ASCO 2010-60000$ FOR 4 MONTH INCREASE IN PFS?

June 7, 2010 (Chicago, Illinois) — Adding bevacizumab (Avastin) to initial chemotherapy, followed by bevacizumab used alone as maintenance therapy, can significantly prolong progression-free survival in women with advanced ovarian cancer, according to the results of a new phase 3 trial.

This is the first time that an antiangiogenic agent has demonstrated a benefit in this population, according to lead author Robert A. Burger, MD, director of the Women's Cancer Center at Fox Chase Cancer Center in Philadelphia, Pennsylvania. There was no impact on overall survival, although these survival data are not yet mature.

Dr. Burger presented his findings during a plenary session here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting.

This was the first positive result in ovarian cancer with bevacizumab, explained Douglas Blayney, MD, the outgoing president of ASCO. "There were 3 arms in the study: chemotherapy alone, chemotherapy plus concurrent bevacizumab, and chemotherapy plus concurrent bevacizumab and then continuous bevacizumab until progression. This last group showed better progression-free survival, although no improvement in overall survival."

In fact, Dr. Blayney told Medscape Oncology, bevacizumab has not shown a survival benefit in any tumor type, even though it improves progression-free survival. He also noted that the dose of bevacizumab used (15 mg/kg) is higher than has been used for other cancers.

"This was a positive study, but it is not clear why," said Dr. Blayney. "Is it that ovarian cancer is susceptible to bevacizumab, is it the higher dose, or is it the continuous use?"

Dr. Burger pointed out that unlike in the case of nongynecologic tumors, bevacizumab has "demonstrated single-agent activity, not only in terms of response rates but also progressive-free survival, in 2 previous phase 2 trials of patients with recurrent ovarian cancer."

On the basis of those results, the current trial was designed to study the effects of bevacizumab added to standard front-line chemotherapy. The original end point of the study was overall survival, but it was changed to progression-free survival for many reasons, explained Dr. Burger, including a "consensus that progression-free survival was a clinically relevant end point in front-line ovarian cancer trials."

Maintenance Bevacizumab Improved Outcomes

The cohort consisted of 1873 women with newly diagnosed stage III (macroscopic residual disease) or stage IV ovarian, primary peritoneal, or fallopian tube cancer, who were enrolled from September 2005 to June 2009.

Patients were randomly assigned to 3 treatment groups: paclitaxel 175 mg/m2 plus carboplatin area under curve (AUC) 6 cycles plus placebo maintenance; paclitaxel plus carboplatin and concurrent bevacizumab (15 mg/kg) and placebo maintenance; and paclitaxel plus carboplatin plus concurrent bevacizumab plus maintenance bevacizumab.

The bevacizumab dose was the same as that used in the previous phase 2 trials, and treatment continued for 22 cycles unless discontinued for disease progression or significant adverse events.

Patients who received chemotherapy alone had a median progression-free survival of 10.3 months, compared with 11.2 months for those who received concurrent bevacizumab but placebo maintenance. This difference, explained Dr. Burger, was not statistically significant.

However, the addition of bevacizumab as maintenance therapy significantly extended progression-free survival (14.1 vs 10.3 months). "This translates into a 28% reduction in the risk of cancer progression," said Dr. Burger.

Adverse Events

The type and severity of adverse events were similar to those previously reported in phase 3 trials of bevacizumab in combination with chemotherapy in the treatment of metastatic nongynecologic cancers, Dr. Burger explained.

Grade 3/4 hypertension was highest in the group receiving concurrent and maintenance bevacizumab (10%), compared with 1.6% in the group receiving chemotherapy alone and 5.4% in the group receiving concurrent bevacizumab and placebo maintenance. There was a concern about the additional risk for gastrointestinal perforation and fistula, explained Dr. Burger, but it was under 3% in all treatment groups.

Grade 3 or higher gastrointestinal perforation, hemorrhage, or fistula was 2.6% in the group receiving concurrent bevacizumab and placebo maintenance and 2.3% in the group receiving concurrent and maintenance bevacizumab, compared with the 0.8% in group receiving chemotherapy alone.

"The rates were almost double in both bevacizumab arms, but they were still low," he said.

Relative to chemotherapy alone, the hazard of first progression or death for concurrent bevacizumab and placebo maintenance was 0.908 (95% confidence interval [CI], 0.795 -1.04; P = .16); for concurrent and maintenance bevacizumab, it was 0.717 (95% CI, 0.625 - 0.824; P < .0001). At this time, survival data are limited, Dr. Burger said.

"This is the first molecule targeted and the first antiangiogenic agent to demonstrate benefit in this population," Dr. Burger concluded. "Bevacizumab combined with chemotherapy and given as maintenance should be considered as one standard option for women with this disease."

Questions Waiting to Be Addressed

This was a large well-conducted, well-powered study, with many strengths and few weaknesses, said Elizabeth Eisenhauer, MD, from Queen's University in Kingston, Ontario, who served as a discussant for the study. "But the results raise many important questions."

Progression-free survival increased with concurrent and maintenance bevacizumab, with a median gain of 3.8 months, she noted. "Why wasn't there a response in the concurrent bevacizumab [and placebo maintenance] group? Would concurrent therapy alone be more effective in recurrent disease?"

It is also not clear if an increase in progression-free survival translates into an overall survival benefit, she said. "We cannot conclude that the delay in progression will translate into overall survival."

Whether progression-free survival "mirrors a gain in overall survival" is not known and, thus far, the survival data are not mature, said Dr. Eisenhauer. "The early data presented today suggest that it may not be."

Another issue was the gain in progression-free survival and what it means for patients. "Is this a surrogate for overall survival or does it offer a better quality of life — we do not have much data on this," said Dr. Eisenhauer.

The results show a clear improvement in progression-free survival, but on the basis of today's results, "use in clinical practice may be immature," she concluded. "These results may not be meaningful to patients.

Coauthor Michael Bookman reports serving in an advisory/consulting role for Genentech. Dr. Blayney reports uncompensated consulting relationships with Allos, Cephalon, and BMS; and receiving research funding from Blue Cross Blue Shield of Michigan and the National Comprehensive Cancer Network.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract LBA1. Presented June 6, 2010.