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CALGB 90206:A phase III trial of Bevacizumab plus

interferon-alpha versusinterferon-alpha monotherapy in metastatic

renal cell carcinoma

Reviewed by: Dr. Daniel Heng and Dr. Lori Wood

Date posted: April 4, 2008

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BACKGROUND

•Previously:•Phase II trials of bevacizumab monotherapy have been performed and showed activity with single agent Bevacizumab

•Dec 2007 Lancet:•The AVOREN phase III trial was published•Study completed in Europe in first line metastatic RCC•Compared IFN + placebo to IFN + Bevacizumab•Showed an improvement in PFS with IFN + Bevacizumab

•This CALGB study:•Designed and conducted at the same time as the AVOREN trial to provide 2 RCTs asking the same question

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RInterferon alpha 9MIU SC 3x/wkBevacizumab 10mg/kg IV q2wks

Interferon alpha 9MIU SC 3x/wkPlacebo IV q2wks

732 PatientsMetastatic RCC

Previously untreated Any clear cell component

No brain metastases No nephrectomy needed

STUDY DESIGN

1o Endpoint:Overall Survival

2o Endpoint:PFS, ORR

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PATIENT CHARACTERISTICS

Characteristic %

Median Age (yrs) (range) 61

MSKCC Risk Profile Score

Favorable

Intermediate

Poor

26%

64%

10%

Prior Nephrectomy 85%

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RESULTS

Bevacizumab +IFN

IFN alone p-valueBevacizumab

+IFNIFN alone p-value

Response Rate

(CR+PR) (%)25.5% 13.1% 0.0001 31% 13% 0.0001

PFS (median, mos)

8.5 5.2 <.0001 10.2 5.4 0.0001

OS

(median, mos)

NA NA NA Not Reached 19.8 0.06701

1OS data immature, only 251 of required 445 deaths have occurred

CALGB 90206 AVOREN

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STUDY COMMENTARY

• This Phase III trial demonstrates PFS benefit.

• The results are very similar to that of the published AVOREN trial with a similar design.

• The major difference between the 2 trials is that the CALGB trial included 15% of patients without nephrectomy and the AVOREN trial included a placebo.

•Additionally, very few patients (10%) with MSKCC poor prognostic profiles were included in this study. Thus, the true effect of bevacizumab in this population is unknown.

•The PFS shown in the IFN + Bev arm appears similar to phase III trials conducted with sunitinib although OS benefit has yet to be demonstrated in any of the trials with VEGF targeted therapy.

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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS

•Bevacizumab has not yet been approved by the FDA or Health Canada for the treatment of mRCC. Regulatory approval based on PFS benefit alone may be more difficult now that there are several standard active agents available.

•Use of this combination first-line is less desirable than the standard oral anti-VEGF inhibitors such as sunitinib because:

•IFN is not well tolerated

•This combination is not orally administered

•The cost of bevacizumab at 10mg/kg plus interferon is higher than sunitinib, sorafenib or temsirolimus

•The efficacy of bevacizumab alone is unknown and many wonder what the results would have been if the 2 arms were IFN versus Bevacizumab alone.

•This drug has potential application in third- or forth-line settings however this has yet to be studied.