SUMMARY: The American Cancer Society estimates that over 21,000 women will be diagnosed with Ovarian cancer in the United States for 2015 and over 14,000 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. The FDA in 2014 approved AVASTIN® (Bevacizumab) in combination with Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan, for the treatment of patients with Platinum-resistant, recurrent epithelial Ovarian, Fallopian tube, or Primary Peritoneal cancer. The approval was based on the AURELIA Open-Label Randomized Phase III Trial which concluded that AVASTIN® in combination with chemotherapy significantly improved Progression Free Survival and Objective Response Rates, in patients with Platinum Resistant, Recurrent Ovarian Cancer.
ICON7 is an open-label, randomized, phase III trial, in which the safety and efficacy of combining AVASTIN® with standard chemotherapy was evaluated, in patients with Newly Diagnosed Ovarian Cancer. One thousand five hundred and twenty eight (n=1528) patients were enrolled and eligible women with newly diagnosed Ovarian cancer had either early stage disease (FIGO Stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO Stage IIb–IV) disease. Patients had undergone debulking, cytoreductive surgery, or in those with advanced disease, had a biopsy for tissue diagnosis, with no further surgery planned. High risk disease in this study was defined as Stage IV disease, inoperable Stage III disease, or suboptimally debulked (more than 1 cm) Stage III disease. Patients were randomly assigned in a 1:1 ratio to receive either 6 cycles of combination chemotherapy with PARAPLATIN® (Carboplatin) AUC of 5 or 6 and TAXOL® (Paclitaxel) 175mg/m2 IV, given every 3 weeks or the same chemotherapy regimen given concurrently with AVASTIN® (Bevacizumab) 7.5mg/kg IV, every 3 weeks for 6 cycles followed maintenance AVASTIN® given IV every 3 weeks for 12 additional cycles or until disease progression, which ever was the earlier. The median age was 57 years. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival and Safety outcomes of adverse events. The median follow up was 48•9 months.
The Primary endpoint of Progression Free Survival (PFS) has been previously reported and was 21•8 months with the addition of AVASTIN® to chemotherapy compared with 20•3 months with chemotherapy alone, in the entire study population (HR=0•81; P=0•004). However, in the predefined high risk population of patients with suboptimally cytoreduced stage III or stage IV disease, the PFS with the addition of AVASTIN® to chemotherapy was 18•1 months versus 14•5 months (HR=0•73; P=0•002).
In this publication, the authors reported the final Overall Survival results of the ICON7 trial. They noted no difference in the Overall Survival between AVASTIN® plus chemotherapy versus chemotherapy alone groups. (45.5 months vs 44.6 months, P=0.85). However, in the predefined group of high risk patients with inoperable or suboptimally cytoreduced stage III or stage IV disease, there was an Overall Survival benefit, with a mean Overall survival of 39•3 months in the AVASTIN® plus chemotherapy group versus 34•5 months in the chemotherapy alone group (P=0•03). This survival benefit was not seen in clear cell, early stage high grade, or low grade serous tumors. It is hypothesized that the effect of AVASTIN® on the tumor microenvironment is dependent on residual tumor burden, which is presumably producing VEGF (Vascular Endothelial Growth Factor). The authors concluded that the Overall Survival benefit with a combination of AVASTIN® and chemotherapy is best accomplished in newly diagnosed Ovarian cancer patients, with poor prognostic factors. Oza AM, Cook AD, Pfisterer J, et al. Lancet Oncol 2015;16:928-936. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial