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In FDA Appeal, Genentech Proposes Biomarker Strategy to Keep Avastin Available for Best Responders

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Originally published Jan. 23.

By Turna Ray

In appealing
the US Food and Drug Administration's decision to pull Avastin off the market as a treatment for metastatic breast cancer, Genentech has raised the possibility of conducting biomarker analysis to "clarify the clinical benefit" of the drug in patients with high levels of VEGF-A.

This week, Genentech filed a 98-page document contesting FDA's attempt to revoke Avastin's market availability in metastatic breast cancer. In the appeal, Genentech focuses mainly on efficacy and safety data from studies that would keep the drug on the market for the general metastatic breast cancer population. Furthermore, the company argues that Avastin was granted accelerated approval by the FDA based on the drug's impact on progression-free survival, and as such, it is inappropriate for the agency to now withdraw the drug based on its inability to prolong overall survival. Genentech does note, however, that it would be open to conducting a clinical trial with a "biomarker component" that would narrow the population for the drug.

In December, the FDA notified Genentech of its intent to revoke Avastin's approval in metastatic breast cancer based on studies that showed that the drug lacks efficacy and causes serious adverse reactions in breast cancer patients. The decision followed that of the FDA's independent expert panel, the Oncologic Drugs Advisory Committee, which in July voted 12 to 1 in favor of removing Avastin from the market in the breast cancer population (PGx Reporter 12/22/10).

Genentech markets Avastin in combination with paclitaxel in patients with HER2-negative metastatic breast cancer who have not yet received chemotherapy for metastatic disease. The drug is not approved for people who have received prior anthracyclines and taxanes for their HER2-negative metastatic breast cancer.

According to Genentech's appeal, the company is willing to conduct a confirmatory 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."

Genentech cites data from the Avastin and Docetaxel trial, or AVADO, presented at the December 2010 San Antonio Breast Cancer Symposium, which 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 PFS 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."

The company adds that Phase III trials of Avastin that used a "first-generation" VEGF assay indicated that VEGF "was a strong prognostic — but not predictive — marker for Avastin’s efficacy." Studies using a "second-generation" VEGF test, however, showed that "VEGF at baseline demonstrated a potential predictive effect in [metastatic breast cancer] and pancreatic cancer for patients with samples available."

A spokesperson for Genentech told PGx Reporter that the first-generation test was an ELISA-based assay. "It suggested that levels of VEGF were a strong prognostic, but not predictive, marker for Avastin’s efficacy," the spokesperson said. The second-generation test is also an ELISA-based multiplex assay, according to the company representative, which "showed a potential predictive effect of VEGF in metastatic breast cancer and pancreatic cancer for patients with samples available."

Since FDA first announced it was considering taking Avastin off the market in metastatic breast cancer last year, Genentech has been reticent in discussing whether a pharmacogenomics strategy would feature prominently in its attempts to convince the agency to maintain the drug's availability in a subpopulation of patients who are best responders. A Genentech spokesperson told PGx Reporter previously that the company is "looking at biomarkers for angiogenesis as part of our independent work as well as our work with academic centers," but would not discuss whether these were PGx markers and would not specify how prominently biomarker data may be used by the company in its appeal to the FDA.

Now, it seems, Genentech is eager to undertake a biomarker-guided approach to gauge which patients would respond to Avastin. "A biomarker program has been an integral part of Genentech’s research on Avastin," the company said in its appeal. "A large number of markers (over 10,000 in preclinical and over 100 in clinical studies) have been studied in a variety of tumor types (including MBC, pancreatic cancer, gastric cancer, colorectal cancer, lung cancer, and brain cancer) for prognostic and predictive biomarkers. These biomarkers include plasma and tumor markers, circulating endothelial and progenitor cells, imaging, and genetic polymorphisms."

These comments suggest that Genentech is exploring various biomarker strategies to direct Avastin treatment to best responders, but the company does not specify its personalization strategy for the drug in its appeal. Although genomic analysis was conducted as part of E2100 — a pivotal study Genentech submitted to the FDA to garner accelerated approval for Avastin in metastatic breast cancer in 2008 — it is unclear to what extent Genentech has validated the PGx leads that came out of that trial.

E2100 showed an improvement in progression-free survival in patients with HER2-negative metastatic breast cancer, but did not show improvements in disease-related symptoms or survival. However, researchers conducted genomic studies within E2100 and identified markers that conferred longer survival and protection against drug-induced hypertension. Specifically, in E2100, researchers uncovered preliminary PGx data linking VEGF-1154 AA and -2578 AA genotypes to an improvement in median overall survival. Additionally, E2100 showed that patients with VEGF-634 CC and -1498 TT genotypes had protection from grade 3-4 hypertension, a common side effect of Avastin.

In its appeal, Genentech did not discuss these VEGF genotype findings, though it acknowledges that its VEGF biomarker leads need further investigation.

After the ODAC's review of Avastin last year, when PGx Reporter asked Genentech whether a pharmacogenomics strategy had come up during discussions with the FDA or with advisory committee members, a company spokesperson said that Genentech had not submitted such data to the agency, and if the topic had come up during the advisory committee meeting, it was "only in passing" (PGx Reporter 08/25/10).

Five months later, after having received a notice from the FDA about the revocation of Avastin's approval — a move that could cost the company around $1 billion in annual sales — the story is very different. In its appeal, Genentech argues that "many stakeholders," including ODAC members, would support a biomarker-based personalized medicine strategy to pinpoint best responders.

Genentech combed the transcript from the July 20 ODAC meeting to highlight in its appeal specific quotes from committee members that support keeping the drug on the market in a biomarker-defined subpopulation of breast cancer patients. For example, Patrick Loehrer, an ODAC member and the director of Indiana University's Cancer Center, is quoted in the appeal as saying, "I do think there is activity for Avastin in breast cancer. I think it is yet to be clarified. … I also would welcome them to identify that patient population that may benefit. I think, again, there are some likely markers out there. … I think to make this a great drug … I think we need to decide who we shouldn’t treat and treat those who are going to benefit."

Similarly, Genentech points out in its appeal that Gregory Curt, an industry representative on ODAC from AstraZeneca's oncology division, commented during the hearing that subpopulation analysis would likely be the "next phase of the research with" Avastin. And committee member Gary Lyman, director of Comparative Effectiveness and Outcomes Research at Duke University, hoped that there would be opportunities for the company to report on patients that have the best benefit and least toxicities.

Finally, Genentech appeals to FDA's growing focus on personalized medicine to attempt to sway the agency in letting it do biomarker analysis, identify best responders, and keep Avastin available as an option in that subpopulation.

"The biomarker component advances FDA’s efforts to encourage personalized medicine," Genentech states.

Indeed, as the company points out, FDA Commissioner Margaret Hamburg noted in remarks at the Personalized Medicine Coalition’s Sixth Annual Keynote Luncheon last year that "clearly, we can have much better outcomes for patients if we can discern what distinguishes one [patient] group from another, in terms of positive response, and design a clinical trial based on that knowledge."

Depending on how mature Genentech's biomarker data on Avastin is, a personalized medicine strategy to keep the drug on the market for a subpopulation of patients may be the company's best bet. There is some precedence for such a pathway.

For example, outside the US, AstraZeneca has been able to successfully relaunch its lung cancer drug Iressa with a companion EGFR test. In 2005, AstraZeneca withdrew its marketing application in the European market for Iressa after it failed to show a survival advantage in clinical trials. In the US where the drug had already received accelerated approval from the FDA, the agency didn't pull Iressa off the market due to low efficacy in clinical trials, but decided to place the drug in a restricted-access program. This meant that only patients already on Iressa and benefiting from it could have access to it, but no new patients could be prescribed the drug.


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