Avastin with Chemo: Standard of Care for a Subset with Advanced NSCLC

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October 14, 2006 - 5:30 pm email to a friend printer friendly view / write comments

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Dr. West

   Avastin (bevacizumab), an antiangiogenic agent that works by blocking the blood vessel stimulating factor vascular endothelial growth factor (VEGF), has already been FDA approved and commercially available for colon cancer, but it has now been approved by the FDA for first-line treatment of non-squamous NSCLC in combination with standard chemo of carboplatin and paclitaxel (taxol). This is because the combination of chemo and Avastin was found in a large randomized trial publsihed in the New England Journal of Medicine (abstract here) that the combination improved survival when combined with chemo alone for patients with advanced/metastatic NSCLC who hadn’t received chemo before. This trial, with nearly 900 patients, compared carboplatin and paclitaxel (Carbo/Taxol) alone to the same two-drug chemo with Avastin every three weeks, and people who went through six cycles of chemo and Avastin without having progression of disease went on to receive Avastin alone as maintenance therapy until their cancer showed progression:

 

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The addition of Avastin to chemo was associated with an improvement in overall survival by more than 20%, and also with significant improvements in time before cancer progressed, and higher likelihood of showing significant tumor shrinkage. In fact, the likelihood of showing a significant tumor response more than doubled with addition of Avastin.

Interestingly, while almost all patient subsets showed similar benefits in survival from addition of Avastin, women showed a quite significant improvement in likelihood of having tumor shrinkage (about three times higher in women who received Avastin with chemo) and a longer time before cancer progressed, their overall survival was not significantly different. We still cannot explain this very well, although the women getting chemo alone did remarkably well compared with what we’d expect, potentially from receiving the benefits of newer second- and third-line treatments. We also know that Avastin improved the time to disease progression in women with breast cancer. Overall, most experts and other practicing oncologists who know these data would not be inclined to restrict use of Avastin to men only. 

   However, there are some concerning restrictions and potential side effects. The trial supporting the survival benefit for Avastin in lung cancer did not include everyone, but only a subset of lung cancer patients, probably something like 40% of the whole lung cancer population, although estimates vary. It excluded patients with squamous cell carcinomas, but also prohibited patients with a history of coughing up blood, of blood clots or other reason to be on blood thinners, and people who had brain metastases were also excluded (out of concern for bleeding into the brain). This was because there have been some fatal or near fatal bleeding complications, primarily from coughing blood, but also some worry about bleeding in the brain. Before they kept out patients with squamous cancer, those patients seemed to have a very high risk, up to 31% of patients in early studies having life-threatening or fatal pulmonary hemorrhages. Even in the more restricted trial, there were more deaths from treatment when Avastin was added, and there were also more patients who died from infections when Avastin was added.  High blood pressure was also more common with avastin, and there was just a non-significant trend toward more clots, both in arteries and veins, in the recipients of Avastin with chemo:

   Despite the toxicity issues, overall the chemo/Avastin combination was more helpful than harmful, improving the median overall survival by about two months.  It’s now considered a standard combination for the subset of patients who would be considered eligible for avastin, although the small but real risk of very serious or even potentially fatal side effects with the triplet combination make this an approach not for everybody.

Posted in: Anti-angiogenic agents, Core Concepts, First-line treatment, Lung Cancer, Metastatic/Recurrent NSCLC, First Line, Non-Small Cell Lung Cancer (NSCLC), Targeted therapies                     email to a friend printer friendly