Tabernero_edit_Layout 1 01/10/2009 13:38 Page 68
Double EGFR and VEGF Inhibition effect between monoclonal antibodies against EGFR (panitumumab
Combining therapies that inhibit different signalling pathways has the or cetuximab) and bevacizumab in combination with oxaliplatin-
potential to be more effective than inhibition of a single pathway and based chemotherapy in first-line therapy of mCRC patients.
to overcome tumour resistance. Pre-clinical models suggest that at
least additive efficacy can be achieved blocking the EGFR and VEGF Conclusions
Recently, Saltz et al. have reported the results of a In recent years the increased knowledge of human cancer biology
randomised phase II trial that compared the concurrent and the development of new targeted therapies have improved
administration of two monoclonal antibodies – cetuximab and outcomes for patients with CRC. So far, three targeted therapies
have been approved for the treatment of mCRC patients. The FDA
and the EMEA have approved bevacizumab in combination with
With the increasing number of new
fluoropyrimidine-based chemotherapy for the treatment of first- and
targeted agents that are being clinically
second-line mCRC patients. Cetuximab has been approved
in combination with chemotherapy in the first-line setting and in
evaluated, hopefully to be approved in the
combination with irinotecan in the refractory situation. Whereas the
near future, there is an ongoing need to
FDA’s approval is for the whole population, EMEA has restricted
the licence to K-Ras wild-type mCRC patients. Finally, the FDA has
identify predictive biomarkers of efficacy.
approved panitumumab as a single agent in mCRC patients
refractory to other chemotherapy regimens and the EMEA
exclusively for those patients with tumours that bear K-Ras wild type.
bevacizumab – with or without irinotecan in irinotecan-refractory
This study showed that the three-drug combination With the increasing number of new targeted agents that are being
produced better results than the two-drug combination with a higher clinically evaluated, hopefully to be approved in the near future, there
RR (37 versus 20%) and an increased median TTP (7.9 versus 5.6 is an ongoing need to identify predictive biomarkers of efficacy.
months). Although the combination of cetuximab and bevacizumab Successful development of these predictive biomarkers will translate
appeared to be effective in a refractory setting, these interesting into the concept of personalised medicine whereby we give ‘the right
results of double VEGF and EGFR inhibition were not confirmed in the drug to the right patient’. Thus, patients with mCRC would benefit
first-line setting in two recently reported phase III trials: the from the sequence of drugs that would more optimally control their
Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) and malignant disease yet avoid the potential toxicities of those drugs that
the CAIRO-2 studies. will not benefit them. Additionally, with new drug approvals pushing
up the cost of therapy, this tailored treatment approach would reduce
The first trial reported, the PACCE study, is a phase III trial evaluating the economic impact of treatment. Several molecular predictive
oxaliplatin- and irinotecan-based chemotherapy and bevacizumab biomarkers are under evaluation in pharmacodynamic, genomic and
with or without panitumumab in the first-line treatment of patients proteomic translational studies in order to achieve this aim. K-Ras
The second study, the CAIRO-2 trial, is a phase III study mutation status analysis constitutes the first step in this process of
of capecitabine, oxaliplatin and bevacizumab with or without personalising targeted therapies in mCRC by defining the population
cetuximab in the first-line therapy of patients with mCRC.
Both that will benefit most from anti-EGFR monoclonal antibodies. As has
studies showed a detrimental effect in the arms that contained already occurred with K-Ras, these biomarkers will be integrated in
bevacizumab and the anti-EGFR monoclonal antibody. The results of the treatment decision algorithms, thus leading to an optimised
these two studies suggest that there is a lack of biological synergistic therapeutic strategy. n
1. Jemal A, Siegel R, Ward E, et al., CA Cancer J Clin, 2009 2008;26:5326–34. 2008;26:1626–34.
(Epub ahead of print). 14. Wolmark N, Yothers G, O’Connell MJ, et al., J Clin Oncol, 25. Sobrero AF, Laurel J, Fehrenbacher L, et al., J Clin Oncol,
2. Saltz L, Cox JV, Blanke C, et al., N Engl J Med, 2009;27:18s, abstract LBA4. 2009;26:2311–19.
2000;343:905–14. 15. Hecht JR, Trarbach T, Jaeger E et al., J Clin Oncol, 26. Van Cutsem E, Köhne CH, Hitre E, et al., N Engl J Med,
3. De Gramont A, Figer A, Seymour M, et al., J Clin Oncol, 2005;23:16s, abstract 3. 2009;360:1408–17.
2000;18:2938–47. 16. Koehne C, Bajetta E, Lin E, et al., J Clin Oncol, 2006;25:18s, 27. Bokemeyer C, Bondarenko I, Makhson A, et al., J Clin Oncol,
4. Advanced Colorectal Cancer Meta-analysis Project, J Clin abstract 3508. 2009;27:663–71.
Oncol, 1992;10:896–903. 17. Major P, Trarbach T, Lenz H et al., J Clin Oncol, 2006;24:18s, 28. Townsley CA, Major P, Siu LL, et al., Br J Cancer,
5. Douillard JY, Cunningham D, Roth AD, et al., Lancet, abstract 3529. 2006;94:1136–43.
2000;355:1041–7. 18. Available at: www.pfizer.com/news/press_releases/
29. Fisher GA, Kuo T, Ramsey M, et al., Clin Cancer Res,
6. Goldberg RM, Sargent DJ, Morton RF, et al., J Clin Oncol, pfizer_press_releases.jsp?rssUrl=http://mediaroom.pf
2004;22:23–30. com/portal/site/pfizer/index.jsp?ndmViewId=news_view& 30. Folprecht G, Tabernero J, Kohne CH, et al., Clin Cancer Res,
7. Falcone A, Ricci S, Brunetti I, et al., J Clin Oncol, ndmConfigId=1016273&newsId=20090630006315&news 2008;14:215–23.
2007;1:1670–76. Lang=en 31. Kuo T, Cho CD, Halsey J, et al., J Clin Oncol, 2005;23:5613–19.
8. Capdevila J, Ramos FJ, Macarulla T, et al., Crit Rev Oncol 19. Hemming AW, Davis NL, Kluftinger A ,et al., J Surg Oncol, 32. Meyerhardt JA, Zhu AX, Enzinger PC, et al., J Clin Oncol,
Hematol, 2009;71:53–61. 1992;51:147–52. 2006;24:1892–7.
9. Kabbinabar F, Hurwitz HI, Fehrenbacher L, et al., J Clin 20. Cunningham D, Humblet Y, Siena S, et al., N Engl J Med, 33. Hanauske AR, Cassidy J, Sastre J, et al.,Clin Cancer Res,
Oncol, 2003;21(1):60–65. 2004;351:337–45. 2007;13:523–31.
10. Hurwitz H, Fehrenbacher L, Novotny W, et al., N Engl J Med, 21. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al., N Engl J Med, 34. Tabernero J. Mol Cancer Res, 2007;5:203–20.
2004;350(23):2335–42. 2007;357:2040–48. 35. Saltz LB, Lenz H-J, Kindler HL, et al., J Clin Oncol,
11. Giantonio BJ, Catalano PJ, Meropol NJ, et al., J Clin Oncol, 22. Van Cutsem E, Peeters M, Siena S, et al., J Clin Oncol, 2007;25:4557–61.
2007;20:1539–44. 2007;25:1658–64. 36. Hecht JR, Mitchell E, Chidiac T, et al., J Clin Oncol,
12. Saltz LB, Clarke S, Díaz-Rubio E, et al., J Clin Oncol, 23. Karapetis CS, Khambata-Ford S, Jonker DJ, et al., N Engl J 2009;27:672–80.
2008;26:2013–19. Med, 2008;359:1757–65. 37. Tol J, Koopman M, Cats A et al. N Engl J Med,
13. Grothey A, Sugrue MM, Purdie DM, et al., J Clin Oncol, 24. Amado RG, Wolf M, Peeters M et al., J Clin Oncol, 2009;360:563–72.
68 EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
| Page 2
| Page 3
| Page 4
| Page 5
| Page 6
| Page 7
| Page 8
| Page 9
| Page 10
| Page 11
| Page 12
| Page 13
| Page 14
| Page 15
| Page 16
| Page 17
| Page 18
| Page 19
| Page 20
| Page 21
| Page 22
| Page 23
| Page 24
| Page 25
| Page 26
| Page 27
| Page 28
| Page 29
| Page 30
| Page 31
| Page 32
| Page 33
| Page 34
| Page 35
| Page 36
| Page 37
| Page 38
| Page 39
| Page 40
| Page 41
| Page 42
| Page 43
| Page 44
| Page 45
| Page 46
| Page 47
| Page 48
| Page 49
| Page 50
| Page 51
| Page 52
| Page 53
| Page 54
| Page 55
| Page 56
| Page 57
| Page 58
| Page 59
| Page 60
| Page 61
| Page 62
| Page 63
| Page 64
| Page 65
| Page 66
| Page 67
| Page 68
| Page 69
| Page 70
| Page 71
| Page 72
| Page 73
| Page 74
| Page 75
| Page 76