With evidence of an overall survival benefit in second-line metastatic colorectal cancer, Regeneron Pharmaceuticals/Sanofi-Aventis SA's Zaltrap (aflibercept) is positioned for regulatory approval. But it remains unclear whether the experimental angiogenesis inhibitor will be positioned to win patients away from Roche/Genentech's Avastin (bevacizumab).

The top-line finding of the Phase III VELOUR trial was announced April 26; full study results will be unveiled at an upcoming medical meeting, most likely the American Society of Clinical Oncology meeting in June. The two companies plan to file an NDA for Zaltrap (also known as VEGF Trap) in second-line mCRC during the second half of 2011.

Sanofi and Regeneron are not necessarily targeting Avastin, which is approved for first-line and second-line mCRC. The VELOUR trial enrolled patients who had been treated with an oxaliplatin-based regimen, which could have included Avastin. Thus, when the full results are detailed, the companies will have data on how Zaltrap performs in Avastin non-responders.

Zaltrap was tested against a background FOLFIRI regimen of leucovorin, 5-fluorouracil and irinotecan in 1,226 patients. Avastin's mCRC trials used a similar but not identical regimen; the same drug combination, but 5-FU administered in a bolus, a larger upfront dose than is provided in FOLFIRI. Comparisons are inevitable, but Sanofi and Regeneron are not conducting any head-to-head trials, and a Regeneron spokesman said he did not want to look too far ahead to consider whether the companies might run such a trial.

In an April 27 note, analyst Tim Anderson of Bernstein Research said Zaltrap could be poised to win market share away from several targeted therapy drugs used in second-line mCRC, mentioning Eli Lilly and Bristol-Myers Squibb's Erbitux (cetuximab) and Amgen's Vectibix (panitumumab) along with Avastin.

"In the case of Avastin, a little less than half of its sales come from the mCRC setting (with the rest coming from use in other tumor types) but most of that is in front-line disease," Anderson wrote. "We estimate that less than 10% of total Avastin sales ... are in the second-line mCRC setting."

Top Sales Estimated At $200 Million Annually

Deutsche Bank analyst Robin Karnauskas, in an April 26 note, projected peak sales for Zaltrap in this setting at about $200 million a year. Based on data provided by Roche last year, she estimated there are about 34,000 second- and third-line mCRC patients in treatment, with 30% of these receiving Avastin, meaning a worldwide market of about $400 million.

"We assume Zaltrap can take 50% of the market worldwide based on cost and the marketing of the fact that this second-line trial enrolled 20%-30% of patients who had previously had Avastin (theoretically, Zaltrap binds more factors than Avastin)," she wrote.

Besides second-line mCRC, Sanofi and Regeneron also are investigating Zaltrap in first-line hormone-refractory metastatic prostate cancer - final results are expected from the Phase III VENICE study next year - and in first-line mCRC. Data from a Phase II trial testing Zaltrap with FOLFOX chemotherapy in that setting are anticipated during the second half of 2011.

Prior to the 2004 merger that created Sanofi-Aventis, Aventis paid $510 million upfront for worldwide exclusive joint licensing and marketing rights, excluding Japan, to VEGF Trap in cancer indications ([See Deal]).

Sanofi unveiled plans in 2007 to develop the angiogenesis inhibitor as an alternative to Avastin in several oncology settings where it failed or has not been approved (Also see "Sanofi Positioning Aflibercept To Compete With Genentech’s Avastin In Certain Settings" - Pink Sheet, 17 September, 2007.). These plans included since-abandoned programs for first-line ovarian cancer, first-line metastatic pancreatic cancer and second-line metastatic non-small cell lung cancer.

Regeneron, along with partner Bayer HealthCare AG, already has aflibercept ophthalmic solution, or VEGF Trap-Eye, under review at FDA for treatment of "wet" age-related macular degeneration (Also see "Regeneron Files BLA For VEGF Trap-Eye In Wet AMD; Second Filing Anticipated This Year" - Pink Sheet, 22 February, 2011.).

-Joseph Haas (j.haas@elsevier.com)

Survival Benefit May Position Zaltrap To Compete With Avastin In Second-Line CRC

More from Archive

More from Pink Sheet