Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Company will present details on a so-called confirmatory study and biomarker data.

A slice of Genentech’s $7.7 billion Avastin franchise is at stake as the company tomorrow tries to persuade the FDA to reinstate Avastin’s metastatic breast cancer (MBC) indication. That slice—estimated last year to be about $1 billion—could get smaller unless the agency reverses its decision last December to withdraw the drug’s approval for MBC. The hearing begins June 28 and will run through the following day at FDA’s White Oak Campus headquarters in Silver Spring, MD.

Avastin was first green-lighted in 2004 for advanced colon cancer and has since been sanctioned for advanced lung, kidney, and brain cancers. It received accelerated approval for MBC in combination with chemo drug paclitaxel in 2008. This was conditioned on Genentech furnishing additional data on Avastin’s clinical benefit.

Genentech and corporate parent Roche hope to sway FDA in part by presenting further details of a “confirmatory” study first proposed by the company last August, Charlotte Arnold, a Genentech spokeswoman, told GEN. That study would examine the effect on MBC of Avastin combined with paclitaxel compared to paclitaxel alone in patients who have not received chemotherapy for metastatic Her2-negative breast cancer. It would also assess VEGF-A, which has been found to be a biomarker for patients more likely to benefit from the treatment.

By identifying patients more likely to benefit, Genentech hopes it can retain at least a limited form of the MBC indication. While not hinting at that possible outcome, FDA has indeed encouraged further research into patient subsets who are likely to benefit the most.

In a May 17 filing, however, two FDA attorneys representing the Center for Drug Evaluation and Research (CDER) told the hearing’s presiding officer, Karen Midthun, M.D., that a new study would not affect the center’s conclusion that Avastin does not prolong overall survival in patients with breast cancer or offer a benefit in slowing the progression of the disease that outweighs the drug’s risks.

A Matter of Endpoint

Despite an advisory panel’s 5–4 recommendation against the drug, FDA conditionally approved Avastin for MBC, citing Genentech’s E2100 study. It showed a 5.5-month increase in progression free survival (PFS) from 5.8 to 11.3 months. Last December, however, FDA began efforts to withdraw the MBC indication in line with a CDER recommendation.

CDER cited four studies of Avastin for MBC. The most favorable study showed patients with MBC living just 2.9 additional months after using Avastin. The other studies showed 2.9 months of PFS with Avastin plus capecitabine (RIBBON1 trial), 1.2 months of PFS with Avastin plus taxane/anthracycline chemotherapy (RIBBON1 trial), and 0.9 months of PFS with docetaxel (AVADO trial).

“To confirm the benefit to patients required for an accelerated approval, CDER expected to see a magnitude of benefit similar to the 5.5 month improvement in progression-free survival seen in E2100 or other real clinical benefit, such as improvement in quality of life or overall survival benefit,” a CDER spokeswoman, Erica V. Jefferson, told GEN. “When the confirmatory studies failed to show a clinical benefit, CDER proposed that the breast cancer indication be withdrawn.”

Genentech has responded by noting that the initial 5.5-month benefit was the largest in median PFS observed in a first-line MBC trial; that the E2100 study had limited power to detect the sort of overall survival the agency seeks; and that the AVADO and RIBBON1 clinical trials verified the clinical benefit of Avastin in MBC because they met their primary endpoint of improved PFS with a high degree of statistical significance.

Genentech says that PFS should be a primary endpoint. It can be objectively measured, and the EU recognizes it as an endpoint in oncology clinical studies, the firm pointed out. FDA says the primary endpoint should instead be overall survival: “FDA has considered PFS as a surrogate endpoint of clinical benefit rather than a direct measure of clinical benefit,” according to a Dec. 15, 2010, memo from Richard Pazdur, M.D., director of FDA’s Office of Oncology Drug Products, to Janet Woodcock, M.D., director of CDER.

Genentech has also questioned the expertise of the FDA’s Oncology Drug Advisory Council (ODAC), which raised an early red flag about Avastin by recommending against the MBC indication in July 2010. Of the 13 ODAC members attending that meeting, two were breast cancer oncologists, Genentech noted.

The firm pointed to the exclusive breast cancer specialization of the National Comprehensive Cancer Network panel, which upheld the indication after reviewing the same postapproval clinical trial data that turned ODAC against the drug. As Genentech itself noted, though, ODAC’s purview includes a broader mix of oncology topics, not just breast cancer.

Additionally, CDER and Genentech have squabbled on procedural issues, notably the number of representatives who can speak for them at the hearing. Genentech has named six presenters and CDER five, but CDER also wants three professionals on hand to answer questions, though they won’t give presentations.

Genentech says that’s unfair, citing rules that anticipate speakers giving presentations, then answering questions. CDER says excluding the three would prevent it “from fully and fairly presenting its case and would impinge the purpose of this hearing to protect the public health.”

Confirmation Needed

Due to its wrangle with the FDA, Roche has downgraded its 2011 sales forecast for Avastin from CHF 9 billion (about $10.7 billion) to between CHF 6 billion and CHF 7 billion; last year the drug brought in CHF 6.461 billion.

Earlier this month, at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO), Roche trumpeted results of OCEANS, a Phase III study showing a median 12.4-month PFS in women with recurrent platinum-sensitive ovarian cancer who received Avastin in combination with chemotherapy (gemcitabine and carboplatin) followed by continued use of Avastin alone. Women receiving chemo alone saw an 8.4-month PFS.

Also presented at ASCO was an interim analysis of overall survival data from another Phase III trial involving Avastin in ovarian cancer, ICON7. When all patients in the study were evaluated, 179 Avastin patients died despite their treatment compared with 200 in the chemo group, a difference not deemed statistically significant.

Among patients who had the highest risk of recurring ovarian cancer, though, 79 from the Avastin group died compared with 109 chemo-treated patients, something researchers did consider significant. A final analysis is not expected until 2013.

These results show how determined Roche is to find additional uses for Avastin and grow the drug’s worldwide revenues. In Europe EMA has said that Avastin in combination with paclitaxel remains a valuable treatment option for patients with metastatic breast cancer, but the agency has revoked Avastin’s use with docetaxel for MBC.

The European agency offers a roadmap for FDA to resolve how Avastin can be used for MBC: Limit its uses to one or more patient subgroups that show the most benefit and restrain the combination regimens in which it is used. Just what those subgroups are will require additional research, and the agency may well wish to consider seeking more than the single confirmatory study Genentech has proposed.

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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