Genentech anticipates continued sales growth for its blockbuster oncologic Avastin regardless of whether it is approved for first-line treatment of metastatic breast cancer.

Avastin currently is prescribed off-label to about a quarter of metastatic breast cancer patients who have not received chemotherapy, and "absent of a major challenge of compendia, I'd expect to retain the majority of that revenue," Genentech Exec VP-Commercial Ian Clark said during the firm's fourth quarter earnings call Jan. 14.

Genentech is bracing for the possibility that its application for Avastin (bevacizumab) for a breast cancer indication will not be approved on its Feb. 23 user fee action date following a negative review by FDA's Oncologic Drugs Advisory Committee.

Formulary Status At Risk?

An unfavorable regulatory action on the Avastin application for first-line breast cancer may be construed as an unfavorable view of the VEGF inhibitor's efficacy by FDA and could result in changes to the product's formulary status.

"Avastin use in this setting has been supported by favorable reimbursement, which is partly due to a compendia listing. If Avastin does not receive regulated approval, the compendia listing may be at risk and could negatively impact reimbursement for some patients," Clark suggests. Compendia listings describe both approved and off-label uses that have gained medical acceptance and often are the reference payers use when deciding to cover unapproved uses.

However, that negative compendia outcome is unlikely for Avastin, which is listed for breast cancer in Drug Points, as well as the American Hospital Formulary Service list and the National Comprehensive Cancer Network physician guidelines, the exec posits.

"We have looked back at situations in the past wherein maybe people have had a compendia listing and it has been removed. In the instances we can find, at least recently, it's usually as a consequence of a subsequent piece of data which was negative. ... That's clearly not our situation," Clark said.

"There is some risk here, but I think what precedent we can find would suggest the risk should not be too high," Clark added.

New Data Could Be Of Help

If the VEGF inhibitor does not get approved, the firm predicts that physicians will turn to emerging clinical data to inform prescribing decisions rather than turn away from the treatment. Results from Roche's AVADO study and Genentech's RIBBON-1 study, both in first-line HER2-negative breast cancer, are expected in 2008.

"The AVADO study, which will be available in the first half of this year, regardless of FDA action, will have an impact on the belief that the [oncology] field has about the use of Avastin in the first line metastatic breast cancer study," President-Product Development Susan Desmond-Hellmann said.

However, results of AVADO could reduce Avandia sales if data show that the treatment effect for lower doses of Avastin is similar to higher doses - as the AVAiL trial did in the non-small cell lung cancer setting (¹ Also see "Genentech AVAiL Trial Results May Lower Avastin Dosing In NSCLC" - Pink Sheet, 26 February, 2007., p. 5). "With lung cancer, we have seen a drop, but not a lot of a drop. We have seen it stabilize and one could speculate you might see the same sort of thing with breast cancer," Clark noted.

"That said, if you compare the two studies, the lung cancer study with a chemo backbone [is] typically not used in the U.S., whereas in the breast cancer study, it is with chemo that U.S. oncologists do use [Avastin]. So there might be a willingness to interpret more completely as a consequence of that," he said.

"Plus the fact you'll have two studies rather than one study [that] possibly support the lower dose. So it would be a reasonable conclusion that if AVADO looked like AVAiL, you will see a [greater] reduction of the ... dose in the breast cancer setting than we've seen so far."

While data from AVADO and RIBBON-1 may influence physician behavior, it is unclear whether they will help assuage FDA's discomfort about the pending application.

At the ODAC meeting, FDA expressed concern about approving Avastin for breast cancer on the basis of improvement in progression-free survival when the pivotal trial, E2100, failed to show significant improvement on overall survival (² Also see "Progression-Free Survival Represents Clinical Benefit, But How Much? – ODAC" - Pink Sheet, 17 December, 2007., p. 15).

Progression-free survival is the primary endpoint for both AVADO and RIBBON-1, and the AVADO protocol does not include an independent review as the trial was designed to meet European regulations.

"Neither the AVADO nor the RIBBON-1 trials are powered as survival trials," Desmond-Hellmann said. "But there would be a read on the trend in survival at the same time that PFS is reported. So I would expect a preliminary assessment of survival - underpowered and early, but one could rule out a negative impact on survival in the first half of the year for AVADO and at the end of the year for RIBBON-1."

Angiogenesis: Genentech's Mechanism Of Action

Despite the AVAiL setback, Avastin showed strong growth and was Genentech's top product in 2007. The oncologic, which is approved for first- or second-line treatment of metastatic colorectal cancer and first-line treatment of metastatic non-small cell lung cancer, posted U.S. sales of $2.3 bil., a 32 percent increase over 2006.

"Year-over-year growth resulted from increased sales in metastatic and non-small cell lung cancer and metastatic breast cancer and unapproved uses of Avastin in the U.S.," Clark said.

At this point, Avastin has an approximately 35 percent share of the total first-line metastatic lung cancer market - or 60 percent of patients eligible for bevacizumab therapy. Following AVAiL, prescribing patterns stabilized in the fourth quarter with approximately two-thirds of patients receiving the higher weekly dose.

Sales of Avastin for colorectal cancer in the fourth quarter were stable compared with the year-ago period, an improvement over the first half of 2007 when increased competition from Amgen's Vectibix (panitumumab) and Bristol-Myers Squibb/ImClone's Erbitux (cetuximab) negatively impacted Avastin usage in second-line CRC (³ Also see "Avastin Growth Cut By Colorectal Cancer Competition, Genentech Says" - Pink Sheet, 16 April, 2007., p. 6). "In spite of the competition," Clark said, "Avastin use in this setting is rebounding."

Another factor in Genentech's favor has been the low enrollment in the firm's patient assistance program, which caps annual Avastin costs at $55,000 per year for approved indications (⁴ Also see "Avastin For Lung Cancer Will Be Free To Patients Who Beat The Average" - Pink Sheet, 16 October, 2006., p. 6). Clark noted that low enrollment allowed the company to add some previously deferred revenue.

Approval and subsequent marketing of Avastin for first-line metastatic breast cancer could provide a major boost for the agent. While market penetration for breast cancer stands at 25 percent, "we think the eligible population is maybe as high as 90 percent, so there is a huge amount of upside attached to that," Clark added.

Continued Growth Predicted For 2008

Overall, the firm sees opportunity for continued growth in 2008 through continued market penetration and potential new indications.

"Penetration in lung cancer is good, but still it's only 60 percent of eligible [patients], so to my mind there's growth left there," Clark said. "Then we do have the possibility of growth that might occur as a consequence of any renal cell or glioblastoma indication as well. So I think there is definitely room for growth, clearly not as much room as we might get should we get the approval of breast cancer."

"We ... have the potential to see data from the Avastin adjuvant colon trial if one of the 2008 interim looks crosses a pre-specified statistical boundary, although of course we are not predicting that this will happen in the coming year," CEO Arthur Levinson said during the JP Morgan Healthcare Conference Jan. 9.

The next efficacy interim analysis of the Phase III NSABP C-08 study comparing Avastin plus FOLFOX6 to FOLFOX6 in adjuvant colon cancer is scheduled for the second quarter.

Genentech is planning to file an sBLA in the third quarter for a first-line renal cell carcinoma indication, based on Roche's AVOREN study supported by data from the CALGB 90206 trial, despite a recent clinical setback (⁵ Also see "Genentech Plans Avastin Renal Cell Cancer, Breast Cancer sBLA Filings" - Pink Sheet, 16 July, 2007., p. 3).

In the SABRE trial evaluating Avastin in combination with Pfizer's Sutent in renal cell carcinoma, microangiopathic hemolytic anemia was seen in patients receiving the higher dose of sunitinib. Although the safety signal was not seen at lower doses of Sutent, Genentech discontinued the trial.

Genentech also is planning a Phase III study in first-line glioblastoma multiforme. The firm released positive Phase II data from the BRAIN study comparing Avastin to Avastin plus irinotecan in the second- and third-line brain cancer setting in November.

"We have a meeting scheduled with the FDA to discuss the feasibility of submitting Phase II data" that show "36 percent of patients treated with Avastin alone and 51 percent of patients treated with Avastin in combination with irinotecan lived without cancer progression for six months," Desmond-Hellmann said.

"These are exciting results when compared to historical data in this setting, in which only an estimated 15 percent of patients with relapsed GBM live without their cancer advancing within six months."

Genentech and Roche, which owns a controlling stake of the biotech firm, have focused R&D efforts on establishing Avastin as the "backbone" of standard care in oncology (⁶ Also see "Roche Sees Avastin As Oncology Backbone, Will Focus On Combinations" - Pink Sheet, 10 July, 2006., p. 6). Bevacizumab currently is in Phase III development for 15 specific indications.

Genentech's Other Oncologics Performance

Overall, sales of Genentech's oncology products in the U.S. increased 15 percent to $6.29 bil. in 2007, compared with the previous year.

Sales of Herceptin grew four percent to $1.29 bil. for the year. "Overall penetration in HER2-positive adjuvant breast cancer remained stable, in the mid 70s in Q4 '07 relative to the prior quarter of that year," Clark said. "Despite new competition, Herceptin's penetration in the first-line metastatic setting also remains stable at approximately 70 percent. The current pattern of use appears to be limited primarily to later lines of metastatic disease." Genentech received FDA approval for expanded adjuvant use based on the HERA trial Jan. 18.

Tarceva also saw a four percent sales increase in 2007. "Penetration and duration in both second-line lung cancer and front-line pancreatic cancer remained stable in Q4," Clark noted. "Tarceva product returns, which negatively impacted reported sales in both Q2 and Q3, did not have an impact on sales in Q4."

"In hematology, sales growth resulted from increased use of Rituxan following first line therapy in indolent [non-Hodgkin's lymphoma] and from increased adoption in front-line [chronic lymphocytic leukemia], an unapproved use. Rituxan's overall adoption in areas other than NHL and CLL remained steady." Genentech's top selling product of 2006 grew 10 percent in 2007, recording $2.29 bil. in sales.

- Brian Marson (b.marson@elsevier.com)

Avastin Growth Not Limited To Breast Cancer In 2008, Genentech Says

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