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ASCO Update 2012: Gastrointestinal Malignancies

ASCO Update 2012: Gastrointestinal Malignancies. Thomas J. Semrad MD, MAS Assistant Professor of Medicine Division of Hematology/Oncology. Disclosure. Speaker’s Bureau: Novartis Consulting: Amgen, Genomic Health Research Funding: Novartis, Millenium , NCI. ASCO 2012: Non-Colorectal Topics.

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ASCO Update 2012: Gastrointestinal Malignancies

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  1. ASCO Update 2012:Gastrointestinal Malignancies Thomas J. Semrad MD, MAS Assistant Professor of Medicine Division of Hematology/Oncology

  2. Disclosure • Speaker’s Bureau: Novartis • Consulting: Amgen, Genomic Health • Research Funding: Novartis, Millenium, NCI

  3. ASCO 2012: Non-Colorectal Topics Esophagogastric Cancer • Locoregional Disease: Alternative to cisplatin / 5-fluorouracil chemoradiation • Advanced Disease: Another negative trial of a biologic in unselected patients Anal Cancer • Timing of response assessment HCC • Optimizing supportive care

  4. Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial. Abstract #LBA4003 Thierry Conroy, Marie-Pierre Galais, Jean Luc Raoul, Olivier Bouche, Sophie Gourgou-Bourgade, Jean-Yves Douillard, Pierre-Luc Etienne, ValérieBoige, Isabelle Martel-Lafay, Pierre Michel, Carmen Llacer-Moscardo, JocelyneBerille, Laurent Bedenne, Antoine Adenis J Clin Oncol 30, 2012 (suppl; abstr LBA4003)

  5. Chemoradiation in Esophageal Cancer RTOG 85-01 • median survival • 14 months vs. 9 months • 5 year survival • 27% vs. 0% • Local failure 45% • Major toxicity 20% NEJM 1992; 326: 1593-8.

  6. Prodige 5 – ACCORD 11 Study Design • Unresectable Esophageal Cancer • AdenoCa or SCCa • No Prior Treatment • No weight loss > 20% • No tracheal invasion or TE fistula • N = 267 FOLFOX + 50Gy Then FOLFOX x 3 cycles Primary Endpoint: Progression Free Survival Secondary Outcomes CR rate Toxicity Time to treatment failure OS QOL 5FU/cisplatin + 50Gy Then 5FU/cisplatin x 2 cycles 90% Power to detect 20% increase in 3-year PFS N = 266 planned (144 events) Stratified By: Histology Weight Loss (+/- 10%) PS Center

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  10. Prodige 5 – ACCORD 11 Efficacy PFS OS

  11. Conclusion • FOLFOX is not superior to 5-FU/cisplatin for definitive chemoradiation treatment for unresectable esophageal cancer • This trial will be used to demonstrate clinical efficacyof definitive FOLFOX chemoradiation • How does this compare to weekly carboplatin / paclitaxel?

  12. Which Regimen? • Carbo/Taxol – CROSS • Neoadjuvant Study (reduced radiation dose) • pCR rate ~30% • Effective in both SCCa and adenoCa • What is the systemic efficacy? • FOLFOX – Prodige 5 • Inoperable study • Not superior to cisplatin/5-FU • Mostly SCCa, but used often in advanced adenoCa • More systemic therapy Reality of practice – neoadjuvant CRT used to select operable patients NEJM 2012; 388:274-284 J Clin Oncol 30, 2012 (suppl; abstr LBA4003)

  13. A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) with or without panitumumab in advanced esophagogastric cancer (REAL3). Abstract #LBA4000 Tom Samuel Waddell, Ian Chau, Yolanda Barbachano, David Gonzalez de Castro, Andrew Wotherspoon, Claire Saffery, Gary William Middleton, Jonathan Wadsley, David Raymond Ferry, WasatMansoor, Tom David Lewis Crosby, Fareeda Y Coxon, David Smith, Justin S. Waters, Timothy Iveson, Stephen Falk, Sarah Slater, Alicia Frances Clare Okines, David Cunningham J Clin Oncol 30, 2012 (suppl; abstr LBA4000)

  14. REAL-3 Background NEJM 2008;358:36-46. GastricCancer 2012;15:252-264.

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  16. Counterintuitive Observations: OS outcome more extreme than PFS outcome RR in opposite direction of OS results

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  19. Dose Intensity J Clin Oncol 30, 2012 (suppl; abstr LBA4000)

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  21. Take Home Points • No evidence of benefit for the addition of panitumumab to EOX • Inferior OS may be due to inferior dose intensity of the experimental regimen • RR was not a good surrogate for survival outcomes, and OS worse than PFS

  22. Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II. Abstract #4004 Robert Glynne-Jones, Roger James, Helen Meadows, Rubina Begum, David Cunningham, John Northover, Jonathan A. Ledermann, Sandra Beare, LathaKadalayil, David Sebag-Montefiore J Clin Oncol 30, 2012 (suppl; abstr 4004)

  23. ACT II Factorial DesignN=940 MMC+ 5-FU + XRT No Maintenance MMC+ 5-FU + XRT Maintenance CisP+ 5-FU + XRT No Maintenance CisP+ 5-FU + XRT Maintenance 1. MMC vs. Cisplatin 2. Maintenance vs. No Maintenance

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  26. Timing of CR Assessment

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  29. [TITLE] Message: Be patient with response assessment

  30. A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma. Abstract #4008 ZhenggangRen, Kangshun Zhu, Haiyan Kang, Minqiang Lu, ZengqiangQu, Ligong Lu, Tianqiang Song, Weiping Zhou, Hui Wang, Weizhu Yang, Xuan Wang, Yongping Yang, Lehua Shi, YuxianBai, Sheng-Long Ye J Clin Oncol 30, 2012 (suppl; abstr 4008)

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  32. HFSR GradingCTCAE v3.0

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  34. ASCO 2012: Colorectal Topics Maintenance • Combining Anti-VEGF and Anti-EGFR therapy Anti-Angiogenic Therapy • Bevacizumab Beyond Progression • Aflibercept in Second Line • A new multi-targeted agent in advanced disease

  35. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev in patients with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial. Abstract #LBA3500^ Christophe Tournigand, Benoit Samson, Werner Scheithauer, Gérard Lledo, FrédéricViret, Thierry Andre, Jean François Ramée, Nicole Tubiana-Mathieu, JérômeDauba, Olivier Dupuis, Yves Rinaldi, May Mabro, Nathalie Aucoin, Ahmed Khalil, Jean Latreille, Christophe Louvet, David Brusquant, Franck Bonnetain, BenoistChibaudel, Aimery De Gramont J Clin Oncol 30, 2012 (suppl; abstr LBA3500^

  36. Combined anti-VEGF and anti-EGFR • CAIRO2 • PACCE N Engl J Med 2009;360:563-72. JCO 2009;27:5672-5680

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  38. OPTIMOX3 – DREAM Schema Bevacizumab 7.5 mg/kg q21 days + Erlotinib 150 mg daily Primary Endpoint: PFS on Maintenance Secondary Outcomes OS OS from maintenance Duration without chemotherapy RR OS according to KRAS Inclusion/Exclusion Metastatic CRCNot suitable for surgery Front-line Treatment mFOLFOX7 + bev(6-12) XELOX2 + bev (6-12) FOLFIRI + bev (12) No PD Bevacizumab 7.5 mg/kg q21 days 80% Power to detect PFS increase 4.5 to 6.5 mo Anticipated 40% dropout N = 700 (418 evaluable) Stratified By: Treatment Regimen

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  41. Conclusion The combination of EGFR- and VEGF-targeted agents is notdead* *But should not (yet) be used in routine clinical practice

  42. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). Abstract #CRA3503 Dirk Arnold, Thierry Andre, JaafarBennouna, Javier Sastre, Pia J. Osterlund, Richard Greil, Eric Van Cutsem, Roger Von Moos, Irmarie Reyes-Rivera, BelguendouzBendahmane, Stefan Kubicka J Clin Oncol 30, 2012 (suppl; abstr CRA3503

  43. BRiTE Registry JCO 2008; 26:5326-5334.

  44. TML Study Design(AIO KRK 0504, ML18147) • Metastatic CRC • Front line chemo (either oxaliplatin- or irinotecan-based) + bevacizumab • Progression within 4 wks • Not surgical candidate • Front-line PFS > 3 months • PD within 3 months of bev • N = 820 Standard Second Line Chemo + Bevacizumab 2.5 mg/kg/wk Primary Endpoint*: OS from randomization Secondary Outcomes PFS RR Safety Standard Second Line Chemo 90% Power to detect 30% increase in median OS N = 810* * Increased from 572 with endpoint change PFS->OS Stratified By: First line chemotherapy First line PFS +/- 9 months Time from last bev dose +/- 45 days PS

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  46. [TITLE] OS PFS

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  50. TML Discussion TOP LINE RESULTS OS 9.8 -> 11.2 months (+1.4 months), HR 0.81 (95% CI 0.69 – 0.94) PFS 4.1 -> 5.7 months (+1.6 months), HR 0.68 (95% CI 0.59 – 0.78) RR low (~5%) in both arms Toxicity is as expected Select Patient Group UNANSWERED QUESTIONS Is it worth it? Third line? Thirteenth line? Aflibercept? -> See next abstract ? ?

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