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: 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.

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

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

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

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

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

CELIM study: Cetx + chemo Folprecht, ASCO 2012

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

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

TRIBE Trial: Addition of Oxaliplatin Falcone, ASCO 2013

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

TRIBE Trial: Overall Survival Falcone, ASCO 2013

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!

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

ARIES: Observational Study Bendell, Oncologist 2012

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

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

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

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

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)

Thank You! wells.messersmith@ucdenver.edu