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NICE Agrees With FDA in Pulling Avastin's Indication for Metastatic Breast Cancer


By Turna Ray

UK's National Institute for Health and Clinical Excellence agrees with US health regulators when it comes to Avastin as a treatment for metastatic breast cancer.

After reviewing the available evidence on Genentech/Roche's Avastin in combination with a taxane therapy to treat metastatic breast cancer in the first-line setting, NICE found this treatment regimen was not cost effective and did not improve patient outcomes compared to available alternatives.

Additionally, according to the final guidance issued by NICE this week, it appears that the drug sponsor did not submit data to the appraisal committee on biomarkers to stratify best responders to Avastin, or bevacizumab.

"For the subgroup of women with triple negative cancers, the [NICE appraisal] committee noted that while it was plausible that [Avastin] could be more effective in some tumor types than others, there was no proposal of a biologically plausible specific mechanism of effect for [the drug] having an increased benefit for this subgroup," NICE wrote in its guidelines.

Women with triple-negative breast cancer do not express the genes for estrogen receptor, progesterone receptor, or HER2. This molecularly defined subpopulation of breast cancer patients usually have a more aggressive form of the disease and don't respond to standard treatments.

The appraisal committee also considered whether Avastin might benefit patients with taxane resistance, but it seems Roche, the parent company to Genentech, did not submit biomarker-driven hypotheses to support the assertion that the drug might work better in this subpopulation. "For the prior taxane-treated subgroup, the [appraisal] committee noted that although there could be taxane resistance in this subgroup, there were no specific biological markers or other hypotheses to suggest why VEGF agents would work more effectively in this subgroup compared with the intention-to-treat population," said NICE, an independent body that provides guidance to UK's National Health Service on the clinical and cost effectiveness of treatments and technologies.

A Roche spokesperson told PGx Reporter that the drug developer did not submit biomarker data to the NICE appraisal committee. "We will be able to go back to NICE with these data but we have no immediate plans to do so," the spokesperson added.

In looking at the totality of evidence presented by Roche on Avastin's impact when given with a taxane to metastatic breast cancer patients, the NICE appraisal committee concluded that "for breast cancer patients whose tumors have spread elsewhere in the body, [Avastin] (when used with the taxane drug, paclitaxel) may slow the growth and spread of the cancer by around five months more than paclitaxel alone. However, due to uncertainties in the evidence, the committee was unable to conclude whether bevacizumab could extend a patient's life, or how long for." Additionally, the committee found no evidence suggesting Avastin improved patients' quality of life more than existing treatments.

After NICE's recommendation, it is unlikely that NHS will pay for Avastin treatment in the metastatic breast cancer population in the UK.

According to Roche, Avastin is estimated to cost between £3,304 ($5,363) to £3,435 ($5,576) per month, depending on the dose and treatment schedule the patient is on. After assessing the clinical data on the impact of Avastin on patients' disease, NICE calculated an unfavorable cost-effectiveness ratio, given that the cost per quality-adjusted life years was £117,803, £115,059 and £105,777 for Avastin with one of three kinds of taxane regimens: paclitaxel, docetaxel, or gemcitabine plus paclitaxel therapy, respectively.

However, NICE also recommended that patients currently receiving Avastin in combination with a taxane for the first-line treatment of metastatic breast cancer should continue to receive treatment until their doctor decides otherwise.

In the US, the process to remove Avastin's metastatic breast cancer indication is still ongoing. In December, the US Food and Drug Administration announced it would revoke the drug's accelerated approval in metastatic breast cancer after reviewing data from studies that showed the drug did not significantly impact the overall survival for patients. FDA's decision sparked controversy among patient groups who urged the agency and Genentech to consider keeping the drug as an option in subpopulations of women who might be benefiting from the drug (PGx Reporter 12/22/10).

Last month, Genentech appealed FDA's decision. In its appeal, the drug developer suggests that short of pulling the drug off the market for all metastatic breast cancer patients, the company is willing to conduct biomarker analysis to identify best responders to the drug (PGx Reporter 01/26/11).

In its appeal to the FDA, Genentech is proposing to conduct a double-blind randomized Phase III study of Avastin that would "confirm the efficacy and safety of Avastin in combination with paclitaxel." This proposed trial "would include a biomarker component to identify patients who may be more likely to derive a more substantial benefit from Avastin."

The Avastin and Docetaxel trial, or AVADO, showed that patients with high levels of plasma VEGF-A, who received standard doses of Avastin, had a progression-free survival hazard ratio of 0.49. Meanwhile, patients with low levels of VEGF-A had a progression-free survival hazard ratio of 0.86.

"This finding suggests that patients with high levels of VEGF-A may be more likely to derive a more substantial benefit from Avastin," the company states in its appeal. "The relevance of VEGF-A is scientifically plausible given Avastin’s inhibitory activity on the biologic actions of VEGF."

If this proposed biomarker analysis focuses on progression-free survival as the primary endpoint, it may still be problematic for the FDA, which is becoming more stringent in approving cancer drugs by demanding that they show a meaningful improvement in the overall survival of patients (PGx Reporter 02/16/11).

In Phase III trials of Avastin, Genentech said it used a "first-generation" VEGF assay that indicated that VEGF "was a strong prognostic — but not predictive — marker for Avastin’s efficacy." However, trials that have employed a "second-generation" VEGF test have shown that "VEGF at baseline demonstrated a potential predictive effect in [metastatic breast cancer] and pancreatic cancer for patients with samples available."

The agency hasn't yet responded to this decision, and as such, the drug hasn't been officially pulled off the market. However, on Genentech's website for Avastin, metastatic breast cancer is no longer listed as an indication for the drug, which is also prescribed to treat lung cancer, colorectal cancer, glioblastoma, and kidney cancer. Yanking FDA's approval for Avastin in breast cancer would shave off around $1 billion in annual drug sales for Roche.

Back in the UK, NICE's guidance on Avastin comes after the European Medicines Agency's Committee for Medicinal Products for Human Use recommended restricting the drug's UK marketing authorization so that doctors only prescribe bevacizumab in combination with the taxane drug, paclitaxel. In a statement, NICE also attempted to bolster its decision about Avastin, by noting that the FDA has moved to completely remove the drug as an option in metastatic breast cancer.

"The evidence for the effectiveness of bevacizumab in prolonging survival was not robust and overall did not show enough of a demonstrable benefit for it to be considered a cost-effective use of NHS resources," NICE Chief Executive Andrew Dillon said in a statement.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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