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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

AVAiL Trial Negative for Overall Survival Benefit
Author
Howard (Jack) West, MD

We got some big news in the form of a press release today: avastin (bevacizumab) didn't produce a survival benefit in the European AVAiL (AVAstin in Lung Cancer) trial of cisplatin/gemcitabine with or without avastin at either a higher dose (15 mg/kg IV every three weeks) or a lower dose (7.5 mg/kg IV every three weeks):

AVAiL trial schema

(Click on image to enlarge)

We learned initially that AVAiL was positive for an improvement in progression-free survival (PFS) with cisplatin/gemcitabine/avastin vs. the same chemo alone from a press release (post here). A subsequent presentation of the trial at ASCO (abstract here)confirmed that each of the two doses improved PFS, but if anything the improvement was more robust with the lower dose of avastin:

AVAiL PFS

At the time of the ASCO presentation, the sponsor company (Roche, which markets avastin in Europe) didn't have mature data on overall survival for the trial, so this was not reported.

But today we received word that there was no overall survival benefit for avastin on this trial, for which PFS was the primary endpoint. In fact, all of the groups did unusually well, with a median survival of more than a year.

So where does this leave us? I don't think it necessarily changes our treatment standards, but it is certainly a disappointment for avastin. We still have evidence that avastin improved survival when given at the 15 mg/kg dose every three weeks with carbo/taxol (abstract here). But you'd hope that the benefit of avastin would be enough to improve survival in another trial. I suspect that the very favorable survival in all groups was a combination of a selected group with a modestly better prognosis (adenocarcinoma, no brain metastases, no prior heart disease or blood clots) and who received the benefit of increasingly helpful treatments after first line that led to patients on chemo alone who started with a lower response rate and progression-free survival but did well enough to catch up with the avastin groups. This is similar to the results for women on the initial ECOG trial with carbo/taxol, which showed that women receiving chemo/avastin had a much better PFS and response rate but the same overall survival as recipients of chemo alone. But if you can "rescue" patients to do as well in the end by giving later treatments, with less risk of a tragic bleeding complication or the high cost of avastin (I saw a patient today who is paying $2400 per three week cycle as a copay), it raises the question of whether that treatment is clearly necessary.

In the meantime, I'm inclined to continue to offer avastin, preferentially with carbo/taxol, and at the FDA-approved dose of 15 mg/kg. I would say, though, that with the negative survival data and the suggestion that the lower dose, if anything, looked more favorable than the standard, higher dose, I would consider the question of dose and clear value for avastin to be more questionable than previously. And when we throw in the fact that erbitux (cetuximab) has also recently been reported to improve survival when given with standard chemotherapy, I suspect we're going to see a further erosion of the fair consensus we've had. Stay tuned.

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