ESMO Congress 2013

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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.

Sara Freeman/IMNG Medical Media

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 – PIK3CA mutations were associated with lower pathologic complete responses in women with human epidermal growth factor receptor 2 breast cancer treated with neoadjuvant anti-HER2 therapy in the phase III NeoALTTO trial.

"The lower pCR rate in PIK3CA-mutant tumors is observed in all treatment arms, irrespective of estrogen receptor status," Dr. José Baselga said at the European multidisciplinary European cancer congresses.

Earlier results from NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) showed that dual HER2 blockade with trastuzumab (Herceptin) and lapatinib (Tykerb) nearly doubled the pCR rate compared with single-agent trastuzumab or lapatinib (51.3% vs. 29.5% vs. 24.7%; P = .0001).

For the analysis, the investigators performed mutational analyses on tumor samples from 355 (78%) of the 455 study participants. Of these, 23% had a PIK3CA mutation, which is highly consistent with other published analyses, said Dr. Baselga, physician-in-chief at Memorial Sloan-Kettering Cancer Center, in New York City.

No BRAF mutations were found, and one patient had a KRAS mutation.

Overall, pCRs occurred in 21% of PIK3CA mutant tumors and 34% of PIK3CA wildtype tumors (P = .03), he said.

The pCR rate was 28.6% in women with a PIK3CA mutation and 55.8% in those without it in the combination trastuzumab/lapatinib arm, 14.8% vs. 20.4% in the lapatinib arm, and 20% vs. 28.4% in the trastuzumab arm. The difference was statistically significant only for the combination arm (P = .012), but Dr. Baselga urged caution in interpreting this because of the small patient numbers.

PIK3CA mutations were also associated with lower pCR rates in both estrogen receptor (ER)–positive (5% vs. 31%) and ER-negative (11% vs. 61%) patients.

In all, PIK3CA mutations were found in 23% of 124 women in the lapatinib arm, 19% of 112 in the trastuzumab arm, 25% of 119 in the combination arm, 23% of 169 ER-positive patients, and 22% of 186 ER-negative patients.

In a logistic regression model that adjusted for treatment arm and ER status, a significant difference was observed in pCR between PIK3CA mutant and wildtype tumors (odds ratio, 0.45; P = .015), by treatment arm (lapatinib vs. trastuzumab: OR, 0.67; P less than .0001 and combination vs. trastuzumab: OR, 2.97; P less than .0001), and by ER status (negative vs. positive: OR, 2.44; P = .0005).

The findings are concordant with two metastatic breast cancer studies, Dr. Baselga said. In the CLEOPATRA trial, women with PIK3CA-mutant tumors had less benefit from first-line trastuzumab with or without pertuzumab (Perjeta), as did those treated with lapatinib plus capecitabine (Xeloda) in the EMILIA trial.

In the FinHER trial, however, PIK3CA mutations were not predictive of resistance to trastuzumab, he said.

"These findings will lead us to analyze carefully PIK3CA mutation status in adjuvant HER2-positive studies. In this setting, PIK3CA status might be both prognostic and predictive," Dr. Baselga concluded.

Invited discussant Prof. Sibylle Loibl, leader of the medicine and research department, University of Frankfurt (Germany)and member of the German Breast Group, observed that ER-positive PIK3CA-mutant tumors achieved the lowest pCR rate of any group in the current analysis and in the NeoSphere trial of pertuzumab/trastuzumab in treatment-naive HER2-positive breast cancer. "This suggests an interaction of the different pathways and a need to better select the HER2-positive patients," she said.

GlaxoSmithKline sponsored the trial. Dr. Baselga reported no relevant financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – PIK3CA mutations were associated with lower pathologic complete responses in women with human epidermal growth factor receptor 2 breast cancer treated with neoadjuvant anti-HER2 therapy in the phase III NeoALTTO trial.

"The lower pCR rate in PIK3CA-mutant tumors is observed in all treatment arms, irrespective of estrogen receptor status," Dr. José Baselga said at the European multidisciplinary European cancer congresses.

Earlier results from NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) showed that dual HER2 blockade with trastuzumab (Herceptin) and lapatinib (Tykerb) nearly doubled the pCR rate compared with single-agent trastuzumab or lapatinib (51.3% vs. 29.5% vs. 24.7%; P = .0001).

For the analysis, the investigators performed mutational analyses on tumor samples from 355 (78%) of the 455 study participants. Of these, 23% had a PIK3CA mutation, which is highly consistent with other published analyses, said Dr. Baselga, physician-in-chief at Memorial Sloan-Kettering Cancer Center, in New York City.

No BRAF mutations were found, and one patient had a KRAS mutation.

Overall, pCRs occurred in 21% of PIK3CA mutant tumors and 34% of PIK3CA wildtype tumors (P = .03), he said.

The pCR rate was 28.6% in women with a PIK3CA mutation and 55.8% in those without it in the combination trastuzumab/lapatinib arm, 14.8% vs. 20.4% in the lapatinib arm, and 20% vs. 28.4% in the trastuzumab arm. The difference was statistically significant only for the combination arm (P = .012), but Dr. Baselga urged caution in interpreting this because of the small patient numbers.

PIK3CA mutations were also associated with lower pCR rates in both estrogen receptor (ER)–positive (5% vs. 31%) and ER-negative (11% vs. 61%) patients.

In all, PIK3CA mutations were found in 23% of 124 women in the lapatinib arm, 19% of 112 in the trastuzumab arm, 25% of 119 in the combination arm, 23% of 169 ER-positive patients, and 22% of 186 ER-negative patients.

In a logistic regression model that adjusted for treatment arm and ER status, a significant difference was observed in pCR between PIK3CA mutant and wildtype tumors (odds ratio, 0.45; P = .015), by treatment arm (lapatinib vs. trastuzumab: OR, 0.67; P less than .0001 and combination vs. trastuzumab: OR, 2.97; P less than .0001), and by ER status (negative vs. positive: OR, 2.44; P = .0005).

The findings are concordant with two metastatic breast cancer studies, Dr. Baselga said. In the CLEOPATRA trial, women with PIK3CA-mutant tumors had less benefit from first-line trastuzumab with or without pertuzumab (Perjeta), as did those treated with lapatinib plus capecitabine (Xeloda) in the EMILIA trial.

In the FinHER trial, however, PIK3CA mutations were not predictive of resistance to trastuzumab, he said.

"These findings will lead us to analyze carefully PIK3CA mutation status in adjuvant HER2-positive studies. In this setting, PIK3CA status might be both prognostic and predictive," Dr. Baselga concluded.

Invited discussant Prof. Sibylle Loibl, leader of the medicine and research department, University of Frankfurt (Germany)and member of the German Breast Group, observed that ER-positive PIK3CA-mutant tumors achieved the lowest pCR rate of any group in the current analysis and in the NeoSphere trial of pertuzumab/trastuzumab in treatment-naive HER2-positive breast cancer. "This suggests an interaction of the different pathways and a need to better select the HER2-positive patients," she said.

GlaxoSmithKline sponsored the trial. Dr. Baselga reported no relevant financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – PIK3CA mutations were associated with lower pathologic complete responses in women with human epidermal growth factor receptor 2 breast cancer treated with neoadjuvant anti-HER2 therapy in the phase III NeoALTTO trial.

"The lower pCR rate in PIK3CA-mutant tumors is observed in all treatment arms, irrespective of estrogen receptor status," Dr. José Baselga said at the European multidisciplinary European cancer congresses.

Earlier results from NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) showed that dual HER2 blockade with trastuzumab (Herceptin) and lapatinib (Tykerb) nearly doubled the pCR rate compared with single-agent trastuzumab or lapatinib (51.3% vs. 29.5% vs. 24.7%; P = .0001).

For the analysis, the investigators performed mutational analyses on tumor samples from 355 (78%) of the 455 study participants. Of these, 23% had a PIK3CA mutation, which is highly consistent with other published analyses, said Dr. Baselga, physician-in-chief at Memorial Sloan-Kettering Cancer Center, in New York City.

No BRAF mutations were found, and one patient had a KRAS mutation.

Overall, pCRs occurred in 21% of PIK3CA mutant tumors and 34% of PIK3CA wildtype tumors (P = .03), he said.

The pCR rate was 28.6% in women with a PIK3CA mutation and 55.8% in those without it in the combination trastuzumab/lapatinib arm, 14.8% vs. 20.4% in the lapatinib arm, and 20% vs. 28.4% in the trastuzumab arm. The difference was statistically significant only for the combination arm (P = .012), but Dr. Baselga urged caution in interpreting this because of the small patient numbers.

PIK3CA mutations were also associated with lower pCR rates in both estrogen receptor (ER)–positive (5% vs. 31%) and ER-negative (11% vs. 61%) patients.

In all, PIK3CA mutations were found in 23% of 124 women in the lapatinib arm, 19% of 112 in the trastuzumab arm, 25% of 119 in the combination arm, 23% of 169 ER-positive patients, and 22% of 186 ER-negative patients.

In a logistic regression model that adjusted for treatment arm and ER status, a significant difference was observed in pCR between PIK3CA mutant and wildtype tumors (odds ratio, 0.45; P = .015), by treatment arm (lapatinib vs. trastuzumab: OR, 0.67; P less than .0001 and combination vs. trastuzumab: OR, 2.97; P less than .0001), and by ER status (negative vs. positive: OR, 2.44; P = .0005).

The findings are concordant with two metastatic breast cancer studies, Dr. Baselga said. In the CLEOPATRA trial, women with PIK3CA-mutant tumors had less benefit from first-line trastuzumab with or without pertuzumab (Perjeta), as did those treated with lapatinib plus capecitabine (Xeloda) in the EMILIA trial.

In the FinHER trial, however, PIK3CA mutations were not predictive of resistance to trastuzumab, he said.

"These findings will lead us to analyze carefully PIK3CA mutation status in adjuvant HER2-positive studies. In this setting, PIK3CA status might be both prognostic and predictive," Dr. Baselga concluded.

Invited discussant Prof. Sibylle Loibl, leader of the medicine and research department, University of Frankfurt (Germany)and member of the German Breast Group, observed that ER-positive PIK3CA-mutant tumors achieved the lowest pCR rate of any group in the current analysis and in the NeoSphere trial of pertuzumab/trastuzumab in treatment-naive HER2-positive breast cancer. "This suggests an interaction of the different pathways and a need to better select the HER2-positive patients," she said.

GlaxoSmithKline sponsored the trial. Dr. Baselga reported no relevant financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – Countries with widespread colorectal cancer screening are reaping the benefits of their efforts.

An analysis involving 11 European countries found that the greater the proportion of people screened, the bigger the reduction in colorectal cancer (CRC) deaths for both males and females. Countries with low rates of CRC screening had sluggish declines or actual increases in CRC mortality over the 22-year study period, despite having health care services that were comparable to those of high-screening countries, Dr. Philippe Autier reported at the European Cancer Congress 2013.

For example, CRC deaths fell 39% for men and 47% for women in Austria, where 35% of men and 36% of women aged 50 years or more had an endoscopic examination of the large bowel between 1989 and 2010. In contrast, CRC mortality rose by 30% among men and 2% among women in Greece, where endoscopic examinations reached a low of 8% for both sexes over the same period.

Patrice Wendling/IMNG Medical Media

Fecal occult blood test screening over the past 10 years reached a high of 61% for both sexes in Austria versus a low of 4% in the Netherlands. CRC mortality declined by 4% for men and 10% for women in the Netherlands, the lowest declines posted in the study (Ab. 1405).

A history of at least one endoscopic exam explained 73% of the decrease in CRC mortality in men and 82% of the decrease in women, according to Dr. Autier, research director at the International Prevention Research Institute, Lyon, France.

The investigators based their calculations on CRC screening data collected from participants, aged 50 years or more, in the Survey of Health, Aging, and Retirement in Europe (SHARE) project and on data from the World Health Organization mortality database. The team is planning to collect additional data from Europe, and to gather data from the United States, Canada, and Australia.

CRC screening is more cost-effective than either mammography or prostate-specific antigen (PSA) testing, and the risk of overdiagnosis is very low since endoscopy involves systematic removal of polyps or precancerous lesions, Dr. Autier said at a press briefing.

Prof. Jack Cuzick, with the Centre for Cancer Prevention at Queen Mary, University of London, commented that "the real challenge now is to get this information out into the public enough and to find ways to get compliance rates up, because this is probably the single most important screening modality we have in terms of a highly effective screening test that actually has an impact on a major cancer."

Future research will also need to determine whether countries can actually build preventive activities into their CRC screening programs.

"We do know how to prevent about 30% of colorectal cancer incidence and mortality by something as simple as a daily aspirin," Prof. Cuzick said. "Whether we should focus that on people just at high risk, because they have an adenoma or other factors, or not, is important."

European CanCer Organisation President Prof. Cornelis van de Velde said in a statement that "it is very disappointing that there are so many differences in outcome due to limitations in the use of screening. People over 50 should be informed of the availability of the test, and pressure should be put on national health services to put more effort into organizing screening programs."

As for whether one screening test should be advocated over another, he told reporters that the American Cancer Society has the right message: "Do something, you have the choice."

Dr. Autier reported having no financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – Countries with widespread colorectal cancer screening are reaping the benefits of their efforts.

An analysis involving 11 European countries found that the greater the proportion of people screened, the bigger the reduction in colorectal cancer (CRC) deaths for both males and females. Countries with low rates of CRC screening had sluggish declines or actual increases in CRC mortality over the 22-year study period, despite having health care services that were comparable to those of high-screening countries, Dr. Philippe Autier reported at the European Cancer Congress 2013.

For example, CRC deaths fell 39% for men and 47% for women in Austria, where 35% of men and 36% of women aged 50 years or more had an endoscopic examination of the large bowel between 1989 and 2010. In contrast, CRC mortality rose by 30% among men and 2% among women in Greece, where endoscopic examinations reached a low of 8% for both sexes over the same period.

Patrice Wendling/IMNG Medical Media

Fecal occult blood test screening over the past 10 years reached a high of 61% for both sexes in Austria versus a low of 4% in the Netherlands. CRC mortality declined by 4% for men and 10% for women in the Netherlands, the lowest declines posted in the study (Ab. 1405).

A history of at least one endoscopic exam explained 73% of the decrease in CRC mortality in men and 82% of the decrease in women, according to Dr. Autier, research director at the International Prevention Research Institute, Lyon, France.

The investigators based their calculations on CRC screening data collected from participants, aged 50 years or more, in the Survey of Health, Aging, and Retirement in Europe (SHARE) project and on data from the World Health Organization mortality database. The team is planning to collect additional data from Europe, and to gather data from the United States, Canada, and Australia.

CRC screening is more cost-effective than either mammography or prostate-specific antigen (PSA) testing, and the risk of overdiagnosis is very low since endoscopy involves systematic removal of polyps or precancerous lesions, Dr. Autier said at a press briefing.

Prof. Jack Cuzick, with the Centre for Cancer Prevention at Queen Mary, University of London, commented that "the real challenge now is to get this information out into the public enough and to find ways to get compliance rates up, because this is probably the single most important screening modality we have in terms of a highly effective screening test that actually has an impact on a major cancer."

Future research will also need to determine whether countries can actually build preventive activities into their CRC screening programs.

"We do know how to prevent about 30% of colorectal cancer incidence and mortality by something as simple as a daily aspirin," Prof. Cuzick said. "Whether we should focus that on people just at high risk, because they have an adenoma or other factors, or not, is important."

European CanCer Organisation President Prof. Cornelis van de Velde said in a statement that "it is very disappointing that there are so many differences in outcome due to limitations in the use of screening. People over 50 should be informed of the availability of the test, and pressure should be put on national health services to put more effort into organizing screening programs."

As for whether one screening test should be advocated over another, he told reporters that the American Cancer Society has the right message: "Do something, you have the choice."

Dr. Autier reported having no financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – Countries with widespread colorectal cancer screening are reaping the benefits of their efforts.

An analysis involving 11 European countries found that the greater the proportion of people screened, the bigger the reduction in colorectal cancer (CRC) deaths for both males and females. Countries with low rates of CRC screening had sluggish declines or actual increases in CRC mortality over the 22-year study period, despite having health care services that were comparable to those of high-screening countries, Dr. Philippe Autier reported at the European Cancer Congress 2013.

For example, CRC deaths fell 39% for men and 47% for women in Austria, where 35% of men and 36% of women aged 50 years or more had an endoscopic examination of the large bowel between 1989 and 2010. In contrast, CRC mortality rose by 30% among men and 2% among women in Greece, where endoscopic examinations reached a low of 8% for both sexes over the same period.

Patrice Wendling/IMNG Medical Media

Fecal occult blood test screening over the past 10 years reached a high of 61% for both sexes in Austria versus a low of 4% in the Netherlands. CRC mortality declined by 4% for men and 10% for women in the Netherlands, the lowest declines posted in the study (Ab. 1405).

A history of at least one endoscopic exam explained 73% of the decrease in CRC mortality in men and 82% of the decrease in women, according to Dr. Autier, research director at the International Prevention Research Institute, Lyon, France.

The investigators based their calculations on CRC screening data collected from participants, aged 50 years or more, in the Survey of Health, Aging, and Retirement in Europe (SHARE) project and on data from the World Health Organization mortality database. The team is planning to collect additional data from Europe, and to gather data from the United States, Canada, and Australia.

CRC screening is more cost-effective than either mammography or prostate-specific antigen (PSA) testing, and the risk of overdiagnosis is very low since endoscopy involves systematic removal of polyps or precancerous lesions, Dr. Autier said at a press briefing.

Prof. Jack Cuzick, with the Centre for Cancer Prevention at Queen Mary, University of London, commented that "the real challenge now is to get this information out into the public enough and to find ways to get compliance rates up, because this is probably the single most important screening modality we have in terms of a highly effective screening test that actually has an impact on a major cancer."

Future research will also need to determine whether countries can actually build preventive activities into their CRC screening programs.

"We do know how to prevent about 30% of colorectal cancer incidence and mortality by something as simple as a daily aspirin," Prof. Cuzick said. "Whether we should focus that on people just at high risk, because they have an adenoma or other factors, or not, is important."

European CanCer Organisation President Prof. Cornelis van de Velde said in a statement that "it is very disappointing that there are so many differences in outcome due to limitations in the use of screening. People over 50 should be informed of the availability of the test, and pressure should be put on national health services to put more effort into organizing screening programs."

As for whether one screening test should be advocated over another, he told reporters that the American Cancer Society has the right message: "Do something, you have the choice."

Dr. Autier reported having no financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – Two-fifths of patients with refractory recurrent or metastatic cancers were successfully matched to an appropriate targeted treatment using molecular profiling, according to research presented at the multidisciplinary European cancer congresses.

Feasibility findings from the phase II, proof-of-concept SHIVA study showed that a molecular abnormality leading to targeted treatment was present in 40% patients.

This is the first randomized trial to consider treating patients purely on the basis of their molecular profile rather than the type of tumor that they have. It is also the first trial designed to determine what the outcome of such an approach will be, with the primary endpoint being progression-free survival.

Currently, the prescription of approved molecularly targeted agents relies on the primary tumor location and histological subtype. For example, a woman with breast cancer overexpressing HER2 may be treated with a HER2-targeting agent such as trastuzumab or lapatinib, or with endocrine therapies such as tamoxifen and letrozole, if there is overexpression of the estrogen or progestogen receptor (ER/PR).

However, it is not clear if this is the best means of using these therapies, as their molecular targets may not be specific to a single tumor type. Indeed, HER2 is overexpressed in several tumor types other than breast cancer, including ovarian, gastric, colorectal, pancreatic, and endometrial cancers.

The idea of giving patients treatment based on their molecular profiles rather than their tumor types represents a new paradigm and requires prospective validation before being implemented in clinical practice, Dr. Christophe Le Tourneau of Institut Curie, Paris, said in an interview.

The SHIVA trial was therefore initiated to compare molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer (Target Oncol. 2012;7:253-65). Although two previous studies have suggested that this approach is possible and could improve patient outcomes (J. Clin. Oncol. 2010;4877-83; Clin. Cancer Res. 2012;18:6373-83), these studies were not randomized against the standard of care and so the conclusions that can be drawn from their results are not robust.

Patients are eligible for inclusion in the ongoing SHIVA trial if they have recurrent or metastatic disease despite standard treatment, an ECOG performance status of 0 or 1, adequate organ function, and measurable disease that can be biopsied not involving the bone or brain.

After recruitment, all patients will have a biopsy taken of one metastasis that is then assessed for gene mutations and amplifications, and for the expression of hormone (estrogen, progestogen and androgen) receptors. If a molecular abnormality is identified for which an approved targeted agent is available, then patients are randomized to receive either the matching targeted therapy or the conventional therapy that they would have received had they not be identified as having a possible molecular target. At progression, patients in the conventional treatment arm may crossover to targeted therapy.

Patients are only randomized if they have a molecular target that is not already known for their disease. So a patient with breast cancer found to have amplified HER2 or a patient with non–small-cell lung cancer and overexpression of EGFR would not be included, Dr. Le Tourneau said.

The SHIVA investigators have developed an algorithm or Molecular Biology Board (MBB) to help guide treatment in the experimental arm. The following targeted agents may be used if an appropriate molecular target is found: KIT or ABL for imatinib; PTEN or mTOR, among others, for everolimus; BRAF for vemurafenib; PDGFRA/B or FLT-3 for sorafenib; EGFR for erlotinib; HER2 for lapatinib in combination with trastuzumab; SRC, and others, for dasatinib; ER and PR for tamoxifen or letrozole; and the androgen receptor for abiraterone.

The trial is using high throughput sequencing, so processing the biopsies involves only two assays – one for gene mutation analysis and one for gene copy number alterations – "so we look at everything at the same time," Dr. Le Tourneau said.

As of September 2013, 350 patients had been included in the study and feasibility of the molecular profiling approach was tested in the first 95 patients. Of these, a complete molecular profile could be obtained in 61%. The median time to obtaining the biopsy sample and performing the MBB was 26 days, ranging from 2 weeks to 42 days. Mutations could be assessed in two-thirds of samples, with gene copy alterations analyzed in 68%, and immunohistochemistry for hormone receptors possible in 92%.

In the experimental arm, 14 patients (15%) with a variety of tumor types are now being treated with abiraterone, 13 (14%) with everolimus, nine (9%) with endocrine treatment, and two (2%) with anti-HER2 treatment or sorafenib.

The primary efficacy analysis for progression-free survival will be performed once 100 patients have been randomized into each study arm. Other analyses will determine the overall response rate (ORR) and overall survival, among other key endpoints.

The SHIVA trial is planned to run for 3 years, and as it is already a year in, "within 2 years the study will be finished," Dr. Le Tourneau said.

The SHIVA trial is funded by Institut Curie. Dr. Le Tourneau had no conflicts of interest.

AMSTERDAM – Two-fifths of patients with refractory recurrent or metastatic cancers were successfully matched to an appropriate targeted treatment using molecular profiling, according to research presented at the multidisciplinary European cancer congresses.

Feasibility findings from the phase II, proof-of-concept SHIVA study showed that a molecular abnormality leading to targeted treatment was present in 40% patients.

This is the first randomized trial to consider treating patients purely on the basis of their molecular profile rather than the type of tumor that they have. It is also the first trial designed to determine what the outcome of such an approach will be, with the primary endpoint being progression-free survival.

Currently, the prescription of approved molecularly targeted agents relies on the primary tumor location and histological subtype. For example, a woman with breast cancer overexpressing HER2 may be treated with a HER2-targeting agent such as trastuzumab or lapatinib, or with endocrine therapies such as tamoxifen and letrozole, if there is overexpression of the estrogen or progestogen receptor (ER/PR).

However, it is not clear if this is the best means of using these therapies, as their molecular targets may not be specific to a single tumor type. Indeed, HER2 is overexpressed in several tumor types other than breast cancer, including ovarian, gastric, colorectal, pancreatic, and endometrial cancers.

The idea of giving patients treatment based on their molecular profiles rather than their tumor types represents a new paradigm and requires prospective validation before being implemented in clinical practice, Dr. Christophe Le Tourneau of Institut Curie, Paris, said in an interview.

The SHIVA trial was therefore initiated to compare molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer (Target Oncol. 2012;7:253-65). Although two previous studies have suggested that this approach is possible and could improve patient outcomes (J. Clin. Oncol. 2010;4877-83; Clin. Cancer Res. 2012;18:6373-83), these studies were not randomized against the standard of care and so the conclusions that can be drawn from their results are not robust.

Patients are eligible for inclusion in the ongoing SHIVA trial if they have recurrent or metastatic disease despite standard treatment, an ECOG performance status of 0 or 1, adequate organ function, and measurable disease that can be biopsied not involving the bone or brain.

After recruitment, all patients will have a biopsy taken of one metastasis that is then assessed for gene mutations and amplifications, and for the expression of hormone (estrogen, progestogen and androgen) receptors. If a molecular abnormality is identified for which an approved targeted agent is available, then patients are randomized to receive either the matching targeted therapy or the conventional therapy that they would have received had they not be identified as having a possible molecular target. At progression, patients in the conventional treatment arm may crossover to targeted therapy.

Patients are only randomized if they have a molecular target that is not already known for their disease. So a patient with breast cancer found to have amplified HER2 or a patient with non–small-cell lung cancer and overexpression of EGFR would not be included, Dr. Le Tourneau said.

The SHIVA investigators have developed an algorithm or Molecular Biology Board (MBB) to help guide treatment in the experimental arm. The following targeted agents may be used if an appropriate molecular target is found: KIT or ABL for imatinib; PTEN or mTOR, among others, for everolimus; BRAF for vemurafenib; PDGFRA/B or FLT-3 for sorafenib; EGFR for erlotinib; HER2 for lapatinib in combination with trastuzumab; SRC, and others, for dasatinib; ER and PR for tamoxifen or letrozole; and the androgen receptor for abiraterone.

The trial is using high throughput sequencing, so processing the biopsies involves only two assays – one for gene mutation analysis and one for gene copy number alterations – "so we look at everything at the same time," Dr. Le Tourneau said.

As of September 2013, 350 patients had been included in the study and feasibility of the molecular profiling approach was tested in the first 95 patients. Of these, a complete molecular profile could be obtained in 61%. The median time to obtaining the biopsy sample and performing the MBB was 26 days, ranging from 2 weeks to 42 days. Mutations could be assessed in two-thirds of samples, with gene copy alterations analyzed in 68%, and immunohistochemistry for hormone receptors possible in 92%.

In the experimental arm, 14 patients (15%) with a variety of tumor types are now being treated with abiraterone, 13 (14%) with everolimus, nine (9%) with endocrine treatment, and two (2%) with anti-HER2 treatment or sorafenib.

The primary efficacy analysis for progression-free survival will be performed once 100 patients have been randomized into each study arm. Other analyses will determine the overall response rate (ORR) and overall survival, among other key endpoints.

The SHIVA trial is planned to run for 3 years, and as it is already a year in, "within 2 years the study will be finished," Dr. Le Tourneau said.

The SHIVA trial is funded by Institut Curie. Dr. Le Tourneau had no conflicts of interest.

AMSTERDAM – Two-fifths of patients with refractory recurrent or metastatic cancers were successfully matched to an appropriate targeted treatment using molecular profiling, according to research presented at the multidisciplinary European cancer congresses.

Feasibility findings from the phase II, proof-of-concept SHIVA study showed that a molecular abnormality leading to targeted treatment was present in 40% patients.

This is the first randomized trial to consider treating patients purely on the basis of their molecular profile rather than the type of tumor that they have. It is also the first trial designed to determine what the outcome of such an approach will be, with the primary endpoint being progression-free survival.

Currently, the prescription of approved molecularly targeted agents relies on the primary tumor location and histological subtype. For example, a woman with breast cancer overexpressing HER2 may be treated with a HER2-targeting agent such as trastuzumab or lapatinib, or with endocrine therapies such as tamoxifen and letrozole, if there is overexpression of the estrogen or progestogen receptor (ER/PR).

However, it is not clear if this is the best means of using these therapies, as their molecular targets may not be specific to a single tumor type. Indeed, HER2 is overexpressed in several tumor types other than breast cancer, including ovarian, gastric, colorectal, pancreatic, and endometrial cancers.

The idea of giving patients treatment based on their molecular profiles rather than their tumor types represents a new paradigm and requires prospective validation before being implemented in clinical practice, Dr. Christophe Le Tourneau of Institut Curie, Paris, said in an interview.

The SHIVA trial was therefore initiated to compare molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer (Target Oncol. 2012;7:253-65). Although two previous studies have suggested that this approach is possible and could improve patient outcomes (J. Clin. Oncol. 2010;4877-83; Clin. Cancer Res. 2012;18:6373-83), these studies were not randomized against the standard of care and so the conclusions that can be drawn from their results are not robust.

Patients are eligible for inclusion in the ongoing SHIVA trial if they have recurrent or metastatic disease despite standard treatment, an ECOG performance status of 0 or 1, adequate organ function, and measurable disease that can be biopsied not involving the bone or brain.

After recruitment, all patients will have a biopsy taken of one metastasis that is then assessed for gene mutations and amplifications, and for the expression of hormone (estrogen, progestogen and androgen) receptors. If a molecular abnormality is identified for which an approved targeted agent is available, then patients are randomized to receive either the matching targeted therapy or the conventional therapy that they would have received had they not be identified as having a possible molecular target. At progression, patients in the conventional treatment arm may crossover to targeted therapy.

Patients are only randomized if they have a molecular target that is not already known for their disease. So a patient with breast cancer found to have amplified HER2 or a patient with non–small-cell lung cancer and overexpression of EGFR would not be included, Dr. Le Tourneau said.

The SHIVA investigators have developed an algorithm or Molecular Biology Board (MBB) to help guide treatment in the experimental arm. The following targeted agents may be used if an appropriate molecular target is found: KIT or ABL for imatinib; PTEN or mTOR, among others, for everolimus; BRAF for vemurafenib; PDGFRA/B or FLT-3 for sorafenib; EGFR for erlotinib; HER2 for lapatinib in combination with trastuzumab; SRC, and others, for dasatinib; ER and PR for tamoxifen or letrozole; and the androgen receptor for abiraterone.

The trial is using high throughput sequencing, so processing the biopsies involves only two assays – one for gene mutation analysis and one for gene copy number alterations – "so we look at everything at the same time," Dr. Le Tourneau said.

As of September 2013, 350 patients had been included in the study and feasibility of the molecular profiling approach was tested in the first 95 patients. Of these, a complete molecular profile could be obtained in 61%. The median time to obtaining the biopsy sample and performing the MBB was 26 days, ranging from 2 weeks to 42 days. Mutations could be assessed in two-thirds of samples, with gene copy alterations analyzed in 68%, and immunohistochemistry for hormone receptors possible in 92%.

In the experimental arm, 14 patients (15%) with a variety of tumor types are now being treated with abiraterone, 13 (14%) with everolimus, nine (9%) with endocrine treatment, and two (2%) with anti-HER2 treatment or sorafenib.

The primary efficacy analysis for progression-free survival will be performed once 100 patients have been randomized into each study arm. Other analyses will determine the overall response rate (ORR) and overall survival, among other key endpoints.

The SHIVA trial is planned to run for 3 years, and as it is already a year in, "within 2 years the study will be finished," Dr. Le Tourneau said.

The SHIVA trial is funded by Institut Curie. Dr. Le Tourneau had no conflicts of interest.

AMSTERDAM – Immunotherapy with ipilimumab provides a durable, long-term survival benefit in patients with metastatic or locally advanced melanoma, a pooled analysis confirms.

Median overall survival was 11.4 months and 3-year survival 22% among 1,861 patients receiving ipilimumab (Yervoy) in a mixture of 12 clinical trials.

When data from 2,985 additional patients in the expanded access program were included, median overall survival was 9.5 months and 3-year survival 21%, Dr. F. Stephen Hodi Jr., director of the Melanoma Center at the Dana-Farber Cancer Institute, Boston, said at the European Cancer Congress 2013.

The pooled analysis, involving eight prospective phase II, two prospective phase III, and two retrospective, observational trials, is the largest survival analysis of ipilimumab to date and provides the most precise estimate yet of its survival benefit.

Patrice Wendling/IMNG Medical Media

The analysis (LBA24) also confirms the observation that the survival benefit of ipilimumab plateaus around 3 years and that patients who are alive at this point maintain a long-term survival benefit, Dr. Hodi said. No deaths have been reported after 7 years, with some patients surviving for up to 10 years.

"A few years ago, we would never imagine using the ‘C’ word, cure, and to see some patients living long term," he said at a press briefing. "Our goal as clinical investigators is to find something that cures patients of their disease, but at least what we’re showing here is that we’re having a great paradigm shift of maybe curing a subset of patients; it’s hard to use that term, but at least turning their disease into a chronic illness, which is a huge paradigm shift from where we were just a few years ago."

The survival benefit was not affected by prior therapy, ipilimumab dose (3 mg vs. 10 mg), or inclusion of the expanded access program (EAP) data, Dr. Hodi said.

Prof. Martin Gore, medical director of the Royal Marsden Hospital and professor of cancer medicine at the Institute of Cancer Research, both in London, who was invited to discuss the study, disagreed with this conclusion. He highlighted a 6% difference in 3-year overall survival between treatment-naïve and previously treated patients (20% vs. 26%) and a 3% difference in 3-year overall survival between those receiving the licensed 3-mg/kg and 10-mg/kg doses (21% vs. 24%). While these differences probably don’t make a difference in the clinic, they could be relevant with large numbers of patients in clinical trials, he said.

The EAP data would have been better utilized as a validation set to evaluate "real world" toxicity with ipilimumab, rather than being included in the pooled analysis, he said.

Prefacing further remarks with the comment, "I have not treated a patient with IL-2 [interleukin-2] for 15 years, so I’m not an apologist for it," Prof. Gore also pointed out that the 9.5-month median survival in the pooled analysis is "within the bounds" of what IL-2 provided 20 years ago when it posted a median survival of 10.5 months and 3-year survival of 15% in 631 patients with stage IV melanoma (J. Clin. Oncol. 1998;16:2921-9).

Still, Prof. Gore said clinicians should advise their patients that ipilimumab produces a 10% improvement in survival over conventional therapy and to say "that if you reach 3 years, you may well be home and dry ...

"I think there’s a potential cure for some patients, I think we can say that," he added. "But it’s not a competition with targeted agents. That’s really, really important. This is an adjunctive treatment in the same way as targeted agents are an adjunctive treatment for those with BRAF mutations. We have to learn to put these together."

The big question going forward is who may be unsuitable for ipilimumab and whether the "old rules for immunotherapy" apply, such as poor performance status, high disease volume, and rapidly progressive disease, Prof. Gore concluded.

It’s currently not possible to predict which patients will respond to ipilimumab, but this issue is an area of very active investigation, along with how to combine or sequence immunotherapy and targeted agents, Dr. Hodi said.

Prof. Alexander Eggermont, past president of the European Cancer Organization and director of the Institut Gustave Roussy Comprehensive Cancer Center in Villejuif, France, said in a statement that the pooled analysis demonstrates that with a response rate of only 10%-15%, one can achieve survival of more than 3-10 years in 17%-25% of patients who have received only a few doses of ipilimumab.

"These survival results could even double or triple with anti-PD1/PDL1 [programmed death 1 protein and its ligand] monoclonal antibodies; and metastatic melanoma could become a curable disease for perhaps more than 50% of patients over the coming 5 to 10 years," he commented.

Dr. Hodi reported having no financial disclosures and no outside funding for the pooled analysis. The National Cancer Institute conducted three of the phase II studies, and Bristol-Myers Squibb conducted the remaining studies. Prof. Gore reported serving on the speakers bureaus for Pfizer, Roche, Novartis, and Bristol-Myers Squibb, and on the advisory boards for Pfizer, Roche, and Astellas.

pwendling@frontlinemedcom.com

AMSTERDAM – Immunotherapy with ipilimumab provides a durable, long-term survival benefit in patients with metastatic or locally advanced melanoma, a pooled analysis confirms.

Median overall survival was 11.4 months and 3-year survival 22% among 1,861 patients receiving ipilimumab (Yervoy) in a mixture of 12 clinical trials.

When data from 2,985 additional patients in the expanded access program were included, median overall survival was 9.5 months and 3-year survival 21%, Dr. F. Stephen Hodi Jr., director of the Melanoma Center at the Dana-Farber Cancer Institute, Boston, said at the European Cancer Congress 2013.

The pooled analysis, involving eight prospective phase II, two prospective phase III, and two retrospective, observational trials, is the largest survival analysis of ipilimumab to date and provides the most precise estimate yet of its survival benefit.

Patrice Wendling/IMNG Medical Media

The analysis (LBA24) also confirms the observation that the survival benefit of ipilimumab plateaus around 3 years and that patients who are alive at this point maintain a long-term survival benefit, Dr. Hodi said. No deaths have been reported after 7 years, with some patients surviving for up to 10 years.

"A few years ago, we would never imagine using the ‘C’ word, cure, and to see some patients living long term," he said at a press briefing. "Our goal as clinical investigators is to find something that cures patients of their disease, but at least what we’re showing here is that we’re having a great paradigm shift of maybe curing a subset of patients; it’s hard to use that term, but at least turning their disease into a chronic illness, which is a huge paradigm shift from where we were just a few years ago."

The survival benefit was not affected by prior therapy, ipilimumab dose (3 mg vs. 10 mg), or inclusion of the expanded access program (EAP) data, Dr. Hodi said.

Prof. Martin Gore, medical director of the Royal Marsden Hospital and professor of cancer medicine at the Institute of Cancer Research, both in London, who was invited to discuss the study, disagreed with this conclusion. He highlighted a 6% difference in 3-year overall survival between treatment-naïve and previously treated patients (20% vs. 26%) and a 3% difference in 3-year overall survival between those receiving the licensed 3-mg/kg and 10-mg/kg doses (21% vs. 24%). While these differences probably don’t make a difference in the clinic, they could be relevant with large numbers of patients in clinical trials, he said.

The EAP data would have been better utilized as a validation set to evaluate "real world" toxicity with ipilimumab, rather than being included in the pooled analysis, he said.

Prefacing further remarks with the comment, "I have not treated a patient with IL-2 [interleukin-2] for 15 years, so I’m not an apologist for it," Prof. Gore also pointed out that the 9.5-month median survival in the pooled analysis is "within the bounds" of what IL-2 provided 20 years ago when it posted a median survival of 10.5 months and 3-year survival of 15% in 631 patients with stage IV melanoma (J. Clin. Oncol. 1998;16:2921-9).

Still, Prof. Gore said clinicians should advise their patients that ipilimumab produces a 10% improvement in survival over conventional therapy and to say "that if you reach 3 years, you may well be home and dry ...

"I think there’s a potential cure for some patients, I think we can say that," he added. "But it’s not a competition with targeted agents. That’s really, really important. This is an adjunctive treatment in the same way as targeted agents are an adjunctive treatment for those with BRAF mutations. We have to learn to put these together."

The big question going forward is who may be unsuitable for ipilimumab and whether the "old rules for immunotherapy" apply, such as poor performance status, high disease volume, and rapidly progressive disease, Prof. Gore concluded.

It’s currently not possible to predict which patients will respond to ipilimumab, but this issue is an area of very active investigation, along with how to combine or sequence immunotherapy and targeted agents, Dr. Hodi said.

Prof. Alexander Eggermont, past president of the European Cancer Organization and director of the Institut Gustave Roussy Comprehensive Cancer Center in Villejuif, France, said in a statement that the pooled analysis demonstrates that with a response rate of only 10%-15%, one can achieve survival of more than 3-10 years in 17%-25% of patients who have received only a few doses of ipilimumab.

"These survival results could even double or triple with anti-PD1/PDL1 [programmed death 1 protein and its ligand] monoclonal antibodies; and metastatic melanoma could become a curable disease for perhaps more than 50% of patients over the coming 5 to 10 years," he commented.

Dr. Hodi reported having no financial disclosures and no outside funding for the pooled analysis. The National Cancer Institute conducted three of the phase II studies, and Bristol-Myers Squibb conducted the remaining studies. Prof. Gore reported serving on the speakers bureaus for Pfizer, Roche, Novartis, and Bristol-Myers Squibb, and on the advisory boards for Pfizer, Roche, and Astellas.

pwendling@frontlinemedcom.com

AMSTERDAM – Immunotherapy with ipilimumab provides a durable, long-term survival benefit in patients with metastatic or locally advanced melanoma, a pooled analysis confirms.

Median overall survival was 11.4 months and 3-year survival 22% among 1,861 patients receiving ipilimumab (Yervoy) in a mixture of 12 clinical trials.

When data from 2,985 additional patients in the expanded access program were included, median overall survival was 9.5 months and 3-year survival 21%, Dr. F. Stephen Hodi Jr., director of the Melanoma Center at the Dana-Farber Cancer Institute, Boston, said at the European Cancer Congress 2013.

The pooled analysis, involving eight prospective phase II, two prospective phase III, and two retrospective, observational trials, is the largest survival analysis of ipilimumab to date and provides the most precise estimate yet of its survival benefit.

Patrice Wendling/IMNG Medical Media

The analysis (LBA24) also confirms the observation that the survival benefit of ipilimumab plateaus around 3 years and that patients who are alive at this point maintain a long-term survival benefit, Dr. Hodi said. No deaths have been reported after 7 years, with some patients surviving for up to 10 years.

"A few years ago, we would never imagine using the ‘C’ word, cure, and to see some patients living long term," he said at a press briefing. "Our goal as clinical investigators is to find something that cures patients of their disease, but at least what we’re showing here is that we’re having a great paradigm shift of maybe curing a subset of patients; it’s hard to use that term, but at least turning their disease into a chronic illness, which is a huge paradigm shift from where we were just a few years ago."

The survival benefit was not affected by prior therapy, ipilimumab dose (3 mg vs. 10 mg), or inclusion of the expanded access program (EAP) data, Dr. Hodi said.

Prof. Martin Gore, medical director of the Royal Marsden Hospital and professor of cancer medicine at the Institute of Cancer Research, both in London, who was invited to discuss the study, disagreed with this conclusion. He highlighted a 6% difference in 3-year overall survival between treatment-naïve and previously treated patients (20% vs. 26%) and a 3% difference in 3-year overall survival between those receiving the licensed 3-mg/kg and 10-mg/kg doses (21% vs. 24%). While these differences probably don’t make a difference in the clinic, they could be relevant with large numbers of patients in clinical trials, he said.

The EAP data would have been better utilized as a validation set to evaluate "real world" toxicity with ipilimumab, rather than being included in the pooled analysis, he said.

Prefacing further remarks with the comment, "I have not treated a patient with IL-2 [interleukin-2] for 15 years, so I’m not an apologist for it," Prof. Gore also pointed out that the 9.5-month median survival in the pooled analysis is "within the bounds" of what IL-2 provided 20 years ago when it posted a median survival of 10.5 months and 3-year survival of 15% in 631 patients with stage IV melanoma (J. Clin. Oncol. 1998;16:2921-9).

Still, Prof. Gore said clinicians should advise their patients that ipilimumab produces a 10% improvement in survival over conventional therapy and to say "that if you reach 3 years, you may well be home and dry ...

"I think there’s a potential cure for some patients, I think we can say that," he added. "But it’s not a competition with targeted agents. That’s really, really important. This is an adjunctive treatment in the same way as targeted agents are an adjunctive treatment for those with BRAF mutations. We have to learn to put these together."

The big question going forward is who may be unsuitable for ipilimumab and whether the "old rules for immunotherapy" apply, such as poor performance status, high disease volume, and rapidly progressive disease, Prof. Gore concluded.

It’s currently not possible to predict which patients will respond to ipilimumab, but this issue is an area of very active investigation, along with how to combine or sequence immunotherapy and targeted agents, Dr. Hodi said.

Prof. Alexander Eggermont, past president of the European Cancer Organization and director of the Institut Gustave Roussy Comprehensive Cancer Center in Villejuif, France, said in a statement that the pooled analysis demonstrates that with a response rate of only 10%-15%, one can achieve survival of more than 3-10 years in 17%-25% of patients who have received only a few doses of ipilimumab.

"These survival results could even double or triple with anti-PD1/PDL1 [programmed death 1 protein and its ligand] monoclonal antibodies; and metastatic melanoma could become a curable disease for perhaps more than 50% of patients over the coming 5 to 10 years," he commented.

Dr. Hodi reported having no financial disclosures and no outside funding for the pooled analysis. The National Cancer Institute conducted three of the phase II studies, and Bristol-Myers Squibb conducted the remaining studies. Prof. Gore reported serving on the speakers bureaus for Pfizer, Roche, Novartis, and Bristol-Myers Squibb, and on the advisory boards for Pfizer, Roche, and Astellas.

pwendling@frontlinemedcom.com

AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.

For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).

In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.

Patrice Wendling/IMNG Medical Media

In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.

"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."

TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.

Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.

EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).

Patrice Wendling/IMNG Medical Media

For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.

The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.

"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.

Dr. Sclafani reported having no relevant financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.

For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).

In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.

Patrice Wendling/IMNG Medical Media

In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.

"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."

TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.

Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.

EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).

Patrice Wendling/IMNG Medical Media

For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.

The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.

"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.

Dr. Sclafani reported having no relevant financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.

For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).

In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.

Patrice Wendling/IMNG Medical Media

In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.

"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."

TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.

Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.

EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).

Patrice Wendling/IMNG Medical Media

For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.

The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.

"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.

Dr. Sclafani reported having no relevant financial disclosures.

pwendling@frontlinemedcom.com

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

AMSTERDAM – A subset of patients with inoperable, locally advanced, or metastatic, nonsquamous non–small cell lung cancer, and high MET expression appear to benefit from a combination of tivantinib and erlotinib, according to research presented at the multidisciplinary European cancer congresses.

"Tivantinib did improve overall survival in the subgroup of tumors with high MET expression suggesting the potential for efficacy in a biomarker-selected population," said Dr. Giorgio Scagliotti of the University of Turin, San Luigi Hospital, Italy, who presented the findings.

Another trial would be needed to confirm the finding, which was the result of an exploratory analysis. The overall findings were negative in the interim results of the phase III MARQUEE (MET Inhibitor ARQ 197 plus Erlotinib vs. Erlotinib plus Placebo in NSCLC) trial. Those results were first revealed in October 2012 and prompted the study’s sponsors, ArQule and Daiichi Sankyo, to halt the trial after its independent data monitoring committee noted that the primary endpoint would not be met with further follow-up.

Sara Freeman/IMNG Medical Media

Overall survival according to MET expression could be determined in 445 patients in the trial, with 211 (47%) exhibiting high expression and 234 (53%) exhibiting low expression. In the subgroup with high expression of MET, median overall survival was 9.3 months with tivantinib plus erlotinib (n = 104) and 5.9 months with placebo plus erlotinib (n = 107). The hazard ratio (HR) of 0.70 (P = .03) for this difference was clearly in favor of the combination treatment. Progression-free survival in this subgroup of patients was 3.6 months and 1.6 months (HR, 0.7; P = .014), respectively, with overall response rate (ORR) of 10.6% vs. 6.5%.

In the MET low expression subgroup, overall survival was not significantly different comparing the combination approach (n = 107) with erlotinib alone (n = 127), at a median of 8.5 months vs. 7.7 months (HR, 0.90; P = .53). Progression-free survival (3.7 vs. 1.9 months; HR, 0.66; P = .006) and ORR (11.2% vs. 5.2%) were improved, however.

Based on data from the entire MARQUEE study group, the dual treatment was associated with a nonsignificant difference in median overall survival of 8.5 months vs. 7.8 months vs. erlotinib alone (HR, 0.98; P = .81).

Progression-free survival was improved, however, at a median of 3.6 vs. 1.9 months (HR, 0.7; P less than .001), respectively. There was also a higher ORR in patients given the dual therapy (10.3% vs. 6.5%; P less than .05).

The rationale for using tivantinib in combination with erlotinib is that the addition of the MET inhibitor might help to overcome the known resistance to drugs that target the epidermal growth factor receptor (EGFR). Dr. Scagliotti noted that in a prior phase II study (J. Clin. Oncol. 2011;29:3307-15), both progression-free and overall survivals were improved by the dual therapy vs. erlotinib alone in patients with nonsquamous histology, a population enriched for MET overexpression.

A total of 1,048 patients with inoperable, locally advanced or metastatic nonsquamous non–small cell lung cancer were recruited. Patients had been previously treated with one or two lines of systemic therapy, including a platinum doublet, but had not received any prior EGFR-targeting treatment. After stratification by the number of prior therapies, sex, smoking history, as well as EGFR and KRAS mutation status, patients were randomized to treatment with tivantinib at a dose of 360 mg twice daily or matching placebo in addition to erlotinib at a dose of 150 mg once daily. Patients were treated until disease progression (Clin. Lung Cancer 2012;13:391-5).

The most common grade 3 or higher side effect seen with the combination treatment arm was neutropenia, affecting 10% of patients (n = 520). The rate of neutropenia in the patients who received placebo plus erlotinib was 1% (n = 517). Other notable side effects that were higher in the combination vs. control arm were fatigue, occurring in 9% and 7.9% of patients, respectively; and anemia (6.5% vs. 2.9%). Conversely there were lower rates of rash (1.9% vs. 3.9%), nausea (0.8% vs. 1.7%), and diarrhea (2.5% vs. 3.7%).

AMSTERDAM – A subset of patients with inoperable, locally advanced, or metastatic, nonsquamous non–small cell lung cancer, and high MET expression appear to benefit from a combination of tivantinib and erlotinib, according to research presented at the multidisciplinary European cancer congresses.

"Tivantinib did improve overall survival in the subgroup of tumors with high MET expression suggesting the potential for efficacy in a biomarker-selected population," said Dr. Giorgio Scagliotti of the University of Turin, San Luigi Hospital, Italy, who presented the findings.

Another trial would be needed to confirm the finding, which was the result of an exploratory analysis. The overall findings were negative in the interim results of the phase III MARQUEE (MET Inhibitor ARQ 197 plus Erlotinib vs. Erlotinib plus Placebo in NSCLC) trial. Those results were first revealed in October 2012 and prompted the study’s sponsors, ArQule and Daiichi Sankyo, to halt the trial after its independent data monitoring committee noted that the primary endpoint would not be met with further follow-up.

Sara Freeman/IMNG Medical Media

Overall survival according to MET expression could be determined in 445 patients in the trial, with 211 (47%) exhibiting high expression and 234 (53%) exhibiting low expression. In the subgroup with high expression of MET, median overall survival was 9.3 months with tivantinib plus erlotinib (n = 104) and 5.9 months with placebo plus erlotinib (n = 107). The hazard ratio (HR) of 0.70 (P = .03) for this difference was clearly in favor of the combination treatment. Progression-free survival in this subgroup of patients was 3.6 months and 1.6 months (HR, 0.7; P = .014), respectively, with overall response rate (ORR) of 10.6% vs. 6.5%.

In the MET low expression subgroup, overall survival was not significantly different comparing the combination approach (n = 107) with erlotinib alone (n = 127), at a median of 8.5 months vs. 7.7 months (HR, 0.90; P = .53). Progression-free survival (3.7 vs. 1.9 months; HR, 0.66; P = .006) and ORR (11.2% vs. 5.2%) were improved, however.

Based on data from the entire MARQUEE study group, the dual treatment was associated with a nonsignificant difference in median overall survival of 8.5 months vs. 7.8 months vs. erlotinib alone (HR, 0.98; P = .81).

Progression-free survival was improved, however, at a median of 3.6 vs. 1.9 months (HR, 0.7; P less than .001), respectively. There was also a higher ORR in patients given the dual therapy (10.3% vs. 6.5%; P less than .05).

The rationale for using tivantinib in combination with erlotinib is that the addition of the MET inhibitor might help to overcome the known resistance to drugs that target the epidermal growth factor receptor (EGFR). Dr. Scagliotti noted that in a prior phase II study (J. Clin. Oncol. 2011;29:3307-15), both progression-free and overall survivals were improved by the dual therapy vs. erlotinib alone in patients with nonsquamous histology, a population enriched for MET overexpression.

A total of 1,048 patients with inoperable, locally advanced or metastatic nonsquamous non–small cell lung cancer were recruited. Patients had been previously treated with one or two lines of systemic therapy, including a platinum doublet, but had not received any prior EGFR-targeting treatment. After stratification by the number of prior therapies, sex, smoking history, as well as EGFR and KRAS mutation status, patients were randomized to treatment with tivantinib at a dose of 360 mg twice daily or matching placebo in addition to erlotinib at a dose of 150 mg once daily. Patients were treated until disease progression (Clin. Lung Cancer 2012;13:391-5).

The most common grade 3 or higher side effect seen with the combination treatment arm was neutropenia, affecting 10% of patients (n = 520). The rate of neutropenia in the patients who received placebo plus erlotinib was 1% (n = 517). Other notable side effects that were higher in the combination vs. control arm were fatigue, occurring in 9% and 7.9% of patients, respectively; and anemia (6.5% vs. 2.9%). Conversely there were lower rates of rash (1.9% vs. 3.9%), nausea (0.8% vs. 1.7%), and diarrhea (2.5% vs. 3.7%).

AMSTERDAM – A subset of patients with inoperable, locally advanced, or metastatic, nonsquamous non–small cell lung cancer, and high MET expression appear to benefit from a combination of tivantinib and erlotinib, according to research presented at the multidisciplinary European cancer congresses.

"Tivantinib did improve overall survival in the subgroup of tumors with high MET expression suggesting the potential for efficacy in a biomarker-selected population," said Dr. Giorgio Scagliotti of the University of Turin, San Luigi Hospital, Italy, who presented the findings.

Another trial would be needed to confirm the finding, which was the result of an exploratory analysis. The overall findings were negative in the interim results of the phase III MARQUEE (MET Inhibitor ARQ 197 plus Erlotinib vs. Erlotinib plus Placebo in NSCLC) trial. Those results were first revealed in October 2012 and prompted the study’s sponsors, ArQule and Daiichi Sankyo, to halt the trial after its independent data monitoring committee noted that the primary endpoint would not be met with further follow-up.

Sara Freeman/IMNG Medical Media

Overall survival according to MET expression could be determined in 445 patients in the trial, with 211 (47%) exhibiting high expression and 234 (53%) exhibiting low expression. In the subgroup with high expression of MET, median overall survival was 9.3 months with tivantinib plus erlotinib (n = 104) and 5.9 months with placebo plus erlotinib (n = 107). The hazard ratio (HR) of 0.70 (P = .03) for this difference was clearly in favor of the combination treatment. Progression-free survival in this subgroup of patients was 3.6 months and 1.6 months (HR, 0.7; P = .014), respectively, with overall response rate (ORR) of 10.6% vs. 6.5%.

In the MET low expression subgroup, overall survival was not significantly different comparing the combination approach (n = 107) with erlotinib alone (n = 127), at a median of 8.5 months vs. 7.7 months (HR, 0.90; P = .53). Progression-free survival (3.7 vs. 1.9 months; HR, 0.66; P = .006) and ORR (11.2% vs. 5.2%) were improved, however.

Based on data from the entire MARQUEE study group, the dual treatment was associated with a nonsignificant difference in median overall survival of 8.5 months vs. 7.8 months vs. erlotinib alone (HR, 0.98; P = .81).

Progression-free survival was improved, however, at a median of 3.6 vs. 1.9 months (HR, 0.7; P less than .001), respectively. There was also a higher ORR in patients given the dual therapy (10.3% vs. 6.5%; P less than .05).

The rationale for using tivantinib in combination with erlotinib is that the addition of the MET inhibitor might help to overcome the known resistance to drugs that target the epidermal growth factor receptor (EGFR). Dr. Scagliotti noted that in a prior phase II study (J. Clin. Oncol. 2011;29:3307-15), both progression-free and overall survivals were improved by the dual therapy vs. erlotinib alone in patients with nonsquamous histology, a population enriched for MET overexpression.

A total of 1,048 patients with inoperable, locally advanced or metastatic nonsquamous non–small cell lung cancer were recruited. Patients had been previously treated with one or two lines of systemic therapy, including a platinum doublet, but had not received any prior EGFR-targeting treatment. After stratification by the number of prior therapies, sex, smoking history, as well as EGFR and KRAS mutation status, patients were randomized to treatment with tivantinib at a dose of 360 mg twice daily or matching placebo in addition to erlotinib at a dose of 150 mg once daily. Patients were treated until disease progression (Clin. Lung Cancer 2012;13:391-5).

The most common grade 3 or higher side effect seen with the combination treatment arm was neutropenia, affecting 10% of patients (n = 520). The rate of neutropenia in the patients who received placebo plus erlotinib was 1% (n = 517). Other notable side effects that were higher in the combination vs. control arm were fatigue, occurring in 9% and 7.9% of patients, respectively; and anemia (6.5% vs. 2.9%). Conversely there were lower rates of rash (1.9% vs. 3.9%), nausea (0.8% vs. 1.7%), and diarrhea (2.5% vs. 3.7%).