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Originally published as JCO Early Release 10.1200/JCO.2005.11.941 on February 28 2005 © 2005 American Society of Clinical Oncology.
Bevacizumab Plus Fluorouracil: The Value of Being Part of a Developing StoryOspedale S. Martino and Istituto Nazionale Ricerca Cancro, Genova, Italy The US Food and Drug Administration has recently approved bevacizumab for the first-line treatment of metastatic colorectal cancer in combination with any intravenous fluorouracil-based chemotherapy. This decision has generated much debate1 because this broad indication implies that the antiangiogenic effect of bevacizumab may be similar when added to any such chemotherapy, whereas this approval was mainly based on a single trial of this agent with the bolus regimen of irinotecan, fluorouracil, and leucovorin (IFL).2 The article by Kabbinavar et al in this issue of the Journal of Clinical Oncology3 adds to the debate on the use of bevacizumab in colorectal cancer. The study has several weaknesses; nevertheless, it conveys a series of important messages that, in turn, generate potentially important clinical implications. Among the weaknesses is the sample size, which is rather small due to an unrealistic and unjustified expectation of survival benefit (hazard ratio of 0.61). However, this was a phase II study, not a phase III trial, making the sample size more acceptable. The eligibility criteria were, at the same time, very broad to define the patients "unfit" for IFL (for example, a perfectly fit 66-year-old man with low tumor bulk was by definition "unfit" for IFL, and the same was true for a 40-year-old man with an Eastern Cooperative Oncology Group performance status of 1, but criteria were strict for the use of bevacizumab [see the exclusion criteria]). Yet, the accrual of these 200 selected patients required 60 centers over 2 years (1.6 patients per center per year), perhaps due to the broad acceptance of combination chemotherapy for most patients with metastatic colorectal cancer in the United States during the accrual period of the trial. The patient characteristics in this study do present worse features than those in the pivotal trial by Hurwitz et al,2 but despite the fact that they were considered unfit for IFL as first-line treatment, almost half were still fit for second-line chemotherapy with irinotecan- or oxaliplatin-based combinations 6 months after enrollment (as the median duration of first-line therapy was 6 to 7 months). Thus, the external validity of the results of this study and its generalizability is limited. Finally, the advantage in overall survival (the primary end point of the study) for the experimental arm over the control arm, although remarkable in relative terms, was statistically insignificant; the times to quality of life deterioration were identical (3.1 v 3 months, respectively); and the bevacizumab-specific adverse effects accounted for a 16% higher frequency of grade 3 to 4 toxicity in the combined arm. Despite these weaknesses, the study is scientifically important and clinically relevant. In fact, when considered in the context of the available information on bevacizumab in colorectal cancer, it strengthens a series of concepts, thus helping the treating physician and regulatory and funding agencies. First, this study replicates the impressive relative increases in progression-free and overall survival observed in the pivotal study,2 providing further evidence that bevacizumab favorably affects the natural history of treated metastatic colorectal cancer. Both in the Hurwitz et al study2 and in this study, bevacizumab almost halved the rate of progression, and the relative increase in median survival was clinically relevant. Second, these relatively large effects in disease-free and overall survival could not have been predicted by an only 10% increment in response rate and the low complete response rates in both studies. Incidentally, no mention is made of the rate of secondary liver resections (expected to be low in elderly patients and contraindicated in two thirds of these patients having two or more metastatic sites), which is a weak, but relevant, surrogate of activity. These observations also apply to two additional studies: the third arm of the pivotal IFL plus bevacizumab study (that was closed after 100 patients were treated with fluorouracil, leucovorin, and bevacizumab)4; and a small phase II (35 patients) study of fluorouracil, leucovorin, and bevacizumab at two different doses.5 The median progression-free survival in these arms of the studies were 8.5 and 9.0 months, respectively, and the median survival times were 18.3 and 21.5 months, respectively, with response rates far from being impressive. Third, the discrepancy between activity (response rate) and efficacy (overall survival) in both studies suggests that there may be an effect of bevacizumab that is independent from chemotherapy. In fact, if bevacizumab potentiates the activity of chemotherapy by specific mechanisms (drug activation or synergy6) or nonspecific mechanisms (drug delivery through altered tumor vasculature7 or decreased intratumoral interstitial pressure8), higher response rates would be expected. And these, in turn, might be agent-specific or nonspecific, depending on the mechanism of interaction. In both studies, the response rate in the bevacizumab-containing arms was only marginally increased, and the increase in progression-free and overall survival was similar for both fluorouracil- and irinotecan-based regimens, suggesting an antitumor mechanism independent from that of chemotherapy and, as a consequence, of the type of chemotherapy. These speculations affirm the appropriateness of the broad US Food and Drug Administration approval of bevacizumab, in contrast with the more limited approval given by the Committee for Medicinal Product for Human Use (CHMP) of the European Medicines Agency: "bevacizumab in combination with intravenous 5-fluorouracil/folinic acid or intravenous 5-fluorouracil/folinic acid/irinotecan is indicated for first line treatment... ." If the CHMP decision was strictly based on available randomized evidence, then only the combination of the IFL regimen plus bevacizumab and fluorouracil/folinic acid plus bevacizumab should have been approved. The European approval of bevacizumab plus fluorouracil/folinic acid/irinotecan implies the speculation that the addition of bevacizumab to any regimen that includes fluorouracil/folinic acid/irinotecan is associated with similar benefits observed in combination with a little-used regimen—IFL—particularly in Europe. However the CHMP did not extend such speculation to include oxaliplatin-containing regimens, despite acceptable data on toxicity from the E3200 trial. Forthcoming efficacy results of the TREE-2 study investigating oxaliplatin-containing regimens plus or minus bevacizumab should help to resolve this issue. Two final general comments generated by the analogies between the Kabbinavar et al and the Hurwitz et al results address the independence of the beneficial effects from prognostic factors (with the possible exception of serum albumin level)2,3,9 and the lack of long-term benefits. In both studies, the survival curves diverge very early, the maximum difference is observed at the median level, and then they tend to converge at 2 years. If the effect of bevacizumab is independent from that of chemotherapy and it does not lead to long-term benefits, we can then speculate that the search for more relevant long-term benefits from the antiangiogenic compound may lie in combination with other biologic agents, in sequence before or after chemotherapy, but not necessarily in combination with chemotherapy. This concept is supported by the finding that patients with non–small-cell lung cancer who were refractory to chemotherapy had an unprecedented median survival of 12.6 months with a combination of bevacizumab and erlotinib.10 As a consequence of our improved understanding of the effects of bevacizumab in advanced colorectal cancer patients, the study reported here by Kabbinavar et al has two important clinical implications. It must be remembered that outside the clinical trial setting, a substantial proportion of patients really are unfit for combination chemotherapy, so that in these conditions, fluorouracil alone is generally prescribed. Unlike trials of other targeted agents, this is the first randomized efficacy study in which one of these novel compounds is combined with fluorouracil and leucovorin alone. In fact, both the anti–epidermal growth factor receptor (EGFR) antibody cetuximab and the small molecules inhibitors of EGFR tyrosine kinase have been studied alone or in combination with doublet regimens (fluorouracil plus irinotecan or oxaliplatin), but none have been investigated with fluorouracil and leucovorin alone. And the same is true for the small molecules inhibitors of the vascular endothelial growth factor receptor tyrosine kinase. The strategy behind these choices is clear: adding efficacy to the most efficacious chemotherapy available today (the doublets) in a search for long-term benefit and potential cure. Thus, the combination of bevacizumab with single-agent fluorouracil may seem suboptimal. However, the results of the study by Kabbinavar et al may become even more important, since definitive evidence is still lacking that starting with combination chemotherapy as first-line treatment followed by second- and perhaps third-line therapy is better in all patients than starting with single-agent fluorouracil, and then giving the doublets as second- or third-line treatment. The randomized large-scale Dutch "DCCG 02-01 CAIRO" study and the British "MRC CR08 FOCUS" study address this issue, and have already completed accrual. Should these studies indicate equivalent survival among the strategies and with comparable survival data, the data by Kabbinavar et al will have an even greater impact on the use of the antiangiogenic agent, as they provide evidence that benefit is maintained, even if single-agent fluorouracil is given as first-line treatment. The other important clinical implication relates to the timing of bevacizumab in the overall treatment strategy of advanced colorectal cancer—early use (first-line) or later use? So far, only first-line data are available for bevacizumab; cross-over was allowed in none of these studies.2,3 In contrast with the other targeted agents, no solid data are available on this antibody given alone or in combination as second-line treatment. The E3200 trial randomly assigned patients to bevacizumab alone, bevacizumab plus oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or to FOLFOX alone as second-line therapy. The efficacy data from this trial are pending. The opposite is true for cetuximab, gefitinib, erlotinib, or vatalanib in combination with chemotherapy, for which first-line randomized efficacy data are not yet available. The demonstration of cetuximab efficacy as salvage, however, is well established.11 The lack of demonstrated efficacy of bevacizumab plus fluorouracil and leucovorin as third-line treatment in colorectal cancer,12 as well as the lack of efficacy of bevacizumab plus capecitabine compared with capecitabine alone in third-line treatment of advanced breast cancer,13 strengthens the suggestion that bevacizumab is beneficial when used in first line, regardless of whether fluorouracil alone or IFL is the companion regimen; hence, the strong rationale for its testing in the adjuvant setting. A final word about cost: Given the high cost of bevacizumab,1 the search for predictors of response and benefit is imperative. So far, this search has been disappointing14 and promises to be difficult.15 The fact that the benefit is demonstrated in every prognostic category of patients2,3,9 and is limited in duration makes the success of this search unlikely in the short run. If the two survival curves in this study and in that by Hurwitz et al stay separated after 2 years of follow-up, the search for the determinant of truly long-term benefit would probably be easier. A general lesson on clinical research can be learned from this study as part of the development plan of bevacizumab: some studies with limited internal validity may become relevant to scientific knowledge and clinical practice when they have the extra value of being part of a more general developing story. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Alberto Sobrero, Aventis, Merck, Pfizer, Sanofi-Synthelabo. Honoraria: Alberto Sobrero, Aventis, Merck, Pfizer, Roche, Sanofi-Synthelabo. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES
1. Mayer RJ: Two steps forward in the treatment of colorectal cancer. N Engl J Med 350:2406-2408, 2004
2. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 3. Kabbinavar FF, Shulz J, McCleod M, et al: Addition of bevacizumab to bolus fluorouracil/leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23: 10.1200/JCO.2005.05.112 4. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Bevacizumab prolongs survival in first line colorectal patients: Results of a phase III trial of bevacizumab in combination with bolus IFL as first line therapy in subjects with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22, 2003 (abstr 3646)
5. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (5-fluorouracil)/leucovorin (LV) with 5-fluorouracil /LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003 6. Wildiers H, Guetens G, De Boeck G, et al: Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979-1986, 2003[CrossRef][Medline] 7. Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 7:987-989, 2001[CrossRef][Medline] 8. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004 [Erratum: Nat Med 10:649, 2004] 9. Fyfe GI, Hurwitz H, Fehrenbacher L, et al: Bevacizumab plus irinotecan 5-fluorouracil/leucovorin for treatment of metastatic colorectal cancer results in survival benefit in all pre-specified patients subgroups. Proc Am Soc Clin Oncol 23:274, 2004 (abstr 3617) 10. Sandler AB, Blumenschein GR, Henderson T, et al: Phase I/II trial evaluating the anti VEGF Mab bevacizumab in combination with erlotinib, a HER1 EGFR TK inhibitor, in patients with recurrent non small cell lung cancer. Proc Am Soc Clin Oncol 23:127, 2004 (abstr 2000)
11. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 12. Chen HX, Mooney M, Boron L, et al: Bevacizumab plus 5-fluorouracil /leucovorin for advanced colorectal cancer that progressed after standard chemotherapies: An NCI Treatment Referral Center trial (TRC0301). Proc Am Soc Clin Oncol 23:249, 2004 (abstr 3515) 13. Miller KD, Rugo H, Cobleigh MA, et al: Phase III trial of capecitabine plus bevacizumab versus capecitabine alone in women with metastatic breast cancer previously treated with an anthracycline and a taxane. Breast Cancer Res Treat 76:s37, 2002 (suppl 1)[CrossRef]
14. Ellis LM: Antiangiogenic therapy at a crossroads: Clinical trial results and 5-fluorouracil future directions. J Clin Oncol 21:281s-283s, 2003 (suppl 23) 15. Davis DW, McConkey DJ, Abbruzzese JL, et al: Surrogate markers in antiangiogenesis clinical trials. Br J Cancer 89:8-14, 2003[CrossRef][Medline] Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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