL PROLIFERATION AND ANGIOGENESIS MANAGEMENT OF HEPATOCELLULAR CARCINOMA: SORAFENIB PHASE II DATA EGF/HGF RAF MEK ERK Tumor cell Autocrine loop Apoptosis RAS Mitochondria HIF-2 EGF/HGF PDGF VEGF Nucleus Proliferation Survival Paracrine stimulation Endothelial cell or Pericyte PDGFR-β Mitochondria Apoptosis PDGF-β RAF MEK ERK Nucleus RAS VEGF VEGFR-2 Angiogenesis: Differentiation Proliferation Migration Tubule formation Child s A + B, untreated 400 mg bid continuous N = 137 PR = 2.2% However, some pts with stable disease exhibited significant tumor necrosis TTP = 4.2 months; OS = 9.2 months Baseline Follow-up 1 Follow-up 2 Wilhelm SM, et al. Cancer Res. 2004;64: Abou-Alfa GK, et al. J Clin Oncol. 2006;24(26):

9 PATIENT CHARACTERISTICS Primary endpoints: Overall survival Time to symptomatic progression (FHSI8-TSP) Secondary endpoints: Time to progression (independent review) Stratification: Macroscopic vascular invasion and/or extrahepatic spread ECOG PS Geographical region Randomization N=602 (n=299) 400 mg po bid continuous dosing Placebo (n=303) 2 tablets po bid continuous dosing Characteristics (n=299) Placebo (n=303) Age (yr, median) Male/Female (%) 87/13 87/13 Region (Europe/N. America/other; %) 88/9/3 87/10/3 Etiology Viral hepatitis (HCV/HBV) Alcohol/other 29/19 26/26 27/18 26/29 Child-Pugh (A/B; %) 95/5 98/2 Prior therapies: Surgical resection Loco-regional therapies 19% 39% 21% 41% Llovet JM, et al. N Engl J Med. 2008;359: PHASE III SHARP TRIAL: SURVIVAL RESULTS (INTENTION- TO-TREAT) Median survival 10.7 vs 7.9 mos (P < 0.001) Overall response Complete response (CR) Partial response (PR) (n = 299) 0 7 (2.3%) Placebo (n = 303) 0 2 (0.7%) Stable disease (SD) 211 (71%) 204 (67%) Progressive disease 54 (18%) 73 (24%) Progression-free rate at 4 mo 62% 42% Duration of treatment (median, weeks) Llovet JM, et al. N Engl J Med. 2008;359: FSHI8-TSP: No significant differences between treatment groups (P = 0.77). Llovet JM, et al. N Engl J Med. 2008;359: SHARP: SUMMARY OF EFFICACY MEASURES BY HCV STATUS PHASE III SHARP TRIAL: TOXICITY EVALUATION (n = 297) Placebo (n = 302) Treatment-emergent SAE (%) Drug-related adverse events (%) 13 9 Drug-related adverse events (%) All Grade 3/4 All Grade 3/4 Diarrhea Pain (abdomen) <1 Weight loss 9 2 <1 0 Anorexia 14 <1 3 <1 Nausea 11 <1 8 1 Hand-foot skin reaction <1 Vomiting <1 Alopecia Liver dysfunction <1 <1 0 0 Bleeding 7 <1 4 <1/<1 Llovet J et al. J Clin Oncol. 2007;25(Suppl 18):LBA

10 ASIA-PACIFIC HCC SORAFENIB TRIAL BASELINE CHARACTERISTICS Eligibility Advanced HCC ECOG 0-2 Child-Pugh A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS Geographic area R A N D O M I Z E 2:1 n = 150 n = mg bid Placebo End points: Overall survival, time to symptomatic progression (FSHI8-TSP), time to progression, response (RECIST), and safety No primary endpoint defined Cheng et al, ASCO, 2008 Cheng et al, ASCO 2008 ASIA-PACIFIC LIVER CANCER STUDY VS SHARP: DIFFERENCES IN PATIENT CHARACTERISTICS Survival Probability Median: 6.5 months (95% CI: ) Placebo Median: 4.2 months (95% CI: ) 0.25 HR (S/P): % CI: P = Patients at Risk Months Placebo Asia-Pacific (n = 226) Median age (yrs) SHARP (n = 602) Hepatitis virus status 73/8 18/28 (HBV/HCV) ECOG PS 0/1/2 26/69/5 54/38/8 Extrahepatic spread 69% 51% 3+ tumor sites 55% 25% Lung involvement 50% 21% EFFICACY AND SAFETY COMPARISONS ACROSS STUDIES WHAT CAN WE SAY ABOUT SORAFENIB IN HCC BASED ON THESE TWO STUDIES Overall survival (mos) Asia-Pacific (n = 226) 6.5 vs 4.2 (2.3 month improvement) TTP (mos) 2.8 vs 1.4 (1.4 month improvement) Hand-foot 45% 21% SHARP (n = 602) 10.7 vs 7.9 (2.8 month improvement) 5.5 vs 2.8 (2.7 month improvement) The sum of the data reinforces the efficacy of sorafenib as a single agent in Child s-pugh A patients. Robust survival benefit seen in particular in patients with HCV infection. Asian patients get comparable benefit from sorafenib, but have much poorer survival overall. More prior treatment More extensive disease Hepatitis B-related 10

11 WHAT ABOUT SORAFENIB FOR CHILD- PUGH B PATIENTS Subset analysis of single-arm phase II study (Abou-Alfa GM. ASCO 2008, Abstract 4518.) Childs A (n = 98), % Childs B (n = 38), % Serious Adverse Events Hand Foot Skin Reaction Diarrhea Bilirubin Increase Ascites Encephalopathy 2 11 SD ( 4 months) 49% 26% TTP 21 weeks 13 weeks OS 41 weeks 14 weeks Similar pharmacokinetic profiles between Childs A and B patients OTHER AGENTS UNDER EVALUATION IN HCC Sunitinib (Zhu AX, et al. J Clin Oncol. 2009;27: ) N = mg/day for 4 weeks followed by 2 weeks off RR, 3%, median PFS, 3.9 months, OS, 9.8 months Bevacizumab/erlotinib (Thomas MB, et al. J Clin Oncol. 2009;27: ) N = 40 Bevacizumab 10 mg/kg q 14 days, erlotinib 150 mg daily RR, 25%, median PFS, 39 weeks, OS, 68 weeks Cetuximab (Zhu AX, et al. Cancer. 2007;110: ) N = mg/m2 loading dose, then 250 mg/m2 weekly RR, 0%, median PFS, 1.4 months, OS, 9.6 months Others: brivanib, thalidomide Utility in sorafenib-resistant HCC PROGRESS IN HCC: NEXT QUESTIONS TO ASK How safe and effective is sorafenib for Child s B and C patients How effective is sorafenib when combined with other therapeutic agents Phase II doxorubicin +/- sorafenib combination rx median surv mos, TTP 8.6 mos (Abou-Alfa, GI Cancers Symposium 2008) Phase III sorafenib +/- doxorubicin (CALGB) Phase III sorafenib +/- erlotinib in the adjuvant setting Post-transplant or resection Post-TACE As a bridge to transplant Other molecularly targeted agents has been shown to improve survival in all populations of patients with hepatocellular carcinoma except which of the following 1. Patients with hepatitis C viral disease 2. Patients with hepatitis B viral disease 3. Patients with multifocal HCC 4. Patients with any degree of liver dysfunction 5. Patients with cirrhosis that is no worse than Child-Pugh A Questions & Answers Thank you for attending Master Class for Oncologists 66 11