Sharon Worcester

LAKE BUENA VISTA, FLA. – Endovascular treatment for critical limb ischemia offered no significant cost savings over open repair in a recent analysis of outcomes in 137 patients.

Of the 148 patients included in the retrospective review, 42% were treated with an endovascular procedure, 47% with an open procedure, and the remaining with a hybrid of the two. The mean costs were $49,802 for an endovascular hospitalization and $45,832 for an open repair hospitalization; these amounts were not significantly different, Dr. Nicholas Gargiulo III reported at the annual meeting of the Society for Clinical Vascular Surgery.

The mean lengths of stay were also similar, at 9.3 days and 10.4 days in the endovascular and open repair groups, respectively, said Dr. Gargiulo of Montefiore Medical Center, New York.

The percentage of patients discharged to a skilled nursing facility was 35% vs. 44% of endovascular and open repair patients, respectively. Although endovascular repair was associated with slightly increased likelihood of recovering enough function to be released to home upon hospital discharge, this difference also did not reach statistical significance.

Rates of readmission within 90 days were similar at 12% and 13% for the endovascular repair and open repair patients, respectively.

For hybrid repair patients, the hospitalization costs ($27,922) and length of stay (9.8 days) were lower, compared with the other groups. However, the readmission rate was much higher, at 50%, and the percentage discharged to home initially was lower at 28%.

The study included all of those patients who presented with critical limb ischemia at Montefiore Medical Center from Jan. 1, 2007, through December 2007, for whom complete data were available. The patients, who had a mean age of 67 years and Rutherford Class 4 or 5 disease, underwent initial diagnostic evaluation with conventional arteriography, and the treatment approach was based on the anatomic TransAtlantic InterSociety Consensus II classification and adequate runoff.

A variety of endovascular interventions and open procedures were used. The perioperative mortality rate was 2.7%, and amputation-free survival was 94.6% at 1 year.

Most of the patients had hypertension and diabetes; a large variety of other comorbidities were seen as well.

About two-thirds of the cohort presented with rest pain, and the remainder presented with gangrene or ulceration. The hospitalization costs were higher in those who presented with gangrene and ulceration, Dr. Gargiulo said. Over the past year, more patients have been presenting with gangrene than with rest pain, and this is a concern, he added.

"Interestingly, the only thing that was different is that those with rest pain cost less than the patients with gangrene and ulceration ... gangrene and ulceration increase the length of stay, increase readmission, and of course increase supplies and nursing services, resulting in an overall increase in mean cost," Dr. Gargiulo said.

Possible cost-cutting measures include educational programs, new alliances with podiatry colleagues, prevention, and new trials, he added.

"In conclusion, endovascular and open procedures were equally cost effective in this diverse ethnic population of patients with critical limb ischemia, and patients with gangrene and ulceration have increased health care costs. It appears it’s not the type of procedure which incurs cost, but the clinical presentation," he said.

Dr. Gargiulo had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular treatment for critical limb ischemia offered no significant cost savings over open repair in a recent analysis of outcomes in 137 patients.

Of the 148 patients included in the retrospective review, 42% were treated with an endovascular procedure, 47% with an open procedure, and the remaining with a hybrid of the two. The mean costs were $49,802 for an endovascular hospitalization and $45,832 for an open repair hospitalization; these amounts were not significantly different, Dr. Nicholas Gargiulo III reported at the annual meeting of the Society for Clinical Vascular Surgery.

The mean lengths of stay were also similar, at 9.3 days and 10.4 days in the endovascular and open repair groups, respectively, said Dr. Gargiulo of Montefiore Medical Center, New York.

The percentage of patients discharged to a skilled nursing facility was 35% vs. 44% of endovascular and open repair patients, respectively. Although endovascular repair was associated with slightly increased likelihood of recovering enough function to be released to home upon hospital discharge, this difference also did not reach statistical significance.

Rates of readmission within 90 days were similar at 12% and 13% for the endovascular repair and open repair patients, respectively.

For hybrid repair patients, the hospitalization costs ($27,922) and length of stay (9.8 days) were lower, compared with the other groups. However, the readmission rate was much higher, at 50%, and the percentage discharged to home initially was lower at 28%.

The study included all of those patients who presented with critical limb ischemia at Montefiore Medical Center from Jan. 1, 2007, through December 2007, for whom complete data were available. The patients, who had a mean age of 67 years and Rutherford Class 4 or 5 disease, underwent initial diagnostic evaluation with conventional arteriography, and the treatment approach was based on the anatomic TransAtlantic InterSociety Consensus II classification and adequate runoff.

A variety of endovascular interventions and open procedures were used. The perioperative mortality rate was 2.7%, and amputation-free survival was 94.6% at 1 year.

Most of the patients had hypertension and diabetes; a large variety of other comorbidities were seen as well.

About two-thirds of the cohort presented with rest pain, and the remainder presented with gangrene or ulceration. The hospitalization costs were higher in those who presented with gangrene and ulceration, Dr. Gargiulo said. Over the past year, more patients have been presenting with gangrene than with rest pain, and this is a concern, he added.

"Interestingly, the only thing that was different is that those with rest pain cost less than the patients with gangrene and ulceration ... gangrene and ulceration increase the length of stay, increase readmission, and of course increase supplies and nursing services, resulting in an overall increase in mean cost," Dr. Gargiulo said.

Possible cost-cutting measures include educational programs, new alliances with podiatry colleagues, prevention, and new trials, he added.

"In conclusion, endovascular and open procedures were equally cost effective in this diverse ethnic population of patients with critical limb ischemia, and patients with gangrene and ulceration have increased health care costs. It appears it’s not the type of procedure which incurs cost, but the clinical presentation," he said.

Dr. Gargiulo had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular treatment for critical limb ischemia offered no significant cost savings over open repair in a recent analysis of outcomes in 137 patients.

Of the 148 patients included in the retrospective review, 42% were treated with an endovascular procedure, 47% with an open procedure, and the remaining with a hybrid of the two. The mean costs were $49,802 for an endovascular hospitalization and $45,832 for an open repair hospitalization; these amounts were not significantly different, Dr. Nicholas Gargiulo III reported at the annual meeting of the Society for Clinical Vascular Surgery.

The mean lengths of stay were also similar, at 9.3 days and 10.4 days in the endovascular and open repair groups, respectively, said Dr. Gargiulo of Montefiore Medical Center, New York.

The percentage of patients discharged to a skilled nursing facility was 35% vs. 44% of endovascular and open repair patients, respectively. Although endovascular repair was associated with slightly increased likelihood of recovering enough function to be released to home upon hospital discharge, this difference also did not reach statistical significance.

Rates of readmission within 90 days were similar at 12% and 13% for the endovascular repair and open repair patients, respectively.

For hybrid repair patients, the hospitalization costs ($27,922) and length of stay (9.8 days) were lower, compared with the other groups. However, the readmission rate was much higher, at 50%, and the percentage discharged to home initially was lower at 28%.

The study included all of those patients who presented with critical limb ischemia at Montefiore Medical Center from Jan. 1, 2007, through December 2007, for whom complete data were available. The patients, who had a mean age of 67 years and Rutherford Class 4 or 5 disease, underwent initial diagnostic evaluation with conventional arteriography, and the treatment approach was based on the anatomic TransAtlantic InterSociety Consensus II classification and adequate runoff.

A variety of endovascular interventions and open procedures were used. The perioperative mortality rate was 2.7%, and amputation-free survival was 94.6% at 1 year.

Most of the patients had hypertension and diabetes; a large variety of other comorbidities were seen as well.

About two-thirds of the cohort presented with rest pain, and the remainder presented with gangrene or ulceration. The hospitalization costs were higher in those who presented with gangrene and ulceration, Dr. Gargiulo said. Over the past year, more patients have been presenting with gangrene than with rest pain, and this is a concern, he added.

"Interestingly, the only thing that was different is that those with rest pain cost less than the patients with gangrene and ulceration ... gangrene and ulceration increase the length of stay, increase readmission, and of course increase supplies and nursing services, resulting in an overall increase in mean cost," Dr. Gargiulo said.

Possible cost-cutting measures include educational programs, new alliances with podiatry colleagues, prevention, and new trials, he added.

"In conclusion, endovascular and open procedures were equally cost effective in this diverse ethnic population of patients with critical limb ischemia, and patients with gangrene and ulceration have increased health care costs. It appears it’s not the type of procedure which incurs cost, but the clinical presentation," he said.

Dr. Gargiulo had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular aortic aneurysm repair was associated with improved early all-cause and early abdominal aortic aneurysm–related mortality, compared with open aortic aneurysm repair in a pooled analysis of data from three large randomized trials.

However, EVAR was also associated with a significant increase in late AAA–related mortality.

The overall mortality rate was similar at 28.1% in 1,243 EVAR patients, and 29.6% in 1,241 open repair patients included in the meta-analysis, as was the overall AAA-related mortality (3.5% vs. 4.9%; odds ratio 0.73), Dr. Caron B. Rockman reported at the annual meeting of the Society for Clinical Vascular Surgery.

However, EVAR was associated with about a 70% reduction in both early all-cause mortality (OR 0.27) and early AAA-related mortality (OR 0.36), said Dr. Rockman of New York University Medical Center.

No significant differences were seen between the groups in regard to late all-cause mortality (OR 0.93), but the findings regarding late AAA-related mortality favored open repair; mortality was 2.2% in the EVAR patients, compared with 0.9% in the open repair patients (OR 2.25).

The trials included in the meta-analysis were the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, the Standard Open Surgery vs. Open Endovascular Repair of AAA (OVER) trial, and the EVAR-1 trial. All three compared various outcomes with EVAR and open repair.

Prior to these trials, EVAR was generally considered the preferred approach for treating AAAs because of its less invasive nature, improved perioperative outcomes (including morbidity, mortality, transfusion requirements, and hospital length of stay), and improved recovery time, but long-term durability remained a matter of controversy, Dr. Rockman explained.

Although the findings of these trials did provide important additional data for the clinician, they also served to continue the debate regarding late outcomes of EVAR, particularly with regard to the issue of higher incidence of late AAA-related mortality, she said.

This meta-analysis of the trials shows that EVAR is clearly better with regard to early all-cause and aneurysm-related mortality, and that the two strategies appear to be equal with regard to late and overall all-cause mortality, cardiovascular mortality, and overall aneurysm-related mortality, while open repair is better in regard to graft-related complications, the need for secondary interventions, and late aneurysm-related mortality, she said.

Two of the trials specifically looked at graft-related complications, and both showed significant benefit with open repair. The pooled data also showed a significant benefit with open repair (OR 6.1), she explained.

In terms of secondary interventions, each of the three trials showed an increase in the EVAR patients, which reached statistical significance in two of the three. In the pooled analysis, EVAR was associated with a twofold increase in the risk of a secondary procedure, Dr. Rockman noted.

As for late mortality, however, she said: "I think we have to remember that the goal of EVAR is to prevent aneurysm rupture–related death – not to provide immortality; late mortality will always equalize in the end," she said.

That is, the longer the follow-up, the more one would expect all-cause mortality to equalize.

"In EVAR-1, when you look at aneurysm mortality, it was essentially equal in both groups, in fairness," she said.

The findings raise some questions, however, and underscore the inherent limitations of any meta-analysis.

For example, the trials used varying definitions of early and late complications, device failures, and secondary interventions, and it is unclear whether the trials represent contemporary devices and practices. They began enrolling patients as early 1999, and it is arguable that things have changed since then, she noted.

Also, there are questions about when secondary interventions are required.

"It’s very easy to say that EVAR has more secondary interventions, but a lot of these interventions, for example, are being done for type 2 endoleaks, and some of us might believe that these interventions are not, in fact, necessary," she said.

"And finally, with regard to secondary interventions, is a hernia repair equivalent to an intervention for a type 1 endoleak? I don’t have a perfect answer for that," she added.

Thus, based on the available evidence, she concluded that "although the success of EVAR in reducing late AAA-related mortality might be suboptimal, the importance of decreased early mortality cannot be minimized, particularly from the patient’s perspective ...EVAR remains the procedure of choice in anatomically suitable aneurysm patients."

Future research should focus on improvements in design and techniques that will decrease device-related complications, reduce the need for secondary interventions, and improve long-term success with EVAR, she added.

Dr. Rockman had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular aortic aneurysm repair was associated with improved early all-cause and early abdominal aortic aneurysm–related mortality, compared with open aortic aneurysm repair in a pooled analysis of data from three large randomized trials.

However, EVAR was also associated with a significant increase in late AAA–related mortality.

The overall mortality rate was similar at 28.1% in 1,243 EVAR patients, and 29.6% in 1,241 open repair patients included in the meta-analysis, as was the overall AAA-related mortality (3.5% vs. 4.9%; odds ratio 0.73), Dr. Caron B. Rockman reported at the annual meeting of the Society for Clinical Vascular Surgery.

However, EVAR was associated with about a 70% reduction in both early all-cause mortality (OR 0.27) and early AAA-related mortality (OR 0.36), said Dr. Rockman of New York University Medical Center.

No significant differences were seen between the groups in regard to late all-cause mortality (OR 0.93), but the findings regarding late AAA-related mortality favored open repair; mortality was 2.2% in the EVAR patients, compared with 0.9% in the open repair patients (OR 2.25).

The trials included in the meta-analysis were the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, the Standard Open Surgery vs. Open Endovascular Repair of AAA (OVER) trial, and the EVAR-1 trial. All three compared various outcomes with EVAR and open repair.

Prior to these trials, EVAR was generally considered the preferred approach for treating AAAs because of its less invasive nature, improved perioperative outcomes (including morbidity, mortality, transfusion requirements, and hospital length of stay), and improved recovery time, but long-term durability remained a matter of controversy, Dr. Rockman explained.

Although the findings of these trials did provide important additional data for the clinician, they also served to continue the debate regarding late outcomes of EVAR, particularly with regard to the issue of higher incidence of late AAA-related mortality, she said.

This meta-analysis of the trials shows that EVAR is clearly better with regard to early all-cause and aneurysm-related mortality, and that the two strategies appear to be equal with regard to late and overall all-cause mortality, cardiovascular mortality, and overall aneurysm-related mortality, while open repair is better in regard to graft-related complications, the need for secondary interventions, and late aneurysm-related mortality, she said.

Two of the trials specifically looked at graft-related complications, and both showed significant benefit with open repair. The pooled data also showed a significant benefit with open repair (OR 6.1), she explained.

In terms of secondary interventions, each of the three trials showed an increase in the EVAR patients, which reached statistical significance in two of the three. In the pooled analysis, EVAR was associated with a twofold increase in the risk of a secondary procedure, Dr. Rockman noted.

As for late mortality, however, she said: "I think we have to remember that the goal of EVAR is to prevent aneurysm rupture–related death – not to provide immortality; late mortality will always equalize in the end," she said.

That is, the longer the follow-up, the more one would expect all-cause mortality to equalize.

"In EVAR-1, when you look at aneurysm mortality, it was essentially equal in both groups, in fairness," she said.

The findings raise some questions, however, and underscore the inherent limitations of any meta-analysis.

For example, the trials used varying definitions of early and late complications, device failures, and secondary interventions, and it is unclear whether the trials represent contemporary devices and practices. They began enrolling patients as early 1999, and it is arguable that things have changed since then, she noted.

Also, there are questions about when secondary interventions are required.

"It’s very easy to say that EVAR has more secondary interventions, but a lot of these interventions, for example, are being done for type 2 endoleaks, and some of us might believe that these interventions are not, in fact, necessary," she said.

"And finally, with regard to secondary interventions, is a hernia repair equivalent to an intervention for a type 1 endoleak? I don’t have a perfect answer for that," she added.

Thus, based on the available evidence, she concluded that "although the success of EVAR in reducing late AAA-related mortality might be suboptimal, the importance of decreased early mortality cannot be minimized, particularly from the patient’s perspective ...EVAR remains the procedure of choice in anatomically suitable aneurysm patients."

Future research should focus on improvements in design and techniques that will decrease device-related complications, reduce the need for secondary interventions, and improve long-term success with EVAR, she added.

Dr. Rockman had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular aortic aneurysm repair was associated with improved early all-cause and early abdominal aortic aneurysm–related mortality, compared with open aortic aneurysm repair in a pooled analysis of data from three large randomized trials.

However, EVAR was also associated with a significant increase in late AAA–related mortality.

The overall mortality rate was similar at 28.1% in 1,243 EVAR patients, and 29.6% in 1,241 open repair patients included in the meta-analysis, as was the overall AAA-related mortality (3.5% vs. 4.9%; odds ratio 0.73), Dr. Caron B. Rockman reported at the annual meeting of the Society for Clinical Vascular Surgery.

However, EVAR was associated with about a 70% reduction in both early all-cause mortality (OR 0.27) and early AAA-related mortality (OR 0.36), said Dr. Rockman of New York University Medical Center.

No significant differences were seen between the groups in regard to late all-cause mortality (OR 0.93), but the findings regarding late AAA-related mortality favored open repair; mortality was 2.2% in the EVAR patients, compared with 0.9% in the open repair patients (OR 2.25).

The trials included in the meta-analysis were the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, the Standard Open Surgery vs. Open Endovascular Repair of AAA (OVER) trial, and the EVAR-1 trial. All three compared various outcomes with EVAR and open repair.

Prior to these trials, EVAR was generally considered the preferred approach for treating AAAs because of its less invasive nature, improved perioperative outcomes (including morbidity, mortality, transfusion requirements, and hospital length of stay), and improved recovery time, but long-term durability remained a matter of controversy, Dr. Rockman explained.

Although the findings of these trials did provide important additional data for the clinician, they also served to continue the debate regarding late outcomes of EVAR, particularly with regard to the issue of higher incidence of late AAA-related mortality, she said.

This meta-analysis of the trials shows that EVAR is clearly better with regard to early all-cause and aneurysm-related mortality, and that the two strategies appear to be equal with regard to late and overall all-cause mortality, cardiovascular mortality, and overall aneurysm-related mortality, while open repair is better in regard to graft-related complications, the need for secondary interventions, and late aneurysm-related mortality, she said.

Two of the trials specifically looked at graft-related complications, and both showed significant benefit with open repair. The pooled data also showed a significant benefit with open repair (OR 6.1), she explained.

In terms of secondary interventions, each of the three trials showed an increase in the EVAR patients, which reached statistical significance in two of the three. In the pooled analysis, EVAR was associated with a twofold increase in the risk of a secondary procedure, Dr. Rockman noted.

As for late mortality, however, she said: "I think we have to remember that the goal of EVAR is to prevent aneurysm rupture–related death – not to provide immortality; late mortality will always equalize in the end," she said.

That is, the longer the follow-up, the more one would expect all-cause mortality to equalize.

"In EVAR-1, when you look at aneurysm mortality, it was essentially equal in both groups, in fairness," she said.

The findings raise some questions, however, and underscore the inherent limitations of any meta-analysis.

For example, the trials used varying definitions of early and late complications, device failures, and secondary interventions, and it is unclear whether the trials represent contemporary devices and practices. They began enrolling patients as early 1999, and it is arguable that things have changed since then, she noted.

Also, there are questions about when secondary interventions are required.

"It’s very easy to say that EVAR has more secondary interventions, but a lot of these interventions, for example, are being done for type 2 endoleaks, and some of us might believe that these interventions are not, in fact, necessary," she said.

"And finally, with regard to secondary interventions, is a hernia repair equivalent to an intervention for a type 1 endoleak? I don’t have a perfect answer for that," she added.

Thus, based on the available evidence, she concluded that "although the success of EVAR in reducing late AAA-related mortality might be suboptimal, the importance of decreased early mortality cannot be minimized, particularly from the patient’s perspective ...EVAR remains the procedure of choice in anatomically suitable aneurysm patients."

Future research should focus on improvements in design and techniques that will decrease device-related complications, reduce the need for secondary interventions, and improve long-term success with EVAR, she added.

Dr. Rockman had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular aortic aneurysm repair was associated with improved early all-cause and early abdominal aortic aneurysm–related mortality, compared with open aortic aneurysm repair in a pooled analysis of data from three large randomized trials.

However, EVAR was also associated with a significant increase in late AAA–related mortality.

The overall mortality rate was similar at 28.1% in 1,243 EVAR patients, and 29.6% in 1,241 open repair patients included in the meta-analysis, as was the overall AAA-related mortality (3.5% vs. 4.9%; odds ratio 0.73), Dr. Caron B. Rockman reported at the annual meeting of the Society for Clinical Vascular Surgery.

However, EVAR was associated with about a 70% reduction in both early all-cause mortality (OR 0.27) and early AAA-related mortality (OR 0.36), said Dr. Rockman of New York University Medical Center.

No significant differences were seen between the groups in regard to late all-cause mortality (OR 0.93), but the findings regarding late AAA-related mortality favored open repair; mortality was 2.2% in the EVAR patients, compared with 0.9% in the open repair patients (OR 2.25).

The trials included in the meta-analysis were the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, the Standard Open Surgery vs. Open Endovascular Repair of AAA (OVER) trial, and the EVAR-1 trial. All three compared various outcomes with EVAR and open repair.

Prior to these trials, EVAR was generally considered the preferred approach for treating AAAs because of its less invasive nature, improved perioperative outcomes (including morbidity, mortality, transfusion requirements, and hospital length of stay), and improved recovery time, but long-term durability remained a matter of controversy, Dr. Rockman explained.

Although the findings of these trials did provide important additional data for the clinician, they also served to continue the debate regarding late outcomes of EVAR, particularly with regard to the issue of higher incidence of late AAA-related mortality, she said.

This meta-analysis of the trials shows that EVAR is clearly better with regard to early all-cause and aneurysm-related mortality, and that the two strategies appear to be equal with regard to late and overall all-cause mortality, cardiovascular mortality, and overall aneurysm-related mortality, while open repair is better in regard to graft-related complications, the need for secondary interventions, and late aneurysm-related mortality, she said.

Two of the trials specifically looked at graft-related complications, and both showed significant benefit with open repair. The pooled data also showed a significant benefit with open repair (OR 6.1), she explained.

In terms of secondary interventions, each of the three trials showed an increase in the EVAR patients, which reached statistical significance in two of the three. In the pooled analysis, EVAR was associated with a twofold increase in the risk of a secondary procedure, Dr. Rockman noted.

As for late mortality, however, she said: "I think we have to remember that the goal of EVAR is to prevent aneurysm rupture–related death – not to provide immortality; late mortality will always equalize in the end," she said.

That is, the longer the follow-up, the more one would expect all-cause mortality to equalize.

"In EVAR-1, when you look at aneurysm mortality, it was essentially equal in both groups, in fairness," she said.

The findings raise some questions, however, and underscore the inherent limitations of any meta-analysis.

For example, the trials used varying definitions of early and late complications, device failures, and secondary interventions, and it is unclear whether the trials represent contemporary devices and practices. They began enrolling patients as early 1999, and it is arguable that things have changed since then, she noted.

Also, there are questions about when secondary interventions are required.

"It’s very easy to say that EVAR has more secondary interventions, but a lot of these interventions, for example, are being done for type 2 endoleaks, and some of us might believe that these interventions are not, in fact, necessary," she said.

"And finally, with regard to secondary interventions, is a hernia repair equivalent to an intervention for a type 1 endoleak? I don’t have a perfect answer for that," she added.

Thus, based on the available evidence, she concluded that "although the success of EVAR in reducing late AAA-related mortality might be suboptimal, the importance of decreased early mortality cannot be minimized, particularly from the patient’s perspective ...EVAR remains the procedure of choice in anatomically suitable aneurysm patients."

Future research should focus on improvements in design and techniques that will decrease device-related complications, reduce the need for secondary interventions, and improve long-term success with EVAR, she added.

Dr. Rockman had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular aortic aneurysm repair was associated with improved early all-cause and early abdominal aortic aneurysm–related mortality, compared with open aortic aneurysm repair in a pooled analysis of data from three large randomized trials.

However, EVAR was also associated with a significant increase in late AAA–related mortality.

The overall mortality rate was similar at 28.1% in 1,243 EVAR patients, and 29.6% in 1,241 open repair patients included in the meta-analysis, as was the overall AAA-related mortality (3.5% vs. 4.9%; odds ratio 0.73), Dr. Caron B. Rockman reported at the annual meeting of the Society for Clinical Vascular Surgery.

However, EVAR was associated with about a 70% reduction in both early all-cause mortality (OR 0.27) and early AAA-related mortality (OR 0.36), said Dr. Rockman of New York University Medical Center.

No significant differences were seen between the groups in regard to late all-cause mortality (OR 0.93), but the findings regarding late AAA-related mortality favored open repair; mortality was 2.2% in the EVAR patients, compared with 0.9% in the open repair patients (OR 2.25).

The trials included in the meta-analysis were the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, the Standard Open Surgery vs. Open Endovascular Repair of AAA (OVER) trial, and the EVAR-1 trial. All three compared various outcomes with EVAR and open repair.

Prior to these trials, EVAR was generally considered the preferred approach for treating AAAs because of its less invasive nature, improved perioperative outcomes (including morbidity, mortality, transfusion requirements, and hospital length of stay), and improved recovery time, but long-term durability remained a matter of controversy, Dr. Rockman explained.

Although the findings of these trials did provide important additional data for the clinician, they also served to continue the debate regarding late outcomes of EVAR, particularly with regard to the issue of higher incidence of late AAA-related mortality, she said.

This meta-analysis of the trials shows that EVAR is clearly better with regard to early all-cause and aneurysm-related mortality, and that the two strategies appear to be equal with regard to late and overall all-cause mortality, cardiovascular mortality, and overall aneurysm-related mortality, while open repair is better in regard to graft-related complications, the need for secondary interventions, and late aneurysm-related mortality, she said.

Two of the trials specifically looked at graft-related complications, and both showed significant benefit with open repair. The pooled data also showed a significant benefit with open repair (OR 6.1), she explained.

In terms of secondary interventions, each of the three trials showed an increase in the EVAR patients, which reached statistical significance in two of the three. In the pooled analysis, EVAR was associated with a twofold increase in the risk of a secondary procedure, Dr. Rockman noted.

As for late mortality, however, she said: "I think we have to remember that the goal of EVAR is to prevent aneurysm rupture–related death – not to provide immortality; late mortality will always equalize in the end," she said.

That is, the longer the follow-up, the more one would expect all-cause mortality to equalize.

"In EVAR-1, when you look at aneurysm mortality, it was essentially equal in both groups, in fairness," she said.

The findings raise some questions, however, and underscore the inherent limitations of any meta-analysis.

For example, the trials used varying definitions of early and late complications, device failures, and secondary interventions, and it is unclear whether the trials represent contemporary devices and practices. They began enrolling patients as early 1999, and it is arguable that things have changed since then, she noted.

Also, there are questions about when secondary interventions are required.

"It’s very easy to say that EVAR has more secondary interventions, but a lot of these interventions, for example, are being done for type 2 endoleaks, and some of us might believe that these interventions are not, in fact, necessary," she said.

"And finally, with regard to secondary interventions, is a hernia repair equivalent to an intervention for a type 1 endoleak? I don’t have a perfect answer for that," she added.

Thus, based on the available evidence, she concluded that "although the success of EVAR in reducing late AAA-related mortality might be suboptimal, the importance of decreased early mortality cannot be minimized, particularly from the patient’s perspective ...EVAR remains the procedure of choice in anatomically suitable aneurysm patients."

Future research should focus on improvements in design and techniques that will decrease device-related complications, reduce the need for secondary interventions, and improve long-term success with EVAR, she added.

Dr. Rockman had no disclosures.

LAKE BUENA VISTA, FLA. – Endovascular aortic aneurysm repair was associated with improved early all-cause and early abdominal aortic aneurysm–related mortality, compared with open aortic aneurysm repair in a pooled analysis of data from three large randomized trials.

However, EVAR was also associated with a significant increase in late AAA–related mortality.

The overall mortality rate was similar at 28.1% in 1,243 EVAR patients, and 29.6% in 1,241 open repair patients included in the meta-analysis, as was the overall AAA-related mortality (3.5% vs. 4.9%; odds ratio 0.73), Dr. Caron B. Rockman reported at the annual meeting of the Society for Clinical Vascular Surgery.

However, EVAR was associated with about a 70% reduction in both early all-cause mortality (OR 0.27) and early AAA-related mortality (OR 0.36), said Dr. Rockman of New York University Medical Center.

No significant differences were seen between the groups in regard to late all-cause mortality (OR 0.93), but the findings regarding late AAA-related mortality favored open repair; mortality was 2.2% in the EVAR patients, compared with 0.9% in the open repair patients (OR 2.25).

The trials included in the meta-analysis were the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, the Standard Open Surgery vs. Open Endovascular Repair of AAA (OVER) trial, and the EVAR-1 trial. All three compared various outcomes with EVAR and open repair.

Prior to these trials, EVAR was generally considered the preferred approach for treating AAAs because of its less invasive nature, improved perioperative outcomes (including morbidity, mortality, transfusion requirements, and hospital length of stay), and improved recovery time, but long-term durability remained a matter of controversy, Dr. Rockman explained.

Although the findings of these trials did provide important additional data for the clinician, they also served to continue the debate regarding late outcomes of EVAR, particularly with regard to the issue of higher incidence of late AAA-related mortality, she said.

This meta-analysis of the trials shows that EVAR is clearly better with regard to early all-cause and aneurysm-related mortality, and that the two strategies appear to be equal with regard to late and overall all-cause mortality, cardiovascular mortality, and overall aneurysm-related mortality, while open repair is better in regard to graft-related complications, the need for secondary interventions, and late aneurysm-related mortality, she said.

Two of the trials specifically looked at graft-related complications, and both showed significant benefit with open repair. The pooled data also showed a significant benefit with open repair (OR 6.1), she explained.

In terms of secondary interventions, each of the three trials showed an increase in the EVAR patients, which reached statistical significance in two of the three. In the pooled analysis, EVAR was associated with a twofold increase in the risk of a secondary procedure, Dr. Rockman noted.

As for late mortality, however, she said: "I think we have to remember that the goal of EVAR is to prevent aneurysm rupture–related death – not to provide immortality; late mortality will always equalize in the end," she said.

That is, the longer the follow-up, the more one would expect all-cause mortality to equalize.

"In EVAR-1, when you look at aneurysm mortality, it was essentially equal in both groups, in fairness," she said.

The findings raise some questions, however, and underscore the inherent limitations of any meta-analysis.

For example, the trials used varying definitions of early and late complications, device failures, and secondary interventions, and it is unclear whether the trials represent contemporary devices and practices. They began enrolling patients as early 1999, and it is arguable that things have changed since then, she noted.

Also, there are questions about when secondary interventions are required.

"It’s very easy to say that EVAR has more secondary interventions, but a lot of these interventions, for example, are being done for type 2 endoleaks, and some of us might believe that these interventions are not, in fact, necessary," she said.

"And finally, with regard to secondary interventions, is a hernia repair equivalent to an intervention for a type 1 endoleak? I don’t have a perfect answer for that," she added.

Thus, based on the available evidence, she concluded that "although the success of EVAR in reducing late AAA-related mortality might be suboptimal, the importance of decreased early mortality cannot be minimized, particularly from the patient’s perspective ...EVAR remains the procedure of choice in anatomically suitable aneurysm patients."

Future research should focus on improvements in design and techniques that will decrease device-related complications, reduce the need for secondary interventions, and improve long-term success with EVAR, she added.

Dr. Rockman had no disclosures.

ORLANDO – People with AIDS have a substantially increased risk of developing stomach and esophageal malignancies, compared with the general public, according to an analysis of data from the large, population-based HIV/AIDS Cancer Match Study.

Among the more than 600,000 people with AIDS who were included in the analysis, 1,166 developed stomach malignancies and 240 developed esophageal malignancies. The overall risks of stomach and esophageal malignancies were 6.9-fold and 2.7-fold higher, respectively, than in the general population, E. Christina Persson, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

Although most of the increased risk was attributable to lymphomas, the risk of carcinomas was also increased. The lymphomas were not surprising, as AIDS patients are known to be at increased risk for these cancers, but the greater risk for carcinomas is a new finding, Dr. Persson said.

People with AIDS who were included in the HIV/AIDS Cancer Match Study (a linkage of 15 U.S. population–based HIV/AIDS and cancer registries) were registered in 1980-2007. This population is known to have a higher prevalence of cancer risk factors, as well an increased risk of infection-related malignancies resulting from a suppressed immune system. As AIDS therapies – and thus, survival - have improved, concern regarding cancer risk is increased.

In the current study, the risk of stomach carcinomas was increased 70% (standardized incidence ratio, 1.7), whereas the risk of stomach lymphomas was 36-fold higher. Similar increases in risk were seen for proximal (cardia) and distal (noncardia) carcinomas (SIR, 1.5 and 1.8, respectively), said Dr. Persson, a postdoctoral fellow at the National Cancer Institute.

The risk for esophageal carcinomas was increased 80% (SIR, 1.8), with a 54% increased risk of squamous cell carcinomas and a 101% increased risk for adenocarcinomas (SIR, 1.5 and 2.0), whereas there was a 261-fold increased risk of esophageal lymphomas, she said.

Dr. Judy E. Garber, the new AACR president and moderator of the press briefing where Dr. Persson discussed her findings, said the report is both fascinating and worrisome.

Given that most AIDS-related cancers are lymphomas, it is "quite remarkable to show solid tumor differences" in the AIDS population vs. the general public, she said, adding that she hopes this is not an indication that people who are surviving AIDS thanks to better treatments will have other problems, such as increased cancer risks, to contend with.

Although the findings do not warrant routine screening for solid tumors in the AIDS population at this time, this increased risk is something for clinicians to keep in mind when they care for AIDS survivors, said Dr. Garber, director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Persson had no disclosures.

ORLANDO – People with AIDS have a substantially increased risk of developing stomach and esophageal malignancies, compared with the general public, according to an analysis of data from the large, population-based HIV/AIDS Cancer Match Study.

Among the more than 600,000 people with AIDS who were included in the analysis, 1,166 developed stomach malignancies and 240 developed esophageal malignancies. The overall risks of stomach and esophageal malignancies were 6.9-fold and 2.7-fold higher, respectively, than in the general population, E. Christina Persson, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

Although most of the increased risk was attributable to lymphomas, the risk of carcinomas was also increased. The lymphomas were not surprising, as AIDS patients are known to be at increased risk for these cancers, but the greater risk for carcinomas is a new finding, Dr. Persson said.

People with AIDS who were included in the HIV/AIDS Cancer Match Study (a linkage of 15 U.S. population–based HIV/AIDS and cancer registries) were registered in 1980-2007. This population is known to have a higher prevalence of cancer risk factors, as well an increased risk of infection-related malignancies resulting from a suppressed immune system. As AIDS therapies – and thus, survival - have improved, concern regarding cancer risk is increased.

In the current study, the risk of stomach carcinomas was increased 70% (standardized incidence ratio, 1.7), whereas the risk of stomach lymphomas was 36-fold higher. Similar increases in risk were seen for proximal (cardia) and distal (noncardia) carcinomas (SIR, 1.5 and 1.8, respectively), said Dr. Persson, a postdoctoral fellow at the National Cancer Institute.

The risk for esophageal carcinomas was increased 80% (SIR, 1.8), with a 54% increased risk of squamous cell carcinomas and a 101% increased risk for adenocarcinomas (SIR, 1.5 and 2.0), whereas there was a 261-fold increased risk of esophageal lymphomas, she said.

Dr. Judy E. Garber, the new AACR president and moderator of the press briefing where Dr. Persson discussed her findings, said the report is both fascinating and worrisome.

Given that most AIDS-related cancers are lymphomas, it is "quite remarkable to show solid tumor differences" in the AIDS population vs. the general public, she said, adding that she hopes this is not an indication that people who are surviving AIDS thanks to better treatments will have other problems, such as increased cancer risks, to contend with.

Although the findings do not warrant routine screening for solid tumors in the AIDS population at this time, this increased risk is something for clinicians to keep in mind when they care for AIDS survivors, said Dr. Garber, director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Persson had no disclosures.

ORLANDO – People with AIDS have a substantially increased risk of developing stomach and esophageal malignancies, compared with the general public, according to an analysis of data from the large, population-based HIV/AIDS Cancer Match Study.

Among the more than 600,000 people with AIDS who were included in the analysis, 1,166 developed stomach malignancies and 240 developed esophageal malignancies. The overall risks of stomach and esophageal malignancies were 6.9-fold and 2.7-fold higher, respectively, than in the general population, E. Christina Persson, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

Although most of the increased risk was attributable to lymphomas, the risk of carcinomas was also increased. The lymphomas were not surprising, as AIDS patients are known to be at increased risk for these cancers, but the greater risk for carcinomas is a new finding, Dr. Persson said.

People with AIDS who were included in the HIV/AIDS Cancer Match Study (a linkage of 15 U.S. population–based HIV/AIDS and cancer registries) were registered in 1980-2007. This population is known to have a higher prevalence of cancer risk factors, as well an increased risk of infection-related malignancies resulting from a suppressed immune system. As AIDS therapies – and thus, survival - have improved, concern regarding cancer risk is increased.

In the current study, the risk of stomach carcinomas was increased 70% (standardized incidence ratio, 1.7), whereas the risk of stomach lymphomas was 36-fold higher. Similar increases in risk were seen for proximal (cardia) and distal (noncardia) carcinomas (SIR, 1.5 and 1.8, respectively), said Dr. Persson, a postdoctoral fellow at the National Cancer Institute.

The risk for esophageal carcinomas was increased 80% (SIR, 1.8), with a 54% increased risk of squamous cell carcinomas and a 101% increased risk for adenocarcinomas (SIR, 1.5 and 2.0), whereas there was a 261-fold increased risk of esophageal lymphomas, she said.

Dr. Judy E. Garber, the new AACR president and moderator of the press briefing where Dr. Persson discussed her findings, said the report is both fascinating and worrisome.

Given that most AIDS-related cancers are lymphomas, it is "quite remarkable to show solid tumor differences" in the AIDS population vs. the general public, she said, adding that she hopes this is not an indication that people who are surviving AIDS thanks to better treatments will have other problems, such as increased cancer risks, to contend with.

Although the findings do not warrant routine screening for solid tumors in the AIDS population at this time, this increased risk is something for clinicians to keep in mind when they care for AIDS survivors, said Dr. Garber, director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Persson had no disclosures.

ORLANDO – People with AIDS have a substantially increased risk of developing stomach and esophageal malignancies, compared with the general public, according to an analysis of data from the large, population-based HIV/AIDS Cancer Match Study.

Among the more than 600,000 people with AIDS who were included in the analysis, 1,166 developed stomach malignancies and 240 developed esophageal malignancies. The overall risks of stomach and esophageal malignancies were 6.9-fold and 2.7-fold higher, respectively, than in the general population, E. Christina Persson, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

Although most of the increased risk was attributable to lymphomas, the risk of carcinomas was also increased. The lymphomas were not surprising, as AIDS patients are known to be at increased risk for these cancers, but the greater risk for carcinomas is a new finding, Dr. Persson said.

People with AIDS who were included in the HIV/AIDS Cancer Match Study (a linkage of 15 U.S. population–based HIV/AIDS and cancer registries) were registered in 1980-2007. This population is known to have a higher prevalence of cancer risk factors, as well an increased risk of infection-related malignancies resulting from a suppressed immune system. As AIDS therapies – and thus, survival - have improved, concern regarding cancer risk is increased.

In the current study, the risk of stomach carcinomas was increased 70% (standardized incidence ratio, 1.7), whereas the risk of stomach lymphomas was 36-fold higher. Similar increases in risk were seen for proximal (cardia) and distal (noncardia) carcinomas (SIR, 1.5 and 1.8, respectively), said Dr. Persson, a postdoctoral fellow at the National Cancer Institute.

The risk for esophageal carcinomas was increased 80% (SIR, 1.8), with a 54% increased risk of squamous cell carcinomas and a 101% increased risk for adenocarcinomas (SIR, 1.5 and 2.0), whereas there was a 261-fold increased risk of esophageal lymphomas, she said.

Dr. Judy E. Garber, the new AACR president and moderator of the press briefing where Dr. Persson discussed her findings, said the report is both fascinating and worrisome.

Given that most AIDS-related cancers are lymphomas, it is "quite remarkable to show solid tumor differences" in the AIDS population vs. the general public, she said, adding that she hopes this is not an indication that people who are surviving AIDS thanks to better treatments will have other problems, such as increased cancer risks, to contend with.

Although the findings do not warrant routine screening for solid tumors in the AIDS population at this time, this increased risk is something for clinicians to keep in mind when they care for AIDS survivors, said Dr. Garber, director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Persson had no disclosures.

ORLANDO – People with AIDS have a substantially increased risk of developing stomach and esophageal malignancies, compared with the general public, according to an analysis of data from the large, population-based HIV/AIDS Cancer Match Study.

Among the more than 600,000 people with AIDS who were included in the analysis, 1,166 developed stomach malignancies and 240 developed esophageal malignancies. The overall risks of stomach and esophageal malignancies were 6.9-fold and 2.7-fold higher, respectively, than in the general population, E. Christina Persson, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

Although most of the increased risk was attributable to lymphomas, the risk of carcinomas was also increased. The lymphomas were not surprising, as AIDS patients are known to be at increased risk for these cancers, but the greater risk for carcinomas is a new finding, Dr. Persson said.

People with AIDS who were included in the HIV/AIDS Cancer Match Study (a linkage of 15 U.S. population–based HIV/AIDS and cancer registries) were registered in 1980-2007. This population is known to have a higher prevalence of cancer risk factors, as well an increased risk of infection-related malignancies resulting from a suppressed immune system. As AIDS therapies – and thus, survival - have improved, concern regarding cancer risk is increased.

In the current study, the risk of stomach carcinomas was increased 70% (standardized incidence ratio, 1.7), whereas the risk of stomach lymphomas was 36-fold higher. Similar increases in risk were seen for proximal (cardia) and distal (noncardia) carcinomas (SIR, 1.5 and 1.8, respectively), said Dr. Persson, a postdoctoral fellow at the National Cancer Institute.

The risk for esophageal carcinomas was increased 80% (SIR, 1.8), with a 54% increased risk of squamous cell carcinomas and a 101% increased risk for adenocarcinomas (SIR, 1.5 and 2.0), whereas there was a 261-fold increased risk of esophageal lymphomas, she said.

Dr. Judy E. Garber, the new AACR president and moderator of the press briefing where Dr. Persson discussed her findings, said the report is both fascinating and worrisome.

Given that most AIDS-related cancers are lymphomas, it is "quite remarkable to show solid tumor differences" in the AIDS population vs. the general public, she said, adding that she hopes this is not an indication that people who are surviving AIDS thanks to better treatments will have other problems, such as increased cancer risks, to contend with.

Although the findings do not warrant routine screening for solid tumors in the AIDS population at this time, this increased risk is something for clinicians to keep in mind when they care for AIDS survivors, said Dr. Garber, director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Persson had no disclosures.

ORLANDO – People with AIDS have a substantially increased risk of developing stomach and esophageal malignancies, compared with the general public, according to an analysis of data from the large, population-based HIV/AIDS Cancer Match Study.

Among the more than 600,000 people with AIDS who were included in the analysis, 1,166 developed stomach malignancies and 240 developed esophageal malignancies. The overall risks of stomach and esophageal malignancies were 6.9-fold and 2.7-fold higher, respectively, than in the general population, E. Christina Persson, Ph.D., reported at the annual meeting of the American Association for Cancer Research.

Although most of the increased risk was attributable to lymphomas, the risk of carcinomas was also increased. The lymphomas were not surprising, as AIDS patients are known to be at increased risk for these cancers, but the greater risk for carcinomas is a new finding, Dr. Persson said.

People with AIDS who were included in the HIV/AIDS Cancer Match Study (a linkage of 15 U.S. population–based HIV/AIDS and cancer registries) were registered in 1980-2007. This population is known to have a higher prevalence of cancer risk factors, as well an increased risk of infection-related malignancies resulting from a suppressed immune system. As AIDS therapies – and thus, survival - have improved, concern regarding cancer risk is increased.

In the current study, the risk of stomach carcinomas was increased 70% (standardized incidence ratio, 1.7), whereas the risk of stomach lymphomas was 36-fold higher. Similar increases in risk were seen for proximal (cardia) and distal (noncardia) carcinomas (SIR, 1.5 and 1.8, respectively), said Dr. Persson, a postdoctoral fellow at the National Cancer Institute.

The risk for esophageal carcinomas was increased 80% (SIR, 1.8), with a 54% increased risk of squamous cell carcinomas and a 101% increased risk for adenocarcinomas (SIR, 1.5 and 2.0), whereas there was a 261-fold increased risk of esophageal lymphomas, she said.

Dr. Judy E. Garber, the new AACR president and moderator of the press briefing where Dr. Persson discussed her findings, said the report is both fascinating and worrisome.

Given that most AIDS-related cancers are lymphomas, it is "quite remarkable to show solid tumor differences" in the AIDS population vs. the general public, she said, adding that she hopes this is not an indication that people who are surviving AIDS thanks to better treatments will have other problems, such as increased cancer risks, to contend with.

Although the findings do not warrant routine screening for solid tumors in the AIDS population at this time, this increased risk is something for clinicians to keep in mind when they care for AIDS survivors, said Dr. Garber, director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Persson had no disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO - Ovarian cancer patients with BRCA1 or BRCA2 gene mutations have better survival than do those with neither mutation, and those with the BRCA2 mutation have better survival than do those with the BRCA1 mutation, according to the findings of a large, multicenter study.

The findings confirm the results of several prior smaller studies showing a survival advantage in mutation carriers vs. nonmutation carriers, and they provide the first direct evidence that BRCA1 and BRCA2 mutations have differing effects on survival, Kelly L. Bolton reported at the annual meeting of the American Association for Cancer Research.

She and her colleagues studied 3,531 women with invasive epithelial ovarian cancer who were enrolled in one of 24 studies in the United States, Europe, Israel, and Asia, and for whom survival data were available. They excluded patients who either were known or were likely not to have received platinum-based therapy. Included were 1,178 women with BRCA1, 367 with BRCA2, and 1,986 who were BRCA negative.

The 5-year survival was 36% in those with no mutation, 46% of those with the BRCA1 mutation, and 61% of those with the BRCA2 mutation, after adjustment for stage, grade, histology, and age at diagnosis, said Ms. Bolton, a predoctoral fellow at the National Cancer Institute.

The difference in survival between the BRCA1 mutation carriers and those with no mutation was modest, although not statistically significant (hazard ratio, 0.84). However, the difference between the BRCA2 mutation carriers and both the noncarriers and the BRCA1 mutation carriers (after adjustment for age at diagnosis) did reach statistical significance (HR, 0.57 and 0.69, respectively).

Even after the exclusion of all but high-grade, advanced-stage serous cases, the survival differences persisted, Ms. Bolton reported.

A possible explanation for the differences, based on in vitro work and some retrospective trials, may lie in patients’ responses to chemotherapy; those with the BRCA2 mutation may have an improved response, but unidentified biological differences among BRCA1 carriers, BRCA2 carriers, and noncarriers could also be driving the association, she said.

The BRCA1 and BRCA2 mutation carriers in this study did not differ in regard to tumor stage, grade, or histology. Compared with noncarriers, however, BRCA1 carriers were younger and BRCA2 carriers were older at diagnosis.

Furthermore, compared with noncarriers, BRCA1 and BRCA2 carriers were more likely to present with advanced-stage disease, high-grade disease, and serous disease.

"The findings don’t have any immediate impact on clinical practice, but they do have important implications [for both] clinical prediction and also trial design, particularly for clinical trials," Ms. Bolton said, noting that although germline mutations in the BRCA1 and BRCA2 genes (which are important in DNA damage repair and have distinct yet complementary functions) are rare in the general population, they are present in 10%-15% of those with ovarian cancer.

Indeed, the findings – which "may be a very faint silver lining" for mutation carriers with a terrible disease that still has terrible survival – do speak to the possibility that women with these mutations need to be identified in the setting of ovarian cancer, as the presence of mutations will affect thinking about treatment, said Dr. Judy E. Garber, the new AACR president and director of the center for cancer genetics and prevention at the Dana-Farber Cancer Institute, Boston. Dr. Garber moderated a press briefing where Ms. Bolton discussed her findings,

Ms. Bolton had no relevant disclosures.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell’s presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn’t appear to be the case. "We’re very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell’s presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We’ve been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.