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Does the Chemo Backbone Matter?
Wells Messersmith, MD, FACPProfessor
Director, Gastrointestinal Medical Oncology ProgramCo-Head, Division of Medical Oncology
Program co-Leader, Developmental TherapeuticsMarch 2014
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.
Outline/Objectives:
1. Cross-Trial Comparisons
2. Randomized Data
3. Clinical Databases
4. Conclusions
Chemotherapy Backbones & Biologics
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(historical)
Cetux + BevP value
Resp Rate 11% 20% 0.05
TTP 1.5 m 5.6 m <0.01
Saltz, “BOND2”, ASCO 2005
CAIRO2: did not confirm
Tol, NEJM 2009
- 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.
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
Outline/Objectives:
1. Cross-Trial Comparisons
2. Randomized Data
3. Clinical Databases
4. Conclusions
Chemotherapy Backbones & Biologics
CELIM study: Cetx + chemo
Folprecht, ASCO 2012
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.
CECOG: Cetuximab + FOLFOX v FOLFIRI
Ocverk, World J GI 2010
Ocverk, World J GI 2010
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.
TRIBE Trial: Addition of Oxaliplatin
Falcone, ASCO 2013
Adding Oxaliplatin to Backbone
Falcone, ASCO 2013
Primary endpoint of PFS was met!
TRIBE Trial: Overall Survival
Falcone, ASCO 2013
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!
Outline/Objectives:
1. Cross-Trial Comparisons
2. Randomized Data
3. Clinical Databases
4. Conclusions
Chemotherapy Backbones & Biologics
ARIES: Observational Study
Bendell, Oncologist 2012
ARIES
Bendell, Oncologist 2012
No difference in PFS or
OS for >1200 “real
world” patients.
ARIES: Efficacy
Bendell, Oncologist 2012
No significant (or even insignificant) differences with regard to chemo backbone when combined with bev.
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.
Outline/Objectives:
1. Cross-Trial Comparisons
2. Randomized Data
3. Clinical Databases
4. Conclusions
Chemotherapy Backbones & Biologics
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.
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.
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)
