does the chemo backbone matter? wells messersmith, md, facp professor

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, etc2. Data Safety Monitoring Board for OncoMed3. PI or Local PI of clinical trials by Genentech/Roche,

GSK, Pfizer, Millenium, Bayer, Onconova, and NIH/CTEP.

Outline/Objectives:

1. Cross-Trial Comparisons2. Randomized Data3. Clinical Databases4. Conclusions

Chemotherapy Backbones & Biologics

Efficacy Comparison (Historical Controls)

Cetux-Irino(historical)

Cetux-Irino + Bev P value

Resp Rate 23% 37% 0.03TTP 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 Comparisons2. Randomized Data3. Clinical Databases4. 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 Comparisons2. Randomized Data3. Clinical Databases4. 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 Comparisons2. Randomized Data3. Clinical Databases4. 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)

Thank You!

wells.messersmith@ucdenver.edu