ODAC recommends removing breast cancer indication from bevacizumab label

Study results do not support use of bevacizumab in this setting, committee said.

The FDA’s Oncologic Drugs Advisory Committee has voted 12-1 to remove bevacizumab’s indication as a first-line therapy for metastatic breast cancer.

Bevacizumab (Avastin, Genentech) was granted accelerated approval for this indication in 2008.

At Tuesday’s meeting, Genentech was asking the FDA to convert the accelerated approval to full approval for bevacizumab in combination with paclitaxel and to expand the label to include use of bevacizumab in combination with other chemotherapies for the first-line treatment of patients with HER-2–negative metastatic breast cancer.

The vote may not lead to the FDA removing the indication for bevacizumab in metastatic breast cancer, although the FDA usually follows the recommendations of its advisory panels. In February 2008, the FDA overruled a 5-4 ODAC vote that recommended against fast-tracking the drug in these patients. However, the agency granted the accelerated approval based on a 52% improvement in PFS and a 5.5-month increase in median PFS demonstrated in the E2100 trial.

“If you look at the totality of the evidence before us today, the answer is quite clear: The results do not support the data that was used to grant the accelerated approval,” said Aman Buzdar, MD, a professor in the department of breast medical oncology at The University of Texas M.D. Anderson Cancer Center.

Committee members said bevacizumab had not been shown to improve quality of life or extend OS, and the drug was associated with increased toxicity. Additionally, they said there was no evidence that PFS was a surrogate marker for extended OS.

“We have no evidence there is any survival advantage. Clearly, there is no signal [bevacizumab] is improving outcome,” said Wyndham Wilson, MD, committee chair and chief of the lymphoma therapeutics section at the NCI’s Center for Cancer Research.

Virginia Mason, RN, executive director of the Inflammatory Breast Cancer Research Foundation in Citronelle, Ala., was the only committee member who voted against removing the indication. She said she was comfortable allowing physicians and patients to decide whether to use the drug.

ODAC also voted 13-0 that the addition of bevacizumab to docetaxel did not represent a favorable risk/benefit analysis for the initial treatment of patients with metastatic breast cancer and 12-1 that the addition of bevacizumab to taxanes, anthracyclines or capecitabine did not provide enough benefit to justify the risk.

In addition, the committee voted 13-0 that the data presented by Genentech did not provide confirmatory evidence of the clinical benefit of the addition of bevacizumab to paclitaxel.

Additional data

An accelerated approval requires Genentech to present additional data supporting the results of E2100. The company argued that combined evidence from the E2100, AVADO and RIBBON1 trials demonstrated that bevacizumab in combination with standard chemotherapy regimens was safe and effective for the first-line treatment of women with HER-2–negative disease.

In briefing materials, Genentech said, “Taken together, these data consistently demonstrate that treatment with bevacizumab in combination with chemotherapy provides clinically meaningful benefit to patients with newly diagnosed, previously untreated HER-2-negative metastatic breast cancer.

However, FDA staff argued that results from AVADO and RIBBON1 did not show that bevacizumab improved OS, and did not demonstrate a magnitude of improvement in PFS similar to that observed in E2100.

“Overall survival data showed hazard ratios favoring the placebo arms for AVADO and RIBBON1 (taxane/anthracycline cohort), indicating an inferior outcome with the addition of bevacizumab to these chemotherapies,” wrote FDA staff. “The improvement in PFS observed in these two studies, as measured by the hazard ratio and as more commonly expressed by clinicians as the difference in median PFS between the treatment arms, failed to confirm the magnitude of PFS improvement observed in the E2100 trial, the basis for the accelerated approval.”

In the double blind, placebo-controlled AVADO trial, researchers randomly assigned treatment-naive patients with HER-2–negative tumors to docetaxel plus placebo (n=241), 7.5 mg/kg bevacizumab plus docetaxel (n=248) or 15 mg/kg bevacizumab plus docetaxel (n=247).

Patients had a 30% increase in PFS in the 7.5 mg/kg bevacizumab arm (HR=0.70; 95% CI 0.55-0.90). Those in the higher-dose bevacizumab group had a 39% increase in PFS (HR=0.62; 95% CI 0.48-0.79). In both groups, bevacizumab improved PFS by less than one month compared with the docetaxel group.

Genentech was also seeking approval to use bevacizumab with taxanes and anthracyclines or with capecitabine (Xeloda, Roche). It submitted the RIBBON 1 trial data to support the indication.

In that double blind study, 415 patients were randomly assigned anthracycline or taxane-based chemotherapy with 15 mg/kg bevacizumab or placebo (n=622), or capecitabine in combination with 15 mg/kg bevacizumab or placebo (n=615).

The addition of bevacizumab to taxane/anthracycline-based chemotherapy improved PFS by 36% (HR=0.64; 95% CI 0.52-0.80) with an observed 1.2-month increase in median PFS. Bevacizumab plus capecitabine improved PFS by 31% (HR=0.69, 95% CI 0.56-0.84) with an increase of 2.9 months in median PFS.

FDA staff determined that the results from a pooled analysis demonstrated no difference in OS between treatment arms (HR=0.97; 95% CI 0.86-1.08).

Additionally, toxicity data from both studies showed that serious adverse events including hypertension, bleeding, and febrile neutropenia were higher in patients assigned bevacizumab.

“The magnitude of treatment effect is clinically important because it is really a measure of delaying symptoms from tumor progression, which has to be weighed against drug toxicity that is present for the duration of treatment,” wrote FDA reviewers. “The risk-benefit ratio of bevacizumab when added to the chemotherapeutic regimens serving as standard of care in the AVADO and RIBBON1 studies may not be considered favorable.”

Bevacizumab is also approved to treat lung, kidney, colon cancer and recurrent glioblastoma. Tuesday’s decision has no affect on those indications. – by Jason Harris

Using PFS as an endpoint in metastatic breast cancer is difficult and ODAC recognizes this weakness. I believe that predictive biomarkers to identify patients who benefit from this type of therapy are needed. The drug is expensive and toxic and we need to find the subset of patients who benefit. If appropriately selected, it is possible that some patients would have prolonged OS by the use of this drug, but we do not have these tools in hand to identify these patients. Asking Genentech to go "back to the drawing board" is reasonable.

– Douglas Yee, MD
HemOnc Today Editorial Board member

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