2 MONTHS INCREASE IN PFS WITH BEVACIZUMAB IN ICON7

October 18, 2010 (Milan, Italy) — The addition of bevacizumab (Avastin) to standard chemotherapy appears to delay the progression of ovarian cancer, according to data presented here at the 35th European Society for Medical Oncology Congress.

At 12 months, women who received bevacizumab plus carboplatin and paclitaxel had a 15% lower risk for disease progression than those who received chemotherapy alone.

Median progression-free survival for the bevacizumab group was 19 months, and for the chemotherapy-alone group was 17.3 months. A hazard ratio of 0.81 (95% confidence interval, 0.70 - 0.94; P = 0.0041) favored the bevacizumab group.

Lead author Tim Perren, MD, who presented the study findings, pointed out that bevacizumab is the first new agent to show effectiveness in ovarian cancer in nearly 2 decades. "We've been using the current treatment regimen for ovarian cancer since the 1990s," he said. "We've seen no new drugs with additional activity against ovarian cancer during that period of time."

Dr. Perren, a consultant medical oncologist and honorary senior lecturer at St. James's University Hospital and the University of Leeds, United Kingdom, also noted that the benefit of bevacizumab treatment varies over time. The effect peaked 12 months after randomization, with a 15% improvement in progression-free survival, and then decreases over time to give a 1.5 month overall improvement.

Second Study to Show Benefit

The current study, known as the ICON7, is the second large phase 3 clinical trial to show a benefit for bevacizumab in women with untreated advanced ovarian cancer. The GOG-0218 trial, which also combined bevacizumab with carboplatin and paclitaxel, met its primary end point of an increase in progression-free survival; those findings were presented at the 2010 annual meeting of the American Society of Clinical Oncology, as reported by Medscape Medical News at that time.

In the GOG-0218 trial, bevacizumab combined with chemotherapy and continued as maintenance therapy significantly extended progression-free survival, compared with chemotherapy alone (14.1 vs 10.3 months). This translated into a 28% reduction in the risk for cancer progression.

Although both studies show improvement in progression-free survival, neither had mature overall survival data available at the time of their presentation.

Dr. Perren explained that longer-term progression-free survival and mature overall survival results will be available in 2012. But the preliminary survival data show an encouraging early trend, with fewer deaths seen in patients treated with bevacizumab.

"We need the longer progression-free survival data and overall data before we can truly assess the impact of bevacizumab in this disease," he said. "We will also have data from translational researchers, which may help us identify biological subsets."

Similar But Different

There are differences between the ICON7 and GOG-0218 trials. The GOG-0218 study used a much higher dose of bevacizumab than the ICON7 study (15 vs 7.5 mg/kg), and continued maintenance therapy for a longer time (up to 15 vs up to 12 months).

The patient populations also differed between the 2 trials. The GOG-0218 trial consisted of patients with stage III (macroscopic residual disease) or stage IV ovarian, primary peritoneal, or fallopian tube cancer. Conversely, the ICON7 consisted of patients with both late-stage disease and high-risk early International Federation of Gynecology and Obstetrics (FIGO) stage I or IIa cancer (9% of cohort).

The GOG-0218 trial had 3 groups: paclitaxel/carboplatin plus placebo maintenance; paclitaxel/carboplatin and concurrent bevacizumab plus placebo maintenance; paclitaxel/carboplatin and concurrent bevacizumab plus maintenance bevacizumab.

"Bevacizumab used as maintenance therapy was not specifically addressed in the ICON7 study, although it was part of the GOG-0218 trial," said Dr. Perren. "It demonstrated a small benefit when bevacizumab was given concurrently with the chemotherapy regimen, but demonstrated a much larger benefit when it was continued as maintenance therapy. Fortunately, I think we chose the 2 correct arms for the ICON7 trial."

Progression-Free Survival Benefit

In the ICON7 trial, Dr. Perren and colleagues from the Gynecologic Cancer InterGroup randomized 1528 women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer to 1 of 2 treatment groups following surgical debulking: 6 cycles of chemotherapy (carboplatin area under the curve 6 and paclitaxel 175 mg/m2), or the same chemotherapy combined with bevacizumab (7.5 mg/kg) for 6 cycles followed by maintenance bevacizumab for 12 additional cycles or until progression.

The primary outcome measure was progression-free survival; secondary outcomes were response, overall survival, safety, and quality of life. To demonstrate a 28% improvement in median progression-free survival from 18 to 23 months (hazard ratio, 0.78) with a 5% significance level and 90% power, 684 progressions/deaths were required.

With bevacizumab, there were 367 events (48%), and median progression-free survival was 19.0 months. With chemotherapy alone, there were 392 events (51%), and median progression-free survival was 17.3 months.

"What we have demonstrated is that there is a strong biological effect against the tumor, and now we have to see how significant that effect is for patients," said Dr. Perren.

Subtypes in other malignancies, such as HER2-positive and -negative breast cancers and epidermal growth-factor receptor mutations in lung cancer are now emerging, but those data are not yet available for ovarian cancer, he pointed out. "What we need to do is to try to identify the patients who would particularly benefit from this treatment."

"If we had done a trial with trastuzumab with the general breast cancer population, we would have seen a very small effect," Dr. Perren added. "But we were able to target it because we knew what the target was — and we saw a very large effect with HER2-positive patients."

Currently, it is not known what specific markers will predict activity with bevacizumab. "It has broad activity against many cancers and many subtypes of those cancers," said Dr. Perren, adding that the challenge is to identify the patients who will derive the most benefit from it.

Adverse events were consistent with previous bevacizumab studies, and no new or unexpected adverse events occurred, he added.

Translate to Overall Survival Benefit?

This is a well-done trial, and is very clearly analyzed and well presented, said Michael Bookman, MD, chief of the hematology/oncology section at the Arizona Cancer Center in Tucson. "It validates and extends observations from GOG-218, and [vascular endothelial growth factor] is clearly an important target based on biology and clinical experience."

However, in a discussion of the paper, Dr. Bookman noted that a benefit for overall survival has not yet been observed. "Does progression-free survival predict well for overall survival?" he asked, adding that this question has been a recurring theme for many of the studies being presented.

"The improvement in progression has not yet been accompanied by an improvement in overall survival, and that does raise questions about the true clinical benefit," he said. "But it does appear that this benefit is perhaps greater in larger-volume disease and also in the setting of recurrent disease."

"But how we should integrate this into primary therapy remains open to conjecture and subject to debate," Dr. Bookman said.

He also pointed out that it is still unclear if a delay in recurrence of progression, in the absence of disease-related symptoms, is a measure of clinical benefit. "I think we need to focus on how to move this forward in terms of achieving benefit. We have to understand our goals, and this will be different in the curative vs noncurative setting with advanced disease," he said.

This study was supported by Genentech/Roche. Dr. Perren reports previously attending remunerated advisory boards concerning the development of trastuzumab, and receiving honoraria/travel expenses from Roche. Coauthor A.M. Swart, from the Medical Research Council Clinical Trials Unit, London, United Kingdom, reports receiving educational grants from Roche.

35th European Society for Medical Oncology (ESMO) Congress: Abstract LBA4. Presented October 11, 2010.