2013 ASCO Annual Meeting

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

[email protected]

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

[email protected]

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

[email protected]

CHICAGO – A full 83% of U.S. oncologists reported being unable to prescribe the preferred chemotherapy agent for their cancer patients because of persistent drug shortages, according to a survey of 250 oncologists.

Nearly 70% of those surveyed said their cancer centers or practices had no formal guidance on how to manage the allocation of cancer drugs in short supply, Dr. Keerthi Gogineni reported in a press briefing at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Due to the shortages, oncologists reported switching regimens (78%), substituting alternate drugs partway through therapy (77%), delaying treatment (43%), omitting doses (29%), reducing doses (20%) and referring patients to other practices (17%).

More than a third (37%) reported having to choose between patients who needed a particular drug, said Dr. Gogineni, a clinical instructor at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. This poses ethical dilemmas for clinicians about who should get preference for a drug – the patient with early stage disease being treated with curative intent, the patient with metastatic disease who needs to abate disease spread, or those enrolled in clinical trials.

Data were not available on whether substitutions or delays affected patients’ quality of life, she said. An earlier study reported showed that a shortage of the chemotherapy drug mechlorethamine, or nitrogen mustard, led to a greater risk of relapse for some young Hodgkin’s lymphoma patients (N. Engl. J. Med. 2012;367:2461-3).

Patrice Wendling/IMNG Medical Media

ASCO’s ethics committee has developed a white paper that is under review and will provide a series of recommendations to help oncologists deal with the allocation of cancer drugs in shortage, Dr. Richard Schilsky, ASCO chief medical officer, told reporters. The paper will provide overall guidance on management strategies, but cannot possibly address the multitude of scenarios that physicians face in each of the various cancers, he said in an interview.

ASCO surveyed 390 members in October 2012 and 462 members in April 2013 to monitor the impact of the shortages and regulatory/legislative efforts such as changes in generic drug user fees that would provide added resources to the Food and Drug Administration to expedite the review of generic drugs.

The ASCO survey results are similar to those in the survey reported by Dr. Gogineni and "suggest there’s been some amelioration of the drug shortages, but not to a major extent," Dr. Schilsky said.

In the 2013 ASCO survey, 58% of physician-members said the shortages were better and 17% said they were worse than in the fall of 2012. The latter may reflect scarcities of supportive care agents such as basic IV fluids, antiemetics, and pain medications that are necessary to provide optimal care to cancer patients, but "are in even worse supply, perhaps, than the chemotherapy drugs themselves," Dr. Schilsky said.

In addition, the continued persistence of unavoidable drug substitutions is troubling both for patient care and cost implications.

Among 202 ASCO members who gave specific examples of ongoing substitutions, 38% mentioned substitution of the branded drug levoleucovorin (Fusilev) for generic leucovorin, and 12% mentioned substitution of capecitabine (Xeloda) for 5-flurouracil/leucovorin.

In the Pennsylvania survey, 22% of physicians faced with shortages of 5-FU, a generic drug that forms the chemotherapy backbone for several gastrointestinal cancers, reported substituting capecitabine, which costs about 140 times as much as 5-FU for one round of colon cancer treatment, according to the investigators.

Overall, nearly 60% of physicians reported substituting more expensive branded drugs when cheaper generic drugs were in shortage, Dr. Gogineni said.

At the time the survey was conducted between September 2012 and January 2013, the top five drugs in shortage were leucovorin (66%), liposomal doxorubicin (62%), 5-FU (19%), bleomycin (17%), and cytarabine (16%).

Nearly 13% of the time, drug shortages prevented enrollment in a clinical trial, delayed administration of a study drug, or disrupted involvement of patients in clinical trials, according to the study, which was coauthored by Dr. Ezekiel Emanuel, chair of medial ethics and medical policy at the University of Pennsylvania.

Dr. Gogineni reported research funding from Pfizer, which supported the study in part through a medical and academic partnership research fellowship.

[email protected]

CHICAGO – A full 83% of U.S. oncologists reported being unable to prescribe the preferred chemotherapy agent for their cancer patients because of persistent drug shortages, according to a survey of 250 oncologists.

Nearly 70% of those surveyed said their cancer centers or practices had no formal guidance on how to manage the allocation of cancer drugs in short supply, Dr. Keerthi Gogineni reported in a press briefing at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Due to the shortages, oncologists reported switching regimens (78%), substituting alternate drugs partway through therapy (77%), delaying treatment (43%), omitting doses (29%), reducing doses (20%) and referring patients to other practices (17%).

More than a third (37%) reported having to choose between patients who needed a particular drug, said Dr. Gogineni, a clinical instructor at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. This poses ethical dilemmas for clinicians about who should get preference for a drug – the patient with early stage disease being treated with curative intent, the patient with metastatic disease who needs to abate disease spread, or those enrolled in clinical trials.

Data were not available on whether substitutions or delays affected patients’ quality of life, she said. An earlier study reported showed that a shortage of the chemotherapy drug mechlorethamine, or nitrogen mustard, led to a greater risk of relapse for some young Hodgkin’s lymphoma patients (N. Engl. J. Med. 2012;367:2461-3).

Patrice Wendling/IMNG Medical Media

ASCO’s ethics committee has developed a white paper that is under review and will provide a series of recommendations to help oncologists deal with the allocation of cancer drugs in shortage, Dr. Richard Schilsky, ASCO chief medical officer, told reporters. The paper will provide overall guidance on management strategies, but cannot possibly address the multitude of scenarios that physicians face in each of the various cancers, he said in an interview.

ASCO surveyed 390 members in October 2012 and 462 members in April 2013 to monitor the impact of the shortages and regulatory/legislative efforts such as changes in generic drug user fees that would provide added resources to the Food and Drug Administration to expedite the review of generic drugs.

The ASCO survey results are similar to those in the survey reported by Dr. Gogineni and "suggest there’s been some amelioration of the drug shortages, but not to a major extent," Dr. Schilsky said.

In the 2013 ASCO survey, 58% of physician-members said the shortages were better and 17% said they were worse than in the fall of 2012. The latter may reflect scarcities of supportive care agents such as basic IV fluids, antiemetics, and pain medications that are necessary to provide optimal care to cancer patients, but "are in even worse supply, perhaps, than the chemotherapy drugs themselves," Dr. Schilsky said.

In addition, the continued persistence of unavoidable drug substitutions is troubling both for patient care and cost implications.

Among 202 ASCO members who gave specific examples of ongoing substitutions, 38% mentioned substitution of the branded drug levoleucovorin (Fusilev) for generic leucovorin, and 12% mentioned substitution of capecitabine (Xeloda) for 5-flurouracil/leucovorin.

In the Pennsylvania survey, 22% of physicians faced with shortages of 5-FU, a generic drug that forms the chemotherapy backbone for several gastrointestinal cancers, reported substituting capecitabine, which costs about 140 times as much as 5-FU for one round of colon cancer treatment, according to the investigators.

Overall, nearly 60% of physicians reported substituting more expensive branded drugs when cheaper generic drugs were in shortage, Dr. Gogineni said.

At the time the survey was conducted between September 2012 and January 2013, the top five drugs in shortage were leucovorin (66%), liposomal doxorubicin (62%), 5-FU (19%), bleomycin (17%), and cytarabine (16%).

Nearly 13% of the time, drug shortages prevented enrollment in a clinical trial, delayed administration of a study drug, or disrupted involvement of patients in clinical trials, according to the study, which was coauthored by Dr. Ezekiel Emanuel, chair of medial ethics and medical policy at the University of Pennsylvania.

Dr. Gogineni reported research funding from Pfizer, which supported the study in part through a medical and academic partnership research fellowship.

[email protected]

CHICAGO – A full 83% of U.S. oncologists reported being unable to prescribe the preferred chemotherapy agent for their cancer patients because of persistent drug shortages, according to a survey of 250 oncologists.

Nearly 70% of those surveyed said their cancer centers or practices had no formal guidance on how to manage the allocation of cancer drugs in short supply, Dr. Keerthi Gogineni reported in a press briefing at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

Due to the shortages, oncologists reported switching regimens (78%), substituting alternate drugs partway through therapy (77%), delaying treatment (43%), omitting doses (29%), reducing doses (20%) and referring patients to other practices (17%).

More than a third (37%) reported having to choose between patients who needed a particular drug, said Dr. Gogineni, a clinical instructor at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. This poses ethical dilemmas for clinicians about who should get preference for a drug – the patient with early stage disease being treated with curative intent, the patient with metastatic disease who needs to abate disease spread, or those enrolled in clinical trials.

Data were not available on whether substitutions or delays affected patients’ quality of life, she said. An earlier study reported showed that a shortage of the chemotherapy drug mechlorethamine, or nitrogen mustard, led to a greater risk of relapse for some young Hodgkin’s lymphoma patients (N. Engl. J. Med. 2012;367:2461-3).

Patrice Wendling/IMNG Medical Media

ASCO’s ethics committee has developed a white paper that is under review and will provide a series of recommendations to help oncologists deal with the allocation of cancer drugs in shortage, Dr. Richard Schilsky, ASCO chief medical officer, told reporters. The paper will provide overall guidance on management strategies, but cannot possibly address the multitude of scenarios that physicians face in each of the various cancers, he said in an interview.

ASCO surveyed 390 members in October 2012 and 462 members in April 2013 to monitor the impact of the shortages and regulatory/legislative efforts such as changes in generic drug user fees that would provide added resources to the Food and Drug Administration to expedite the review of generic drugs.

The ASCO survey results are similar to those in the survey reported by Dr. Gogineni and "suggest there’s been some amelioration of the drug shortages, but not to a major extent," Dr. Schilsky said.

In the 2013 ASCO survey, 58% of physician-members said the shortages were better and 17% said they were worse than in the fall of 2012. The latter may reflect scarcities of supportive care agents such as basic IV fluids, antiemetics, and pain medications that are necessary to provide optimal care to cancer patients, but "are in even worse supply, perhaps, than the chemotherapy drugs themselves," Dr. Schilsky said.

In addition, the continued persistence of unavoidable drug substitutions is troubling both for patient care and cost implications.

Among 202 ASCO members who gave specific examples of ongoing substitutions, 38% mentioned substitution of the branded drug levoleucovorin (Fusilev) for generic leucovorin, and 12% mentioned substitution of capecitabine (Xeloda) for 5-flurouracil/leucovorin.

In the Pennsylvania survey, 22% of physicians faced with shortages of 5-FU, a generic drug that forms the chemotherapy backbone for several gastrointestinal cancers, reported substituting capecitabine, which costs about 140 times as much as 5-FU for one round of colon cancer treatment, according to the investigators.

Overall, nearly 60% of physicians reported substituting more expensive branded drugs when cheaper generic drugs were in shortage, Dr. Gogineni said.

At the time the survey was conducted between September 2012 and January 2013, the top five drugs in shortage were leucovorin (66%), liposomal doxorubicin (62%), 5-FU (19%), bleomycin (17%), and cytarabine (16%).

Nearly 13% of the time, drug shortages prevented enrollment in a clinical trial, delayed administration of a study drug, or disrupted involvement of patients in clinical trials, according to the study, which was coauthored by Dr. Ezekiel Emanuel, chair of medial ethics and medical policy at the University of Pennsylvania.

Dr. Gogineni reported research funding from Pfizer, which supported the study in part through a medical and academic partnership research fellowship.

[email protected]

CHICAGO – Giving the telomerase peptide vaccine GV1001, either sequentially or concurrently, with standard chemotherapy added no overall survival benefit in one of the largest trials ever performed in locally advanced or metastatic pancreatic cancer.

Median overall survival was 7.9 months for gemcitabine (Gemzar) and capecitabine (Xeloda) chemotherapy alone, 6.9 months for 8 weeks of gemcitabine and capecitabine followed by GV1001 vaccinations until progressive disease then gemcitabine and capecitabine, and 8.4 months for GV1001 given concurrently with gemcitabine and capecitabine chemotherapy.

One-year survival rates were 33.7%, 25.3%, and 32.3%. The difference in overall survival did not meet the criterion for statistical significance (P value less than .0175) for sequential (hazard ratio, 1.19; P = .046) or concurrent (HR, 1.05; P = .63) chemoimmunotherapy.

Further, sequential chemoimmunotherapy was associated with a statistically poorer response rate, compared with standard chemotherapy (8.6% vs. 17.6%; unadjusted P = .000), and shorter time to progression (4.54 months vs. 6.35 months; P less than .001), Dr. Gary W. Middleton reported at the annual meeting of the American Society of Clinical Oncology.

The results of the 1,062-patient TeloVac study are disappointing in light of phase I/II results in which an intermediate dose of GV1001, without any chemotherapy at all, produced an immune response in 75% of patients and a median overall survival of 8.3 months, explained Dr. Middleton of the University of Birmingham, England.

Invited discussant Dr. Hedy Lee Kindler, medical director of gastrointestinal oncology at the University of Chicago Medical Center, questioned whether this signal was sufficiently robust to proceed directly to a 1,000-plus–patient phase III trial, given that the phase I/II trial was not randomized, did not include chemotherapy, and had significant imbalances in performance status and disease extent between arms that made it difficult to draw conclusions about the outcomes.

"Perhaps a randomized phase II trial of chemotherapy plus/minus vaccine would have been informative," she said.

Although TeloVac is one of a long line of negative phase III trials in pancreatic cancer, recent data challenge the assumption that pancreas cancer is poorly immunogenic, Dr. Kindler said. Going forward, the optimal immunotherapy trial will need to use the best antigen, increase vaccine potency by optimizing the adjuvant, uncouple tolerance mechanisms either by blocking immunologic checkpoints or manipulating the tumor microenvironment using agonistic anti-CD40 antibodies, and identify predictive biomarkers, she said.

Chemoradiotherapy in LAP 07

During the same session at ASCO, final results were reported from the phase III international LAP 07 study evaluating chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine chemotherapy with or without erlotinib (Tarceva).

Median overall survival in patients allocated to 2 additional months of chemotherapy was 16.4 months vs. 15.2 months in those allocated to receive 54 Gy and capecitabine (HR, 1.03; P = .83). Progression-free survival was also similar at 11.8 months and 12.5 months (HR, 0.9; P = .21).

The internal data monitoring committee confirmed that the futility boundary was crossed for the hypothesis of chemoradiotherapy superiority, and that the second interim analysis could be considered the study’s final analysis. "It was clear that to continue the study would not change the final results," said Dr. Pascal Hammel, Beaujon Hospital, Clichy, France.

When survival was analyzed based on first-round chemotherapy, there was a trend for inferior survival with gemcitabine plus erlotinib compared with gemcitabine alone, although the data are not mature (median 11.9 months vs. 13.6 months; HR 1.19; P = .09). The addition of erlotinib was not beneficial in locally advanced pancreatic cancer and increased toxicity, he said.

"In locally advanced pancreatic cancer, standard of care should remain chemotherapy; chemoradiotherapy being an option after tumor control by chemotherapy," Dr. Hammel concluded.

An audience member objected to CRT as an option, in light of the negative results, but Dr. Kindler agreed with the authors’ conclusion.

There are many potential explanations for "these somewhat surprising results," including inadequate radiation or inadequate chemotherapy during the first round or during radiotherapy. It’s also possible that only a subset of patients benefit from CRT, something that is being examined in ongoing correlative studies from LAP 07. Two ongoing trials – Radiation Therapy Oncology Group 1201 of high vs. standard intensity local or systemic therapy and the proposed Alliance/Eastern Cooperative Oncology Group phase II trial – could also help answer some of these questions, she said.

TeloVac was funded by Cancer Research UK; Roche supplied capecitabine for the trial; and KAEL-GemVax provided the vaccine and additional support to the Cancer Research UK Liverpool Cancer Trials Unit. Dr. Middleton and his coauthors reported no relevant disclosures.

LAP 07 was sponsored by Groupe Cooperateur Multidisciplinaire en Oncologie. Dr. Hammel reported honoraria from Roche.

[email protected]

CHICAGO – Giving the telomerase peptide vaccine GV1001, either sequentially or concurrently, with standard chemotherapy added no overall survival benefit in one of the largest trials ever performed in locally advanced or metastatic pancreatic cancer.

Median overall survival was 7.9 months for gemcitabine (Gemzar) and capecitabine (Xeloda) chemotherapy alone, 6.9 months for 8 weeks of gemcitabine and capecitabine followed by GV1001 vaccinations until progressive disease then gemcitabine and capecitabine, and 8.4 months for GV1001 given concurrently with gemcitabine and capecitabine chemotherapy.

One-year survival rates were 33.7%, 25.3%, and 32.3%. The difference in overall survival did not meet the criterion for statistical significance (P value less than .0175) for sequential (hazard ratio, 1.19; P = .046) or concurrent (HR, 1.05; P = .63) chemoimmunotherapy.

Further, sequential chemoimmunotherapy was associated with a statistically poorer response rate, compared with standard chemotherapy (8.6% vs. 17.6%; unadjusted P = .000), and shorter time to progression (4.54 months vs. 6.35 months; P less than .001), Dr. Gary W. Middleton reported at the annual meeting of the American Society of Clinical Oncology.

The results of the 1,062-patient TeloVac study are disappointing in light of phase I/II results in which an intermediate dose of GV1001, without any chemotherapy at all, produced an immune response in 75% of patients and a median overall survival of 8.3 months, explained Dr. Middleton of the University of Birmingham, England.

Invited discussant Dr. Hedy Lee Kindler, medical director of gastrointestinal oncology at the University of Chicago Medical Center, questioned whether this signal was sufficiently robust to proceed directly to a 1,000-plus–patient phase III trial, given that the phase I/II trial was not randomized, did not include chemotherapy, and had significant imbalances in performance status and disease extent between arms that made it difficult to draw conclusions about the outcomes.

"Perhaps a randomized phase II trial of chemotherapy plus/minus vaccine would have been informative," she said.

Although TeloVac is one of a long line of negative phase III trials in pancreatic cancer, recent data challenge the assumption that pancreas cancer is poorly immunogenic, Dr. Kindler said. Going forward, the optimal immunotherapy trial will need to use the best antigen, increase vaccine potency by optimizing the adjuvant, uncouple tolerance mechanisms either by blocking immunologic checkpoints or manipulating the tumor microenvironment using agonistic anti-CD40 antibodies, and identify predictive biomarkers, she said.

Chemoradiotherapy in LAP 07

During the same session at ASCO, final results were reported from the phase III international LAP 07 study evaluating chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine chemotherapy with or without erlotinib (Tarceva).

Median overall survival in patients allocated to 2 additional months of chemotherapy was 16.4 months vs. 15.2 months in those allocated to receive 54 Gy and capecitabine (HR, 1.03; P = .83). Progression-free survival was also similar at 11.8 months and 12.5 months (HR, 0.9; P = .21).

The internal data monitoring committee confirmed that the futility boundary was crossed for the hypothesis of chemoradiotherapy superiority, and that the second interim analysis could be considered the study’s final analysis. "It was clear that to continue the study would not change the final results," said Dr. Pascal Hammel, Beaujon Hospital, Clichy, France.

When survival was analyzed based on first-round chemotherapy, there was a trend for inferior survival with gemcitabine plus erlotinib compared with gemcitabine alone, although the data are not mature (median 11.9 months vs. 13.6 months; HR 1.19; P = .09). The addition of erlotinib was not beneficial in locally advanced pancreatic cancer and increased toxicity, he said.

"In locally advanced pancreatic cancer, standard of care should remain chemotherapy; chemoradiotherapy being an option after tumor control by chemotherapy," Dr. Hammel concluded.

An audience member objected to CRT as an option, in light of the negative results, but Dr. Kindler agreed with the authors’ conclusion.

There are many potential explanations for "these somewhat surprising results," including inadequate radiation or inadequate chemotherapy during the first round or during radiotherapy. It’s also possible that only a subset of patients benefit from CRT, something that is being examined in ongoing correlative studies from LAP 07. Two ongoing trials – Radiation Therapy Oncology Group 1201 of high vs. standard intensity local or systemic therapy and the proposed Alliance/Eastern Cooperative Oncology Group phase II trial – could also help answer some of these questions, she said.

TeloVac was funded by Cancer Research UK; Roche supplied capecitabine for the trial; and KAEL-GemVax provided the vaccine and additional support to the Cancer Research UK Liverpool Cancer Trials Unit. Dr. Middleton and his coauthors reported no relevant disclosures.

LAP 07 was sponsored by Groupe Cooperateur Multidisciplinaire en Oncologie. Dr. Hammel reported honoraria from Roche.

[email protected]

CHICAGO – Giving the telomerase peptide vaccine GV1001, either sequentially or concurrently, with standard chemotherapy added no overall survival benefit in one of the largest trials ever performed in locally advanced or metastatic pancreatic cancer.

Median overall survival was 7.9 months for gemcitabine (Gemzar) and capecitabine (Xeloda) chemotherapy alone, 6.9 months for 8 weeks of gemcitabine and capecitabine followed by GV1001 vaccinations until progressive disease then gemcitabine and capecitabine, and 8.4 months for GV1001 given concurrently with gemcitabine and capecitabine chemotherapy.

One-year survival rates were 33.7%, 25.3%, and 32.3%. The difference in overall survival did not meet the criterion for statistical significance (P value less than .0175) for sequential (hazard ratio, 1.19; P = .046) or concurrent (HR, 1.05; P = .63) chemoimmunotherapy.

Further, sequential chemoimmunotherapy was associated with a statistically poorer response rate, compared with standard chemotherapy (8.6% vs. 17.6%; unadjusted P = .000), and shorter time to progression (4.54 months vs. 6.35 months; P less than .001), Dr. Gary W. Middleton reported at the annual meeting of the American Society of Clinical Oncology.

The results of the 1,062-patient TeloVac study are disappointing in light of phase I/II results in which an intermediate dose of GV1001, without any chemotherapy at all, produced an immune response in 75% of patients and a median overall survival of 8.3 months, explained Dr. Middleton of the University of Birmingham, England.

Invited discussant Dr. Hedy Lee Kindler, medical director of gastrointestinal oncology at the University of Chicago Medical Center, questioned whether this signal was sufficiently robust to proceed directly to a 1,000-plus–patient phase III trial, given that the phase I/II trial was not randomized, did not include chemotherapy, and had significant imbalances in performance status and disease extent between arms that made it difficult to draw conclusions about the outcomes.

"Perhaps a randomized phase II trial of chemotherapy plus/minus vaccine would have been informative," she said.

Although TeloVac is one of a long line of negative phase III trials in pancreatic cancer, recent data challenge the assumption that pancreas cancer is poorly immunogenic, Dr. Kindler said. Going forward, the optimal immunotherapy trial will need to use the best antigen, increase vaccine potency by optimizing the adjuvant, uncouple tolerance mechanisms either by blocking immunologic checkpoints or manipulating the tumor microenvironment using agonistic anti-CD40 antibodies, and identify predictive biomarkers, she said.

Chemoradiotherapy in LAP 07

During the same session at ASCO, final results were reported from the phase III international LAP 07 study evaluating chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine chemotherapy with or without erlotinib (Tarceva).

Median overall survival in patients allocated to 2 additional months of chemotherapy was 16.4 months vs. 15.2 months in those allocated to receive 54 Gy and capecitabine (HR, 1.03; P = .83). Progression-free survival was also similar at 11.8 months and 12.5 months (HR, 0.9; P = .21).

The internal data monitoring committee confirmed that the futility boundary was crossed for the hypothesis of chemoradiotherapy superiority, and that the second interim analysis could be considered the study’s final analysis. "It was clear that to continue the study would not change the final results," said Dr. Pascal Hammel, Beaujon Hospital, Clichy, France.

When survival was analyzed based on first-round chemotherapy, there was a trend for inferior survival with gemcitabine plus erlotinib compared with gemcitabine alone, although the data are not mature (median 11.9 months vs. 13.6 months; HR 1.19; P = .09). The addition of erlotinib was not beneficial in locally advanced pancreatic cancer and increased toxicity, he said.

"In locally advanced pancreatic cancer, standard of care should remain chemotherapy; chemoradiotherapy being an option after tumor control by chemotherapy," Dr. Hammel concluded.

An audience member objected to CRT as an option, in light of the negative results, but Dr. Kindler agreed with the authors’ conclusion.

There are many potential explanations for "these somewhat surprising results," including inadequate radiation or inadequate chemotherapy during the first round or during radiotherapy. It’s also possible that only a subset of patients benefit from CRT, something that is being examined in ongoing correlative studies from LAP 07. Two ongoing trials – Radiation Therapy Oncology Group 1201 of high vs. standard intensity local or systemic therapy and the proposed Alliance/Eastern Cooperative Oncology Group phase II trial – could also help answer some of these questions, she said.

TeloVac was funded by Cancer Research UK; Roche supplied capecitabine for the trial; and KAEL-GemVax provided the vaccine and additional support to the Cancer Research UK Liverpool Cancer Trials Unit. Dr. Middleton and his coauthors reported no relevant disclosures.

LAP 07 was sponsored by Groupe Cooperateur Multidisciplinaire en Oncologie. Dr. Hammel reported honoraria from Roche.

[email protected]

CHICAGO – The VeriStrat test is useful in guiding second-line treatment decisions in non–small-cell lung cancer patients with unknown or wild-type epidermal growth factor receptor status, according to results from the prospective phase III PROSE trial.

Patients classified as VeriStrat "good" had the same median overall survival of 10.92 months with chemotherapy and of 10.95 months with erlotinib (Tarceva) (hazard ratio 1.06; P = .714).

VeriStrat "poor" patients, however, derived a significant survival benefit from chemotherapy, with a median survival of 6.38 months vs. 2.98 months with erlotinib (HR 1.72; P = .022).

The interaction between treatment outcome and VeriStrat classification was statistically significant (HR 1.85; P = .031), Dr. Vanessa Gregorc reported at the annual meeting of the American Society of Clinical Oncology.

Erlotinib, an antiepidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is frequently used in patients who harbor an EGFR mutation, but about 90% of non-Asian patients are EGFR wild-type and 35%-45% are never tested for EGFR status.

Patrice Wendling/IMNG Medical Media

VeriStrat is a serum protein test that uses mass spectrometry technique – Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) – and proprietary algorithms to analyze proteins in a patient’s serum, according to the manufacturer, Biodesix.

The VeriStrat test is already known to be of value in identifying good versus poor prognosis in NSCLC patients. Initial retrospective validation studies showed that pretreatment classification with VeriStrat correlated with overall survival after treatment with EGFR-TKIs, but not with chemotherapy. Additional retrospective studies have shown the test to be both predictive and prognostic, explained Dr. Gregorc of the San Raffaele Scientific Institute, Milan.

There have been some doubts about whether the VeriStrat signature was only prognostic, but now "... we know VeriStrat is also predictive," said Dr. Luis Paz-Ares of Virgen Del Rocio University Hospital, Seville, Spain, who was invited to discuss the study.

Possibly more important, in a subanalysis restricted to only EGFR wild-type patients, the hazard ratio was even higher (1.94) and the VeriStrat treatment interaction was significant (P = .024), he added.

PROSE study

PROSE (Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib versus Chemotherapy in Patients with Inoperable Non–Small-Cell Lung Cancer) involved 285 patients at 14 centers across Italy who had stage IIIb or IV inoperable NSCLC treated with one previous line of platinum-based chemotherapy and no EGFR-TKIs. Patients were stratified by ECOG performance status, smoking status, and blinded pretreatment VeriStrat classification, and randomly assigned within 5 working days of their blood draw to receive erlotinib or chemotherapy with pemetrexed or docetaxel at standard doses.

Among the 263 patients evaluable for the primary analysis, 129 received chemotherapy, of which 88 were VeriStrat classified as good and 41 as poor, and 134 received erlotinib, of which 96 were VeriStrat classified as good and 38 as poor.

EGFR mutation status analysis was performed in 190 of the 263 evaluable patients and indicated that 91 of 97 (94%) chemotherapy patients tested and 85 of 93 (91%) erlotinib patients tested were EGFR wild-type.

Median overall survival was 9.0 months with chemotherapy and 7.7 months with erlotinib (HR 1.14; P = .313), Dr. Gregorc reported.

In a survival analysis adjusted for several potential confounding factors, ECOG performance status 2 vs. 0-1 (HR 2.55; P less than .001) and VeriStrat poor vs. good classification (HR 1.89; P = .002) were prognostic for outcome independent of treatment. VeriStrat was predictive of a significant differential treatment benefit between chemotherapy and erlotinib (HR 1.98; P = .022).

During a discussion of the study, Dr. Tony Mok, lead investigator for the pivotal IPASS (Iressa Pan Asian Study), said he agreed that VeriStrat was predictive in patients with EGFR-negative status, but wasn’t sure about this conclusion for patients with unknown mutation status "because the proportion with EGFR-mutation positive likely had higher predictive power than what the VeriStrat can offer."

Dr. Gregorc said the sample sizes aren’t representative of what they’d planned to show, but that additional analyses are supportive of the findings.

"Our suggestion is, if you can, do the analysis with tissue," she said. "If you can’t or the patients have EGFR mutations, this is what you have to drive your clinical decision."

Another attendee described PROSE as an important trial, but said it "feels like the cake is only half baked" without data on progression-free survival and response rates. Dr. Gregorc responded that they didn’t have sufficient time to complete a thorough progression-free survival analysis before the meeting, and that these data will be presented at the European Society for Medical Oncology meeting this fall.

DELTA study

Data presented during the same session from the phase III DELTA (Docetaxel and Erlotinib Lung Cancer Trial) reinforced the role of chemotherapy over erlotinib in the second- and third-line setting of advanced NSCLC patients with EGFR wild-type status.

Among all 301 EGFR-unselected Japanese patients, docetaxel chemotherapy and erlotinib resulted in similar median progression-free (3.2 months vs. 2.0 months; HR 1.22; P = .092) and overall survival (12.2 months vs. 14.8 months; HR 0.90; P = .527).

Among the subset of 199 patients found to be EGFR wild-type, however, median progression-free survival was significantly longer at 2.9 months with chemotherapy vs. 1.3 months with erlotinib (HR 1.45; P = .01). A Cox regression analysis that adjusted for gender, performance status, and histology confirmed this benefit of chemotherapy on progression (HR 1.57; no P value given), said Dr. Yoshio Okana of Kochi (Japan) National Hospital.

Further, EGFR wild-type patients given chemotherapy had significantly better response rates (20% vs. 5.6%; P = .003) and disease control (70.6% vs. 53%; P = .017), although overall survival was similar (10.1 months vs. 9.0 months; HR 0.97; P .907), he said.

PROSE was funded by the Italian Ministry of Health, Italian Association for Cancer Research, and a grant from Biodesix. Dr. Gregorc reported no financial conflicts; several coauthors reported ties with Biodesix. DELTA was funded by the Japanese National Health Organization. Dr. Okano reported no conflicts; several coauthors reported ties with Chugai Pharma and Sanofi.

[email protected]

CHICAGO – The VeriStrat test is useful in guiding second-line treatment decisions in non–small-cell lung cancer patients with unknown or wild-type epidermal growth factor receptor status, according to results from the prospective phase III PROSE trial.

Patients classified as VeriStrat "good" had the same median overall survival of 10.92 months with chemotherapy and of 10.95 months with erlotinib (Tarceva) (hazard ratio 1.06; P = .714).

VeriStrat "poor" patients, however, derived a significant survival benefit from chemotherapy, with a median survival of 6.38 months vs. 2.98 months with erlotinib (HR 1.72; P = .022).

The interaction between treatment outcome and VeriStrat classification was statistically significant (HR 1.85; P = .031), Dr. Vanessa Gregorc reported at the annual meeting of the American Society of Clinical Oncology.

Erlotinib, an antiepidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is frequently used in patients who harbor an EGFR mutation, but about 90% of non-Asian patients are EGFR wild-type and 35%-45% are never tested for EGFR status.

Patrice Wendling/IMNG Medical Media

VeriStrat is a serum protein test that uses mass spectrometry technique – Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) – and proprietary algorithms to analyze proteins in a patient’s serum, according to the manufacturer, Biodesix.

The VeriStrat test is already known to be of value in identifying good versus poor prognosis in NSCLC patients. Initial retrospective validation studies showed that pretreatment classification with VeriStrat correlated with overall survival after treatment with EGFR-TKIs, but not with chemotherapy. Additional retrospective studies have shown the test to be both predictive and prognostic, explained Dr. Gregorc of the San Raffaele Scientific Institute, Milan.

There have been some doubts about whether the VeriStrat signature was only prognostic, but now "... we know VeriStrat is also predictive," said Dr. Luis Paz-Ares of Virgen Del Rocio University Hospital, Seville, Spain, who was invited to discuss the study.

Possibly more important, in a subanalysis restricted to only EGFR wild-type patients, the hazard ratio was even higher (1.94) and the VeriStrat treatment interaction was significant (P = .024), he added.

PROSE study

PROSE (Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib versus Chemotherapy in Patients with Inoperable Non–Small-Cell Lung Cancer) involved 285 patients at 14 centers across Italy who had stage IIIb or IV inoperable NSCLC treated with one previous line of platinum-based chemotherapy and no EGFR-TKIs. Patients were stratified by ECOG performance status, smoking status, and blinded pretreatment VeriStrat classification, and randomly assigned within 5 working days of their blood draw to receive erlotinib or chemotherapy with pemetrexed or docetaxel at standard doses.

Among the 263 patients evaluable for the primary analysis, 129 received chemotherapy, of which 88 were VeriStrat classified as good and 41 as poor, and 134 received erlotinib, of which 96 were VeriStrat classified as good and 38 as poor.

EGFR mutation status analysis was performed in 190 of the 263 evaluable patients and indicated that 91 of 97 (94%) chemotherapy patients tested and 85 of 93 (91%) erlotinib patients tested were EGFR wild-type.

Median overall survival was 9.0 months with chemotherapy and 7.7 months with erlotinib (HR 1.14; P = .313), Dr. Gregorc reported.

In a survival analysis adjusted for several potential confounding factors, ECOG performance status 2 vs. 0-1 (HR 2.55; P less than .001) and VeriStrat poor vs. good classification (HR 1.89; P = .002) were prognostic for outcome independent of treatment. VeriStrat was predictive of a significant differential treatment benefit between chemotherapy and erlotinib (HR 1.98; P = .022).

During a discussion of the study, Dr. Tony Mok, lead investigator for the pivotal IPASS (Iressa Pan Asian Study), said he agreed that VeriStrat was predictive in patients with EGFR-negative status, but wasn’t sure about this conclusion for patients with unknown mutation status "because the proportion with EGFR-mutation positive likely had higher predictive power than what the VeriStrat can offer."

Dr. Gregorc said the sample sizes aren’t representative of what they’d planned to show, but that additional analyses are supportive of the findings.

"Our suggestion is, if you can, do the analysis with tissue," she said. "If you can’t or the patients have EGFR mutations, this is what you have to drive your clinical decision."

Another attendee described PROSE as an important trial, but said it "feels like the cake is only half baked" without data on progression-free survival and response rates. Dr. Gregorc responded that they didn’t have sufficient time to complete a thorough progression-free survival analysis before the meeting, and that these data will be presented at the European Society for Medical Oncology meeting this fall.

DELTA study

Data presented during the same session from the phase III DELTA (Docetaxel and Erlotinib Lung Cancer Trial) reinforced the role of chemotherapy over erlotinib in the second- and third-line setting of advanced NSCLC patients with EGFR wild-type status.

Among all 301 EGFR-unselected Japanese patients, docetaxel chemotherapy and erlotinib resulted in similar median progression-free (3.2 months vs. 2.0 months; HR 1.22; P = .092) and overall survival (12.2 months vs. 14.8 months; HR 0.90; P = .527).

Among the subset of 199 patients found to be EGFR wild-type, however, median progression-free survival was significantly longer at 2.9 months with chemotherapy vs. 1.3 months with erlotinib (HR 1.45; P = .01). A Cox regression analysis that adjusted for gender, performance status, and histology confirmed this benefit of chemotherapy on progression (HR 1.57; no P value given), said Dr. Yoshio Okana of Kochi (Japan) National Hospital.

Further, EGFR wild-type patients given chemotherapy had significantly better response rates (20% vs. 5.6%; P = .003) and disease control (70.6% vs. 53%; P = .017), although overall survival was similar (10.1 months vs. 9.0 months; HR 0.97; P .907), he said.

PROSE was funded by the Italian Ministry of Health, Italian Association for Cancer Research, and a grant from Biodesix. Dr. Gregorc reported no financial conflicts; several coauthors reported ties with Biodesix. DELTA was funded by the Japanese National Health Organization. Dr. Okano reported no conflicts; several coauthors reported ties with Chugai Pharma and Sanofi.

[email protected]

CHICAGO – The VeriStrat test is useful in guiding second-line treatment decisions in non–small-cell lung cancer patients with unknown or wild-type epidermal growth factor receptor status, according to results from the prospective phase III PROSE trial.

Patients classified as VeriStrat "good" had the same median overall survival of 10.92 months with chemotherapy and of 10.95 months with erlotinib (Tarceva) (hazard ratio 1.06; P = .714).

VeriStrat "poor" patients, however, derived a significant survival benefit from chemotherapy, with a median survival of 6.38 months vs. 2.98 months with erlotinib (HR 1.72; P = .022).

The interaction between treatment outcome and VeriStrat classification was statistically significant (HR 1.85; P = .031), Dr. Vanessa Gregorc reported at the annual meeting of the American Society of Clinical Oncology.

Erlotinib, an antiepidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is frequently used in patients who harbor an EGFR mutation, but about 90% of non-Asian patients are EGFR wild-type and 35%-45% are never tested for EGFR status.

Patrice Wendling/IMNG Medical Media

VeriStrat is a serum protein test that uses mass spectrometry technique – Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) – and proprietary algorithms to analyze proteins in a patient’s serum, according to the manufacturer, Biodesix.

The VeriStrat test is already known to be of value in identifying good versus poor prognosis in NSCLC patients. Initial retrospective validation studies showed that pretreatment classification with VeriStrat correlated with overall survival after treatment with EGFR-TKIs, but not with chemotherapy. Additional retrospective studies have shown the test to be both predictive and prognostic, explained Dr. Gregorc of the San Raffaele Scientific Institute, Milan.

There have been some doubts about whether the VeriStrat signature was only prognostic, but now "... we know VeriStrat is also predictive," said Dr. Luis Paz-Ares of Virgen Del Rocio University Hospital, Seville, Spain, who was invited to discuss the study.

Possibly more important, in a subanalysis restricted to only EGFR wild-type patients, the hazard ratio was even higher (1.94) and the VeriStrat treatment interaction was significant (P = .024), he added.

PROSE study

PROSE (Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib versus Chemotherapy in Patients with Inoperable Non–Small-Cell Lung Cancer) involved 285 patients at 14 centers across Italy who had stage IIIb or IV inoperable NSCLC treated with one previous line of platinum-based chemotherapy and no EGFR-TKIs. Patients were stratified by ECOG performance status, smoking status, and blinded pretreatment VeriStrat classification, and randomly assigned within 5 working days of their blood draw to receive erlotinib or chemotherapy with pemetrexed or docetaxel at standard doses.

Among the 263 patients evaluable for the primary analysis, 129 received chemotherapy, of which 88 were VeriStrat classified as good and 41 as poor, and 134 received erlotinib, of which 96 were VeriStrat classified as good and 38 as poor.

EGFR mutation status analysis was performed in 190 of the 263 evaluable patients and indicated that 91 of 97 (94%) chemotherapy patients tested and 85 of 93 (91%) erlotinib patients tested were EGFR wild-type.

Median overall survival was 9.0 months with chemotherapy and 7.7 months with erlotinib (HR 1.14; P = .313), Dr. Gregorc reported.

In a survival analysis adjusted for several potential confounding factors, ECOG performance status 2 vs. 0-1 (HR 2.55; P less than .001) and VeriStrat poor vs. good classification (HR 1.89; P = .002) were prognostic for outcome independent of treatment. VeriStrat was predictive of a significant differential treatment benefit between chemotherapy and erlotinib (HR 1.98; P = .022).

During a discussion of the study, Dr. Tony Mok, lead investigator for the pivotal IPASS (Iressa Pan Asian Study), said he agreed that VeriStrat was predictive in patients with EGFR-negative status, but wasn’t sure about this conclusion for patients with unknown mutation status "because the proportion with EGFR-mutation positive likely had higher predictive power than what the VeriStrat can offer."

Dr. Gregorc said the sample sizes aren’t representative of what they’d planned to show, but that additional analyses are supportive of the findings.

"Our suggestion is, if you can, do the analysis with tissue," she said. "If you can’t or the patients have EGFR mutations, this is what you have to drive your clinical decision."

Another attendee described PROSE as an important trial, but said it "feels like the cake is only half baked" without data on progression-free survival and response rates. Dr. Gregorc responded that they didn’t have sufficient time to complete a thorough progression-free survival analysis before the meeting, and that these data will be presented at the European Society for Medical Oncology meeting this fall.

DELTA study

Data presented during the same session from the phase III DELTA (Docetaxel and Erlotinib Lung Cancer Trial) reinforced the role of chemotherapy over erlotinib in the second- and third-line setting of advanced NSCLC patients with EGFR wild-type status.

Among all 301 EGFR-unselected Japanese patients, docetaxel chemotherapy and erlotinib resulted in similar median progression-free (3.2 months vs. 2.0 months; HR 1.22; P = .092) and overall survival (12.2 months vs. 14.8 months; HR 0.90; P = .527).

Among the subset of 199 patients found to be EGFR wild-type, however, median progression-free survival was significantly longer at 2.9 months with chemotherapy vs. 1.3 months with erlotinib (HR 1.45; P = .01). A Cox regression analysis that adjusted for gender, performance status, and histology confirmed this benefit of chemotherapy on progression (HR 1.57; no P value given), said Dr. Yoshio Okana of Kochi (Japan) National Hospital.

Further, EGFR wild-type patients given chemotherapy had significantly better response rates (20% vs. 5.6%; P = .003) and disease control (70.6% vs. 53%; P = .017), although overall survival was similar (10.1 months vs. 9.0 months; HR 0.97; P .907), he said.

PROSE was funded by the Italian Ministry of Health, Italian Association for Cancer Research, and a grant from Biodesix. Dr. Gregorc reported no financial conflicts; several coauthors reported ties with Biodesix. DELTA was funded by the Japanese National Health Organization. Dr. Okano reported no conflicts; several coauthors reported ties with Chugai Pharma and Sanofi.

[email protected]

CHICAGO – When paired with rituximab, the experimental agent idelalisib was associated with durable progression-free survival rates in older patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma, Dr. Susan M. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

Among 64 patients in an open-label phase II study, the overall response rate was 97%, consisting of 19% complete responses and 78% partial responses. Among 9 patients with chromosome 17 abnormalities, which are associated with a poor prognosis, 3 had a complete response and 6 had a partial response, said Dr. O’Brien, of the University of Texas MD Anderson Cancer Center in Houston.

Progression-free survival (PFS) at 24 months was 93% among all patients, and 100% among the 9 patients with the poor-prognosis TP53 mutation or a deletion in chromosome 17 (17p).

"I think that these data, particularly the PFS, really support further evaluation of this agent in front-line CLL [chronic lymphocytic leukemia]," she said.

Idelalisib (GS-1101) is a targeted, highly selective oral inhibitor of the P13 kinase delta isoform (P13K-delta). The oral drug inhibits proliferation of many B-cell malignancies and induces apoptosis, and it inhibits homing and retention of malignant B cells in lymphoid tissues, Dr. O’Brien explained.

In a phase I trial also reported at this year’s ASCO meeting, 72% of 54 patients with relapsed/refractory CLL treated with single agent idelalisib had a partial response, with a 1-month median time to response and a response duration of 16-plus months, reported Dr. Jennifer R. Brown, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston.

In the phase II study conducted by Dr. O’Brien, patients aged 65 years and older with previously untreated CLL were given idelalisib 150 mg twice daily for 48 weeks and rituximab 375 mg/m² once weekly for 8 weeks. Disease status was determined by investigators. Those patients who did not have disease progression after 48 weeks were allowed to stay on therapy in an extension study.

In the primary study, 62 of 64 patients completed the 8 weeks of therapy with rituximab and idelalisib, and 43 completed all 48 weeks. Of the 21 who discontinued therapy, 17 did so because of adverse events, 3 died, and 1 withdrew consent. Of 40 patients enrolled in the extension phase of the trial, 33 were still on study as of May 2013. Of the 7 patients who withdrew from the extension study, 6 did so because of adverse events and 1 withdrew consent.

Of the 64 patients started on the drug combination in the primary study, 12 had a complete response, and 3 of these patients had a 17p deletion and/or TP53 mutation. Partial responses occurred in 50 patients, 6 of whom had mutations or deletions.

In all, 23% of patients in the primary and extension studies had grade 3 diarrhea and/or colitis. Grade 3 or greater pneumonia occurred in 17%, transaminase elevations in 23%, and neutropenia in 28%. Of the patients who discontinued therapy due to adverse events, 5 did so because of respiratory events in the first 24 weeks, and 5 did so because of diarrhea/colitis during the extension study. Other causes of discontinuation were anemia and elevated transaminases.

The study was sponsored by Gilead Sciences. Dr. O’Brien disclosed receiving research funding from the company. Dr. Brown reported having no relevant financial disclosures.

CHICAGO – When paired with rituximab, the experimental agent idelalisib was associated with durable progression-free survival rates in older patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma, Dr. Susan M. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

Among 64 patients in an open-label phase II study, the overall response rate was 97%, consisting of 19% complete responses and 78% partial responses. Among 9 patients with chromosome 17 abnormalities, which are associated with a poor prognosis, 3 had a complete response and 6 had a partial response, said Dr. O’Brien, of the University of Texas MD Anderson Cancer Center in Houston.

Progression-free survival (PFS) at 24 months was 93% among all patients, and 100% among the 9 patients with the poor-prognosis TP53 mutation or a deletion in chromosome 17 (17p).

"I think that these data, particularly the PFS, really support further evaluation of this agent in front-line CLL [chronic lymphocytic leukemia]," she said.

Idelalisib (GS-1101) is a targeted, highly selective oral inhibitor of the P13 kinase delta isoform (P13K-delta). The oral drug inhibits proliferation of many B-cell malignancies and induces apoptosis, and it inhibits homing and retention of malignant B cells in lymphoid tissues, Dr. O’Brien explained.

In a phase I trial also reported at this year’s ASCO meeting, 72% of 54 patients with relapsed/refractory CLL treated with single agent idelalisib had a partial response, with a 1-month median time to response and a response duration of 16-plus months, reported Dr. Jennifer R. Brown, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston.

In the phase II study conducted by Dr. O’Brien, patients aged 65 years and older with previously untreated CLL were given idelalisib 150 mg twice daily for 48 weeks and rituximab 375 mg/m² once weekly for 8 weeks. Disease status was determined by investigators. Those patients who did not have disease progression after 48 weeks were allowed to stay on therapy in an extension study.

In the primary study, 62 of 64 patients completed the 8 weeks of therapy with rituximab and idelalisib, and 43 completed all 48 weeks. Of the 21 who discontinued therapy, 17 did so because of adverse events, 3 died, and 1 withdrew consent. Of 40 patients enrolled in the extension phase of the trial, 33 were still on study as of May 2013. Of the 7 patients who withdrew from the extension study, 6 did so because of adverse events and 1 withdrew consent.

Of the 64 patients started on the drug combination in the primary study, 12 had a complete response, and 3 of these patients had a 17p deletion and/or TP53 mutation. Partial responses occurred in 50 patients, 6 of whom had mutations or deletions.

In all, 23% of patients in the primary and extension studies had grade 3 diarrhea and/or colitis. Grade 3 or greater pneumonia occurred in 17%, transaminase elevations in 23%, and neutropenia in 28%. Of the patients who discontinued therapy due to adverse events, 5 did so because of respiratory events in the first 24 weeks, and 5 did so because of diarrhea/colitis during the extension study. Other causes of discontinuation were anemia and elevated transaminases.

The study was sponsored by Gilead Sciences. Dr. O’Brien disclosed receiving research funding from the company. Dr. Brown reported having no relevant financial disclosures.

CHICAGO – When paired with rituximab, the experimental agent idelalisib was associated with durable progression-free survival rates in older patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma, Dr. Susan M. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

Among 64 patients in an open-label phase II study, the overall response rate was 97%, consisting of 19% complete responses and 78% partial responses. Among 9 patients with chromosome 17 abnormalities, which are associated with a poor prognosis, 3 had a complete response and 6 had a partial response, said Dr. O’Brien, of the University of Texas MD Anderson Cancer Center in Houston.

Progression-free survival (PFS) at 24 months was 93% among all patients, and 100% among the 9 patients with the poor-prognosis TP53 mutation or a deletion in chromosome 17 (17p).

"I think that these data, particularly the PFS, really support further evaluation of this agent in front-line CLL [chronic lymphocytic leukemia]," she said.

Idelalisib (GS-1101) is a targeted, highly selective oral inhibitor of the P13 kinase delta isoform (P13K-delta). The oral drug inhibits proliferation of many B-cell malignancies and induces apoptosis, and it inhibits homing and retention of malignant B cells in lymphoid tissues, Dr. O’Brien explained.

In a phase I trial also reported at this year’s ASCO meeting, 72% of 54 patients with relapsed/refractory CLL treated with single agent idelalisib had a partial response, with a 1-month median time to response and a response duration of 16-plus months, reported Dr. Jennifer R. Brown, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston.

In the phase II study conducted by Dr. O’Brien, patients aged 65 years and older with previously untreated CLL were given idelalisib 150 mg twice daily for 48 weeks and rituximab 375 mg/m² once weekly for 8 weeks. Disease status was determined by investigators. Those patients who did not have disease progression after 48 weeks were allowed to stay on therapy in an extension study.

In the primary study, 62 of 64 patients completed the 8 weeks of therapy with rituximab and idelalisib, and 43 completed all 48 weeks. Of the 21 who discontinued therapy, 17 did so because of adverse events, 3 died, and 1 withdrew consent. Of 40 patients enrolled in the extension phase of the trial, 33 were still on study as of May 2013. Of the 7 patients who withdrew from the extension study, 6 did so because of adverse events and 1 withdrew consent.

Of the 64 patients started on the drug combination in the primary study, 12 had a complete response, and 3 of these patients had a 17p deletion and/or TP53 mutation. Partial responses occurred in 50 patients, 6 of whom had mutations or deletions.

In all, 23% of patients in the primary and extension studies had grade 3 diarrhea and/or colitis. Grade 3 or greater pneumonia occurred in 17%, transaminase elevations in 23%, and neutropenia in 28%. Of the patients who discontinued therapy due to adverse events, 5 did so because of respiratory events in the first 24 weeks, and 5 did so because of diarrhea/colitis during the extension study. Other causes of discontinuation were anemia and elevated transaminases.

The study was sponsored by Gilead Sciences. Dr. O’Brien disclosed receiving research funding from the company. Dr. Brown reported having no relevant financial disclosures.

CHICAGO – BROCA, a genetic screening panel that combines BRCA1 and BRCA2 testing with screening for all 18 known breast cancer genes, detected at least one loss of function mutation in 56 of 249 unrelated African American women with breast cancer.

African American women are disproportionately affected by early-onset and triple-negative breast cancers, possibly because of a higher frequency of inherited mutations in DNA repair pathways. The finding of abnormalities in 22% of these women represents the first comprehensive screen of all known breast cancer susceptibility genes using next-generation sequencing in African American women, according to Dr. Jane E. Churpek, who reported the results at the annual meeting of the American Society of Clinical Oncology.

These high carrier frequencies suggest the importance of screening for all gene mutations in African American breast cancer patients who are diagnosed at a young age, have a family history, or have triple-negative breast cancer. The results should be used to encourage testing of at-risk family members to identify those who would benefit from lifesaving interventions, said Dr. Churpek of the University of Chicago.

In the 249-patient study, inherited damaging mutations were seen in 44 of 144 patients with a family history and in 12 of 145 women without a family history of breast and ovarian cancer. Of the 67 women who had triple-negative disease, 20 (30%) had mutations; in the 146 women under age 45, 67 (27%) had mutations.

"Even in the absence of triple-negative disease and family history, there are patients with gene mutations," she said.

While the majority of the 56 women with mutations were positive for BRCA1 (26 patients) or BRCA2 (20 patients), other inherited mutations detected in the BROCA panel were found in 10 patients. Those mutations included CHEK2 (n = 3), PALB2 (n = 3), ATM (n = 5), and PTEN (n = 1), she reported. The study population consisted of women who were treated at the University of Chicago cancer risk and breast cancer clinics.

Having an all-encompassing test like BROCA would allow women to undergo a single test, Dr. Churpek said. Further, advances in technology via targeted genomic capture and next generation sequencing allow this test to be performed inexpensively using 3 mcg of peripheral blood. The current clinical approach to testing requires BRCA1 and BRCA2 testing (BRACAnalysis, Myriad) and possible further testing via a genetic panel, which can be expensive and sometimes difficult to get covered by payers, Dr. Churpek said.

She said there are no plans to market the BROCA test, however. Myriad Genetics holds the U.S. patent on the BRCA genes in the context of cancer diagnostics until 2015. The U.S. Supreme Court is considering the legal issues surrounding the gene patent in the case of Association for Molecular Pathology v. Myriad Genetics. Oral arguments in the case were heard in April, and a decision from the court is expected before July.

Dr. Churpek had no financial disclosures.

[email protected]

On Twitter @maryjodales

CHICAGO – BROCA, a genetic screening panel that combines BRCA1 and BRCA2 testing with screening for all 18 known breast cancer genes, detected at least one loss of function mutation in 56 of 249 unrelated African American women with breast cancer.

African American women are disproportionately affected by early-onset and triple-negative breast cancers, possibly because of a higher frequency of inherited mutations in DNA repair pathways. The finding of abnormalities in 22% of these women represents the first comprehensive screen of all known breast cancer susceptibility genes using next-generation sequencing in African American women, according to Dr. Jane E. Churpek, who reported the results at the annual meeting of the American Society of Clinical Oncology.

These high carrier frequencies suggest the importance of screening for all gene mutations in African American breast cancer patients who are diagnosed at a young age, have a family history, or have triple-negative breast cancer. The results should be used to encourage testing of at-risk family members to identify those who would benefit from lifesaving interventions, said Dr. Churpek of the University of Chicago.

In the 249-patient study, inherited damaging mutations were seen in 44 of 144 patients with a family history and in 12 of 145 women without a family history of breast and ovarian cancer. Of the 67 women who had triple-negative disease, 20 (30%) had mutations; in the 146 women under age 45, 67 (27%) had mutations.

"Even in the absence of triple-negative disease and family history, there are patients with gene mutations," she said.

While the majority of the 56 women with mutations were positive for BRCA1 (26 patients) or BRCA2 (20 patients), other inherited mutations detected in the BROCA panel were found in 10 patients. Those mutations included CHEK2 (n = 3), PALB2 (n = 3), ATM (n = 5), and PTEN (n = 1), she reported. The study population consisted of women who were treated at the University of Chicago cancer risk and breast cancer clinics.

Having an all-encompassing test like BROCA would allow women to undergo a single test, Dr. Churpek said. Further, advances in technology via targeted genomic capture and next generation sequencing allow this test to be performed inexpensively using 3 mcg of peripheral blood. The current clinical approach to testing requires BRCA1 and BRCA2 testing (BRACAnalysis, Myriad) and possible further testing via a genetic panel, which can be expensive and sometimes difficult to get covered by payers, Dr. Churpek said.

She said there are no plans to market the BROCA test, however. Myriad Genetics holds the U.S. patent on the BRCA genes in the context of cancer diagnostics until 2015. The U.S. Supreme Court is considering the legal issues surrounding the gene patent in the case of Association for Molecular Pathology v. Myriad Genetics. Oral arguments in the case were heard in April, and a decision from the court is expected before July.

Dr. Churpek had no financial disclosures.

[email protected]

On Twitter @maryjodales

CHICAGO – BROCA, a genetic screening panel that combines BRCA1 and BRCA2 testing with screening for all 18 known breast cancer genes, detected at least one loss of function mutation in 56 of 249 unrelated African American women with breast cancer.

African American women are disproportionately affected by early-onset and triple-negative breast cancers, possibly because of a higher frequency of inherited mutations in DNA repair pathways. The finding of abnormalities in 22% of these women represents the first comprehensive screen of all known breast cancer susceptibility genes using next-generation sequencing in African American women, according to Dr. Jane E. Churpek, who reported the results at the annual meeting of the American Society of Clinical Oncology.

These high carrier frequencies suggest the importance of screening for all gene mutations in African American breast cancer patients who are diagnosed at a young age, have a family history, or have triple-negative breast cancer. The results should be used to encourage testing of at-risk family members to identify those who would benefit from lifesaving interventions, said Dr. Churpek of the University of Chicago.

In the 249-patient study, inherited damaging mutations were seen in 44 of 144 patients with a family history and in 12 of 145 women without a family history of breast and ovarian cancer. Of the 67 women who had triple-negative disease, 20 (30%) had mutations; in the 146 women under age 45, 67 (27%) had mutations.

"Even in the absence of triple-negative disease and family history, there are patients with gene mutations," she said.

While the majority of the 56 women with mutations were positive for BRCA1 (26 patients) or BRCA2 (20 patients), other inherited mutations detected in the BROCA panel were found in 10 patients. Those mutations included CHEK2 (n = 3), PALB2 (n = 3), ATM (n = 5), and PTEN (n = 1), she reported. The study population consisted of women who were treated at the University of Chicago cancer risk and breast cancer clinics.

Having an all-encompassing test like BROCA would allow women to undergo a single test, Dr. Churpek said. Further, advances in technology via targeted genomic capture and next generation sequencing allow this test to be performed inexpensively using 3 mcg of peripheral blood. The current clinical approach to testing requires BRCA1 and BRCA2 testing (BRACAnalysis, Myriad) and possible further testing via a genetic panel, which can be expensive and sometimes difficult to get covered by payers, Dr. Churpek said.

She said there are no plans to market the BROCA test, however. Myriad Genetics holds the U.S. patent on the BRCA genes in the context of cancer diagnostics until 2015. The U.S. Supreme Court is considering the legal issues surrounding the gene patent in the case of Association for Molecular Pathology v. Myriad Genetics. Oral arguments in the case were heard in April, and a decision from the court is expected before July.

Dr. Churpek had no financial disclosures.

[email protected]

On Twitter @maryjodales

CHICAGO – A new approach to treating the axilla in women with early breast cancer has considerably less morbidity than the current approach, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In the randomized phase III trial – After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) – 1,425 women with early breast cancer were randomized roughly evenly to the current standard of surgical axillary lymph node dissection (ALND) or to axillary radiation therapy. Each participant had a positive sentinel node but clinically negative axillary nodes.

After 5 years of follow-up, the groups had a similarly low rates of cancer recurrence in the axilla of roughly 1%, Dr. Emiel J.T. Rutgers reported on behalf of his coinvestigators with the European Organisation for Research and Treatment of Cancer (EORTC). The radiation therapy group, however, was half as likely as the ALND group to develop lymphedema.

"The trial shows that, if treatment of the axillary lymph nodes in breast cancer is deemed necessary due to larger tumor size and sentinel lymph node involvement, radiotherapy to the axilla is a good alternative – maybe for us a better alternative – as compared to surgery because it’s associated with less side effects and has an extremely good regional cancer control," Dr. Rutgers commented in a press briefing.

The incidence of observed side effects in the radiation therapy group has been decreasing with time, and there is no reason to think that trend will reverse, said Dr. Rutgers, a surgical oncologist at the Netherlands Cancer Institute in Amsterdam. Yet, as late effects can emerge over time, the patients will be followed up for at least another 5 years.

Even though they might perceive surgery to be more effective, women can be reassured that radiation therapy will be adequate treatment, for several reasons, he said. First, only a minority of women with a positive sentinel node actually have other affected nodes. Second, the effectiveness of radiation for local control has been established in the breast conservation setting.

The findings are part of a general trend toward less extensive treatment in breast cancer. "We have shifted from 20 or 30 years ago from mastectomy to breast conservation. And now we will shift from complete axillary treatment to axillary-conserving strategies," he noted.

"It’s really incredible how quickly it seems in the last few years we are rethinking the locoregional management of breast cancer, with less surgery, and perhaps now, maybe an increase for the role of radiotherapy for local control," commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

He agreed that there is a growing philosophy of less is more in the sentinel-node era. "So I would certainly try to assure patients that we try to rely on high-level evidence-based medicine ... that you can do this safely," he said.

There has been increasing uptake of radiation therapy of the axilla in the Netherlands, although it is not yet the standard of care, according to Dr. Rutgers.

Whether it will become standard of care in the United States "will remain to be seen over the next few months when people have a chance to critically review and absorb the data that will be presented today," Dr. Seidman said. "I do expect it is going to change practice at my institution and widely. Extensive surgery in the axilla can be a particular problem for certain selected medical comorbidities, and I suspect at least initially, radiation therapy will be used selectively and thoughtfully based on these data."

The AMAROS trial was open to patients with early invasive breast cancer who had tumors up to 5 cm in diameter and clinically negative lymph nodes. Those with a positive sentinel node were randomized to ALND (n = 744) or axillary radiation therapy (n = 681).

The radiation therapy was to levels I, II, and III and the supraclavicular area. The investigators used contemporary techniques to minimize exposure of healthy tissue. "There was a heavy quality control program for radiotherapy to spare lung and nerves," Dr. Rutgers said.

In the ALND group, the median number of nodes removed was 15. Two-thirds of patients did not have any additional positive nodes, other than the sentinel node.

After a median follow-up of 6.1 years, the rate of axillary recurrence was "extremely low," Dr. Rutgers reported: 0.54% with ALND and 1.03% with axillary radiation therapy.

"The axillary recurrence rate was to me, happily enough, far below that hypothesized [during the trial’s planning]; hence, the trial was underpowered," he noted in the session where the findings were presented.

The groups were statistically indistinguishable in estimated 5-year rates of overall survival, at about 93%, and disease-free survival, at about 85%.

The 5-year rate of lymphedema – defined in the study as the need for treatment with a sleeve garment, compression therapy, or lymph drainage therapy, or presence of the condition on physical examination – was 28% with ALND and 14% with axillary radiation therapy (P less than .0001), according to Dr. Rutgers.

"The side effects of radiotherapy cannot be neglected but are limited," he commented. "We looked at many other potential side effects of radiotherapy. There was no excess of cardiac problems, a very small excess of radiation pneumonitis; there was no effect on the brachial nerves."

The groups did not differ with respect to overall quality of life, but there were trends toward greater difficulty moving the arm after radiation therapy and greater swelling after ALND.

Dr. Rutgers disclosed no conflicts of interest related to the research.

CHICAGO – A new approach to treating the axilla in women with early breast cancer has considerably less morbidity than the current approach, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In the randomized phase III trial – After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) – 1,425 women with early breast cancer were randomized roughly evenly to the current standard of surgical axillary lymph node dissection (ALND) or to axillary radiation therapy. Each participant had a positive sentinel node but clinically negative axillary nodes.

After 5 years of follow-up, the groups had a similarly low rates of cancer recurrence in the axilla of roughly 1%, Dr. Emiel J.T. Rutgers reported on behalf of his coinvestigators with the European Organisation for Research and Treatment of Cancer (EORTC). The radiation therapy group, however, was half as likely as the ALND group to develop lymphedema.

"The trial shows that, if treatment of the axillary lymph nodes in breast cancer is deemed necessary due to larger tumor size and sentinel lymph node involvement, radiotherapy to the axilla is a good alternative – maybe for us a better alternative – as compared to surgery because it’s associated with less side effects and has an extremely good regional cancer control," Dr. Rutgers commented in a press briefing.

The incidence of observed side effects in the radiation therapy group has been decreasing with time, and there is no reason to think that trend will reverse, said Dr. Rutgers, a surgical oncologist at the Netherlands Cancer Institute in Amsterdam. Yet, as late effects can emerge over time, the patients will be followed up for at least another 5 years.

Even though they might perceive surgery to be more effective, women can be reassured that radiation therapy will be adequate treatment, for several reasons, he said. First, only a minority of women with a positive sentinel node actually have other affected nodes. Second, the effectiveness of radiation for local control has been established in the breast conservation setting.

The findings are part of a general trend toward less extensive treatment in breast cancer. "We have shifted from 20 or 30 years ago from mastectomy to breast conservation. And now we will shift from complete axillary treatment to axillary-conserving strategies," he noted.

"It’s really incredible how quickly it seems in the last few years we are rethinking the locoregional management of breast cancer, with less surgery, and perhaps now, maybe an increase for the role of radiotherapy for local control," commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

He agreed that there is a growing philosophy of less is more in the sentinel-node era. "So I would certainly try to assure patients that we try to rely on high-level evidence-based medicine ... that you can do this safely," he said.

There has been increasing uptake of radiation therapy of the axilla in the Netherlands, although it is not yet the standard of care, according to Dr. Rutgers.

Whether it will become standard of care in the United States "will remain to be seen over the next few months when people have a chance to critically review and absorb the data that will be presented today," Dr. Seidman said. "I do expect it is going to change practice at my institution and widely. Extensive surgery in the axilla can be a particular problem for certain selected medical comorbidities, and I suspect at least initially, radiation therapy will be used selectively and thoughtfully based on these data."

The AMAROS trial was open to patients with early invasive breast cancer who had tumors up to 5 cm in diameter and clinically negative lymph nodes. Those with a positive sentinel node were randomized to ALND (n = 744) or axillary radiation therapy (n = 681).

The radiation therapy was to levels I, II, and III and the supraclavicular area. The investigators used contemporary techniques to minimize exposure of healthy tissue. "There was a heavy quality control program for radiotherapy to spare lung and nerves," Dr. Rutgers said.

In the ALND group, the median number of nodes removed was 15. Two-thirds of patients did not have any additional positive nodes, other than the sentinel node.

After a median follow-up of 6.1 years, the rate of axillary recurrence was "extremely low," Dr. Rutgers reported: 0.54% with ALND and 1.03% with axillary radiation therapy.

"The axillary recurrence rate was to me, happily enough, far below that hypothesized [during the trial’s planning]; hence, the trial was underpowered," he noted in the session where the findings were presented.

The groups were statistically indistinguishable in estimated 5-year rates of overall survival, at about 93%, and disease-free survival, at about 85%.

The 5-year rate of lymphedema – defined in the study as the need for treatment with a sleeve garment, compression therapy, or lymph drainage therapy, or presence of the condition on physical examination – was 28% with ALND and 14% with axillary radiation therapy (P less than .0001), according to Dr. Rutgers.

"The side effects of radiotherapy cannot be neglected but are limited," he commented. "We looked at many other potential side effects of radiotherapy. There was no excess of cardiac problems, a very small excess of radiation pneumonitis; there was no effect on the brachial nerves."

The groups did not differ with respect to overall quality of life, but there were trends toward greater difficulty moving the arm after radiation therapy and greater swelling after ALND.

Dr. Rutgers disclosed no conflicts of interest related to the research.

CHICAGO – A new approach to treating the axilla in women with early breast cancer has considerably less morbidity than the current approach, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In the randomized phase III trial – After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) – 1,425 women with early breast cancer were randomized roughly evenly to the current standard of surgical axillary lymph node dissection (ALND) or to axillary radiation therapy. Each participant had a positive sentinel node but clinically negative axillary nodes.

After 5 years of follow-up, the groups had a similarly low rates of cancer recurrence in the axilla of roughly 1%, Dr. Emiel J.T. Rutgers reported on behalf of his coinvestigators with the European Organisation for Research and Treatment of Cancer (EORTC). The radiation therapy group, however, was half as likely as the ALND group to develop lymphedema.

"The trial shows that, if treatment of the axillary lymph nodes in breast cancer is deemed necessary due to larger tumor size and sentinel lymph node involvement, radiotherapy to the axilla is a good alternative – maybe for us a better alternative – as compared to surgery because it’s associated with less side effects and has an extremely good regional cancer control," Dr. Rutgers commented in a press briefing.

The incidence of observed side effects in the radiation therapy group has been decreasing with time, and there is no reason to think that trend will reverse, said Dr. Rutgers, a surgical oncologist at the Netherlands Cancer Institute in Amsterdam. Yet, as late effects can emerge over time, the patients will be followed up for at least another 5 years.

Even though they might perceive surgery to be more effective, women can be reassured that radiation therapy will be adequate treatment, for several reasons, he said. First, only a minority of women with a positive sentinel node actually have other affected nodes. Second, the effectiveness of radiation for local control has been established in the breast conservation setting.

The findings are part of a general trend toward less extensive treatment in breast cancer. "We have shifted from 20 or 30 years ago from mastectomy to breast conservation. And now we will shift from complete axillary treatment to axillary-conserving strategies," he noted.

"It’s really incredible how quickly it seems in the last few years we are rethinking the locoregional management of breast cancer, with less surgery, and perhaps now, maybe an increase for the role of radiotherapy for local control," commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

He agreed that there is a growing philosophy of less is more in the sentinel-node era. "So I would certainly try to assure patients that we try to rely on high-level evidence-based medicine ... that you can do this safely," he said.

There has been increasing uptake of radiation therapy of the axilla in the Netherlands, although it is not yet the standard of care, according to Dr. Rutgers.

Whether it will become standard of care in the United States "will remain to be seen over the next few months when people have a chance to critically review and absorb the data that will be presented today," Dr. Seidman said. "I do expect it is going to change practice at my institution and widely. Extensive surgery in the axilla can be a particular problem for certain selected medical comorbidities, and I suspect at least initially, radiation therapy will be used selectively and thoughtfully based on these data."

The AMAROS trial was open to patients with early invasive breast cancer who had tumors up to 5 cm in diameter and clinically negative lymph nodes. Those with a positive sentinel node were randomized to ALND (n = 744) or axillary radiation therapy (n = 681).

The radiation therapy was to levels I, II, and III and the supraclavicular area. The investigators used contemporary techniques to minimize exposure of healthy tissue. "There was a heavy quality control program for radiotherapy to spare lung and nerves," Dr. Rutgers said.

In the ALND group, the median number of nodes removed was 15. Two-thirds of patients did not have any additional positive nodes, other than the sentinel node.

After a median follow-up of 6.1 years, the rate of axillary recurrence was "extremely low," Dr. Rutgers reported: 0.54% with ALND and 1.03% with axillary radiation therapy.

"The axillary recurrence rate was to me, happily enough, far below that hypothesized [during the trial’s planning]; hence, the trial was underpowered," he noted in the session where the findings were presented.

The groups were statistically indistinguishable in estimated 5-year rates of overall survival, at about 93%, and disease-free survival, at about 85%.

The 5-year rate of lymphedema – defined in the study as the need for treatment with a sleeve garment, compression therapy, or lymph drainage therapy, or presence of the condition on physical examination – was 28% with ALND and 14% with axillary radiation therapy (P less than .0001), according to Dr. Rutgers.

"The side effects of radiotherapy cannot be neglected but are limited," he commented. "We looked at many other potential side effects of radiotherapy. There was no excess of cardiac problems, a very small excess of radiation pneumonitis; there was no effect on the brachial nerves."

The groups did not differ with respect to overall quality of life, but there were trends toward greater difficulty moving the arm after radiation therapy and greater swelling after ALND.

Dr. Rutgers disclosed no conflicts of interest related to the research.

CHICAGO – Weekly paclitaxel is just as efficacious as dose-dense paclitaxel when it comes to adjuvant chemotherapy for breast cancer, but the weekly schedule has lower rates of certain important toxicities, according to data presented at the annual meeting of the American Society of Clinical Oncology.

The Southwest Oncology Group’s S0221 randomized trial tested combination chemotherapy regimens among 3,294 patients who had completed local therapy for early breast cancer.

Half of the patients received lower-dose paclitaxel (Taxol) weekly for twelve cycles, while the other half received standard-dose paclitaxel every 2 weeks for six cycles according to a dose-dense schedule. The dose-dense schedule used in the trial was longer than the standard dose-dense schedule (six cycles vs. four cycles) so that the groups would be on treatment for the same total duration (12 weeks).

The 5-year rate of disease-free survival was equally high, about 80%, with each schedule, reported lead study author Dr. G. Thomas Budd, a medical oncologist at the Cleveland Clinic. The weekly schedule, however, yielded significantly lower rates of grade 3/4 musculoskeletal pain, allergy, and neurotoxicity.

"Either schedule of administration can be recommended based on efficacy, so in practice, treatment can be selected based on other considerations such as toxicity. ... It can be individualized by the patient and their physician," he said. "I think there will be a move to more weekly treatment since hematopoietic growth factor support is not required."

Treatment duration and frequency also might tip the decision one way or another for some patients, he added in a related press briefing, as patients given paclitaxel every 2 weeks with the current practice of four cycles will finish chemotherapy sooner, and patients on the weekly schedule will have to travel to the infusion center more often.

"I think that it’s remarkable that after two decades [since paclitaxel’s approval] we are still asking questions on how to teach an old dog new tricks, so to speak," commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

"For me, this is actually going to change my practice because I have generally given" paclitaxel every 2 weeks, he said. "These data suggest to me that I can get the same benefit with less toxicity [with the weekly schedule], possibly with less cost. Although there was no formal economic analysis, the cost of growth factor support is not trivial."

In addition, "there are patients for whom fine motor skills are very important to their livelihood, and they will be happy to hear this news" about less neurotoxicity with weekly scheduling, he said.

The S0221 trial enrolled patients with stage I-III breast cancer who had received adequate local therapy (resection and radiation therapy). Investigators randomized them twice with a factorial design.

The first randomization was for a doxorubicin and cyclophosphamide schedule – investigational (weekly) versus standard (every 2 weeks). This randomization was discontinued because the investigational schedule was not more efficacious; all patients thereafter received the standard schedule, according to Dr. Budd.

The second randomization was for the schedule of paclitaxel – either a lower-dose weekly schedule (80 mg/m² every week × 12 weeks) or a dose-dense schedule (175 mg/m² every 2 weeks × 6 weeks) – with granulocytecolony-stimulating factor (pegfilgrastim) support.

Efficacy results showed that the weekly and every-2-week schedules yielded statistically indistinguishable estimated 5-year disease-free survival (82% for the former and 81% for the latter).

"Since this was not conducted as a noninferiority study, we cannot make a conclusion about the lack of difference. However, the Kaplan-Meier curves and the computed hazard ratios suggest little difference in efficacy between these two arms," Dr. Budd commented.

There was also no significant difference between the paclitaxel schedules in overall survival; median values have not been reached.

The findings were generally similar in patient subgroups stratified according to tumor hormone receptor and HER2 status, and, within the HER2-positive group, according to receipt of trastuzumab (Herceptin).

There was no significant difference in the overall rate of grade 3/4 adverse events with the weekly versus every-2-week schedules (35% vs. 36%), but there were differences in rates of individual types of events.

The weekly schedule was associated with significantly lower rates of allergic reaction (0.6% vs. 1.4%), musculoskeletal pain (3% vs. 11%), and neurotoxicity (10% vs. 17%), although the difference in neurotoxicity may have been smaller had the patients in the dose-dense group received only four cycles of every-2-week paclitaxel (as is current practice) rather than six cycles, Dr. Budd acknowledged.

On the flip side, the weekly schedule was associated with significantly higher rates of grade 3/4 hematologic toxicity (17% vs. 6%), leukopenia (6% vs. 1%), and neutropenia (11% vs. 2%). It’s important to remember, however, that "these patients had their counts checked more frequently, they did not receive hematopoietic growth factors, and the rates of infectious complications were not different between the two arms," he said.

The investigators have not performed a formal pharmacoeconomic analysis, according to Dr. Budd, but "the weekly schedule is somewhere between a third and two-thirds less expensive, just on the basis of calculating drug costs."

Dr. Budd disclosed that he is a consultant to Amgen, maker of pegfilgrastim (Neulasta).

CHICAGO – Weekly paclitaxel is just as efficacious as dose-dense paclitaxel when it comes to adjuvant chemotherapy for breast cancer, but the weekly schedule has lower rates of certain important toxicities, according to data presented at the annual meeting of the American Society of Clinical Oncology.

The Southwest Oncology Group’s S0221 randomized trial tested combination chemotherapy regimens among 3,294 patients who had completed local therapy for early breast cancer.

Half of the patients received lower-dose paclitaxel (Taxol) weekly for twelve cycles, while the other half received standard-dose paclitaxel every 2 weeks for six cycles according to a dose-dense schedule. The dose-dense schedule used in the trial was longer than the standard dose-dense schedule (six cycles vs. four cycles) so that the groups would be on treatment for the same total duration (12 weeks).

The 5-year rate of disease-free survival was equally high, about 80%, with each schedule, reported lead study author Dr. G. Thomas Budd, a medical oncologist at the Cleveland Clinic. The weekly schedule, however, yielded significantly lower rates of grade 3/4 musculoskeletal pain, allergy, and neurotoxicity.

"Either schedule of administration can be recommended based on efficacy, so in practice, treatment can be selected based on other considerations such as toxicity. ... It can be individualized by the patient and their physician," he said. "I think there will be a move to more weekly treatment since hematopoietic growth factor support is not required."

Treatment duration and frequency also might tip the decision one way or another for some patients, he added in a related press briefing, as patients given paclitaxel every 2 weeks with the current practice of four cycles will finish chemotherapy sooner, and patients on the weekly schedule will have to travel to the infusion center more often.

"I think that it’s remarkable that after two decades [since paclitaxel’s approval] we are still asking questions on how to teach an old dog new tricks, so to speak," commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

"For me, this is actually going to change my practice because I have generally given" paclitaxel every 2 weeks, he said. "These data suggest to me that I can get the same benefit with less toxicity [with the weekly schedule], possibly with less cost. Although there was no formal economic analysis, the cost of growth factor support is not trivial."

In addition, "there are patients for whom fine motor skills are very important to their livelihood, and they will be happy to hear this news" about less neurotoxicity with weekly scheduling, he said.

The S0221 trial enrolled patients with stage I-III breast cancer who had received adequate local therapy (resection and radiation therapy). Investigators randomized them twice with a factorial design.

The first randomization was for a doxorubicin and cyclophosphamide schedule – investigational (weekly) versus standard (every 2 weeks). This randomization was discontinued because the investigational schedule was not more efficacious; all patients thereafter received the standard schedule, according to Dr. Budd.

The second randomization was for the schedule of paclitaxel – either a lower-dose weekly schedule (80 mg/m² every week × 12 weeks) or a dose-dense schedule (175 mg/m² every 2 weeks × 6 weeks) – with granulocytecolony-stimulating factor (pegfilgrastim) support.

Efficacy results showed that the weekly and every-2-week schedules yielded statistically indistinguishable estimated 5-year disease-free survival (82% for the former and 81% for the latter).

"Since this was not conducted as a noninferiority study, we cannot make a conclusion about the lack of difference. However, the Kaplan-Meier curves and the computed hazard ratios suggest little difference in efficacy between these two arms," Dr. Budd commented.

There was also no significant difference between the paclitaxel schedules in overall survival; median values have not been reached.

The findings were generally similar in patient subgroups stratified according to tumor hormone receptor and HER2 status, and, within the HER2-positive group, according to receipt of trastuzumab (Herceptin).

There was no significant difference in the overall rate of grade 3/4 adverse events with the weekly versus every-2-week schedules (35% vs. 36%), but there were differences in rates of individual types of events.

The weekly schedule was associated with significantly lower rates of allergic reaction (0.6% vs. 1.4%), musculoskeletal pain (3% vs. 11%), and neurotoxicity (10% vs. 17%), although the difference in neurotoxicity may have been smaller had the patients in the dose-dense group received only four cycles of every-2-week paclitaxel (as is current practice) rather than six cycles, Dr. Budd acknowledged.

On the flip side, the weekly schedule was associated with significantly higher rates of grade 3/4 hematologic toxicity (17% vs. 6%), leukopenia (6% vs. 1%), and neutropenia (11% vs. 2%). It’s important to remember, however, that "these patients had their counts checked more frequently, they did not receive hematopoietic growth factors, and the rates of infectious complications were not different between the two arms," he said.

The investigators have not performed a formal pharmacoeconomic analysis, according to Dr. Budd, but "the weekly schedule is somewhere between a third and two-thirds less expensive, just on the basis of calculating drug costs."

Dr. Budd disclosed that he is a consultant to Amgen, maker of pegfilgrastim (Neulasta).

CHICAGO – Weekly paclitaxel is just as efficacious as dose-dense paclitaxel when it comes to adjuvant chemotherapy for breast cancer, but the weekly schedule has lower rates of certain important toxicities, according to data presented at the annual meeting of the American Society of Clinical Oncology.

The Southwest Oncology Group’s S0221 randomized trial tested combination chemotherapy regimens among 3,294 patients who had completed local therapy for early breast cancer.

Half of the patients received lower-dose paclitaxel (Taxol) weekly for twelve cycles, while the other half received standard-dose paclitaxel every 2 weeks for six cycles according to a dose-dense schedule. The dose-dense schedule used in the trial was longer than the standard dose-dense schedule (six cycles vs. four cycles) so that the groups would be on treatment for the same total duration (12 weeks).

The 5-year rate of disease-free survival was equally high, about 80%, with each schedule, reported lead study author Dr. G. Thomas Budd, a medical oncologist at the Cleveland Clinic. The weekly schedule, however, yielded significantly lower rates of grade 3/4 musculoskeletal pain, allergy, and neurotoxicity.

"Either schedule of administration can be recommended based on efficacy, so in practice, treatment can be selected based on other considerations such as toxicity. ... It can be individualized by the patient and their physician," he said. "I think there will be a move to more weekly treatment since hematopoietic growth factor support is not required."

Treatment duration and frequency also might tip the decision one way or another for some patients, he added in a related press briefing, as patients given paclitaxel every 2 weeks with the current practice of four cycles will finish chemotherapy sooner, and patients on the weekly schedule will have to travel to the infusion center more often.

"I think that it’s remarkable that after two decades [since paclitaxel’s approval] we are still asking questions on how to teach an old dog new tricks, so to speak," commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.

"For me, this is actually going to change my practice because I have generally given" paclitaxel every 2 weeks, he said. "These data suggest to me that I can get the same benefit with less toxicity [with the weekly schedule], possibly with less cost. Although there was no formal economic analysis, the cost of growth factor support is not trivial."

In addition, "there are patients for whom fine motor skills are very important to their livelihood, and they will be happy to hear this news" about less neurotoxicity with weekly scheduling, he said.

The S0221 trial enrolled patients with stage I-III breast cancer who had received adequate local therapy (resection and radiation therapy). Investigators randomized them twice with a factorial design.

The first randomization was for a doxorubicin and cyclophosphamide schedule – investigational (weekly) versus standard (every 2 weeks). This randomization was discontinued because the investigational schedule was not more efficacious; all patients thereafter received the standard schedule, according to Dr. Budd.

The second randomization was for the schedule of paclitaxel – either a lower-dose weekly schedule (80 mg/m² every week × 12 weeks) or a dose-dense schedule (175 mg/m² every 2 weeks × 6 weeks) – with granulocytecolony-stimulating factor (pegfilgrastim) support.

Efficacy results showed that the weekly and every-2-week schedules yielded statistically indistinguishable estimated 5-year disease-free survival (82% for the former and 81% for the latter).

"Since this was not conducted as a noninferiority study, we cannot make a conclusion about the lack of difference. However, the Kaplan-Meier curves and the computed hazard ratios suggest little difference in efficacy between these two arms," Dr. Budd commented.

There was also no significant difference between the paclitaxel schedules in overall survival; median values have not been reached.

The findings were generally similar in patient subgroups stratified according to tumor hormone receptor and HER2 status, and, within the HER2-positive group, according to receipt of trastuzumab (Herceptin).

There was no significant difference in the overall rate of grade 3/4 adverse events with the weekly versus every-2-week schedules (35% vs. 36%), but there were differences in rates of individual types of events.

The weekly schedule was associated with significantly lower rates of allergic reaction (0.6% vs. 1.4%), musculoskeletal pain (3% vs. 11%), and neurotoxicity (10% vs. 17%), although the difference in neurotoxicity may have been smaller had the patients in the dose-dense group received only four cycles of every-2-week paclitaxel (as is current practice) rather than six cycles, Dr. Budd acknowledged.

On the flip side, the weekly schedule was associated with significantly higher rates of grade 3/4 hematologic toxicity (17% vs. 6%), leukopenia (6% vs. 1%), and neutropenia (11% vs. 2%). It’s important to remember, however, that "these patients had their counts checked more frequently, they did not receive hematopoietic growth factors, and the rates of infectious complications were not different between the two arms," he said.

The investigators have not performed a formal pharmacoeconomic analysis, according to Dr. Budd, but "the weekly schedule is somewhere between a third and two-thirds less expensive, just on the basis of calculating drug costs."

Dr. Budd disclosed that he is a consultant to Amgen, maker of pegfilgrastim (Neulasta).

CHICAGO – A second study shows that 10 years of adjuvant tamoxifen is superior to the standard five years in women with estrogen receptor-positive early breast cancer.

Among nearly 7,000 women randomized in the aTTom (Adjuvant Tamoxifen Treatment Offers More) study, extended tamoxifen significantly reduced the risk of recurrence from 32% to 28% in the 10 years or more after diagnosis (P = .003).

This translated into a borderline significant difference in breast cancer mortality, reducing it from 24% to 21% (P = .06), Richard Gray, M.Sc., reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Just 6 months ago, Prof. Gray reported that recurrences were down 25% and breast cancer deaths down 29% in years 10-14 after diagnosis in women on tamoxifen for 10 years in the companion ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial.

The benefits came at a cost, however. Extended exposure to tamoxifen in aTTom more than doubled the number of endometrial cancers (102 vs. 45 cases; rate ratio, 2.20; P less than .0001) and significantly increased the risk of dying from it (37 vs. 20 deaths; RR, 1.83; P = .02).

On a population basis, the benefits in reduced breast cancer mortality outweigh the risks, according to Prof. Gray, professor of medical statistics at the University of Oxford (U.K.).

Monitoring with ultrasound for endometrial changes could improve early detection and reduce the impact of this known toxicity, Dr. Hope S. Rugo, director of the breast oncology clinical trials program at the University of California, San Francisco, said in an interview. This risk is also known to vary considerably by age.

"The dramatic findings presented in the aTTom study today will clearly have a significant impact on clinical practice on Monday and are arguably some of the most important data for the treatment of women with early-stage, hormone receptor–positive breast cancer," she said.

The decision to continue tamoxifen beyond the recommended 5 years should be based on the extent of residual risk of recurrence, and must be balanced against tolerability and alternative options, Dr. Rugo said. Extended-duration tamoxifen is a particularly important option for women at risk for late relapse, who are not candidates for aromatase inhibitors because of menopausal status or tolerability.

Great option for premenopausal women

For women who remain premenopausal on tamoxifen, "extended tamoxifen is a great option where there has been no prior standard," said Dr. Ann H. Partridge, who founded the young women with breast cancer program at Boston’s Dana-Farber Cancer Institute and who was invited to discuss the study during the plenary session. These women have a higher risk of disease, and therefore potentially have the greatest risk reduction and lowest risk of serious toxicity, including an almost negligible risk of endometrial cancer.

She went on to say that the personal cost, however, in this population may be the greatest, referring to fertility. Interestingly, ATLAS also reported a significant increase in pulmonary embolism, but it was coupled with a decrease in ischemic heart disease (Lancet 2012 ;805-16 [doi:10.1016/s0140-6736(12)61963-1]). Cardiovascular events have not been reported for aTTOM.

Adherence, which is a challenge in the real world, quality of life, and symptoms such as vasomotor symptoms, alterations in mood, sexual functioning, and musculoskeletal problems also must be considered, Dr. Partridge said.

"We all know that minor side effects can become deeply troubling over time in this setting," she said.

ASCO spokesperson Dr. Sylvia Adams, a breast cancer specialist at New York University Langone Medical Center said in a statement that the results are practice changing for premenopausal women with hormone receptor–positive breast cancer, and especially relevant for women at high risk of recurrence.

A retrospective analysis of combined data from aTTom, ATLAS, and three smaller trials is planned to determine whether certain subgroups of women are most likely to benefit from longer tamoxifen treatment, according to Prof. Gray.

Tamoxifen compliance was about 75%

The aTTom study randomly assigned 6,953 women with estrogen receptor–positive (40%) or ER-untested invasive breast cancer (80% estimated to be ER+) who had been taking tamoxifen for 5 years to continue tamoxifen for another 5 years or stop immediately. Tamoxifen compliance in the continuation arm was about 75%.

Breast cancer recurred in 580 women allocated to continue tamoxifen and 672 randomized to stop (RR, 0.85; P = .003). There was no benefit in years 5-6 after diagnosis (odds ratio, 1.17), but began to emerge later on, in years 7-9 (OR, 0.99), years 10-14 (OR, 0.79) and 15 years or later (0.75), Prof. Gray said.

Breast cancer deaths were reported in 404 patients on extended tamoxifen and 452 patients in the 5-year group (RR, 0.88; P = .06).

Tamoxifen had little effect on all-cause mortality in the extended and 5-year groups (885 vs. 939 deaths; P = .2).

The aTTom study was funded by Cancer Research UK and the UK Medical Research Council. Prof. Gray reported having no financial conflicts. Dr. Partridge said she had no relevant disclosures.

[email protected]

CHICAGO – A second study shows that 10 years of adjuvant tamoxifen is superior to the standard five years in women with estrogen receptor-positive early breast cancer.

Among nearly 7,000 women randomized in the aTTom (Adjuvant Tamoxifen Treatment Offers More) study, extended tamoxifen significantly reduced the risk of recurrence from 32% to 28% in the 10 years or more after diagnosis (P = .003).

This translated into a borderline significant difference in breast cancer mortality, reducing it from 24% to 21% (P = .06), Richard Gray, M.Sc., reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Just 6 months ago, Prof. Gray reported that recurrences were down 25% and breast cancer deaths down 29% in years 10-14 after diagnosis in women on tamoxifen for 10 years in the companion ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial.

The benefits came at a cost, however. Extended exposure to tamoxifen in aTTom more than doubled the number of endometrial cancers (102 vs. 45 cases; rate ratio, 2.20; P less than .0001) and significantly increased the risk of dying from it (37 vs. 20 deaths; RR, 1.83; P = .02).

On a population basis, the benefits in reduced breast cancer mortality outweigh the risks, according to Prof. Gray, professor of medical statistics at the University of Oxford (U.K.).

Monitoring with ultrasound for endometrial changes could improve early detection and reduce the impact of this known toxicity, Dr. Hope S. Rugo, director of the breast oncology clinical trials program at the University of California, San Francisco, said in an interview. This risk is also known to vary considerably by age.

"The dramatic findings presented in the aTTom study today will clearly have a significant impact on clinical practice on Monday and are arguably some of the most important data for the treatment of women with early-stage, hormone receptor–positive breast cancer," she said.

The decision to continue tamoxifen beyond the recommended 5 years should be based on the extent of residual risk of recurrence, and must be balanced against tolerability and alternative options, Dr. Rugo said. Extended-duration tamoxifen is a particularly important option for women at risk for late relapse, who are not candidates for aromatase inhibitors because of menopausal status or tolerability.

Great option for premenopausal women

For women who remain premenopausal on tamoxifen, "extended tamoxifen is a great option where there has been no prior standard," said Dr. Ann H. Partridge, who founded the young women with breast cancer program at Boston’s Dana-Farber Cancer Institute and who was invited to discuss the study during the plenary session. These women have a higher risk of disease, and therefore potentially have the greatest risk reduction and lowest risk of serious toxicity, including an almost negligible risk of endometrial cancer.

She went on to say that the personal cost, however, in this population may be the greatest, referring to fertility. Interestingly, ATLAS also reported a significant increase in pulmonary embolism, but it was coupled with a decrease in ischemic heart disease (Lancet 2012 ;805-16 [doi:10.1016/s0140-6736(12)61963-1]). Cardiovascular events have not been reported for aTTOM.

Adherence, which is a challenge in the real world, quality of life, and symptoms such as vasomotor symptoms, alterations in mood, sexual functioning, and musculoskeletal problems also must be considered, Dr. Partridge said.

"We all know that minor side effects can become deeply troubling over time in this setting," she said.

ASCO spokesperson Dr. Sylvia Adams, a breast cancer specialist at New York University Langone Medical Center said in a statement that the results are practice changing for premenopausal women with hormone receptor–positive breast cancer, and especially relevant for women at high risk of recurrence.

A retrospective analysis of combined data from aTTom, ATLAS, and three smaller trials is planned to determine whether certain subgroups of women are most likely to benefit from longer tamoxifen treatment, according to Prof. Gray.

Tamoxifen compliance was about 75%

The aTTom study randomly assigned 6,953 women with estrogen receptor–positive (40%) or ER-untested invasive breast cancer (80% estimated to be ER+) who had been taking tamoxifen for 5 years to continue tamoxifen for another 5 years or stop immediately. Tamoxifen compliance in the continuation arm was about 75%.

Breast cancer recurred in 580 women allocated to continue tamoxifen and 672 randomized to stop (RR, 0.85; P = .003). There was no benefit in years 5-6 after diagnosis (odds ratio, 1.17), but began to emerge later on, in years 7-9 (OR, 0.99), years 10-14 (OR, 0.79) and 15 years or later (0.75), Prof. Gray said.

Breast cancer deaths were reported in 404 patients on extended tamoxifen and 452 patients in the 5-year group (RR, 0.88; P = .06).

Tamoxifen had little effect on all-cause mortality in the extended and 5-year groups (885 vs. 939 deaths; P = .2).

The aTTom study was funded by Cancer Research UK and the UK Medical Research Council. Prof. Gray reported having no financial conflicts. Dr. Partridge said she had no relevant disclosures.

[email protected]

CHICAGO – A second study shows that 10 years of adjuvant tamoxifen is superior to the standard five years in women with estrogen receptor-positive early breast cancer.

Among nearly 7,000 women randomized in the aTTom (Adjuvant Tamoxifen Treatment Offers More) study, extended tamoxifen significantly reduced the risk of recurrence from 32% to 28% in the 10 years or more after diagnosis (P = .003).

This translated into a borderline significant difference in breast cancer mortality, reducing it from 24% to 21% (P = .06), Richard Gray, M.Sc., reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Just 6 months ago, Prof. Gray reported that recurrences were down 25% and breast cancer deaths down 29% in years 10-14 after diagnosis in women on tamoxifen for 10 years in the companion ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial.

The benefits came at a cost, however. Extended exposure to tamoxifen in aTTom more than doubled the number of endometrial cancers (102 vs. 45 cases; rate ratio, 2.20; P less than .0001) and significantly increased the risk of dying from it (37 vs. 20 deaths; RR, 1.83; P = .02).

On a population basis, the benefits in reduced breast cancer mortality outweigh the risks, according to Prof. Gray, professor of medical statistics at the University of Oxford (U.K.).

Monitoring with ultrasound for endometrial changes could improve early detection and reduce the impact of this known toxicity, Dr. Hope S. Rugo, director of the breast oncology clinical trials program at the University of California, San Francisco, said in an interview. This risk is also known to vary considerably by age.

"The dramatic findings presented in the aTTom study today will clearly have a significant impact on clinical practice on Monday and are arguably some of the most important data for the treatment of women with early-stage, hormone receptor–positive breast cancer," she said.

The decision to continue tamoxifen beyond the recommended 5 years should be based on the extent of residual risk of recurrence, and must be balanced against tolerability and alternative options, Dr. Rugo said. Extended-duration tamoxifen is a particularly important option for women at risk for late relapse, who are not candidates for aromatase inhibitors because of menopausal status or tolerability.

Great option for premenopausal women

For women who remain premenopausal on tamoxifen, "extended tamoxifen is a great option where there has been no prior standard," said Dr. Ann H. Partridge, who founded the young women with breast cancer program at Boston’s Dana-Farber Cancer Institute and who was invited to discuss the study during the plenary session. These women have a higher risk of disease, and therefore potentially have the greatest risk reduction and lowest risk of serious toxicity, including an almost negligible risk of endometrial cancer.

She went on to say that the personal cost, however, in this population may be the greatest, referring to fertility. Interestingly, ATLAS also reported a significant increase in pulmonary embolism, but it was coupled with a decrease in ischemic heart disease (Lancet 2012 ;805-16 [doi:10.1016/s0140-6736(12)61963-1]). Cardiovascular events have not been reported for aTTOM.

Adherence, which is a challenge in the real world, quality of life, and symptoms such as vasomotor symptoms, alterations in mood, sexual functioning, and musculoskeletal problems also must be considered, Dr. Partridge said.

"We all know that minor side effects can become deeply troubling over time in this setting," she said.

ASCO spokesperson Dr. Sylvia Adams, a breast cancer specialist at New York University Langone Medical Center said in a statement that the results are practice changing for premenopausal women with hormone receptor–positive breast cancer, and especially relevant for women at high risk of recurrence.

A retrospective analysis of combined data from aTTom, ATLAS, and three smaller trials is planned to determine whether certain subgroups of women are most likely to benefit from longer tamoxifen treatment, according to Prof. Gray.

Tamoxifen compliance was about 75%

The aTTom study randomly assigned 6,953 women with estrogen receptor–positive (40%) or ER-untested invasive breast cancer (80% estimated to be ER+) who had been taking tamoxifen for 5 years to continue tamoxifen for another 5 years or stop immediately. Tamoxifen compliance in the continuation arm was about 75%.

Breast cancer recurred in 580 women allocated to continue tamoxifen and 672 randomized to stop (RR, 0.85; P = .003). There was no benefit in years 5-6 after diagnosis (odds ratio, 1.17), but began to emerge later on, in years 7-9 (OR, 0.99), years 10-14 (OR, 0.79) and 15 years or later (0.75), Prof. Gray said.

Breast cancer deaths were reported in 404 patients on extended tamoxifen and 452 patients in the 5-year group (RR, 0.88; P = .06).

Tamoxifen had little effect on all-cause mortality in the extended and 5-year groups (885 vs. 939 deaths; P = .2).

The aTTom study was funded by Cancer Research UK and the UK Medical Research Council. Prof. Gray reported having no financial conflicts. Dr. Partridge said she had no relevant disclosures.

[email protected]