The addition of bevacizumab (Avastin) to standard first-line chemotherapy for newly diagnosed ovarian cancer reduced the risk of disease progression at a median follow-up of 19.4 months in the phase III Gynaecologic Cancer InterGroup (GCIC) ICON7 trial. The results were presented at the 35th ESMO Congress, held October 8-12 in Milan.¹

"ICON7 met its primary endpoint and demonstrated that at 12 months, the absolute risk of further progression of ovarian cancer was reduced by 15% with the addition of bevacizumab compared with chemotherapy alone," said Tim Perren, MD, Leeds Teaching Hospital NHS Trust, Leeds, UK.

Different Perspectives

"This is an exciting step forward. Bevacizumab is the first new drug since the mid 1990s to show a significant treatment effect [in ovarian cancer]," he noted. These results will undoubtedly influence the discussion between oncologists and patients about treatment selection and affect design of the next generation of clinical trials."
Formal discussant of this trial, Michael Bookman, MD, Section Chief of Hematology/Oncology at University of Arizona Cancer Center in Tucson, was more temperate in his remarks, noting that bevacizumab should not be considered standard therapy for ovarian cancer at this point (see "Expert Point of View," here).

Dr. Perren told listeners that these data compliment the Gynecologic Oncology Group (GOG) 218 study showing a benefit for bevacizumab in ovarian cancer, which was presented at the ASCO Annual Meeting this past June.²
Preliminary results of ICON7 demonstrated a trend toward fewer deaths in the bevacizumab arm, but Dr. Perren cautioned that the data need to mature for 2 more years before a true survival advantage can be claimed.

Study Details

The large ICON7 randomized, controlled trial enrolled 1,528 women from 263 centers with early-stage high-risk, or advanced-stage, epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Baseline characteristics were well balanced between the two arms. Median age was 57 years.

Following surgery, women were randomly assigned to either 6 cycles of standard chemotherapy with carboplatin/paclitaxel given once every 3 weeks or the same chemotherapy plus concurrent bevacizumab (7.5 mg/kg) for 6 cycles followed by bevacizumab as maintenance therapy for 12 additional cycles.

Bevacizumab improved progression-free survival (PFS) from a median of 17.3 months with standard chemotherapy to a median of 19 months, a statistically significant difference (P = .0041). The absolute difference in PFS was 1.7 months in this preliminary analysis, with a hazard ratio of 0.81.

The maximum effect of bevacizumab on PFS was observed at about 12 months after initiation of treatment; after that, the curves for the two arms converged. Dr. Perren said that it was unusual for survival curves to diverge and then converge and attributed this to the nonproportional hazards between the two arms of the trial. This means that the benefit of the addition of bevacizumab varies over time, as described above. A separate analysis (required by regulatory authorities) assessed patients who were still alive and progression-free at the data cutoff point. These patients were censored at the date of the last CT scan rather than the date of the last clinical follow-up. In that analysis, the median PFS was 16 months for the standard chemotherapy arm vs 18.3 months for the experimental arm (HR = 0.79, P = .0041).

'Complicated' Benefits

Regarding the two different analyses of PFS he presented (academic and regulatory), Dr. Perren stated, "Due to nonproportional hazard ratios, the benefits are complicated to describe."

A consistent benefit for the addition of bevacizumab was observed across all subgroups, regardless of age, FIGO stage, and grade. An exploratory analysis showed that patients with advanced disease (ie, stage III suboptimally debulked or stage IV debulked) had a superior PFS if they received bevacizumab: Median PFS was 10.5 months for standard chemotherapy vs 15.9 months for the bevacizumab-containing arm (P < .001).

The treatment was well tolerated, with no new safety signals for bevacizumab.

Selected adverse events known to be associated with bevacizumab included hypertension (6.2% for standard chemotherapy, 25.9% for bevacizumab) and minor bleeding (11% vs 40%, respectively). Approximately 18% of patients treated with bevacizumab required additional antihypertensive drugs.

Identifying Patient Subgroups

"In summary, we demonstrated for the second time that adding bevacizumab to standard chemotherapy significantly delays progression of ovarian cancer," Dr. Perren said. "The difference between the two treatment arms is reduced over time."

Moving forward, as in all cancers, it will be important to identify which patient characteristics are associated with treatment benefit. The ICON7 investigators have collected blood and tumor samples from women at different time points in the trial, and these samples will be helpful in identifying subgroups of patients that will benefit from bevacizumab. ■

References

1. Perren T, Swart AM, Pfisterer J, et al: ICON7: A phase III randomized gynaecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab versus chemotherapy alone in women with newly diagnosed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. 35th ESMO Congress. Abstract LBA4. Presented October 11, 2010.

2. Burger RA, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.