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AMSTERDAM – Despite finding no overall survival benefit by adding bevacizumab to standard chemotherapy for newly diagnosed or platinum-resistant advanced ovarian cancer, the results of two phase III clinical trials remain "practice changing," according to a commentator Dr. Rebecca Kristeleit at the the multidisciplinary European cancer congresses.
Final overall survival results from the ICON7 trial showed that, in more than 1,500 women with newly diagnosed advanced ovarian cancer, there was a nonstatistical (P =.85) difference in overall survival of about 0.9 months using the restricted mean when all patients were considered.
In the AURELIA trial, conducted in 361 women with platinum-resistant disease, the hazard ratio for overall survival was 0.85, in favor of the addition of bevacizumab to chemotherapy, although this was not statistically significant (P = .174). The median overall survival was 16.6 months vs. 13.3 months in the control arm.
"The message I take from ICON7 is that there is a significant overall survival benefit in the high-risk group," said Dr. Kristeleit. "It’s an important clinical improvement, and it’s most important in the poor-prognosis patients, the ones who are inoperable, and the ones who are stage IV."
Regarding AURELIA, Dr. Kristeleit, a senior lecturer and consultant medical oncologist at University College London, said, "The study has shown a significant progression-free survival benefit, and we need to remember that it has doubled this in this really hard to treat group of ovarian cancer patients where there is significant clinical need."
ICON7: Bevacizumab in front-line treatment
The ICON7 (International Collaboration on Ovarian Neoplasms) study investigated the safety and efficacy of adding bevacizumab (7.5 mg/kg every 3 weeks) to standard chemotherapy in women with newly diagnosed ovarian cancer who were recruited and treated at 253 centers. The mean age of patients in the trial was 57 years.
The primary efficacy findings from the study were reported 3 years ago at the annual Congress of the European Society for Medical Oncology and published in the New England Journal of Medicine (2011;365:2484-96). These findings showed a clear benefit of adding the targeted agent to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2) given every 3 weeks for six cycles vs. chemotherapy alone, with median progression-free survival times of 19.0 vs. 17.3 months (HR, 0.81; P = .0041), respectively.
Now, with a median follow-up of 49 months, "it’s reassuring to see the progression-free survival is essentially the same [19.9 vs. 17.5 months]," observed study investigator Dr. Amit Oza of the Princess Margaret Cancer Centre at the University of Toronto.
Dr. Oza noted that 502 (33%) women met prespecified criteria for having a "poor prognosis," including women with suboptimally debulked stage III disease, those with stage IV disease, and those who could not have surgery, potentially putting them at high risk of progression. In those women, bevacizumab improved progression-free survival by a median of 5.5 months (HR, 0.73, P =.001), or 4.1 months using the restricted mean as the data were found to be non-proportional.
Final overall survival in these high-risk women was improved by a median of 9.4 months by the additional use of bevacizumab (HR, 0.78, P = .03), or 4.8 months using the restricted mean, from 34.5 months with chemotherapy alone to 39.3 months by the addition of the targeted agent.
"The overall survival difference in the high-risk subgroup is clinically meaningful," Dr. Oza said.
AURELIA: Bevacizumab in platinum-resistant disease
AURELIA was an open-label, randomized trial involving women who had progressive ovarian cancer within 6 months of receiving platinum-based chemotherapy. Women were randomized to receive chemotherapy alone (n = 182) or to chemotherapy plus bevacizumab (n = 179). The choice of chemotherapy was at the investigators’ discretion from a choice of weekly paclitaxel (80 mg/m2 on days 1, 8, 15, and 22), topotecan (4 mg/m2 on days 1, 8, and 15), or pegylated liposomal doxorubicin (PLD, 40 mg/m2 on day 1). Bevacizumab was given at a dose of 15 mg/kg every 3 weeks.
The primary endpoint was progression-free survival, with secondary endpoints of overall survival, quality of life, and, of course, safety and tolerability. The primary endpoint findings were presented last year at the annual meeting American Society of Clinical Oncology (J. Clin. Oncol. 2012;30 Suppl:LBA5002) and showed that the addition of bevacizumab almost doubled progression-free survival from 3.4 months with chemotherapy alone to 6.7 months when bevacizumab was added (HR, 0.48, P less than .001).
"The study was not powered to detect a significant difference in overall survival," said Dr. Petronella O. Witteveen, who was one of the AURELIA study investigators. Dr. Witteveen of the University Medical Center Utrecht in the Netherlands commented that overall survival was a key secondary endpoint for the trial and that interpretation of these data were complicated by the high percentage (40%) of patients in the chemotherapy arm that were allowed to crossover to additional treatment with bevacizumab.
Although no difference between the treatment arms could be seen in the final overall survival analysis, exploratory findings hinted that patients who received bevacizumab in combination with weekly paclitaxel might have had a survival advantage. The median overall survival in the cohort of patients who received bevacizumab in addition to weekly paclitaxel (n = 60) was 22.4 months vs. 13.2 months in the patients who received the chemotherapy alone (n = 55; HR, 0.65). Overall survival in the topotecan and PLD cohorts did not show any benefit of the addition of bevacizumab, with median overall survival times of just over 13-14 months whether or not bevacizumab was added to chemotherapy.
Updated safety findings showed no undue concerns or new side effects, with a higher percentage of patients experiencing hypertension if treated with bevacizumab rather than chemotherapy alone (7.8% vs. 1.1%). "There were strict instructions to try to reduce the number of gastrointestinal perforations," Dr. Witteveen noted. This resulted in a low rate (1.1% vs. 0%) of this adverse event, she observed
"Practice-changing trials"
"I think these are practice-changing trials," Dr. Kristeleit commented, stating that bevacizumab is clearly an active drug in advanced bulky ovarian cancer.
Based on the ICON7 findings, "first-line bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high risk ovarian cancer," she said.
Meanwhile AURELIA shows, "Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer."
Bevacizumab (Avastin) was recently approved for use in combination with chemotherapy in the first- and second-line treatment of advanced ovarian cancer in Europe. In the second-line setting, it is indicated in platinum-sensitive disease and not platinum-resistant disease as tested in the AURELIA trial. Bevacizumab is not currently licensed for ovarian cancer treatment in the United States.
Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GlaxoSmithKline, and Novartis. ICON-7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.
AMSTERDAM – Despite finding no overall survival benefit by adding bevacizumab to standard chemotherapy for newly diagnosed or platinum-resistant advanced ovarian cancer, the results of two phase III clinical trials remain "practice changing," according to a commentator Dr. Rebecca Kristeleit at the the multidisciplinary European cancer congresses.
Final overall survival results from the ICON7 trial showed that, in more than 1,500 women with newly diagnosed advanced ovarian cancer, there was a nonstatistical (P =.85) difference in overall survival of about 0.9 months using the restricted mean when all patients were considered.
In the AURELIA trial, conducted in 361 women with platinum-resistant disease, the hazard ratio for overall survival was 0.85, in favor of the addition of bevacizumab to chemotherapy, although this was not statistically significant (P = .174). The median overall survival was 16.6 months vs. 13.3 months in the control arm.
"The message I take from ICON7 is that there is a significant overall survival benefit in the high-risk group," said Dr. Kristeleit. "It’s an important clinical improvement, and it’s most important in the poor-prognosis patients, the ones who are inoperable, and the ones who are stage IV."
Regarding AURELIA, Dr. Kristeleit, a senior lecturer and consultant medical oncologist at University College London, said, "The study has shown a significant progression-free survival benefit, and we need to remember that it has doubled this in this really hard to treat group of ovarian cancer patients where there is significant clinical need."
ICON7: Bevacizumab in front-line treatment
The ICON7 (International Collaboration on Ovarian Neoplasms) study investigated the safety and efficacy of adding bevacizumab (7.5 mg/kg every 3 weeks) to standard chemotherapy in women with newly diagnosed ovarian cancer who were recruited and treated at 253 centers. The mean age of patients in the trial was 57 years.
The primary efficacy findings from the study were reported 3 years ago at the annual Congress of the European Society for Medical Oncology and published in the New England Journal of Medicine (2011;365:2484-96). These findings showed a clear benefit of adding the targeted agent to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2) given every 3 weeks for six cycles vs. chemotherapy alone, with median progression-free survival times of 19.0 vs. 17.3 months (HR, 0.81; P = .0041), respectively.
Now, with a median follow-up of 49 months, "it’s reassuring to see the progression-free survival is essentially the same [19.9 vs. 17.5 months]," observed study investigator Dr. Amit Oza of the Princess Margaret Cancer Centre at the University of Toronto.
Dr. Oza noted that 502 (33%) women met prespecified criteria for having a "poor prognosis," including women with suboptimally debulked stage III disease, those with stage IV disease, and those who could not have surgery, potentially putting them at high risk of progression. In those women, bevacizumab improved progression-free survival by a median of 5.5 months (HR, 0.73, P =.001), or 4.1 months using the restricted mean as the data were found to be non-proportional.
Final overall survival in these high-risk women was improved by a median of 9.4 months by the additional use of bevacizumab (HR, 0.78, P = .03), or 4.8 months using the restricted mean, from 34.5 months with chemotherapy alone to 39.3 months by the addition of the targeted agent.
"The overall survival difference in the high-risk subgroup is clinically meaningful," Dr. Oza said.
AURELIA: Bevacizumab in platinum-resistant disease
AURELIA was an open-label, randomized trial involving women who had progressive ovarian cancer within 6 months of receiving platinum-based chemotherapy. Women were randomized to receive chemotherapy alone (n = 182) or to chemotherapy plus bevacizumab (n = 179). The choice of chemotherapy was at the investigators’ discretion from a choice of weekly paclitaxel (80 mg/m2 on days 1, 8, 15, and 22), topotecan (4 mg/m2 on days 1, 8, and 15), or pegylated liposomal doxorubicin (PLD, 40 mg/m2 on day 1). Bevacizumab was given at a dose of 15 mg/kg every 3 weeks.
The primary endpoint was progression-free survival, with secondary endpoints of overall survival, quality of life, and, of course, safety and tolerability. The primary endpoint findings were presented last year at the annual meeting American Society of Clinical Oncology (J. Clin. Oncol. 2012;30 Suppl:LBA5002) and showed that the addition of bevacizumab almost doubled progression-free survival from 3.4 months with chemotherapy alone to 6.7 months when bevacizumab was added (HR, 0.48, P less than .001).
"The study was not powered to detect a significant difference in overall survival," said Dr. Petronella O. Witteveen, who was one of the AURELIA study investigators. Dr. Witteveen of the University Medical Center Utrecht in the Netherlands commented that overall survival was a key secondary endpoint for the trial and that interpretation of these data were complicated by the high percentage (40%) of patients in the chemotherapy arm that were allowed to crossover to additional treatment with bevacizumab.
Although no difference between the treatment arms could be seen in the final overall survival analysis, exploratory findings hinted that patients who received bevacizumab in combination with weekly paclitaxel might have had a survival advantage. The median overall survival in the cohort of patients who received bevacizumab in addition to weekly paclitaxel (n = 60) was 22.4 months vs. 13.2 months in the patients who received the chemotherapy alone (n = 55; HR, 0.65). Overall survival in the topotecan and PLD cohorts did not show any benefit of the addition of bevacizumab, with median overall survival times of just over 13-14 months whether or not bevacizumab was added to chemotherapy.
Updated safety findings showed no undue concerns or new side effects, with a higher percentage of patients experiencing hypertension if treated with bevacizumab rather than chemotherapy alone (7.8% vs. 1.1%). "There were strict instructions to try to reduce the number of gastrointestinal perforations," Dr. Witteveen noted. This resulted in a low rate (1.1% vs. 0%) of this adverse event, she observed
"Practice-changing trials"
"I think these are practice-changing trials," Dr. Kristeleit commented, stating that bevacizumab is clearly an active drug in advanced bulky ovarian cancer.
Based on the ICON7 findings, "first-line bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high risk ovarian cancer," she said.
Meanwhile AURELIA shows, "Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer."
Bevacizumab (Avastin) was recently approved for use in combination with chemotherapy in the first- and second-line treatment of advanced ovarian cancer in Europe. In the second-line setting, it is indicated in platinum-sensitive disease and not platinum-resistant disease as tested in the AURELIA trial. Bevacizumab is not currently licensed for ovarian cancer treatment in the United States.
Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GlaxoSmithKline, and Novartis. ICON-7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.
AMSTERDAM – Despite finding no overall survival benefit by adding bevacizumab to standard chemotherapy for newly diagnosed or platinum-resistant advanced ovarian cancer, the results of two phase III clinical trials remain "practice changing," according to a commentator Dr. Rebecca Kristeleit at the the multidisciplinary European cancer congresses.
Final overall survival results from the ICON7 trial showed that, in more than 1,500 women with newly diagnosed advanced ovarian cancer, there was a nonstatistical (P =.85) difference in overall survival of about 0.9 months using the restricted mean when all patients were considered.
In the AURELIA trial, conducted in 361 women with platinum-resistant disease, the hazard ratio for overall survival was 0.85, in favor of the addition of bevacizumab to chemotherapy, although this was not statistically significant (P = .174). The median overall survival was 16.6 months vs. 13.3 months in the control arm.
"The message I take from ICON7 is that there is a significant overall survival benefit in the high-risk group," said Dr. Kristeleit. "It’s an important clinical improvement, and it’s most important in the poor-prognosis patients, the ones who are inoperable, and the ones who are stage IV."
Regarding AURELIA, Dr. Kristeleit, a senior lecturer and consultant medical oncologist at University College London, said, "The study has shown a significant progression-free survival benefit, and we need to remember that it has doubled this in this really hard to treat group of ovarian cancer patients where there is significant clinical need."
ICON7: Bevacizumab in front-line treatment
The ICON7 (International Collaboration on Ovarian Neoplasms) study investigated the safety and efficacy of adding bevacizumab (7.5 mg/kg every 3 weeks) to standard chemotherapy in women with newly diagnosed ovarian cancer who were recruited and treated at 253 centers. The mean age of patients in the trial was 57 years.
The primary efficacy findings from the study were reported 3 years ago at the annual Congress of the European Society for Medical Oncology and published in the New England Journal of Medicine (2011;365:2484-96). These findings showed a clear benefit of adding the targeted agent to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2) given every 3 weeks for six cycles vs. chemotherapy alone, with median progression-free survival times of 19.0 vs. 17.3 months (HR, 0.81; P = .0041), respectively.
Now, with a median follow-up of 49 months, "it’s reassuring to see the progression-free survival is essentially the same [19.9 vs. 17.5 months]," observed study investigator Dr. Amit Oza of the Princess Margaret Cancer Centre at the University of Toronto.
Dr. Oza noted that 502 (33%) women met prespecified criteria for having a "poor prognosis," including women with suboptimally debulked stage III disease, those with stage IV disease, and those who could not have surgery, potentially putting them at high risk of progression. In those women, bevacizumab improved progression-free survival by a median of 5.5 months (HR, 0.73, P =.001), or 4.1 months using the restricted mean as the data were found to be non-proportional.
Final overall survival in these high-risk women was improved by a median of 9.4 months by the additional use of bevacizumab (HR, 0.78, P = .03), or 4.8 months using the restricted mean, from 34.5 months with chemotherapy alone to 39.3 months by the addition of the targeted agent.
"The overall survival difference in the high-risk subgroup is clinically meaningful," Dr. Oza said.
AURELIA: Bevacizumab in platinum-resistant disease
AURELIA was an open-label, randomized trial involving women who had progressive ovarian cancer within 6 months of receiving platinum-based chemotherapy. Women were randomized to receive chemotherapy alone (n = 182) or to chemotherapy plus bevacizumab (n = 179). The choice of chemotherapy was at the investigators’ discretion from a choice of weekly paclitaxel (80 mg/m2 on days 1, 8, 15, and 22), topotecan (4 mg/m2 on days 1, 8, and 15), or pegylated liposomal doxorubicin (PLD, 40 mg/m2 on day 1). Bevacizumab was given at a dose of 15 mg/kg every 3 weeks.
The primary endpoint was progression-free survival, with secondary endpoints of overall survival, quality of life, and, of course, safety and tolerability. The primary endpoint findings were presented last year at the annual meeting American Society of Clinical Oncology (J. Clin. Oncol. 2012;30 Suppl:LBA5002) and showed that the addition of bevacizumab almost doubled progression-free survival from 3.4 months with chemotherapy alone to 6.7 months when bevacizumab was added (HR, 0.48, P less than .001).
"The study was not powered to detect a significant difference in overall survival," said Dr. Petronella O. Witteveen, who was one of the AURELIA study investigators. Dr. Witteveen of the University Medical Center Utrecht in the Netherlands commented that overall survival was a key secondary endpoint for the trial and that interpretation of these data were complicated by the high percentage (40%) of patients in the chemotherapy arm that were allowed to crossover to additional treatment with bevacizumab.
Although no difference between the treatment arms could be seen in the final overall survival analysis, exploratory findings hinted that patients who received bevacizumab in combination with weekly paclitaxel might have had a survival advantage. The median overall survival in the cohort of patients who received bevacizumab in addition to weekly paclitaxel (n = 60) was 22.4 months vs. 13.2 months in the patients who received the chemotherapy alone (n = 55; HR, 0.65). Overall survival in the topotecan and PLD cohorts did not show any benefit of the addition of bevacizumab, with median overall survival times of just over 13-14 months whether or not bevacizumab was added to chemotherapy.
Updated safety findings showed no undue concerns or new side effects, with a higher percentage of patients experiencing hypertension if treated with bevacizumab rather than chemotherapy alone (7.8% vs. 1.1%). "There were strict instructions to try to reduce the number of gastrointestinal perforations," Dr. Witteveen noted. This resulted in a low rate (1.1% vs. 0%) of this adverse event, she observed
"Practice-changing trials"
"I think these are practice-changing trials," Dr. Kristeleit commented, stating that bevacizumab is clearly an active drug in advanced bulky ovarian cancer.
Based on the ICON7 findings, "first-line bevacizumab and 3-weekly chemotherapy should be considered a standard of care in high risk ovarian cancer," she said.
Meanwhile AURELIA shows, "Bevacizumab with weekly paclitaxel should be considered a new paradigm in platinum-resistant ovarian cancer."
Bevacizumab (Avastin) was recently approved for use in combination with chemotherapy in the first- and second-line treatment of advanced ovarian cancer in Europe. In the second-line setting, it is indicated in platinum-sensitive disease and not platinum-resistant disease as tested in the AURELIA trial. Bevacizumab is not currently licensed for ovarian cancer treatment in the United States.
Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GlaxoSmithKline, and Novartis. ICON-7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.
AT THE EUROPEAN CANCER CONGRESS 2013
Major findings: The hazard ratios for overall survival were 0.78 (P = .007) in "high-risk" newly diagnosed patients and 0.85 (P = .174) in platinum-resistant patients.
Data source: Two multicenter, randomized, phase III, controlled trials of bevacizumab added to chemotherapy for the first-line (ICON7; n = 1,528) or platinum-resistant (AURELIA; n = 361) treatment of advanced ovarian cancer.
Disclosures: Roche sponsored the AURELIA study. Dr. Witteveen had no conflicts of interest; some of her coinvestigators disclosed ties with Roche, GSK, and Novartis. ICON7 was funded by Roche and the National Institute for Health Research through the National Cancer Research Network in the United Kingdom. Dr. Oza disclosed ties with Roche. Dr. Kristeleit disclosed ties with Roche, Clovis, Janssen, Lytix, and Novartis.
