1. Updates in hepatocellular cancer and pancreas cancer Jordan Berlin, M.D. Ingram Associate Professor, Medicine

2. Disclosures Advisory Boards here and there –Genentech –BMS –Imclone –Sanofi-Aventis –Pfizer –Abbott –Astra Zeneca –Cephalon (not paid) –Roche Spoke for: –Genentech –Nestle »Not being paid in chocolate DSMB –Pfizer Presented a lot of data resulting in trips to Europe (ESMO and ECCO) –Amgen

3. Hepatocellular Cancer What we know about HCC Known risk factors include hepatitis B and C –Most common etiology is hep C in the US, but in certain ethnic groups, recent immigrants and in much of the world, hep B is more common –Other causes: alcohol, Wilson’s, hemochromatosis, idiopathic to name a few –Previously, SEER data showed a rise in HCC

4. Hepatocellular Cancer SEER Data update –Rising incidence with a tripling form 1975 to 2005 »1.6/100,000 in 1975, 4.9 per 100,000 in 2005 –Steady decrease in mortality »1 year survival rose from 25% to 47% »2 year survival rose from 16% to 35% Altekruse SF< et al JCO 27:1845-51, 2009

5. Altekruse, S. F. et al. J Clin Oncol; 27:1485-1491 2009 Fig 1. Annual age-adjusted incidence rates per 100,000 and trends, all hepatocellular carcinoma cases and by sex, 1975 to 2005 (Surveillance, Epidemiology, and End Results 9 [SEER9])

6. Treatments Transplantation Surgery TACE PEI RFA Chemo (doxorubicin, fluoropyrimidine) Sorafenib

7. TACE vs Doxorubicin Beads TACE with doxorubicin vs DCE (drug- eluting bead embolization) Child’s A or B, PS 0-1 212 patients in 23 European Centers –After dropout, 93 in DCE vs 102 in TACE –RR 52% DCE vs 44% in TACE, p = 0.11 –Gr 3-4 AE’s, 13% DCE vs 19% TACE –Doxorubicin related AE’s any grade was less likely with DCE vs TACE p < 0.0001 R Lencioni, et al. GI Symposium 2009 and abstract 4523 at ASCO 2009

8. Drug-eluting Beads 2009 73 patients randomized to drug-eluting –OS 610 vs 284 days (p, 0.03) –Benefit was limited to Child’s A and B patients Dhanasekaran, et al

9. Targeted Therapies Sorafenib –Sharp trial: »602 Child’s A patients randomized to sorafenib vs placebo »Median survival 10,7 months vs 7.9 months, HR 0.69, p < 0.001 –Asian Trial »226 Child’s A patients »Median Survival 6.2 months vs 4.1 months, HR 0.67, p = 0.0155 »Median PFS =2.8 vs 1.4 months, p = 0.009 Toh, et al,ASCO 2009, Llovet, et al NEJM 359:378-, 2009

10. What about other VEGF inhibitors? Sunitinib –Phase II study in 34 patients »PFS 3.9 months »OS 9.8 months »RR 2.9%, SD 50% »Increased levels of inflammatory molecules predicted poorer outcomes Zhu, et al. JCO 2008

11. Other VEGF inhibitors Bevacizumab –Phase II study of 46 patients –PFS 6.9 months –OS 12. months –1, 2, and 3 year survivals: 53%, 28%, 23% –RR 13%, 65% progression fre at 6 months –Gr 3 HTN 15%, Gr 3 bleed Siegel AB, JCO 26:2992-8, 2008

12. ASCO 2009 Brivanib in HCC –Median OS 10 months, TTP 2.8 months, RR <10% (Raoul, et al) Continuous Sunitinib in HCC –Median OS 9.3 months, PFS 2.8 months and RR <10% (Koeberle, et al) ABT 869 in HCC –Median OS 9.9 moths, PFS 3.7 months, RR <10% (Toh, et al)

13. Combined Targeted Agents Bevacizumab + erlotinib –Phase II study of 40 patients »PFS 9 months »OS 15.6 months »RR 25% »PFS at 16 weeks – 62.5% »Gr 3-4 fatigue, 20%, HTN 15% and diarrhea 10% Thomas MB, et al JCO 27:843-50, 2009

14. Bevacizumab + erlotinib in HCC ASCO 2009, abstract Bev 10 mg/kg q 2weeks with erlotinib 150 mg daily 58 patients –14 PR (28%), 32 SD (62%), 4 (10%) PD –Median PFS 7.9 months, OS 12.8 months (ABSTRACT), but closer to 15 months for patients with no prior therapy 2 other trials of similar regimens at ASCO as well Kaseb, et al

15. HCC Conclusions Drug-eluting beads show promise in comparison to TACE –Larger trials needed VEGF inhibition appears effective in this disease, regardless of agent Combined VEGF/EGFR inhibition is also showing promise (bevacizumab/erlotinib) –Results of the randomized phase II trial will be crucial

16. Pancreas Cancer

17. CONKO-001: Trial Design Gem Obs Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks Observation: d1; q 4 weeks RandomisationRandomisation Follow up every 8 weeks Gem Ultrasound after week 8 Ultrasound after week 16 CT Scan after week 32 Obs Gem Obs Gem Obs Gem Obs Gem Obs Gem Obs CA 19-9 4 weeks CA 19-9. Oettle H, et al JAMA 297:267-77, 2007

18. CONKO-001: Results Intent-to-Treat Gem vs obs Qualified Gem vs obs DFS (months)13.4 vs 6.9 P < 0.001 13.7 vs 6.9 P < 0.001 Median OS (months)22.1 vs 20.2 P= 0.06 24.2 vs 20.5 P = 0.02 5-year Survival22.5% vs 11.5%N/A. Oettle H, et al JAMA 297:267-77, 2007

19. CONKO-001 Updated results: –DFS: 13.4 months vs 6.9 months, p < 0.001 »At 3 years: DFS 23.5% vs 8.5% »At 5 years: DFS 16.0% vs 6.5% –OS: Median 22.8 vs 20.2 months, p = 0.005 »At 3 years: 36.5% vs 19.5% »At 5 years: 21% vs 9% –DFS data, all tested subsets benefitted Neuhaus, et al asco LBA4504, 2008

20. ESPAC 3 Randomized trial of 5FU/LV (Mayo regimen) vs gemcitabine –To be presented this PM

21. Picozzi Regimen Phase II trial –43 patients –Treated with 54Gy XRT + »Cisplat 30 mg/m2/week + CI 5-FU 200 mg/m2/d + interferon 3,000,000 units/d »Followed by 5-FU 200mg/m2/d x 6 weeks repeated x1 (total + 2 cycles) –Results »42% hospitalized, no deaths »Median survival not defined »1,2 and 5-yr actuarial survival: 95%, 64%, and 55%, respectively –Conclusion: Should be evaluated further »ACOSOG Trial is repeating this trial with careful monitoring Picozzi VJ, et al Am J Surg 185:476-80, 2003

22. Adjuvant pancreas cancer ACOSOG Z5031 phase II trial –Cisplat/ifn/5FU + XRT followed by 2 cycles of infusional 5FU –Planned 93 patients, but stopped early for toxicity endpoint, although there were no study deaths »96% had grade ¾ toxicity »56% initiated all cycles of therapy –89 patients »Median OS: 27.1 months »Median PFS: 14.1 months »2 year survival: 58% Piccozzi, et al ASCO 2008

23. So, chemo or chemo-XRT? EORTC/FFCD/GERCOR randomized phase II trial –90 patients randomized to gem vs gem- XRT »DFS was 12 vs 11 months »OS was 24 months on both arms »Local recurrence as first site was lower with chemoradiation (24 vs 11%) »The conclusions by the EORTC were very appropriate and this was an extremely well done poster: Gem-XRT was safe and a larger trial is needed to discern if there is benefit to chemoxrt Van Laethem ASCO 2009

24. RTOG 0848 RANDOMIZERANDOMIZE GEM X 5 CYCLES RANDOMIZERANDOMIZE GEM + ERLOTINIB X 5 CYCLES GEM X 1 CYCLE THEN STOP GEM X 1 CYCLE THEN CHEMOXRT GEM + ERLOTINIB X 1 CYCLE THEN STOP GEM + ERLOTINIB X 1 CYCLE THEN CHEMOXRT

25. Metastatic Pancreas Cancer Over the last decade or so, numerous trials of gemcitabine alone vs gemcitabine + any drug was negative, except with the addition of erlotinib CALGB 80303, gem vs gem + beva –590 patients randomized –Phase II trial had median survival > 8.5 months (> 12 months initially but as tie went on, this went down) –Phase III trial was negative

26. AVITA Gem-erlotinib vs gem-erlotinib-bevacizumab –607 patients randomized phase III trial »Median OS: 6.0 vs 7.1 months, HR 0.89, P, 0.21 »Median PFS: 3.6 vs 4.6 months, HR 0.73, P, 0.0002 »RR 8.6 vs 13.5% »Time to KPS deterioration 10.1 vs 7.9 months, p 0.08 »SAE’s similar Vervenne W, et al ASCO 2008 abst 4507

27. Rationale for new VEGF targeted Phase III trials? Gem vs gem-axitinib randomized phase II –Endpoints: OS 10 vs 6 months or alternative, HR of 0.6 –Results: »OS 6.9 vs 5.6 months (p, NS) »HR 0.76 uncorrected (p, NS) »HR 0.71, corrected (p, NS) »Toxicity greater in gem-axitinib »Looked better in PS 0-1 patients than in PS =2 »My favorite: QOL favored gemcitabine alone

28. Gem vs gem-enzastaurin Randomized phase II, 130 patients (2:1 randomization) –Median Survival: 5.4 vs 5.1 months –1-year survival: 20% vs 16% –No further study warranted. Thank you Dr. Richards and Lilly for reading and interpreting your own study correctly Richards DA, et al GI Symposium 2009

29. Old ideas in new ways 2 trials with novel delivery of taxanes –Nab-paclitaxel + gemcitabine »All patients (n = 67) PFS 6.9 months, OS 10.3 months »Patients at phase II dose (n =44) 40% RR by CT, PFS 7.9 months, OS >15 months so far –Cationic liposomal paclitaxel »Randomized phase II of gem vs gem + one of 3 dose levels of cationic liposomal paclitaxel »RR 13-16% »PFS: 2.5, 4.6, 5.0 and 4.5 months »OS: 7.2, 8.4, 8.7 and 9.4 months Von Hoff, et al and Loehr, et al

30. 2 nd Line? 5FU is de facto “standard” CONKO-003 –Randomization (168 patients) to Folinic acid/5FU vs oxali/Folinic acid/5FU »160 patients eligible »Median PFS 13 weeks vs 9 weeks, p 0.012 »Median OS 26 weeks vs 13 weeks, p 0.014 Pelzer U, et al ASCO 2009, abst 4508

31. Pancreas Cancer Adjuvant therapy –Chemo definitely benefits patients (only gemcitabine data shown) –Chemo-XRT regimens may also help, but full role of XRT not elucidated »Local control may matter a lot more once we have better systemic therapy Metastatic Disease –Angiogenesis inhibition—didn’t work, doesn’t work, unlikely to work—STOP IT –Nab-paclitaxel has promising data worthy of phase III trial, not standard care

32. Can we stop this pattern? RANDOMIZERANDOMIZE Gemcitabine Alone Gemcitabine + Your Drug Here Your Drug =Tecans platinums fluoropyrimidines EGFR inhibitors VEGF inhibitors and lots of them Many have a hard time considering treatment without gem first

33. Javle Polymorphisms and gemcitabine effect –120 patients in 2 neoadjuvant trials, 1 of chemo before chemoxrt and the other just chemoxrt –2 alleles, one of cytidine deaminase and one of deoxycytidine kinase predicted for poorer survival and less neutropenia –Looking at 7 deleterious alleles, number of alleles, 0 vs 1-2 vs 3 that were present predicted survival Javle, ASCO 2008

34. Overall Data like Javle’s needs further development –Not proven at this time, but encouraging that we may some day be able to determine who will benefit from which treatment We need to figure out which patients benefit from gemcitabine and which don’t