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Updates in hepatocellular cancer and pancreas cancer

Updates in hepatocellular cancer and pancreas cancer. Jordan Berlin, M.D. Ingram Associate Professor, Medicine. Advisory Boards here and there Genentech BMS Imclone Sanofi-Aventis Pfizer Abbott Astra Zeneca Cephalon (not paid) Roche. Spoke for: Genentech Nestle

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Updates in hepatocellular cancer and pancreas cancer

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

  2. 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 Disclosures

  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. 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]) Altekruse, S. F. et al. J Clin Oncol; 27:1485-1491 2009

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

  7. TACE vs Doxorubicin Beads R Lencioni, et al. GI Symposium 2009 and abstract 4523 at ASCO 2009 • 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

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

  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? Zhu, et al. JCO 2008 • 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

  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 Kaseb, et al • 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

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

  18. CONKO-001: Results .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 GEM X 1 CYCLE THEN STOP R A N D O MI Z E R A N D O MI Z E GEM X 5 CYCLES GEM X 1 CYCLE THEN CHEMOXRT GEM + ERLOTINIB X 1 CYCLE THEN STOP GEM + ERLOTINIB X 5 CYCLES 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 Richards DA, et al GI Symposium 2009 • 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

  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. 2nd 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? RANDOMIZE 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 Javle, ASCO 2008 • 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

  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

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