Roche is gearing up for a planned year-end submission of Avastin in advanced ovarian cancer in the EU after making a splash at the European Society for Medical Oncology meeting with updated data from its Phase III ICON7 study showing a progression-free survival benefit.

This was the first release of PFS data from the Phase III ICON7 study, which was conducted in Europe, though top-line results data were previously released (Also see "Another Phase III Study Supports Avastin Expansion To Ovarian Cancer" - Pink Sheet, 2 July, 2010.). Roche already had unveiled a U.S. Phase III trial in ovarian cancer, GOG-0218, at the American Society of Clinical Oncology meeting in June.

The ICON7 trial tested Avastin (bevacizumab) in 1,500 newly diagnosed patients with advanced ovarian, fallopian tube and peritoneal cancer after surgery. Patients taking Avastin with chemotherapy followed by Avastin maintenance had a 27% improvement in the primary endpoint of PFS compared to women taking chemotherapy alone, Roche reported on Oct. 11.

The latest results were highlighted during the Presidential Symposium at the ESMO meeting in Milan, held from Oct. 8-12. It’s rare to see positive Phase III data in ovarian cancer and encouraging that the results were given such prominence at the ESMO meeting, commented Robert Burger, director of the Fox Chase Women’s Cancer Center in Philadelphia.

Ovarian cancer is difficult to treat and is not a high-prevalence disease, with some 240,000 new annual cases worldwide, including about 22,000 in the U.S. Compared to more common cancers, not as many late-stage trials are undertaken for this disease.

Earlier U.S. Study Showed Stronger Effect

Burger was lead investigator on the first large Phase III study of Avastin in front-line ovarian cancer – the U.S. GOG-0218 trial – which also found a PFS benefit. In that study, a higher dose of Avastin given for a longer treatment duration of 15 months (compared to a total of 12 months in ICON7) was shown to improve progression-free survival by 54% (Also see "Roche's Long View: ASCO Marks Progress In Shifting To Lengthier Treatment Duration For Avastin, Rituxan" - Pink Sheet, 14 June, 2010.).

In an Oct. 14 third-quarter earnings report, Roche noted that Avastin sales have been sliding in the U.S., most likely because the drug’s approval for metastatic breast cancer is under review by FDA and may be withdrawn. Roche COO for Pharmaceuticals Pascal Soriot described ovarian cancer as a “growth driver” going forward, noting that better results in the U.S. GOG-0218 trial could reflect the use of the higher dose and longer treatment duration.

Burger cautions, however, that there were many differences in the designs of the two trials and it is not scientifically appropriate to compare results – further study is needed to assess the impact of treatment duration. The important thing is that the same basic findings in GOG-0218 were confirmed in the ICON7 study, he said.

European Society for Medical Oncology meeting also features negative ovarian cancer trial results for Novartis’ patupilone and AstraZeneca’s olaparib, among others.

Jennifer Obel, an ASCO official who had moderated the news briefing about the GOG-0218 results at the 2010 ASCO meeting, said that even with the updated ICON7 results, the “jury is still out” on Avastin in ovarian cancer. Experience in metastatic breast cancer has made oncologists wary about other indications like ovarian cancer and overall survival and quality-of-life data are needed to assess the drug’s real benefit for patients, said Obel, an attending physician at Northshore University Health System in Illinois.

“Something that is statistically meaningful may not be clinically meaningful,” she cautioned.

Roche: PFS Is Best Endpoint

It’s unclear when data for overall survival – a secondary endpoint in both trials – will become available. In any case, ICON7 was powered to show an overall survival benefit while GOG-0218 was not. Analysis of the overall survival data is unlikely to be straightforward because cross-over following treatment failure was allowed.

Roche argues that PFS is a true measure of first-line drug activity since it is not confounded by post-study therapies in later lines. In general, it is “an acceptable primary endpoint for many regulatory authorities,” including the European Medicines Agency, the company said in an e-mailed statement. The European application will be filed by the end of this year and the U.S. filing is slated for an undisclosed time in 2011. Discussions with FDA are ongoing.

Amgen Moving Into Phase III With Peptibody

Amgen also had positive updated data to report for an ovarian cancer candidate. Amgen’s AMG-386 compound is a first-in-class investigational “peptibody,” a recombinant Fc-peptide fusion protein that binds to and inhibits both angiopoietin-1 and angiopoietin-2.

Angiogenesis of tumors can be targeted in different ways, and Amgen has been active in research with angiopoietins, substances involved in the signaling that is responsible for generating new blood vessels (Also see "Amgen Senior VP-Research and Development Joseph Miletich: An Interview With “The Pink Sheet” DAILY (Part 3 of 3)" - Pink Sheet, 1 June, 2007.).

Median PFS with AMG-386 in a Phase II trial presented at ESMO was 5 months for patients on placebo, compared to 7.4 months for the 3 mg dose and 7.3 months for the 10 mg dose. The company maintains that the data hint of a benefit for overall survival.

In November, Amgen plans to take the compound into a 100-site, international Phase III study testing AMG-386 in combination with paclitaxel in 900 patients with recurrent ovarian, primary peritoneal and fallopian tube cancer. The primary endpoint of the study will be PFS, with overall survival and improvements in performance among the secondary endpoints.

Negative Patupilone Results Presented

Results from a number of negative trials were also presented at the ESMO meeting, though observers say that the failures in some cases don’t necessarily spell the end for the compounds or classes tested.

Novartis had announced in late May that its patupilone – a microtubule-targeting epothilone – did not meet its overall survival primary endpoint in a head-to-head Phase III superiority trial against standard of care Doxil/Caelix (pegylated liposomal doxorubicin) in more than 800 women with recurrent disease resistant to platinum-based chemotherapy. Novartis had been planning a 2010 filing for patupilone in ovarian cancer to help stock up its pipeline ahead of a patent cliff (Also see "Beyond Gleevec: What's Next For Novartis Oncology?" - Pink Sheet, 14 December, 2009.). Novartis said it is currently evaluating development of patupilone in multiple other tumor types to determine whether the broader patupilone clinical program will continue.

The Phase III results were presented and discussed for the first time at the ESMO meeting. The study’s primary endpoint was superiority in terms of overall survival and the secondary endpoints included PFS and overall response. There was no statistically significant difference in OS or PFS, though patupilone did show a statistically significant improvement in response rate.

Though the trial was technically a failure, Burger said his impression was that patupilone and other drugs in its class could still find a role in ovarian cancer. Proving superiority over the standard of care is a high bar and coming close to equivalence – though this study was not designed as an equivalence study – is promising, he said. It could be that the drug works well in certain subsets of patients and would be a good addition to the oncology armamentarium, he added.

Similarly, in Burger’s view, negative overall Phase II results for AstraZeneca’s PARP inhibitor olaparib included some positive signs of activity. Two doses (200 mg and 400 mg) of olaparib were tested against liposomal doxorubicin in about 100 BRCA1 and BRCA2 carriers with recurrent disease resistant to platinum-based chemotherapy. The drug failed to meet its endpoint overall, but the results showed numerically better response rates and PFS for the drug at the higher dose compared to the lower dose and placebo. A trial of a higher dose could produce better results, Burger said.

“For a negative trial, these were encouraging results,” he concluded.

Among other drugs with negative showings at the ESMO meeting was AstraZeneca’s Src tyrosine kinase inhibitor saracatanib. The drug failed to meet its endpoints of improvements in objective response and median PFS in a Phase II trial of 189 women with recurrent epithelial, platinum-resistant ovarian cancer.

Genentech/Curis’ hedgehog pathway inhibitor GDC-0449 fell short in a Phase II, randomized, controlled study as a maintenance therapy for patients in second or third complete remission. Median time to disease progression was 7.5 months for the patients on GDC-0449, versus 5.8 months for placebo.

Top-line results had previously been released (Also see "Genentech/Curis Hedgehog Inhibitor Gets Unclear Results In Ovarian Cancer Maintenance Study" - Pink Sheet, 9 August, 2010.).

Curis announced on Oct. 11 that based on further analysis of the trial, Genentech was dropping development of GDC-0449 in ovarian cancer, but moving forward with a Phase II study of the compound as a single agent in operable basal cell carcinoma.

By Emily Hayes

Avastin Stakes Claim In Ovarian Cancer; Other Ovarian Updates At ESMO Are Mixed

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