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)
Cetux-Irino
(historical)
Cetux-Irino + Bev
P value
Resp Rate
23%
37%
0.03
TTP
4 m
7.9 m
<0.01
Cetux alone
Cetux + Bev
11%
20%
0.05
1.5 m
5.6 m
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
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. No difference in PFS or OS for >1200 “real world” patients.
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 ).
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!