GI CARCINOID INCIDENCE INCREASES

NEW YORK (Reuters Health) Oct 16 - Women with platinum-resistant ovarian cancer may benefit from vintafolide (EC145) plus pegylated liposomal doxorubicin (PLD), a new paper reports.

An imaging agent, 99mTc-etarfolatide, can identify those most likely to benefit from the added vintafolide, the authors say.

"Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer," the authors wrote in their article online in the Journal of Clinical Oncology.

"It's like using smart bombs: we're not targeting every cell for treatment -- only the cancer cells. We're taking advantage of the difference between normal cells and cancer cells," said principal investigator Dr. R. Wendel Naumann, from the Levine Cancer Institute of Carolinas Medical Center in Charlotte, North Carolina, in a phone interview with Reuters Health.

"Vintafolide binds to the folate receptor (FR), which is on the majority of epithelial ovarian cancers," Dr. Naumann added.

He continued, "This could easily become the standard care for platinum-resistant ovarian cancer patients, and vintafolide could also potentially be used with lung, endometrial and many other cancers that carry folate receptors. Because of its limited toxicity, we can add vintafolide to pretty much any combination."

The randomized phase II PRECEDENT trial compared vintafolide plus PLD to PLD alone. It also assessed the usefulness of the FR-targeted imaging agent, 99mTc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide.

To compare progression-free survival (PFS) between the two groups, they looked at 195 ovarian cancer patients at 61 clinical centers in the United States, Canada, and Poland who were at least 18 years old and had received prior platinum-based chemotherapy.

The 162 women in the study had all undergone one or two prior cytotoxic regimens. They were randomly assigned in a 2:1 ratio to receive IV vintafolide (2.5 mg three times per week during weeks 1 and 3, every 28 days) plus IV PLD (50 mg/m2 on day 1, every 28 days) or PLD alone. Scanning with etarfolatide was optional.

Patients had computed tomography (CT) imaging at baseline, every 1.5 months for the first six months, and then every two months. To identify patients with functionally active FR, patients had SPECT imaging with etarfolatide when available at least seven days before the start of therapy.

Patients were grouped as FR 100% (all lesions FR positive), FR 10% to 90% (one or more FR-positive lesion), and FR 0% (no FR-positive lesions).

Treatment continued until disease progression, intolerable toxicity, or maximum allowable cumulative dose of PLD (550 mg/m2 of doxorubicin hydrochloride). Some women treated with vintafolide plus PLD continued to receive vintafolide alone.

Patients who had 100% of lesions positive for FR had the greatest benefit, with median PFS of 5.5 months, compared with 1.5 months for PLD alone (HR, 0.38; p=0.013). Women with 10% to 90% FR-positive disease experienced some PFS improvement (HR, 0.87); and those with no FR expression had no PFS benefit (HR, 1.80).

"I was somewhat skeptical that we would see a benefit in this randomized phase II trial because there had been around 12 randomized trials of ovarian cancer and every single one has been negative, even some very large trials," Dr. Naumann said.

Dr. Tate Thigpen, director of the Division of Oncology-Hematology of the University of Mississippi Medical Center in Jackson, agreed with the potential clinical impact of this trial. "This is an excellent example of the sort of targeted therapy that everyone raves about. In ovarian cancer this is particularly significant because ovarian cancer is characterized by 'genomic instability,' which means essentially that specific targets like the folate receptor have been hard to come by," he said in an email.

"This is a potential breakthrough for patients who have the folate receptor on their tumor cells. Whether it will lead to an improved overall survival or cure rate is not clear yet, but the approach clearly improves progression-free survival, which is a very important and perhaps the best measure of patient benefit that we have in ovarian cancer," he added.

"If confirmed, this approach would allow us to provide far greater patient benefit to those positive for the folate receptor while avoiding the toxicities of the treatment for those without the receptor and thus unlikely to benefit from vintafolide," he said.

Dr. Naumann is looking forward to the confirmatory PROCEED randomized phase III trial, which is now recruiting patients and has conditional approval in Europe, he said. While he can't say how long it will take for approval in Europe, he estimated that in the US it will be a minimum of two to three years before the phase III trial is completed and vintafolide is approved for patient use outside of clinical trials.

Dr. Naumann's institution has received funding from Endocyte, the original developer of vintafolide, which was bought out by Merck. Dr. Thigpen has served on advisory boards for Endocyte and currently is a member of the Data and Safety Monitoring Board for an ongoing trial involving vintafolide.

SOURCE: http://bit.ly/H4HNM5

J Clin Oncol 2013.