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Bevacizumab in Combination with Oxaliplatin-Based Chemotherapy as First-Line Therapy in

Metastatic Colorectal Cancer: A Randomized Phase III Study

Authors: Saltz et alDate Published: JCO April 2008

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RTreatment A: XELOX/FOLFOX 4 + Bevacizumab Bev 7.5 mg/kg q 3 weeks in XELOX pts Bev 5 mg/kg q 2 weeks in FOLFOX pts

Treatment B: XELOX/FOLFOX 4

1st line mCRC2x2 factorial

Primary endpoint PFS1401 pts

2x2 Factorial design evaluating …

XELOX vs FOLFOX 4

Oxaliplatin chemo +/- Bevacizumab

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RESULTS

Treatment A

Treatment B

p-value

Response Rate (%) 47% 49% NS

PFS (median,

mos) 9.4 mos 8.0 mos HR 0.83,

p=0.0023

OS (median,

mos)21.3 mos 19.9 mos

HR 0.89,p=0.077

A clinically relevant and statistically significant treatment interaction was ruled out (p=0.7025), therefore the pooled analysis of Chemo/Bev vs Chemo/Placebo was conducted.

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STUDY COMMENTARY

• Well designed trial evaluating an important question

• Primary endpoint of improved PFS met statistical significance but the absolute improvement (1.4 mos) is not clinically meaningful.

• No improvement in RR or overall survival.

• Clinical toxicity profile was consistent with what is known about Bevacizumab.

•

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STUDY COMMENTARY

•Unlike previous trials, overall treatment duration of Bev and Placebo was similar (~6mos) despite improved PFS in Bev arm. Protocol specified that treatment could continue until PD.

•Hypothesis: is duration of Bev therapy important and is treatment until PD needed to derive clinical benefit??

•This is a possible explanation of results but does not justify author’s conclusion that : “continuation of bevacizumab, and most likely fluoropyrimidine therapy as well, until PD appears to be critical with regards to the magnitude of clinical benefit derived from bevacizumab.”

• This hypothesis does not explain lack of increase in RR and as author’s point out “the finding of a lack of improvement in RR cannot be easily dismissed”

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BOTTOM LINE FOR CANADIAN

MEDICAL ONCOLOGISTS

• It is important to put the results of this large, well designed, and contemporary RCT in context with what we have seen to date with Bev in mCRC…

• Hurwitz: Bev improved OS by a clinically important 4.7 months when given with IFL in the first line setting.

Problem: we don’t use IFL in 2008

• Giantonio: Bev improved OS by 2.1 months when given with FOLFOX in the 2nd line setting.

• BRITE/BEAT: Phase IV observational studies show impressive OS among patients who receive Bev.

Problem: Limitations of observational data are well known

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BOTTOM LINE FOR CANADIAN

MEDICAL ONCOLOGISTS

• The results of the study by Saltz (in isolation) do not support the use of Bev with first line FOLFOX

• However, given the totality of evidence for and against Bev the benefit of Bev is in first line mCRC with currently used regimens remains unclear

•Future work in identifying predictive biomarkers (ala. K-ras) would allow oncologists to identify patients who will benefit from Bev and avoid treating patients with an expensive and potentially toxic drug who are not likely to benefit.

• Given the existing literature, appropriate 1st line therapy for mCRC remains FOLFOX or FOLFIRI. The addition of Bev may be considered on an individual basis after discussion with individual patients.