Susan London

SAN DIEGO – Heart transplant recipients who develop circulating antibodies to human tissues in the first year post transplantation are at heightened risk for poor outcomes and may therefore need closer monitoring, suggests a prospective observational study.

One in seven of the patients studied developed circulating antibodies that specifically targeted human leukocyte antigens on donor tissue, and one in three developed nonspecific antibodies, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Relative to their counterparts who did not develop any antibodies, patients who developed either type were more likely to experience both antibody-mediated and cellular rejection. In addition, those developing the donor-specific type were more likely to experience cardiac allograft vasculopathy and to die.

"Patients with donor-specific antibodies or nonspecific antibodies may require more intensive monitoring and augmented immunosuppression to improve their long-term outcomes," commented lead investigator Dr. Jignesh Patel, co–medical director of the heart transplant program at the Cedars-Sinai Heart Institute in Los Angeles. "Further studies are needed to determine the optimum therapy for these patients."

He acknowledged that the issue is complicated, because some patients with donor-specific antibodies (DSA) never experienced rejection, yet others with nonspecific antibodies did. These outcomes suggest that the nature of the antibodies is key. As a result, it is tricky to manage patients who develop antibodies but don’t have any symptoms of rejection.

At his institution, Dr. Patel said, clinicians don’t step up the number of biopsies performed to monitor for rejection in heart transplant recipients who develop antibodies unless they become symptomatic. However, they are cautious about long-term management of immunosuppression. "We will think twice about weaning them off prednisone," he noted. "More likely, we are kind of tending to switch them to a proliferation signaling inhibitor earlier when we see donor-specific antibodies."

Dr. Patel and his coinvestigators studied 144 patients who underwent heart transplantation in 2003-2010 and had serial antibody monitoring by solid-phase assays at baseline (the time of transplantation) and at 1, 3, 6, 9, and 12 months, at minimum.

"More recently introduced methods using solid-phase matrices coated with HLA antigens have demonstrated the ability to detect and identify HLA antibodies with high sensitivity and accuracy," he said.

Because the study period preceded the guidelines that recommended antibody monitoring, these patients were being followed more closely than usual out of concern that they were at heightened risk for antibody development, he said.

On average, the patients had seven antibody measurements during their first year post transplantation.

Study results showed that in the first year after transplantation, 14% of patients developed DSA and 32% developed non–donor-specific antibodies (non-DSA), while the rest did not develop any.

The mean age (approximately 53 years) was similar across groups. Relative to those who did not develop any antibodies, patients who developed non-DSA were more likely to be female (54% vs. 22%). Also, ischemic time was shorter for patients who developed DSA (183 minutes) or non-DSA (195 minutes) than for their counterparts who did not develop any antibodies (230 minutes).

The three groups of patients were generally similar with respect to immunosuppressive therapy at baseline, including receipt of calcineurin inhibitors and antiproliferative agents.

But the group developing DSA was significantly less likely than the group not developing antibodies to be weaned off prednisone (7% vs. 46%), and both the DSA and non-DSA groups were more likely than their counterparts with no antibodies to have received induction therapy (45% and 39% vs. 15%).

The 1-year rate of freedom from antibody-mediated rejection was poorer for patients who developed DSA (65%) or non-DSA (76%), compared with their peers who developed no antibodies (94%). The findings were similar with respect to rates of freedom from acute cellular rejection (80% and 87% vs. 99%, respectively).

The temporal patterns did differ somewhat according to type of rejection, according to Dr. Patel.

"With regard to cellular rejection, it appeared that a lot of events in the patients who developed donor-specific antibodies occurred toward the end of the first year, in comparison to the patients who developed antibody-mediated rejection, where most of the events tended to occur early" post transplant, he observed.

Relative to their counterparts who did not develop antibodies, the patients who developed DSA also had significantly poorer 3-year rates of survival (65% vs. 85%) and freedom from cardiac allograft vasculopathy, which was defined as the development of vascular stenosis exceeding 30% (70% vs. 88%).

Dr. Patel reported that he had no conflicts of interest related to the study.

SAN DIEGO – Heart transplant recipients who develop circulating antibodies to human tissues in the first year post transplantation are at heightened risk for poor outcomes and may therefore need closer monitoring, suggests a prospective observational study.

One in seven of the patients studied developed circulating antibodies that specifically targeted human leukocyte antigens on donor tissue, and one in three developed nonspecific antibodies, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Relative to their counterparts who did not develop any antibodies, patients who developed either type were more likely to experience both antibody-mediated and cellular rejection. In addition, those developing the donor-specific type were more likely to experience cardiac allograft vasculopathy and to die.

"Patients with donor-specific antibodies or nonspecific antibodies may require more intensive monitoring and augmented immunosuppression to improve their long-term outcomes," commented lead investigator Dr. Jignesh Patel, co–medical director of the heart transplant program at the Cedars-Sinai Heart Institute in Los Angeles. "Further studies are needed to determine the optimum therapy for these patients."

He acknowledged that the issue is complicated, because some patients with donor-specific antibodies (DSA) never experienced rejection, yet others with nonspecific antibodies did. These outcomes suggest that the nature of the antibodies is key. As a result, it is tricky to manage patients who develop antibodies but don’t have any symptoms of rejection.

At his institution, Dr. Patel said, clinicians don’t step up the number of biopsies performed to monitor for rejection in heart transplant recipients who develop antibodies unless they become symptomatic. However, they are cautious about long-term management of immunosuppression. "We will think twice about weaning them off prednisone," he noted. "More likely, we are kind of tending to switch them to a proliferation signaling inhibitor earlier when we see donor-specific antibodies."

Dr. Patel and his coinvestigators studied 144 patients who underwent heart transplantation in 2003-2010 and had serial antibody monitoring by solid-phase assays at baseline (the time of transplantation) and at 1, 3, 6, 9, and 12 months, at minimum.

"More recently introduced methods using solid-phase matrices coated with HLA antigens have demonstrated the ability to detect and identify HLA antibodies with high sensitivity and accuracy," he said.

Because the study period preceded the guidelines that recommended antibody monitoring, these patients were being followed more closely than usual out of concern that they were at heightened risk for antibody development, he said.

On average, the patients had seven antibody measurements during their first year post transplantation.

Study results showed that in the first year after transplantation, 14% of patients developed DSA and 32% developed non–donor-specific antibodies (non-DSA), while the rest did not develop any.

The mean age (approximately 53 years) was similar across groups. Relative to those who did not develop any antibodies, patients who developed non-DSA were more likely to be female (54% vs. 22%). Also, ischemic time was shorter for patients who developed DSA (183 minutes) or non-DSA (195 minutes) than for their counterparts who did not develop any antibodies (230 minutes).

The three groups of patients were generally similar with respect to immunosuppressive therapy at baseline, including receipt of calcineurin inhibitors and antiproliferative agents.

But the group developing DSA was significantly less likely than the group not developing antibodies to be weaned off prednisone (7% vs. 46%), and both the DSA and non-DSA groups were more likely than their counterparts with no antibodies to have received induction therapy (45% and 39% vs. 15%).

The 1-year rate of freedom from antibody-mediated rejection was poorer for patients who developed DSA (65%) or non-DSA (76%), compared with their peers who developed no antibodies (94%). The findings were similar with respect to rates of freedom from acute cellular rejection (80% and 87% vs. 99%, respectively).

The temporal patterns did differ somewhat according to type of rejection, according to Dr. Patel.

"With regard to cellular rejection, it appeared that a lot of events in the patients who developed donor-specific antibodies occurred toward the end of the first year, in comparison to the patients who developed antibody-mediated rejection, where most of the events tended to occur early" post transplant, he observed.

Relative to their counterparts who did not develop antibodies, the patients who developed DSA also had significantly poorer 3-year rates of survival (65% vs. 85%) and freedom from cardiac allograft vasculopathy, which was defined as the development of vascular stenosis exceeding 30% (70% vs. 88%).

Dr. Patel reported that he had no conflicts of interest related to the study.

SAN DIEGO – Heart transplant recipients who develop circulating antibodies to human tissues in the first year post transplantation are at heightened risk for poor outcomes and may therefore need closer monitoring, suggests a prospective observational study.

One in seven of the patients studied developed circulating antibodies that specifically targeted human leukocyte antigens on donor tissue, and one in three developed nonspecific antibodies, according to results reported at the annual meeting of the International Society for Heart and Lung Transplantation.

Relative to their counterparts who did not develop any antibodies, patients who developed either type were more likely to experience both antibody-mediated and cellular rejection. In addition, those developing the donor-specific type were more likely to experience cardiac allograft vasculopathy and to die.

"Patients with donor-specific antibodies or nonspecific antibodies may require more intensive monitoring and augmented immunosuppression to improve their long-term outcomes," commented lead investigator Dr. Jignesh Patel, co–medical director of the heart transplant program at the Cedars-Sinai Heart Institute in Los Angeles. "Further studies are needed to determine the optimum therapy for these patients."

He acknowledged that the issue is complicated, because some patients with donor-specific antibodies (DSA) never experienced rejection, yet others with nonspecific antibodies did. These outcomes suggest that the nature of the antibodies is key. As a result, it is tricky to manage patients who develop antibodies but don’t have any symptoms of rejection.

At his institution, Dr. Patel said, clinicians don’t step up the number of biopsies performed to monitor for rejection in heart transplant recipients who develop antibodies unless they become symptomatic. However, they are cautious about long-term management of immunosuppression. "We will think twice about weaning them off prednisone," he noted. "More likely, we are kind of tending to switch them to a proliferation signaling inhibitor earlier when we see donor-specific antibodies."

Dr. Patel and his coinvestigators studied 144 patients who underwent heart transplantation in 2003-2010 and had serial antibody monitoring by solid-phase assays at baseline (the time of transplantation) and at 1, 3, 6, 9, and 12 months, at minimum.

"More recently introduced methods using solid-phase matrices coated with HLA antigens have demonstrated the ability to detect and identify HLA antibodies with high sensitivity and accuracy," he said.

Because the study period preceded the guidelines that recommended antibody monitoring, these patients were being followed more closely than usual out of concern that they were at heightened risk for antibody development, he said.

On average, the patients had seven antibody measurements during their first year post transplantation.

Study results showed that in the first year after transplantation, 14% of patients developed DSA and 32% developed non–donor-specific antibodies (non-DSA), while the rest did not develop any.

The mean age (approximately 53 years) was similar across groups. Relative to those who did not develop any antibodies, patients who developed non-DSA were more likely to be female (54% vs. 22%). Also, ischemic time was shorter for patients who developed DSA (183 minutes) or non-DSA (195 minutes) than for their counterparts who did not develop any antibodies (230 minutes).

The three groups of patients were generally similar with respect to immunosuppressive therapy at baseline, including receipt of calcineurin inhibitors and antiproliferative agents.

But the group developing DSA was significantly less likely than the group not developing antibodies to be weaned off prednisone (7% vs. 46%), and both the DSA and non-DSA groups were more likely than their counterparts with no antibodies to have received induction therapy (45% and 39% vs. 15%).

The 1-year rate of freedom from antibody-mediated rejection was poorer for patients who developed DSA (65%) or non-DSA (76%), compared with their peers who developed no antibodies (94%). The findings were similar with respect to rates of freedom from acute cellular rejection (80% and 87% vs. 99%, respectively).

The temporal patterns did differ somewhat according to type of rejection, according to Dr. Patel.

"With regard to cellular rejection, it appeared that a lot of events in the patients who developed donor-specific antibodies occurred toward the end of the first year, in comparison to the patients who developed antibody-mediated rejection, where most of the events tended to occur early" post transplant, he observed.

Relative to their counterparts who did not develop antibodies, the patients who developed DSA also had significantly poorer 3-year rates of survival (65% vs. 85%) and freedom from cardiac allograft vasculopathy, which was defined as the development of vascular stenosis exceeding 30% (70% vs. 88%).

Dr. Patel reported that he had no conflicts of interest related to the study.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don't want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor's effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don't want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor's effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don't want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor's effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don’t want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor’s effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don’t want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor’s effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don’t want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor’s effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – In findings that are likely to change clinical practice, a randomized phase III trial has shown that extending the duration of adjuvant imatinib therapy markedly improves outcomes in patients with resected gastrointestinal stromal tumor who are at high risk for recurrence.

Compared with their counterparts given imatinib (Gleevec) for just 1 year after surgery, patients given the drug for 3 years were 54% less likely to have had a recurrence and 55% less likely to have died at the 5-year mark.

In addition, extended treatment with the drug, an oral agent that inhibits multiple tyrosine kinases, was generally well tolerated.

Lead author Dr. Heikki Joensuu presented the trial’s findings in a press briefing and later in a plenary session at the annual meeting of the American Society of Clinical Oncology.

"These data are pretty compelling," commented Dr. Joensuu, professor of oncology at Helsinki University Central Hospital. "I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future."

At present, there are no data from randomized trials to suggest that taking this therapy out further will yield even greater benefit, Dr. Joensuu said. Instead, he predicted, the strategy going forward will be to stop imatinib at 3 years but closely follow up patients to catch any recurrences early.

"There is evidence that when we restart imatinib, the patients will respond to imatinib again," he explained. "And those patients who have a small tumor volume will have a good chance of responding to imatinib rechallenge for many years, even after 10 years."

Dr. Mark G. Kris, moderator of the press briefing, commented, "I think the entire oncology community was extremely excited when we saw that survival curve and those numbers at 5 years, and I think that’s one of the reasons that this paper was chosen for the plenary session. It’s one of the amazing stories in oncology that ... patients who had a 50% death likelihood at 5 years, by taking four pills [of imatinib] a day, are alive at 5 years, and the vast majority alive are cancer free."

The data will likely be taken into consideration by professional oncology organizations as they update their practice guidelines, according to Dr. Kris, chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York. "This is the kind of data that does change guidelines, absolutely, and I believe that’s what we are going to see," he said.

Participants in the trial, formally known as the SSGXVIII/AIO trial, were 400 patients in Finland, Germany, Norway, and Sweden who underwent resection of stem cell growth factor (KIT)-positive gastrointestinal stromal tumor (GIST), and were at high risk for recurrence according to modified Consensus Criteria.

In the pre-imatinib era, such patients had at least 50% risks of recurrence and death in the first 5 years after resection, according to Dr. Joensuu.

The patients were assigned in equal numbers to treatment with imatinib 400 mg/day for either 1 year (shown to improve recurrence-free survival in a previous trial) or 3 years on an open-label basis. The drug targets the KIT and platelet-derived growth factor receptor (PDGFR)-alpha tyrosine kinases, the genes for which are mutated in most GISTs, as well as the BCR-ABL tyrosine kinase.

Safety results showed that "the treatment was generally well tolerated," Dr. Joensuu reported. The most common adverse events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all of which were generally mild.

Relative to their counterparts in the 1-year group, patients in the 3-year group were more likely to experience grade 3/4 adverse events (33% vs. 20%) and to stop treatment because of adverse events (14% vs. 8%), however.

Intention-to-treat efficacy results showed that after a 54-month median follow-up, the 5-year rate of recurrence-free survival was significantly better with 3 years of imatinib than with 1 year (65.6% vs. 47.9%; hazard ratio, 0.46; P less than .0001). "Resistance was not a big problem in the current study," Dr. Joensuu noted.

In addition, although the 5-year rate of overall survival was high in both groups, it was likewise superior with 3 years of imatinib (92.0% vs. 81.7%; HR, 0.45; P = .019). The majority of deaths were due to GIST.

There may be other pharmacotherapy options for patients at high risk for GIST recurrence, he acknowledged. "We need to have the next generation of trials, and we also may need to address sequential treatment and combinations. And we need to learn more about the biology of the disease."

Abstract discussant Dr. Charles D. Blanke, chief of medical oncology at the University of British Columbia, Vancouver, said, "If you have a patient who has a high-risk GIST – at least as defined by the study – giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting hoping to ‘catch up’ when a patient has recurrent metastatic disease."

That said, the optimal duration of therapy remains unknown. "There are plenty of reasons to think giving imatinib for a longer period would be better, but that theory remains unproven," he said. "For now, if I were a patient with resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely."

However, Dr. Blanke added, "I reserve the right to change my mind pending the longer-term overall survival results of SSGXVIII and the findings in PERSIST-5," a trial assessing 5 years of adjuvant imatinib. "But I don’t think GISTs are curable, even in the adjuvant setting, and I bet I won’t [change my mind]."

Oncologists must also decide for themselves which patients to treat, as the high-risk category used in the SSGXVIII trial included patients with possible recurrence risks ranging from 34% up to nearly 100%.

"But given the possibility that we need to treat for a very long time, coupled with the difficulty patients have taking long-duration drugs, I probably will recommend therapy for those with a 50% chance or greater of recurrence following surgery alone," he said. "I suspect many of you will choose a lower number."

Dr. Joensuu reported being a consultant to and receiving honoraria from Novartis. Novartis provided the drug and partly funded the trial. Dr. Kris reported being a consultant to GlaxoSmithKline, Merck, and Sanofi-Aventis. Dr. Blanke reported being a consultant to Novartis.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer – that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It’s also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial’s primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer – that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It’s also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial’s primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer – that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It’s also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial’s primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer – that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It’s also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial’s primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer – that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It’s also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial’s primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer – that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It’s also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial’s primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

DENVER – The majority of patients with chronic obstructive pulmonary disease who acquire a rhinovirus infection develop a secondary bacterial infection shortly thereafter, suggesting that early antiviral therapy might do double duty.

In a study reported at the International Conference of the American Thoracic Society, 60% of patients with COPD who were experimentally infected with rhinovirus and who gave serial sputum samples developed a bacterial infection as well, approximately a week later. This rate was six times higher than the rates seen among smokers with normal lung function and among nonsmokers.

Temporal patterns of pathogen loads and molecular markers suggested that the virus may incite inflammation that, in turn, results in degradation of key defense peptides in the airways, leaving patients vulnerable to bacteria.

The findings raise the possibility that "dual infection is a lot more common than has been reported in [previous] studies," said lead investigator Dr. Patrick Mallia, a U.K. National Institute for Health Research clinical lecturer at the Imperial College London.

"In terms of therapeutics, this may suggest that antiviral drugs may not only be effective against virus-induced exacerbations, but also potentially could prevent or reduce secondary bacterial infection," he commented.

At his institution, COPD patients with an exacerbation are not routinely tested for viruses. But that may change, given the advent of rapid PCR (polymerase chain reaction) assays for detecting viruses and, possibly, expansion of the indications for antiviral agents.

"So although at the moment [testing for viruses] is very much a research exercise, I think the possibility of using antiviral treatment in the future is not that far away," he said.

Interest in the role of viruses and of dual viral-bacterial infection in COPD exacerbations has intensified recently, according to Dr. Mallia. As both types of infections are common in this population, one might expect that dual infection is common as well; yet, on average, studies have found dual infection in only 13% of exacerbations.

"This tends to suggest that actually it’s not so common, but I think there are a number of reasons why these studies may have underestimated the rate of dual infection," he said, such as their cross-sectional or retrospective nature, and one-time testing for pathogens.

"Studies using a single sampling time point during exacerbation will probably underestimate the true prevalence of coinfection, and also can’t tell us what the sequence of infection is," he explained.

To get around these issues, the investigators used their newly developed model of experimental rhinovirus-induced COPD exacerbation. "These patients catch a cold, get lower respiratory symptoms, and get an exacerbation with increased airflow obstruction and airway inflammation," he said.

The study included 30 patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD who were using only short-acting bronchodilators, 28 smokers with normal lung function, and 18 nonsmokers.

They were experimentally inoculated with rhinovirus, the virus most commonly detected in COPD exacerbations. Induced sputum was collected before inoculation and at 5, 9, 12, 15, 21, and 42 days afterward.

None of the participants received treatment for infections because their symptoms did not become severe enough to meet preestablished study criteria for treatment initiation, according to Dr. Mallia.

The load of rhinovirus in sputum was assessed with PCR. The load of bacteria that were classified as potentially pathogenic microorganisms (PPMs) was assessed with semiquantitative bacterial culture.

Study results showed that 20 of the COPD patients, 21 of the smokers, and 11 of the nonsmokers developed rhinovirus infection after inoculation.

Fully 60% of the rhinovirus-infected COPD patients developed secondary bacterial infections (mainly with Haemophilus influenzae and Streptococcus pneumoniae), compared with just 9.5% of the smokers and 10% of the nonsmokers (P less than .001).

Within the COPD group, bacterial infections were significantly more common among the patients who acquired rhinovirus infection than among those who did not. "This suggests that the bacterial infections we were detecting were a consequence of the rhinovirus infections," Dr. Mallia commented.

Both viral and bacterial loads rose and fell over time, but the former infection preceded the latter: The viral load peaked on day 9, whereas the bacterial load peaked almost a week later, on day 15. These are "really the first data that [show] a temporal sequence, that first you get the rhinovirus infection, and then you get the bacterial infection following this," he noted.

Moreover, "you can see immediately that if you take a single sample and you sample early, you may pick up a virus and call it a viral exacerbation, but not pick up the subsequent bacterial infection," he added. "Whereas if the patient happens to present later, you might detect the bacterial infection but not detect ... the virus infection that actually initiated it."

To assess potential mechanisms whereby rhinovirus might induce bacterial infections, the investigators measured sputum levels of two antimicrobial peptides found in the airways that are part of the lung’s innate defenses against infection: secretory leukocyte protease inhibitor (SLPI) and elafin.

Levels of both peptides fell in rhinovirus-infected COPD patients who developed bacterial infection before or at the time when bacterial load peaked. In contrast, levels remained the same or rose slightly in those who did not develop bacterial infection. Furthermore, lower levels of the peptides were correlated with higher bacterial loads.

"This would suggest that bacterial infection is a consequence of low SLPI and elafin levels in the airways," Dr. Mallia commented.

Finally, sputum levels of neutrophil elastase (an enzyme that could degrade the protective peptides) rose in rhinovirus-infected COPD patients who developed bacterial infection but remained essentially at baseline levels in their counterparts who did not.

"We hypothesize that possibly you have a sequence of events – viral infection, high neutrophil elastase levels, and degradation of SLPI and elafin – and that may progress to secondary bacterial infection," he said.

The study gives rise to several potential, related avenues of research, according to Dr. Mallia.

"Certainly, one of the things we are interested in is, Are there markers that can identify those people who are going to go on to develop bacterial infections?" he said. And some evidence suggests that in addition to having antibacterial activity, macrolide antibiotics also have antirhinovirus activity, which the investigators plan to test using their model.

Dr. Mallia reported previously having received research grants from Pfizer and GlaxoSmithKline, and currently receiving a travel grant from Boehringer Ingelheim. The study was funded in part by Pfizer and GlaxoSmithKline.

DENVER – The majority of patients with chronic obstructive pulmonary disease who acquire a rhinovirus infection develop a secondary bacterial infection shortly thereafter, suggesting that early antiviral therapy might do double duty.

In a study reported at the International Conference of the American Thoracic Society, 60% of patients with COPD who were experimentally infected with rhinovirus and who gave serial sputum samples developed a bacterial infection as well, approximately a week later. This rate was six times higher than the rates seen among smokers with normal lung function and among nonsmokers.

Temporal patterns of pathogen loads and molecular markers suggested that the virus may incite inflammation that, in turn, results in degradation of key defense peptides in the airways, leaving patients vulnerable to bacteria.

The findings raise the possibility that "dual infection is a lot more common than has been reported in [previous] studies," said lead investigator Dr. Patrick Mallia, a U.K. National Institute for Health Research clinical lecturer at the Imperial College London.

"In terms of therapeutics, this may suggest that antiviral drugs may not only be effective against virus-induced exacerbations, but also potentially could prevent or reduce secondary bacterial infection," he commented.

At his institution, COPD patients with an exacerbation are not routinely tested for viruses. But that may change, given the advent of rapid PCR (polymerase chain reaction) assays for detecting viruses and, possibly, expansion of the indications for antiviral agents.

"So although at the moment [testing for viruses] is very much a research exercise, I think the possibility of using antiviral treatment in the future is not that far away," he said.

Interest in the role of viruses and of dual viral-bacterial infection in COPD exacerbations has intensified recently, according to Dr. Mallia. As both types of infections are common in this population, one might expect that dual infection is common as well; yet, on average, studies have found dual infection in only 13% of exacerbations.

"This tends to suggest that actually it’s not so common, but I think there are a number of reasons why these studies may have underestimated the rate of dual infection," he said, such as their cross-sectional or retrospective nature, and one-time testing for pathogens.

"Studies using a single sampling time point during exacerbation will probably underestimate the true prevalence of coinfection, and also can’t tell us what the sequence of infection is," he explained.

To get around these issues, the investigators used their newly developed model of experimental rhinovirus-induced COPD exacerbation. "These patients catch a cold, get lower respiratory symptoms, and get an exacerbation with increased airflow obstruction and airway inflammation," he said.

The study included 30 patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD who were using only short-acting bronchodilators, 28 smokers with normal lung function, and 18 nonsmokers.

They were experimentally inoculated with rhinovirus, the virus most commonly detected in COPD exacerbations. Induced sputum was collected before inoculation and at 5, 9, 12, 15, 21, and 42 days afterward.

None of the participants received treatment for infections because their symptoms did not become severe enough to meet preestablished study criteria for treatment initiation, according to Dr. Mallia.

The load of rhinovirus in sputum was assessed with PCR. The load of bacteria that were classified as potentially pathogenic microorganisms (PPMs) was assessed with semiquantitative bacterial culture.

Study results showed that 20 of the COPD patients, 21 of the smokers, and 11 of the nonsmokers developed rhinovirus infection after inoculation.

Fully 60% of the rhinovirus-infected COPD patients developed secondary bacterial infections (mainly with Haemophilus influenzae and Streptococcus pneumoniae), compared with just 9.5% of the smokers and 10% of the nonsmokers (P less than .001).

Within the COPD group, bacterial infections were significantly more common among the patients who acquired rhinovirus infection than among those who did not. "This suggests that the bacterial infections we were detecting were a consequence of the rhinovirus infections," Dr. Mallia commented.

Both viral and bacterial loads rose and fell over time, but the former infection preceded the latter: The viral load peaked on day 9, whereas the bacterial load peaked almost a week later, on day 15. These are "really the first data that [show] a temporal sequence, that first you get the rhinovirus infection, and then you get the bacterial infection following this," he noted.

Moreover, "you can see immediately that if you take a single sample and you sample early, you may pick up a virus and call it a viral exacerbation, but not pick up the subsequent bacterial infection," he added. "Whereas if the patient happens to present later, you might detect the bacterial infection but not detect ... the virus infection that actually initiated it."

To assess potential mechanisms whereby rhinovirus might induce bacterial infections, the investigators measured sputum levels of two antimicrobial peptides found in the airways that are part of the lung’s innate defenses against infection: secretory leukocyte protease inhibitor (SLPI) and elafin.

Levels of both peptides fell in rhinovirus-infected COPD patients who developed bacterial infection before or at the time when bacterial load peaked. In contrast, levels remained the same or rose slightly in those who did not develop bacterial infection. Furthermore, lower levels of the peptides were correlated with higher bacterial loads.

"This would suggest that bacterial infection is a consequence of low SLPI and elafin levels in the airways," Dr. Mallia commented.

Finally, sputum levels of neutrophil elastase (an enzyme that could degrade the protective peptides) rose in rhinovirus-infected COPD patients who developed bacterial infection but remained essentially at baseline levels in their counterparts who did not.

"We hypothesize that possibly you have a sequence of events – viral infection, high neutrophil elastase levels, and degradation of SLPI and elafin – and that may progress to secondary bacterial infection," he said.

The study gives rise to several potential, related avenues of research, according to Dr. Mallia.

"Certainly, one of the things we are interested in is, Are there markers that can identify those people who are going to go on to develop bacterial infections?" he said. And some evidence suggests that in addition to having antibacterial activity, macrolide antibiotics also have antirhinovirus activity, which the investigators plan to test using their model.

Dr. Mallia reported previously having received research grants from Pfizer and GlaxoSmithKline, and currently receiving a travel grant from Boehringer Ingelheim. The study was funded in part by Pfizer and GlaxoSmithKline.

DENVER – The majority of patients with chronic obstructive pulmonary disease who acquire a rhinovirus infection develop a secondary bacterial infection shortly thereafter, suggesting that early antiviral therapy might do double duty.

In a study reported at the International Conference of the American Thoracic Society, 60% of patients with COPD who were experimentally infected with rhinovirus and who gave serial sputum samples developed a bacterial infection as well, approximately a week later. This rate was six times higher than the rates seen among smokers with normal lung function and among nonsmokers.

Temporal patterns of pathogen loads and molecular markers suggested that the virus may incite inflammation that, in turn, results in degradation of key defense peptides in the airways, leaving patients vulnerable to bacteria.

The findings raise the possibility that "dual infection is a lot more common than has been reported in [previous] studies," said lead investigator Dr. Patrick Mallia, a U.K. National Institute for Health Research clinical lecturer at the Imperial College London.

"In terms of therapeutics, this may suggest that antiviral drugs may not only be effective against virus-induced exacerbations, but also potentially could prevent or reduce secondary bacterial infection," he commented.

At his institution, COPD patients with an exacerbation are not routinely tested for viruses. But that may change, given the advent of rapid PCR (polymerase chain reaction) assays for detecting viruses and, possibly, expansion of the indications for antiviral agents.

"So although at the moment [testing for viruses] is very much a research exercise, I think the possibility of using antiviral treatment in the future is not that far away," he said.

Interest in the role of viruses and of dual viral-bacterial infection in COPD exacerbations has intensified recently, according to Dr. Mallia. As both types of infections are common in this population, one might expect that dual infection is common as well; yet, on average, studies have found dual infection in only 13% of exacerbations.

"This tends to suggest that actually it’s not so common, but I think there are a number of reasons why these studies may have underestimated the rate of dual infection," he said, such as their cross-sectional or retrospective nature, and one-time testing for pathogens.

"Studies using a single sampling time point during exacerbation will probably underestimate the true prevalence of coinfection, and also can’t tell us what the sequence of infection is," he explained.

To get around these issues, the investigators used their newly developed model of experimental rhinovirus-induced COPD exacerbation. "These patients catch a cold, get lower respiratory symptoms, and get an exacerbation with increased airflow obstruction and airway inflammation," he said.

The study included 30 patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD who were using only short-acting bronchodilators, 28 smokers with normal lung function, and 18 nonsmokers.

They were experimentally inoculated with rhinovirus, the virus most commonly detected in COPD exacerbations. Induced sputum was collected before inoculation and at 5, 9, 12, 15, 21, and 42 days afterward.

None of the participants received treatment for infections because their symptoms did not become severe enough to meet preestablished study criteria for treatment initiation, according to Dr. Mallia.

The load of rhinovirus in sputum was assessed with PCR. The load of bacteria that were classified as potentially pathogenic microorganisms (PPMs) was assessed with semiquantitative bacterial culture.

Study results showed that 20 of the COPD patients, 21 of the smokers, and 11 of the nonsmokers developed rhinovirus infection after inoculation.

Fully 60% of the rhinovirus-infected COPD patients developed secondary bacterial infections (mainly with Haemophilus influenzae and Streptococcus pneumoniae), compared with just 9.5% of the smokers and 10% of the nonsmokers (P less than .001).

Within the COPD group, bacterial infections were significantly more common among the patients who acquired rhinovirus infection than among those who did not. "This suggests that the bacterial infections we were detecting were a consequence of the rhinovirus infections," Dr. Mallia commented.

Both viral and bacterial loads rose and fell over time, but the former infection preceded the latter: The viral load peaked on day 9, whereas the bacterial load peaked almost a week later, on day 15. These are "really the first data that [show] a temporal sequence, that first you get the rhinovirus infection, and then you get the bacterial infection following this," he noted.

Moreover, "you can see immediately that if you take a single sample and you sample early, you may pick up a virus and call it a viral exacerbation, but not pick up the subsequent bacterial infection," he added. "Whereas if the patient happens to present later, you might detect the bacterial infection but not detect ... the virus infection that actually initiated it."

To assess potential mechanisms whereby rhinovirus might induce bacterial infections, the investigators measured sputum levels of two antimicrobial peptides found in the airways that are part of the lung’s innate defenses against infection: secretory leukocyte protease inhibitor (SLPI) and elafin.

Levels of both peptides fell in rhinovirus-infected COPD patients who developed bacterial infection before or at the time when bacterial load peaked. In contrast, levels remained the same or rose slightly in those who did not develop bacterial infection. Furthermore, lower levels of the peptides were correlated with higher bacterial loads.

"This would suggest that bacterial infection is a consequence of low SLPI and elafin levels in the airways," Dr. Mallia commented.

Finally, sputum levels of neutrophil elastase (an enzyme that could degrade the protective peptides) rose in rhinovirus-infected COPD patients who developed bacterial infection but remained essentially at baseline levels in their counterparts who did not.

"We hypothesize that possibly you have a sequence of events – viral infection, high neutrophil elastase levels, and degradation of SLPI and elafin – and that may progress to secondary bacterial infection," he said.

The study gives rise to several potential, related avenues of research, according to Dr. Mallia.

"Certainly, one of the things we are interested in is, Are there markers that can identify those people who are going to go on to develop bacterial infections?" he said. And some evidence suggests that in addition to having antibacterial activity, macrolide antibiotics also have antirhinovirus activity, which the investigators plan to test using their model.

Dr. Mallia reported previously having received research grants from Pfizer and GlaxoSmithKline, and currently receiving a travel grant from Boehringer Ingelheim. The study was funded in part by Pfizer and GlaxoSmithKline.