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Regulatory Issues: FDA

FDA Drug Approval Summary: Bevacizumab Plus FOLFOX4 as Second-Line Treatment of Colorectal Cancer

Division of Biological Oncology Products, Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Colorectal cancer • Advanced disease • Second-line therapy • Bevacizumab • FOLFOX4

Correspondence: Martin H. Cohen, M.D., U.S. Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: 301-594-2473; Fax: 301-594-0499; e-mail: cohenma{at}cder.fda.gov

Received September 14, 2006; accepted for publication January 2, 2007.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Add bevacizumab (Avastin®) to the FOLFOX4 chemotherapy regimen.
   
2. Evaluate the contribution of bevacizumab and FOLFOX4 to treatment results.
   
3. Understand FDA criteria for the analysis of response rate and progression-free survival.
   

	ABSTRACT

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On June 20, 2006, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA), administered in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) for the second-line treatment of metastatic carcinoma of the colon or rectum. Efficacy and safety were demonstrated in one Eastern Cooperative Oncology Group (ECOG) open-label, multicenter, randomized, three-arm, active-controlled trial enrolling 829 adult patients. Patients had received a fluoropyrimidine- and irinotecan-based regimen as initial therapy for metastatic disease; or they had received prior adjuvant irinotecan-based chemotherapy and had recurred within 6 months of completing therapy. Treatments included bevacizumab, 10 mg/kg, as a 90-minute i.v. infusion on day 1, every 2 weeks, either alone or in combination with FOLFOX4, or FOLFOX4 alone. The bevacizumab monotherapy arm was closed to accrual after an interim efficacy analysis suggested a possibly shorter survival in that arm. Overall survival (OS), the primary study endpoint, was significantly longer for patients receiving bevacizumab in combination with FOLFOX4 than for those receiving FOLFOX4 alone. The objective response rate was significantly higher in the FOLFOX4 plus bevacizumab arm than in the FOLFOX4 alone arm. The duration of response was approximately 6 months for both treatment arms. Patients treated with the bevacizumab combination were also reported, based on investigator assessment, to have significantly longer progression-free survival. There were no new bevacizumab safety signals. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, and congestive heart failure.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

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Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA) is a recombinant humanized monoclonal IgG₁ antibody that binds to human vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF with its receptors (Flt-1 and KDR) on the surface of endothelial cells. The result is inhibition of endothelial cell proliferation and new blood vessel formation [1–3].

Bevacizumab, in combination with i.v. 5-fluorouracil (5-FU)–based chemotherapy, was approved by the U.S. Food and Drug Administration (FDA) in February of 2004 for the first-line treatment of patients with metastatic carcinoma of the colon and rectum. In the pivotal trial, patients were randomized to irinotecan, 5-FU, and leucovorin (LV) either alone (the IFL regimen) or with bevacizumab (5 mg/kg every 2 weeks), or to 5-FU/LV plus bevacizumab (5 mg/kg every 2 weeks). The latter arm was discontinued, as prespecified, when the toxicity of bevacizumab in combination with IFL was deemed acceptable.

Eight hundred thirteen patients were randomized—402 received IFL plus bevacizumab and 411 received IFL plus placebo. Overall survival (OS) was significantly longer in the IFL plus bevacizumab arm (median, 20.3 months versus 15.6 months; p < .001 by stratified log-rank test). Similarly, the progression-free survival duration and response rate were also significantly greater in the combination arm [4]. Based on these data, bevacizumab became the first anti-VEGF agent to be approved by the FDA for cancer patients. The present report evaluates bevacizumab plus FOLFOX chemotherapy in the second-line treatment of metastatic carcinoma of the colon or rectum.

	PATIENTS AND METHODS

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A single Eastern Cooperative Oncology Group (ECOG) open-label, three-arm, randomized, multicenter, active-controlled trial of FOLFOX4 (day 1: oxaliplatin, 85 mg/m², and leucovorin, 200 mg/m², concurrently i.v., then 5-FU, 400 mg/m² i.v. bolus followed by 600 mg/m² continuous i.v.; day 2: leucovorin, 200 mg/m² i.v., then 5-FU, 400 mg/m² i.v. bolus, followed by 600 mg/m² continuous i.v.; repeated every 2 weeks; n = 292) versus FOLFOX4 plus bevacizumab (n = 293) versus bevacizumab monotherapy (n = 244) in subjects with recurrent, advanced, or metastatic colorectal cancer who had previously received a fluoropyrimidine- and irinotecan-based regimen was submitted. The study was conducted from November 13, 2001 to August 1, 2005. The bevacizumab monotherapy arm was closed to further enrollment on March 11, 2003, based on a Data Monitoring Committee review of early efficacy results. After the discontinuation of the bevacizumab monotherapy arm, subjects were randomized in a 1:1 ratio between the FOLFOX4 and FOLFOX4 plus bevacizumab arms. A schematic of the study design is shown in Figure 1.

View larger version (29K): [in this window] [in a new window]   Figure 1. Study schematic. Protocol therapies were to be administered every 2 weeks. Oxaliplatin and leucovorin could be administered simultaneously. Dose calculations were based on actual body weight at the beginning of each cycle. aReferred to in the protocol as arm B. bReferred to in the protocol as arm A. cReferred to in the protocol as arm C. Abbreviation: 5-FU, 5-fluorouracil.

Eligibility criteria required that patients have measurable, histologically confirmed, advanced or metastatic adenocarcinoma of the colon and rectum previously treated with a fluoropyrimidine- and irinotecan-based regimen (concomitant or sequential) and recovery from any treatment-related toxicities. A history of relapse within 6 months of concluding adjuvant therapy with 5-FU and subsequent progression following single-agent irinotecan treatment was permitted, as was relapse within 6 months of concluding adjuvant therapy with 5-FU in combination with irinotecan. Adequate laboratory values were required as was an ECOG performance status score of 0–2.

Exclusion criteria included prior treatment with oxaliplatin or bevacizumab, history of thrombotic or hemorrhagic disorders, use of therapeutic anticoagulation therapy, known brain metastases, history of hypertension (unless blood pressure was well controlled, i.e., <150/100 mmHg on a stable regimen of antihypertensive therapy), major surgical procedure within 28 days prior to randomization, use of aspirin on a regular basis (>325 mg/day) within 10 days prior to randomization, use of antiplatelet agents (specifically, dipyridamole, ticlopidine, clopidogrel, or cilostazol), serious, nonhealing wound, ulcer, or bone fracture, and history of myocardial infarction, uncontrolled congestive heart failure, or unstable angina within 3 months prior to randomization. Prophylactic anticoagulation for venous access devices was allowed provided that the international normalized ratio was 1.5 and prothrombin time was less than or equal to the institutional upper limit of normal (ULN).

Protocol therapy was given in repeating 2-week cycles. Treatment was to be continued until disease progression, except that treatment was discontinued for patients who either achieved a partial response (PR) and underwent surgical resection of all existing disease or achieved a complete response and completed up to two additional cycles of treatment. There was no limit on the maximum number of cycles of protocol therapy.

Bevacizumab treatment was modified or discontinued for the following toxicities: hemorrhage, proteinuria, liver function test elevation, coagulopathy, hypertension, or arterial thrombotic events.

	RESULTS

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The baseline characteristics of the study subjects are shown in Table 1. There were no clinically relevant baseline imbalances between study arms. All of the subjects had colorectal cancer. It was not possible from the case report forms or study data to identify subjects who entered the study following adjuvant chemotherapy and subsequent relapse; however, approximately 12% of subjects had disease confined to the primary site or tumor bed, most likely representing a subset of subjects who relapsed following adjuvant chemotherapy. The remaining subjects had advanced or metastatic disease with a similar distribution of tumor site involvement between treatment groups. Ninety-three percent of subjects had prior tumor resection surgery, 26% had received radiotherapy, and 80% received adjuvant chemotherapy.

View larger version (10K): [in this window] [in a new window]   Figure 2. Overall survival.

Secondary efficacy endpoints included PFS and objective response rate. The median PFS was longer in the FOLFOX4 plus bevacizumab arm (7.5 months) than in the FOLFOX4 only arm (4.5 months). The log-rank p-value was < .0001 (Table 3).

	SAFETY

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	DISCUSSION

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Data from a randomized, multicenter trial demonstrated that FOLFOX4 plus bevacizumab, compared with FOLFOX4 alone, produced a longer duration of survival by a clinically meaningful increment of 2.2 months in subjects with colorectal cancer who had previously received 5-FU and irinotecan for advanced or metastatic disease or who had recurred after adjuvant 5-FU– and irinotecan-based chemotherapy.

Although the study met the primary endpoint of longer survival, the analyses for PFS and objective response were less robust. Generally, the FDA prefers that assessment of radiographic images for determination of tumor response and progression be made blindly, whether conducted by investigators or special assessment groups (e.g., Endpoint Assessment Committees). In addition, the FDA usually requests complete sets of films from several participating sites for a spot audit to assess data reliability. Blinded review and radiologic audit were not feasible in the current submission.

Adverse events identified in the current study appear consistent with the information already contained in the Avastin® prescribing information, including intestinal perforation, hemorrhage, arteriothromboembolic events, hypertension, and proteinuria. Data from the current study suggest a higher incidence of emesis in subjects who received FOLFOX plus bevacizumab than in subjects who received FOLFOX alone that has not been previously seen with other chemotherapy regimens. The study data also revealed a possible relationship between bevacizumab and a higher incidence of oxaliplatin-induced peripheral neuropathy.

In conclusion, the addition of bevacizumab to FOLFOX4 chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival compared with FOLFOX4 alone in patients whose disease had progressed after adjuvant chemotherapy with 5-FU and irinotecan and in patients with advanced or metastatic disease who had received prior 5-FU and irinotecan. The secondary endpoints of PFS and objective response rate supported the superior OS duration. The safety profile of bevacizumab, as demonstrated in this study, did not reveal new significant safety signals or adversely impact on subjects' quality of life. Subset analyses did not reveal any group that did not benefit from the addition of bevacizumab to FOLFOX4 chemotherapy.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicate no potential conflicts of interest. The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration.

	REFERENCES

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1. Jain RK, Duda DG, Clark JW et al. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 2006;3:24–40.[CrossRef][Medline]
2. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002;2:727–739.[CrossRef][Medline]
3. Ferrara N, Hillan KJ, Gerber HP et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391–400.[CrossRef][Medline]
4. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cohen, M. H. Articles by Pazdur, R. Search for Related Content PubMed PubMed Citation Articles by Cohen, M. H. Articles by Pazdur, R.