Novel Agents Potentially Beneficial in Recurrent Ovarian Cancer

Roxanne Nelson

September 19, 2008

September 19, 2008 (Stockholm, Sweden) — Recurrent disease remains a considerable problem in ovarian cancer, even though most patients will respond initially to first-line therapy. Two novel therapeutic agents showed encouraging results in the treatment of recurrent ovarian cancer, according to data presented here at the 33rd European Society for Medical Oncology Congress.

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The investigational angiogenesis inhibitor pazopanib (gw786034, GlaxoSmithKline) demonstrated significant biologic single-agent activity among patients with relapsed ovarian cancer. A greater-than-50% decrease in CA-125 levels was observed in 31% of the cohort, with a 113-day median duration of response.

"Chemotherapy has been the standard management for ovarian cancer for many years, but despite an enormous amount of effort, the overall prognosis for women with advanced disease is still poor, and the majority of women will unfortunately relapse," said lead author Michael Friedlander, MD, from the Prince of Wales Cancer Centre, in Sydney, Australia.

"But we now know that angiogenesis plays a critical role in ovarian cancer, and it is a very attractive target," he added.

Pazopanib is an oral, investigational angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit, which play an essential role in the angiogenic process. VEGF plays a major role in the biology of ovarian cancer, as it is overexpressed in the disease and associated with the formation of ascites and a poor prognosis, said Dr. Friedlander. Angiogenesis inhibitors have previously demonstrated single-agent activity in ovarian cancer.

CA-125 is an established and accepted biomarker in ovarian cancer for both response and progression, correlates with clinical response, and is widely used clinically. "We reasoned that patients with a rising CA-125, after relapsing after first- or second-line therapy with small-volume tumors, would present an ideal opportunity to look at a novel agent such as pazopanib, where we thought response rates would be higher," said Dr. Friedlander during a press briefing. "It is also interesting to speculate that with some of these newer agents, we may not always see objective responses because they can be cytostatic. That was the rationale for the study."

Within 3 to 9 months, CA-125 levels rise in most patients with recurrent ovarian cancer. Therefore, it is an attractive marker to use in assessing the efficacy of novel targeted therapy.

Dr. Friedlander and colleagues enrolled 35 patients with recurrent epithelial ovarian cancer or fallopian tube or primary peritoneal carcinoma, of whom 17 had measurable disease at baseline. Three-quarters of the patients were sensitive to their most recent platinum therapy, and 61% had 1 prior line of chemotherapy. More than two-thirds (33%) had relapsed within 6 months, 33% within 6 to 12 months, and 28% more than12 months from their last treatment.

The patients received 800 mg of pazopanib daily, and CA-125 responses were observed in 11 (31%) patients, with a median time to response of 29 days. Sixteen of the patients with measurable disease at baseline had evaluable data, and of this subgroup, 4 experienced stable disease by the Response Evaluation Criteria in Solid Tumors (RECIST) standard for more than 100 days.

Adverse events were similar to those generally experienced with angiogenesis or tyrosine kinase inhibitors and were predominantly hypertension, nausea, diarrhea, fatigue, and abdominal pain. Most of the reported adverse effects were grade 1 and 2.

"Patients continued on treatment until disease progression, withdrawal due to toxicity, or withdrawal due to consent," he said. "There are still 3 patients in the study, up to 2 years."

In light of these data, further studies are being planned, and a phase 3 trial is being considered at this time, he concluded.

Hypertension was lower with pazopanib than is seen with similar agents, commented Cristiana Sessa, MD, PhD, from the Istituto Oncologico della Svizzera Italiana, in Bellinzona, Switzerland, who served as a discussant of the paper. "That is a very important factor."

Pazopanib is a good inhibitor of VEGFR-1, -2 and -3; other tyrosine kinase inhibitors may be more useful than pazopanib for different targets, she said.

There are currently a number of compounds targeting VEGF that are being studied, said Dr. Sessa, "But optimal schedules for combination therapy still need to be designed."

Combination Trabectedin and PLD Improve Progression-Free Survival

The second trial investigated the use of a non–platinum-based doublet therapy for second-line recurrent ovarian cancer. Trabectedin (Yondelis, PharmaMar and Johnson & Johnson), a novel marine-derived alkaloid, was combined with pegylated liposomal doxorubicin (PLD), and the efficacy of the combination therapy was compared with PLD monotherapy. Women who received the combination therapy had a median progression-free survival of 7.3 months, compared to 5.8 months for those who received PLD alone.

Those on combination therapy who relapsed more than 6 months after receiving first-line therapy had a median progression-free survival of 9.2 months, vs 7.5 months for patients receiving PLD alone. The risk of disease progression was reduced by 21% in the group receiving combination therapy.

"The study was powered for overall survival," said lead author Bradley Monk, MD, an associate professor at the Chao Family Comprehensive Cancer Center at the University of California, Irvine. "But the data is not mature, and it is premature to give an analysis."

Trabectedin is a DNA minor groove-binding drug with a distinct mechanism of action and has been studied in the treatment of several malignancies, including sarcoma, and prostate, breast, and ovarian cancers. It has been approved in Europe for the treatment of advanced soft-tissue sarcoma but has not yet received Food and Drug Administration (FDA) approval in the United States.

Phase 1 and 2 trials in ovarian cancer have been favorable, explained Dr. Monk. "Phase 2 trials showed a 30% to 43% response in second- and third-line platinum-sensitive patients and 6% to16% in second-line platinum-resistant patients," he said.

In this phase 3 trial, Dr. Monk and colleagues randomized 672 women to PLD 30 mg/m² plus trabectedin 1.1 mg/m² every 3 weeks or to PLD alone, 50 mg/m² every 4 weeks. Treatment response was based on an independent radiology review using RECIST, and the primary end point was progression-free survival.

Fatigue, nausea and vomiting, and neutropenia were higher among patients who received trabectedin, while skin toxicities, including hand and foot syndrome, were lower in the combination-therapy group.

"Positive trials in recurrent ovarian cancer are rare and have almost always led to newly approved therapeutic regimens," Dr. Monk said in a statement. "This combination will undoubtedly be carefully monitored by the FDA and, if approved, would give women with ovarian cancer another much-needed option."

Dr. Sessa, who also served as a discussant for this paper, noted that the response to the second-line therapy correlated to the duration of response from the end of first-line treatment. "It is still a matter of debate," she said, "as to which is the best second-line treatment in the platinum-sensitive patient."

The role of trabectedin in the treatment of ovarian cancer is still unclear. Trabectedin possibly shows a therapeutic index better than standard therapies, she said, but it has not yet shown antitumor activity in resistant disease. Further studies will better define trabectedin's role in ovarian cancer and its possible benefit.

33rd European Society for Medical Oncology Congress: Abstracts 6630 and LBA4. Presented September 15, 2008.

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