GSK Set To File Votrient For Ovarian Cancer On Strong PFS

Votrient demonstrated a 5.6 month PFS improvement compared to placebo in a Phase III ovarian cancer study presented at the ASCO annual meeting, but no overall survival benefit yet. Nevertheless, GSK believes that the risk/benefit profile is good enough now to support filings in the U.S. and Europe.

CHICAGO – GlaxoSmithKline PLC is gearing up to file for a new indication for Votrient (pazopanib) as a maintenance treatment for ovarian cancer after demonstrating a 5.6 month progression-free survival benefit over placebo in a Phase III trial presented at the American Society of Clinical Oncology annual meeting, rather than wait for overall survival data.

Roche/Genentech are waiting for overall survival data before submitting Avastin for FDA approval for ovarian cancer.

Votrient, which is a tyrosine kinase inhibitor that hits VEGF and PDGF, among other targets, was approved by FDA in 2009 for renal cell carcinoma and cleared in Europe for that indication in 2010. In 2012, the drug added a new indication in the U.S. and Europe for soft tissue sarcoma (Also see "FDA Opts For Full, Rather Than Accelerated, Approval Of GSK’s Votrient In Sarcoma" - Pink Sheet, 27 Apr, 2012.). Drug sales reached $183 million in 2012, up by 88% from the previous year.

Based on the results from the Phase III AGO-OVAR16 study presented June 1 at ASCO, GSK said it is preparing packages for Votrient as a maintenance therapy after surgery and first-line chemotherapy and will be looking to discuss its plans with FDA. Furthermore, as an anti-angiogenic drug, GSK believes Votrient is well positioned to play a role in multiple tumor types and the company is also now considering moving the drug into Phase III for bladder cancer and neuroendocrine tumors.

Maintenance therapies are given to extend periods of disease-free survival following first-line and subsequent treatments. In the case of ovarian cancer, patients typically receive multiple rounds of chemo after relapses.

“What this drug does is give the patient an option to keep chemotherapy at bay,” Lini Pandite, GSK’s clinical lead for all Votrient indications, said in an interview at the meeting.

A new indication in ovarian cancer would clearly have potential to increase sales. The pool of advanced cancer patients who will get first-line drug therapy for ovarian cancer is larger than the populations with Stage IV RCC or soft tissue sarcoma, Votrient’s current indications, commented Stephanie Hawthorne, a consultant with Kantar Health. Maintenance therapy is given for extended periods of time – in this study it lasted for up to 24 months – which increases sales per patient.

But success would depend on GSK’s ability to penetrate the market and develop utilization of maintenance therapy in first-line advanced ovarian cancer patients, many of whom don’t currently get maintenance therapy, Hawthorne said.

The intention to submit for FDA approval based on PFS alone is a more aggressive approach than key competitor Roche is taking with its anti-VEGF Avastin (bevacizumab).

Roche has tested bevacizumab for induction followed by maintenance therapy in ovarian cancer trials. Avastin is used off label for ovarian cancer in the U.S., with the support of national compendia recommendations, and has an ovarian cancer indication in Europe (Also see "Genentech Likely To Wait For Survival Data For U.S. Filing Of Avastin In Ovarian Cancer" - Pink Sheet, 3 Jun, 2012.). Avastin has demonstrated PFS benefit in a number of studies. The company has signaled that it is waiting for final overall survival data before filing for approval with FDA.

“There are differences in opinion worldwide what is clinically meaningful in ovarian cancer,” Genentech Senior VP-Clinical Development for Hematology/Oncology Sandra Horning said about the regulatory climate for ovarian cancer during an interview at the meeting.

Overall survival is difficult to show in ovarian cancer, and Genentech has the experience of losing the accelerated approval for Avastin in breast cancer after subsequent OS and PFS analyses failed to match the initial benefit.

Considering Roche’s experience, which suggests FDA wants overall survival data in ovarian cancer, Kantar Health’s Hawthorne believes that Votrient is currently unlikely to win approval in the U.S. as a maintenance therapy for ovarian cancer, but that its prospects are better in Europe.

GSK’s Data Package

GSK’s pivotal trial evaluated Votrient in 940 patients with advanced epithelial ovarian cancer after surgery and first-line platinum-taxane chemotherapy. Patients were treated daily for up to 24 months. In that setting, Votrient improved progression-free survival – the primary endpoint – against placebo by 23% (p=0.0021), with median PFS of 17.9 months versus 12.3 months for placebo.

The 12.3 month figure in the placebo arm is similar to what has been reported in other trials and lends validity to the finding that pazopanib is providing a real benefit, Pandite said.

However, in an interim analysis the drug did not show a benefit for overall survival. But Pandite points out that only 20% of the patients in the trial have died, so the interim analysis was based on limited data. As more become available, it may be possible for Votrient to show a benefit for overall survival, as well as PFS, she said.

“We expect to get more mature data in the years to come,” she said.

GSK said that it has been advised that while overall survival is FDA’s preferred endpoint, PFS would be acceptable, as long as the risk/benefit profile is favorable. Pandite noted that the agency already has extensive data for Votrient in other indications.

In the Phase III study, the most common side effects included hypertension and diarrhea (see table). The rate of serious adverse events was 26% for Votrient, versus 11% for placebo. For those on Votrient, the most common serious adverse events were increased ALT (4%), pyrexia (2%), increased AST (2%) and hypertension (2%). Votrient has a boxed warning for hepatotoxicity. There were also three deaths in the Votrient arm of the study in which the drug’s contribution could not be ruled out. These deaths were related to myocardial infarction, stroke and pneumonia.

Pandite noted that gynecologists are not familiar with the drug and could be educated about how to manage its toxicities.

Most Common (>20%) Side Effects in Votrient Ovarian Cancer Maintenance Trial
Side Effect	Votrient	Placebo
Hypertension	54%	19%
Diarrhea	53%	17%
Nausea	37%	18%
Headache	29%	15%
Fatigue	28%	14%
Source: GlaxoSmithKline