Colorectal Cancer: New Data, New Insights

Eric Van Cutsem, MD, PhD


October 06, 2011

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Updated Findings in Colorectal Cancer

This is Eric Van Cutsem, Professor at the University of Leuven and Head of the Digestive Oncology Department at University Hospital Gasthuisberg in Leuven, Belgium. Welcome to the Medscape Oncology Insights on gastrointestinal cancer. I am here in Stockholm at the European Multidisciplinary Cancer Congress, [a collaborative meeting of the European Society for Medical Oncology (ESMO), the European Cancer Organization (ECCO), and the European Society for Therapeutic Radiology and Oncology (ESTRO)], where I am privileged to participate on the scientific committee and to present some of the highlights on colorectal cancer.

Aflibercept Improves Survival, But...

At this meeting we have seen some very interesting data. One of the highlights was the update of the VELOUR study, presented here by Dr. Josep Tabernero.[1] This was a study that looked into the activity of aflibercept in combination with FOLFIRI [leucovorin, 5-fluorouracil, and irinotecan]. Dr. Tabernero presented the study of these agents in second-line treatment in patients with metastatic colorectal cancer. All patients in this phase 3 study were pretreated with oxaliplatin and then randomly assigned to FOLFIRI or FOLFIRI plus aflibercept or vascular endothelial growth factor (VEGF) Trap. The addition of aflibercept to standard chemotherapy in the second-line treatment of metastatic colorectal cancer improves survival, progression-free survival, and increases response rate. That would have been acceptable, but it also increased toxicity. The adverse event profile was acceptable, but we saw slightly elevated rates of diarrhea and febrile neutropenia in patients treated with FOLFIRI plus aflibercept compared with patients treated with FOLFIRI. On the other hand, with respect to efficacy, the primary endpoint for survival was clearly met. We saw a hazard ratio in the range of 0.8 in favor of the combination with aflibercept. On top of that, progression-free survival and response rate were also increased. The response rate went up from 11% to 20%.

These data were in patients both pretreated and not pretreated with bevacizumab in first-line therapy because, in this trial, 30% of the patients were pretreated with bevacizumab and 70% of the patients were not. In subgroup analysis, survival and progression-free survival clearly improved in a similar way in both groups of patients. These data are, therefore, important. In the future, they may bring us a new drug for the treatment of metastatic colorectal cancer.

We will have to see more first-line data looking at the role of aflibercept in combination with, for instance, an oxaliplatin-based regimen. We hope to see data on which patients benefit most and least. We also hope to look into biomarkers and find some predictive biomarkers, although that is going to be a big challenge.

TKIs: Agents of Interest in mCRC

At this meeting, we heard other interesting data from the RESPECT study.[2] In the RESPECT study, patients in first-line treatment were randomly assigned to FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] plus or minus sorafenib, which is a VEGF receptor/tyrosine kinase inhibitor that also has potential activity in patients with BRAF-mutated tumors. Therefore, this study was of interest and was important. Unfortunately no difference was found between patients treated with FOLFOX/sorafenib and FOLFOX.

Another study[3] looked into a newer broad-spectrum VEGF receptor/tyrosine kinase inhibitor, known as BIBF, and compared BIBF plus FOLFOX with bevacizumab plus FOLFOX. BIBF showed similar activity but with a fairly favorable safety profile. It is a randomized, phase 2 study, so there will be further discussions to see whether we can use BIBF in clinical practice and whether we can design further phase 3 studies to look at the real value of this broad spectrum tyrosine kinase inhibitor.

PICCOLO Trial Hits a Flat Note

The UK groups were quite active. Dr. Seymour[4] presented updated results from the complex PICCOLO study. Many UK studies are quite complex, but they also have the advantage of being pragmatic and flexible in design, meaning that while the study was ongoing, they changed the design of the study to update it and to reflect newer scientific data. The data that were presented here by Dr. Seymour looked at patients with metastatic colorectal cancer who were pretreated with oxaliplatin and randomly assigned to irinotecan or irinotecan plus panitumumab. This trial was focused on patients with KRAS wild-type tumors. The primary endpoint of survival was not met. No survival difference in KRAS wild-type patients between irinotecan or irinotecan plus panitumumab was found; however, the secondary endpoints were met. A clear difference in progression-free survival and response rate was consistent with previous studies of FOLFIRI plus or minus panitumumab and of irinotecan plus or minus cetuximab in second-line treatment for metastatic colorectal cancer.

Especially interesting in this study were data on biomarkers. The UK group looked further into biomarkers (BRAF, PI3 kinase, and NRAS mutations) and showed that patients with these mutations were unlikely to benefit. In patients with a complete wild-type spectrum for KRAS, NRAS, BRAF, and PI3 kinase, there was a bit more benefit. So, it seems that markers other than KRAS are coming through, at least in the later lines of treatment.

Cetuximab Maintenance: A Benefit?

Finally, another study[5] that was of interest was also from the UK group, the COIN-B study in which patients in first-line treatment after 3 months of treatment with FOLFOX/cetuximab were randomly assigned to maintenance with cetuximab or to a complete drug holiday. Patients on the maintenance treatment with cetuximab had a longer time to tumor progression and progression-free survival, suggesting but not proving -- because it was phase 2 study -- that maintenance with cetuximab may also be of benefit. This has to be further worked out and looked at in view of other data with fluoropyrimidines, and with bevacizumab plus maintenance treatments, but the data are beginning to establish this benefit.

Closing Remarks

At this ECCO/ESMO meeting, we are learning more about the best strategies for patients with colorectal cancer. These are the rich aspects of a meeting like this here in Stockholm, where we are really learning and integrating some of the translational science in our clinical practice. Thank you for joining me at this Medscape Oncology Insights. This is Eric Van Cutsem reporting from the ECCO/ESMO meeting in Stockholm.


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