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Does the Chemo Backbone Matter? Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head, Division of Medical.

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Presentation on theme: "Does the Chemo Backbone Matter? Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head, Division of Medical."— Presentation transcript:

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: 1.No employment, speaker’s bureaus, stock ownership, royalties, patents, etc 2.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 Outline/Objectives: 1.Cross-Trial Comparisons 2.Randomized Data 3.Clinical Databases 4.Conclusions Chemotherapy Backbones & Biologics

4 Efficacy Comparison (Historical Controls) Cetux-Irino (historical) Cetux-Irino + Bev P value Resp Rate23%37%0.03 TTP4 m7.9 m<0.01 Cetux alone (historical) Cetux + Bev P value Resp Rate11%20%0.05 TTP1.5 m5.6 m<0.01 Saltz, “BOND2”, ASCO 2005

5 CAIRO2: did not confirm Tol, NEJM 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.

6 The dangers of cross-trial comparisons 1.Lining up trials side by side, and drawing conclusions based on patterns that are seen, represents good scholarship and can generate important hypotheses. 2.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 Outline/Objectives: 1.Cross-Trial Comparisons 2.Randomized Data 3.Clinical Databases 4.Conclusions Chemotherapy Backbones & Biologics

8 CELIM study: Cetx + chemo Folprecht, ASCO 2012

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

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.

12 TRIBE Trial: Addition of Oxaliplatin Falcone, ASCO 2013

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

14 TRIBE Trial: Overall Survival Falcone, ASCO 2013

15 Randomized Trials for chemo “backbones: 1.CELIM trial - Cetuximab + FOLFOX vs. FOLFIRI 2.CECOG trial - Cetuximab + FOLFOX vs. FOLFIRI 3.TRIBE - Bevacizumab + FOLFIRI vs FOLFOXIRI Zero for three in terms of showing any specific detriment or advantage to the chemo backbone!

16 Outline/Objectives: 1.Cross-Trial Comparisons 2.Randomized Data 3.Clinical Databases 4.Conclusions Chemotherapy Backbones & Biologics

17 ARIES: Observational Study Bendell, Oncologist 2012

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

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

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

21 Outline/Objectives: 1.Cross-Trial Comparisons 2.Randomized Data 3.Clinical Databases 4.Conclusions Chemotherapy Backbones & Biologics

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 ). -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 (NCT ), n=360, randomized pII -FOLFIRI/bev vs FOLFOX/bev -PLANET (NCT ), n=80, pII -FOLFIRI/Pmab vs FOLFOX/Pmab -VISNU-1 (NCT ), n=350, pIII -FOLFOXIRI/bev vs FOLFOX/bev -CELIM2 (NCT ), n=256, pII -FOLFOXIRI vs FOLFIRI + Bev (KRAS MT) or Cetuximab (KRAS WT)

25 Thank You!


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