Authors: Saltz et al Date Published: JCO April 2008

1. Bevacizumab in Combination with Oxaliplatin-Based Chemotherapy as First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study Authors: Saltz et al Date Published: JCO April 2008

2. 2x2 Factorial design evaluating … XELOX vs FOLFOX 4 Oxaliplatin chemo +/- Bevacizumab Treatment 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 R Treatment B: XELOX/FOLFOX 4 1st line mCRC 2x2 factorial Primary endpoint PFS 1401 pts

3. RESULTS 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.

4. 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.

5. 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”

6. 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

7. 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.