You’ve probably already seen the headlines noting the disappointing outcomes of two phase III studies of bevacizumab (brand name Avastin, made by Genentech) for ovarian cancer. I’ve been trying to familiarize myself with the data this morning—I am pretty certain that practicing interpreting study reports can add years to my brain functioning—and figured I’d post a quick summary here.
There were two phase III studies published in the New England Journal of Medicine on December 29. (And don’t you want to know how that came about? Were the studies planned from the get-go to end at around the same time? Or were the analyses specifically timed to be reported simultaneously? And were there women with ovarian cancer being treated with Avastin off-label in the meantime, while these studies, funded in part by public dollars, were being prepared for publication?) One study looked at a couple of different ways of incorporating the drug into primary treatment. The other study was a direct comparison of two regimens.
First, the more complicated trial. Here, 1,873 women with stage III or IV ovarian cancer were randomly assigned (double-blind) to one of three groups:
Group 1: Chemotherapy in cycles 1–6, with a placebo added for cycles 2–22.
Group 2: Chemotherapy plus bevacizumab, cycles 2–6; chemotherapy plus placebo, cycles 7–22
Group 3: Chemotherapy plus bevacizumab, cycles 2–22
The primary endpoint was progression-free survival. Maybe this is common knowledge by now, but in case not, let’s remember that PFS is not a measure of real benefit. Rather, it’s a surrogate marker, indicating a potential for actual benefit. The real benefit would be if the addition of bevacizumab improved overall survival by a clinically meaningful amount of time. PFS does not necessarily indicate (in fact, it rarely indicates) an extension in actual survival time.
But, the primary endpoint was PFS, so here are those numbers. For group 1, the median PFS was 10.3 months. Group 2 was 11.2 months, and Group 3 was 14.1 months. The study duration was for up to 10 months. The authors note that there was no significant different in overall survival at the time the data were analyzed, although it’s important to remember that OS wasn’t the primary endpoint, so even a negative outcome there isn’t necessarily meaningful. And the rate of hypertension requiring medical intervention was at least double among women receiving bevacizumab (7.2% for Group 1, 16.5% for Group 2, and 22.9% for Group 3).
The conclusion in the study’s abstract is interesting. It reads:
The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer.
Would you agree with that statement, based on the numbers above?
Now, the other study. Here, 1,528 women from 11 countries were treated with either carboplatin + paclitaxel, or this chemotherapy combination plus bevacizumab. I haven’t read the full study, only the abstract, so I don’t know what the primary endpoint, determined before the study launched, was intended to be. However, the abstract states that the outcome measures were PFS analyzed per protocol, then PFS updated, and interim overall survival. From this, I’d infer that the primary endpoint was PFS at 36 months (the updated PFS was at 42 months).
So, the results. PFS at 36 months for the control arm (standard chemotherapy) was 20.3 months, meaning that women receiving combination chemotherapy went for, on average, 20.3 months without cancer progressing. Women who received chemotherapy + bevacizumab experienced disease progression at a median 21.8 months. At 42 months, the PFS was 22.4 months and 24.1 months, respectively.
The authors also provide a subset analysis for women who were at high risk for progression when they enrolled in the study; that was about 30% of the study population. Among this group, PFS at 42 months was 14.5 and 18.1 months, respectively. Overall survival for these women was 28.8 months and 36.6 months, respectively.
The abstract conclusion for this study reads:
Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression.
Again, would you agree with that statement? Here is a great example of distinguishing between numbers that are statistically significant and numbers that are clinically meaningful.
Many news outlets reported on these studies. One interesting article by the Los Angeles Times provided a look at the cost of this treatment. This article (a blog post, actually) draws on a study from the Journal of Clinical Oncology (JCO) analyzing the cost-effectiveness of bevacizumab in ovarian cancer. This study was published back in April 2011, six months before the NEJM reports of these two phase 3 trials.
The JCO cost-effectiveness analysis was based on preliminary data from the three-group study discussed above (the trial is also known as Gynecology Oncology Group, or GOG, 218). The cost analysis estimated the cost of treating 600 patients on each arm of that study, using the baseline estimates of PFS and also bowel perforation, a side effect of bevacizumab. According to the analysis, the cost of treating women who received chemotherapy alone was $2.5 million. The cost for Group 2 was $21.4 million. The cost for Group 3 was $78.3 million. According to these numbers, the “incremental cost effectiveness ratio”—which measures the cost per year of progression-free life saved—was over $400,000 for both bevacizumab-containing groups. Reducing the cost of this drug by 25% brought that number down to $100,000 for Group 3. But, treatment of bowel perforation adds costs that drive that figure back up.
That cost-effectiveness analysis concluded:
The addition of bevacizumab to standard chemotherapy in patients with advanced ovarian cancer is not cost effective. Treatment with maintenance bevacizumab leads to improved PFS but is associated with both direct and indirect costs. The cost effectiveness of bevacizumab in the adjuvant treatment of ovarian cancer is primarily dependent on drug costs.
You can have nothing but compassion for anyone experiencing ovarian cancer, and women with this disease are definitely in need of improved treatments. It appears that bevacizumab probably isn’t next on the horizon, though.
All that being said, you have to wonder if the search for biomarkers that might indicate the likelihood of someone benefiting from Avastin will yield fruit. Time will tell. But it might be a long, long time.