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Does the Chemo Backbone Matter? Wells Messersmith, MD, FACP Professor

Does the Chemo Backbone Matter? Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head , Division of Medical Oncology Program co-Leader, Developmental Therapeutics March 2014. Conflict of Interest:

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Does the Chemo Backbone Matter? Wells Messersmith, MD, FACP Professor

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  1. Does the Chemo Backbone Matter? Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head, Division of Medical Oncology Program co-Leader, Developmental Therapeutics March 2014

  2. Conflict of Interest: • No employment, speaker’s bureaus, stock ownership, royalties, patents, etc • Data Safety Monitoring Board for OncoMed • 3. PI or Local PI of clinical trials by Genentech/Roche, GSK, Pfizer, Millenium, Bayer, Onconova, and NIH/CTEP.

  3. Chemotherapy Backbones & Biologics • Outline/Objectives: • Cross-Trial Comparisons • Randomized Data • Clinical Databases • Conclusions

  4. Efficacy Comparison (Historical Controls) Saltz, “BOND2”, ASCO 2005

  5. CAIRO2: did not confirm - Worse outcomes (PFS and strong trend in OS) when “double biologics” are used. - Unexpected, and still mostly unexplained, result which shows why randomized trials are needed. Tol, NEJM 2009

  6. The dangers of cross-trial comparisons • Lining up trials side by side, and drawing conclusions based on patterns that are seen, represents good scholarship and can generate important hypotheses. • However, there are known and unknown factors with various studies: different countries, standards, tolerance, etc • Whenever possible, randomized studies are needed to actually change practice

  7. Chemotherapy Backbones & Biologics • Outline/Objectives: • Cross-Trial Comparisons • Randomized Data • Clinical Databases • Conclusions

  8. CELIM study: Cetx + chemo Folprecht, ASCO 2012

  9. CELIM study: No difference between chemo backbones This was a randomized phase II study with RR as primary endpoint However, no difference is response or survival based on chemo backbone. FOLFIRI/Cetx FOLFOX/Cetx Folprecht, ASCO 2012

  10. CECOG: Cetuximab + FOLFOX v FOLFIRI Ocverk, World J GI 2010

  11. CECOG: No difference between chemo backbones This was a randomized phase II study with PFS at 9m as primary endpoint. Again, no difference in response or survival based on chemo backbone. Ocverk, World J GI 2010

  12. TRIBE Trial: Addition of Oxaliplatin Falcone, ASCO 2013

  13. Adding Oxaliplatin to Backbone Primary endpoint of PFS was met! Falcone, ASCO 2013

  14. TRIBE Trial: Overall Survival Falcone, ASCO 2013

  15. Randomized Trials for chemo “backbones: • CELIM trial • - Cetuximab + FOLFOX vs. FOLFIRI • CECOG trial • - Cetuximab + FOLFOX vs. FOLFIRI • TRIBE • - Bevacizumab + FOLFIRI vs FOLFOXIRI • Zero for three in terms of showing any specific detriment or advantage to the • chemo backbone!

  16. Chemotherapy Backbones & Biologics • Outline/Objectives: • Cross-Trial Comparisons • Randomized Data • Clinical Databases • Conclusions

  17. ARIES: Observational Study Bendell, Oncologist 2012

  18. ARIES No difference in PFS or OS for >1200 “real world” patients. Bendell, Oncologist 2012

  19. ARIES: Efficacy No significant (or even insignificant) differences with regard to chemo backbone when combined with bev. Bendell, Oncologist 2012

  20. ARIES: adverse events Small differences in protocol-specified adverse events with regard to chemo backbone when combined with bev; but overall incidence very low. Bendell, Oncologist 2012

  21. Chemotherapy Backbones & Biologics • Outline/Objectives: • Cross-Trial Comparisons • Randomized Data • Clinical Databases • Conclusions

  22. Conclusions (1) • Head-to-head randomized studies show no difference in terms of which chemo backbone is paired with biologics. • Many of these are phase II • For bevacizumab, large clinical databases show no difference. • Cross-trial comparisons are complicated and can lead us down the wrong path (think of all of the patients treated with double biologics from 2005-2007). • Until we know biomarkers (with positive predictive value) for biologics, difficult to assess and model whether specific chemotherapies modify them.

  23. Conclusions (2) • Unclear whether investment of increasingly precious resources (patients, $$$, time) is worthwhile. • Study design: “rum and coke” v. “rum and pepsi” • Overlapping toxicities and PK issues usually more relevant. • The number of possible agents and combinations allow plenty of flexibility for oncologists uncomfortable with specific combinations. • Would be better to dedicate resources to prevention, novel agents, and patient subsets/personalized medicine.

  24. Ongoing “Chemo Backbone” Trials • MAVERICC (NCT01374425), n=360, randomized pII • FOLFIRI/bev vs FOLFOX/bev • PLANET (NCT00885885), n=80, pII • FOLFIRI/Pmab vs FOLFOX/Pmab • VISNU-1 (NCT01640405), n=350, pIII • FOLFOXIRI/bev vs FOLFOX/bev • CELIM2 (NCT01802645), n=256, pII • FOLFOXIRI vs FOLFIRI + Bev (KRAS MT) or Cetuximab (KRAS WT)

  25. Thank You! wells.messersmith@ucdenver.edu

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