2012 ASCO Annual Meeting

CHICAGO – First-line afatinib delayed progression for nearly a year in patients with advanced lung cancer carrying epidermal growth factor mutations, according to much-anticipated results from the phase III LUX-Lung 3 trial.

Median progression-free survival reached 11.1 months with the experimental oral agent, compared with 6.9 months with cisplatin plus pemetrexed (Alimta) chemotherapy (hazard ratio, 0.58; P = .0004), investigators reported. At 1 year, more than twice as many patients were progression free on afatinib (47% vs. 22%).

The median reached 13.6 months in afatinib-treated patients who harbored the most common EGFR (epidermal growth factor receptor) mutations – exon deletion 19 or exon 21 L858R – which account for 90% of all EGFR mutations, but stayed at 6.9 months in the control group (HR, 0.47; P less than .0001). The progression-free survival rate was more than twice as high at 1 year with afatinib (51% vs. 21%).

Patrice Wendling/IMNG Medical Media

Patients who were treated with the novel, second-generation TKI (tyrosine kinase inhibitor) also had better sustained tumor shrinkage and improved quality of life than did those treated with standard cisplatin plus pemetrexed chemotherapy, Dr. James Chih-Hsin Yang said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data, from what was described as the largest global prospective trial in EGFR mutation–positive lung cancer to date, are expected in about 18-24 months, he said.

Discussant Benjamin J. Solomon, Ph.D., said, "It’s clear that this study establishes afatinib as another proven option for the first-line treatment of EGFR-mutation–positive patients, alongside gefitinib [Iressa] and erlotinib [Tarceva]."

That afatinib beats chemotherapy is not surprising, added Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.

The available data cannot, however, answer questions of how afatinib compares against the first-generation TKIs in this setting, nor whether the increased efficacy outweighs any additional toxicity, he said. Notably, the LUX-Lung 7 trial has begun comparing afatinib 40 mg/day with gefitinib 250 mg/day in EGFR mutation–positive, non–small cell lung cancer.

In the current trial, the efficacy of afatinib came at a cost of increased rates of diarrhea, rash, stomatitis, and paronychia that appear higher than those observed with the first-generation TKIs, Dr. Solomon said. On the other hand, he observed that the investigators appeared to have developed strategies to deal with these side effects, as the rate of afatinib discontinuation was lower than with chemotherapy.

Many Asians, Women in International Trial

LUX-Lung 3 investigators at 133 sites in 25 countries in North and South America, Europe, and Asia randomized 345 chemotherapy-naive patients with stage IIIB or IV adenocarcinoma of the lung and EGFR mutations confirmed by central lab testing. In all, 230 were assigned to afatinib 40 mg daily and 115 to intravenous pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) every 21 days for up to six cycles.

In all, 61% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 1, 65% were women, 72% were Asian, 89% had stage IV disease, 49% had the exon 19 deletion, 40% had the L858R mutation, and 11% had other mutations. Their median age was 61 years. Median follow-up was 16.4 months.

The investigators had hypothesized that afatinib would be stronger than first-generation, reversible EGFR TKIs because it irreversibly binds to and inhibits the entire ErbB family of receptors (ErbB1, HER2, ErbB3, and ErbB4). The ErbB family plays a critical role in tumor cell growth and is overexpressed or mutated in most cancers, including lung, breast, and head and neck cancers.

In all, 56% of afatinib and 22.6% of the chemotherapy patients had an objective response by independent review (P less than .001), said Dr. Yang of the National Taiwan University Hospital in Taipei. The median duration of response was 11.1 months with afatinib vs. 5.5 months with chemotherapy.

There was also a delay in the time to deterioration of the lung cancer–related symptoms of cough (HR, 0.60; P = .007), dyspnea (HR, 0.68; P = .015), and pain (HR, 0.83; P = .19).

A subgroup analysis revealed that the benefit of afatinib on progression extended to most subgroups, including different races and EGFR mutations, never-smokers, and smokers with less than 15 pack-years who had stopped for at least 1 year, he said. Only current and "other" ex-smokers did not benefit.

QoL Better With Afatinib

Quality of life for those treated with afatinib was better than with cisplatin plus pemetrexed in all five domains measured on the EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Questionnaire-C30 including physical, cognitive, and social functioning.

The most common grade 3 adverse events with afatinib were diarrhea (14.4%), rash (16.2%), stomatitis/mucositis (8.3%) and paronychia (11.4%), with one case of grade 4 stomatitis/mucositis (0.4%). There were four deaths related to afatinib.

The duration of treatment likely had an impact on adverse events, as patients received 16 cycles of afatinib (median, 336 days) vs. just 6 cycles of chemotherapy, Dr. Yang pointed out. Drug-related adverse events leading to discontinuation were reported in 7.9% of patients who were given afatinib and in 11.7% of those given cisplatin plus pemetrexed chemotherapy.

Acquired Resistance Anticipated

Finally, Dr. Solomon said that "as impressive as the progression free survival seen with afatinib is ... all these patients eventually develop acquired resistance." He highlighted a recent study in which the T790M secondary mutation was implicated as a mechanism of acquired resistance to second-generation irreversible TKI inhibitors in a clinical case and in an in vitro cell culture model (Mol. Cancer Ther. 2012;11:784-91).

Patrice Wendling/IMNG Medical Media

"While the mechanisms of resistance may not completely overlap with the mechanisms of resistance due to first-generation inhibitors, we know at least in the case of afatinib and also dacomitinib [Pfizer] that T790M, potentially in association with amplification of the EGFR gene, is in part responsible," he said. This may be particularly troublesome in the clinical setting, "where it’s probably difficult to achieve high-enough concentrations of afatinib to inhibit T790M."

Dr. Yang reported serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim, the study sponsor. Several coauthors had financial relationships with firms including Boehringer Ingelheim. Dr. Solomon reports serving as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer, and Roche.

* This story was updated 6/29/2012.

CHICAGO – First-line afatinib delayed progression for nearly a year in patients with advanced lung cancer carrying epidermal growth factor mutations, according to much-anticipated results from the phase III LUX-Lung 3 trial.

Median progression-free survival reached 11.1 months with the experimental oral agent, compared with 6.9 months with cisplatin plus pemetrexed (Alimta) chemotherapy (hazard ratio, 0.58; P = .0004), investigators reported. At 1 year, more than twice as many patients were progression free on afatinib (47% vs. 22%).

The median reached 13.6 months in afatinib-treated patients who harbored the most common EGFR (epidermal growth factor receptor) mutations – exon deletion 19 or exon 21 L858R – which account for 90% of all EGFR mutations, but stayed at 6.9 months in the control group (HR, 0.47; P less than .0001). The progression-free survival rate was more than twice as high at 1 year with afatinib (51% vs. 21%).

Patrice Wendling/IMNG Medical Media

Patients who were treated with the novel, second-generation TKI (tyrosine kinase inhibitor) also had better sustained tumor shrinkage and improved quality of life than did those treated with standard cisplatin plus pemetrexed chemotherapy, Dr. James Chih-Hsin Yang said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data, from what was described as the largest global prospective trial in EGFR mutation–positive lung cancer to date, are expected in about 18-24 months, he said.

Discussant Benjamin J. Solomon, Ph.D., said, "It’s clear that this study establishes afatinib as another proven option for the first-line treatment of EGFR-mutation–positive patients, alongside gefitinib [Iressa] and erlotinib [Tarceva]."

That afatinib beats chemotherapy is not surprising, added Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.

The available data cannot, however, answer questions of how afatinib compares against the first-generation TKIs in this setting, nor whether the increased efficacy outweighs any additional toxicity, he said. Notably, the LUX-Lung 7 trial has begun comparing afatinib 40 mg/day with gefitinib 250 mg/day in EGFR mutation–positive, non–small cell lung cancer.

In the current trial, the efficacy of afatinib came at a cost of increased rates of diarrhea, rash, stomatitis, and paronychia that appear higher than those observed with the first-generation TKIs, Dr. Solomon said. On the other hand, he observed that the investigators appeared to have developed strategies to deal with these side effects, as the rate of afatinib discontinuation was lower than with chemotherapy.

Many Asians, Women in International Trial

LUX-Lung 3 investigators at 133 sites in 25 countries in North and South America, Europe, and Asia randomized 345 chemotherapy-naive patients with stage IIIB or IV adenocarcinoma of the lung and EGFR mutations confirmed by central lab testing. In all, 230 were assigned to afatinib 40 mg daily and 115 to intravenous pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) every 21 days for up to six cycles.

In all, 61% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 1, 65% were women, 72% were Asian, 89% had stage IV disease, 49% had the exon 19 deletion, 40% had the L858R mutation, and 11% had other mutations. Their median age was 61 years. Median follow-up was 16.4 months.

The investigators had hypothesized that afatinib would be stronger than first-generation, reversible EGFR TKIs because it irreversibly binds to and inhibits the entire ErbB family of receptors (ErbB1, HER2, ErbB3, and ErbB4). The ErbB family plays a critical role in tumor cell growth and is overexpressed or mutated in most cancers, including lung, breast, and head and neck cancers.

In all, 56% of afatinib and 22.6% of the chemotherapy patients had an objective response by independent review (P less than .001), said Dr. Yang of the National Taiwan University Hospital in Taipei. The median duration of response was 11.1 months with afatinib vs. 5.5 months with chemotherapy.

There was also a delay in the time to deterioration of the lung cancer–related symptoms of cough (HR, 0.60; P = .007), dyspnea (HR, 0.68; P = .015), and pain (HR, 0.83; P = .19).

A subgroup analysis revealed that the benefit of afatinib on progression extended to most subgroups, including different races and EGFR mutations, never-smokers, and smokers with less than 15 pack-years who had stopped for at least 1 year, he said. Only current and "other" ex-smokers did not benefit.

QoL Better With Afatinib

Quality of life for those treated with afatinib was better than with cisplatin plus pemetrexed in all five domains measured on the EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Questionnaire-C30 including physical, cognitive, and social functioning.

The most common grade 3 adverse events with afatinib were diarrhea (14.4%), rash (16.2%), stomatitis/mucositis (8.3%) and paronychia (11.4%), with one case of grade 4 stomatitis/mucositis (0.4%). There were four deaths related to afatinib.

The duration of treatment likely had an impact on adverse events, as patients received 16 cycles of afatinib (median, 336 days) vs. just 6 cycles of chemotherapy, Dr. Yang pointed out. Drug-related adverse events leading to discontinuation were reported in 7.9% of patients who were given afatinib and in 11.7% of those given cisplatin plus pemetrexed chemotherapy.

Acquired Resistance Anticipated

Finally, Dr. Solomon said that "as impressive as the progression free survival seen with afatinib is ... all these patients eventually develop acquired resistance." He highlighted a recent study in which the T790M secondary mutation was implicated as a mechanism of acquired resistance to second-generation irreversible TKI inhibitors in a clinical case and in an in vitro cell culture model (Mol. Cancer Ther. 2012;11:784-91).

Patrice Wendling/IMNG Medical Media

"While the mechanisms of resistance may not completely overlap with the mechanisms of resistance due to first-generation inhibitors, we know at least in the case of afatinib and also dacomitinib [Pfizer] that T790M, potentially in association with amplification of the EGFR gene, is in part responsible," he said. This may be particularly troublesome in the clinical setting, "where it’s probably difficult to achieve high-enough concentrations of afatinib to inhibit T790M."

Dr. Yang reported serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim, the study sponsor. Several coauthors had financial relationships with firms including Boehringer Ingelheim. Dr. Solomon reports serving as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer, and Roche.

* This story was updated 6/29/2012.

CHICAGO – First-line afatinib delayed progression for nearly a year in patients with advanced lung cancer carrying epidermal growth factor mutations, according to much-anticipated results from the phase III LUX-Lung 3 trial.

Median progression-free survival reached 11.1 months with the experimental oral agent, compared with 6.9 months with cisplatin plus pemetrexed (Alimta) chemotherapy (hazard ratio, 0.58; P = .0004), investigators reported. At 1 year, more than twice as many patients were progression free on afatinib (47% vs. 22%).

The median reached 13.6 months in afatinib-treated patients who harbored the most common EGFR (epidermal growth factor receptor) mutations – exon deletion 19 or exon 21 L858R – which account for 90% of all EGFR mutations, but stayed at 6.9 months in the control group (HR, 0.47; P less than .0001). The progression-free survival rate was more than twice as high at 1 year with afatinib (51% vs. 21%).

Patrice Wendling/IMNG Medical Media

Patients who were treated with the novel, second-generation TKI (tyrosine kinase inhibitor) also had better sustained tumor shrinkage and improved quality of life than did those treated with standard cisplatin plus pemetrexed chemotherapy, Dr. James Chih-Hsin Yang said at the annual meeting of the American Society of Clinical Oncology.

Overall survival data, from what was described as the largest global prospective trial in EGFR mutation–positive lung cancer to date, are expected in about 18-24 months, he said.

Discussant Benjamin J. Solomon, Ph.D., said, "It’s clear that this study establishes afatinib as another proven option for the first-line treatment of EGFR-mutation–positive patients, alongside gefitinib [Iressa] and erlotinib [Tarceva]."

That afatinib beats chemotherapy is not surprising, added Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.

The available data cannot, however, answer questions of how afatinib compares against the first-generation TKIs in this setting, nor whether the increased efficacy outweighs any additional toxicity, he said. Notably, the LUX-Lung 7 trial has begun comparing afatinib 40 mg/day with gefitinib 250 mg/day in EGFR mutation–positive, non–small cell lung cancer.

In the current trial, the efficacy of afatinib came at a cost of increased rates of diarrhea, rash, stomatitis, and paronychia that appear higher than those observed with the first-generation TKIs, Dr. Solomon said. On the other hand, he observed that the investigators appeared to have developed strategies to deal with these side effects, as the rate of afatinib discontinuation was lower than with chemotherapy.

Many Asians, Women in International Trial

LUX-Lung 3 investigators at 133 sites in 25 countries in North and South America, Europe, and Asia randomized 345 chemotherapy-naive patients with stage IIIB or IV adenocarcinoma of the lung and EGFR mutations confirmed by central lab testing. In all, 230 were assigned to afatinib 40 mg daily and 115 to intravenous pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) every 21 days for up to six cycles.

In all, 61% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 1, 65% were women, 72% were Asian, 89% had stage IV disease, 49% had the exon 19 deletion, 40% had the L858R mutation, and 11% had other mutations. Their median age was 61 years. Median follow-up was 16.4 months.

The investigators had hypothesized that afatinib would be stronger than first-generation, reversible EGFR TKIs because it irreversibly binds to and inhibits the entire ErbB family of receptors (ErbB1, HER2, ErbB3, and ErbB4). The ErbB family plays a critical role in tumor cell growth and is overexpressed or mutated in most cancers, including lung, breast, and head and neck cancers.

In all, 56% of afatinib and 22.6% of the chemotherapy patients had an objective response by independent review (P less than .001), said Dr. Yang of the National Taiwan University Hospital in Taipei. The median duration of response was 11.1 months with afatinib vs. 5.5 months with chemotherapy.

There was also a delay in the time to deterioration of the lung cancer–related symptoms of cough (HR, 0.60; P = .007), dyspnea (HR, 0.68; P = .015), and pain (HR, 0.83; P = .19).

A subgroup analysis revealed that the benefit of afatinib on progression extended to most subgroups, including different races and EGFR mutations, never-smokers, and smokers with less than 15 pack-years who had stopped for at least 1 year, he said. Only current and "other" ex-smokers did not benefit.

QoL Better With Afatinib

Quality of life for those treated with afatinib was better than with cisplatin plus pemetrexed in all five domains measured on the EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Questionnaire-C30 including physical, cognitive, and social functioning.

The most common grade 3 adverse events with afatinib were diarrhea (14.4%), rash (16.2%), stomatitis/mucositis (8.3%) and paronychia (11.4%), with one case of grade 4 stomatitis/mucositis (0.4%). There were four deaths related to afatinib.

The duration of treatment likely had an impact on adverse events, as patients received 16 cycles of afatinib (median, 336 days) vs. just 6 cycles of chemotherapy, Dr. Yang pointed out. Drug-related adverse events leading to discontinuation were reported in 7.9% of patients who were given afatinib and in 11.7% of those given cisplatin plus pemetrexed chemotherapy.

Acquired Resistance Anticipated

Finally, Dr. Solomon said that "as impressive as the progression free survival seen with afatinib is ... all these patients eventually develop acquired resistance." He highlighted a recent study in which the T790M secondary mutation was implicated as a mechanism of acquired resistance to second-generation irreversible TKI inhibitors in a clinical case and in an in vitro cell culture model (Mol. Cancer Ther. 2012;11:784-91).

Patrice Wendling/IMNG Medical Media

"While the mechanisms of resistance may not completely overlap with the mechanisms of resistance due to first-generation inhibitors, we know at least in the case of afatinib and also dacomitinib [Pfizer] that T790M, potentially in association with amplification of the EGFR gene, is in part responsible," he said. This may be particularly troublesome in the clinical setting, "where it’s probably difficult to achieve high-enough concentrations of afatinib to inhibit T790M."

Dr. Yang reported serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim, the study sponsor. Several coauthors had financial relationships with firms including Boehringer Ingelheim. Dr. Solomon reports serving as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer, and Roche.

* This story was updated 6/29/2012.

CHICAGO – Abiraterone acetate plus prednisone significantly delays progression and initiation of chemotherapy in asymptomatic or mildly symptomatic, chemotherapy-naive, metastatic, castration-resistant prostate cancer, according to much-anticipated data from a pivotal clinical trial.

The second preplanned interim analysis of the COU-AA-302 trial also revealed a strong overall survival trend favoring abiraterone (Zytiga) over prednisone and placebo, leading to unblinding of the phase III trial in March 2012 and crossover treatment for the control arm.

Median overall survival was 27.2 months with prednisone and placebo, but had not been reached in the abiraterone arm at the time of the analysis, with 43% of total events reported. This corresponds to a hazard ratio of 0.75 and P value of .0097 that fell shy of the prespecified significance level of .0008.

No subgroup of patients is driving the overall survival benefit, nor is there a particular group of patients who experienced an unfavorable outcome from treatment with abiraterone relative to the control group, reported Dr. Charles J. Ryan, lead author of a late-breaking abstract presented at the annual meeting of the American Society of Clinical Oncology.

"These data merit consideration as providing a new standard approach in this highly prevalent patient population faced with an unmet medical need," said Dr. Ryan of the University of California, San Francisco.

This is the first trial to show progression and overall survival benefits in this setting. Janssen Research & Development announced it will seek a new indication for abiraterone in chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC) in the second half of 2012.

The combination of abiraterone plus prednisone has already demonstrated an overall survival benefit in patients with prior chemotherapy, leading to its approval in April 2011 for mCRPC that had previously been treated with docetaxel (Taxotere) chemotherapy.

Invited discussant Susan Halabi, Ph.D., a biostatistician at Duke University Medical Center in Durham, N.C., said the trial represents a paradigm shift, but faulted the investigators for stopping the trial before a statistically significant overall survival benefit was seen. Stopping a trial too early may fail to persuade some clinicians to change medical practice, she observed.

COU-AA-302 investigators at 151 sites in 12 countries, including the United States, randomized 546 men to abiraterone at the standard dosage of 1,000 mg daily plus prednisone 5 mg twice daily, and 542 men to the same prednisone dosage plus daily placebo.

At initial diagnosis, 54% of the abiraterone and 50% of the control patients had a Gleason score of 8 or greater. Median prostate-specific antigen (PSA) levels at baseline were 42 ng/mL and 37.7 ng/mL, respectively. The patients’ median age was about 70 years.

After a median follow-up of 22.3 months, the co–primary end point of radiographic progression by blinded central review was reached at a median of 8.3 months in the control arm, but had not been reached in the abiraterone arm (HR, 0.43; P less than .0001). A subset analysis revealed that the benefit of abiraterone on progression-free survival occurred across all subgroups tested, said Dr. Ryan, The investigators also looked at several secondary end points that are hallmarks of disease progression and clinically meaningful to patients over the prolonged natural history of progressive mCRPC, he said.

Abiraterone significantly delayed the time to chemotherapy initiation from 16.8 months with prednisone plus placebo to 25.2 months (HR, 0.58; P less than .0001), to ECOG performance status deterioration from 10.9 months to 12.3 months (HR, 0.82; P = .0053), and to PSA progression from 5.6 months to 11.1 months (HR, 0.49; P less than .0001). Time to opiate use for cancer-related pain was 23.7 months in the control arm, but had not been reached with abiraterone (HR, 0.69; P = .0001).

Subsequent therapy, which can influence both survival and the secondary end points, was reported in 60% of the control arm and 44% of the abiraterone arm, he said. Docetaxel was most commonly used at 53% and 38%, respectively, although abiraterone was subsequently used in 10% of control and 5% of abiraterone patients.

Patients received a median of 15 cycles of abiraterone (range, 1-33 cycles), which is longer than in other trials, but the extended treatment did not lead to any new safety signals, Dr. Ryan said. The abiraterone arm reported more grade 3 and 4 adverse events than did the control arm, notably cardiac events (6% vs. 3%), hypertension (4% vs. 3%) and elevations in alanine aminotransferase (5.4% vs. 0.8%) and aspartate aminotransferase (3% vs. 0.9%). In all, 7% of abiraterone patients discontinued therapy due to an adverse event, compared with 5% of those on prednisone plus placebo.

Ortho Biotech Oncology Research & Development sponsored the study. Dr. Ryan reported no disclosures; his coauthors reported financial relationships with several companies, including Janssen.

CHICAGO – Abiraterone acetate plus prednisone significantly delays progression and initiation of chemotherapy in asymptomatic or mildly symptomatic, chemotherapy-naive, metastatic, castration-resistant prostate cancer, according to much-anticipated data from a pivotal clinical trial.

The second preplanned interim analysis of the COU-AA-302 trial also revealed a strong overall survival trend favoring abiraterone (Zytiga) over prednisone and placebo, leading to unblinding of the phase III trial in March 2012 and crossover treatment for the control arm.

Median overall survival was 27.2 months with prednisone and placebo, but had not been reached in the abiraterone arm at the time of the analysis, with 43% of total events reported. This corresponds to a hazard ratio of 0.75 and P value of .0097 that fell shy of the prespecified significance level of .0008.

No subgroup of patients is driving the overall survival benefit, nor is there a particular group of patients who experienced an unfavorable outcome from treatment with abiraterone relative to the control group, reported Dr. Charles J. Ryan, lead author of a late-breaking abstract presented at the annual meeting of the American Society of Clinical Oncology.

"These data merit consideration as providing a new standard approach in this highly prevalent patient population faced with an unmet medical need," said Dr. Ryan of the University of California, San Francisco.

This is the first trial to show progression and overall survival benefits in this setting. Janssen Research & Development announced it will seek a new indication for abiraterone in chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC) in the second half of 2012.

The combination of abiraterone plus prednisone has already demonstrated an overall survival benefit in patients with prior chemotherapy, leading to its approval in April 2011 for mCRPC that had previously been treated with docetaxel (Taxotere) chemotherapy.

Invited discussant Susan Halabi, Ph.D., a biostatistician at Duke University Medical Center in Durham, N.C., said the trial represents a paradigm shift, but faulted the investigators for stopping the trial before a statistically significant overall survival benefit was seen. Stopping a trial too early may fail to persuade some clinicians to change medical practice, she observed.

COU-AA-302 investigators at 151 sites in 12 countries, including the United States, randomized 546 men to abiraterone at the standard dosage of 1,000 mg daily plus prednisone 5 mg twice daily, and 542 men to the same prednisone dosage plus daily placebo.

At initial diagnosis, 54% of the abiraterone and 50% of the control patients had a Gleason score of 8 or greater. Median prostate-specific antigen (PSA) levels at baseline were 42 ng/mL and 37.7 ng/mL, respectively. The patients’ median age was about 70 years.

After a median follow-up of 22.3 months, the co–primary end point of radiographic progression by blinded central review was reached at a median of 8.3 months in the control arm, but had not been reached in the abiraterone arm (HR, 0.43; P less than .0001). A subset analysis revealed that the benefit of abiraterone on progression-free survival occurred across all subgroups tested, said Dr. Ryan, The investigators also looked at several secondary end points that are hallmarks of disease progression and clinically meaningful to patients over the prolonged natural history of progressive mCRPC, he said.

Abiraterone significantly delayed the time to chemotherapy initiation from 16.8 months with prednisone plus placebo to 25.2 months (HR, 0.58; P less than .0001), to ECOG performance status deterioration from 10.9 months to 12.3 months (HR, 0.82; P = .0053), and to PSA progression from 5.6 months to 11.1 months (HR, 0.49; P less than .0001). Time to opiate use for cancer-related pain was 23.7 months in the control arm, but had not been reached with abiraterone (HR, 0.69; P = .0001).

Subsequent therapy, which can influence both survival and the secondary end points, was reported in 60% of the control arm and 44% of the abiraterone arm, he said. Docetaxel was most commonly used at 53% and 38%, respectively, although abiraterone was subsequently used in 10% of control and 5% of abiraterone patients.

Patients received a median of 15 cycles of abiraterone (range, 1-33 cycles), which is longer than in other trials, but the extended treatment did not lead to any new safety signals, Dr. Ryan said. The abiraterone arm reported more grade 3 and 4 adverse events than did the control arm, notably cardiac events (6% vs. 3%), hypertension (4% vs. 3%) and elevations in alanine aminotransferase (5.4% vs. 0.8%) and aspartate aminotransferase (3% vs. 0.9%). In all, 7% of abiraterone patients discontinued therapy due to an adverse event, compared with 5% of those on prednisone plus placebo.

Ortho Biotech Oncology Research & Development sponsored the study. Dr. Ryan reported no disclosures; his coauthors reported financial relationships with several companies, including Janssen.

CHICAGO – Abiraterone acetate plus prednisone significantly delays progression and initiation of chemotherapy in asymptomatic or mildly symptomatic, chemotherapy-naive, metastatic, castration-resistant prostate cancer, according to much-anticipated data from a pivotal clinical trial.

The second preplanned interim analysis of the COU-AA-302 trial also revealed a strong overall survival trend favoring abiraterone (Zytiga) over prednisone and placebo, leading to unblinding of the phase III trial in March 2012 and crossover treatment for the control arm.

Median overall survival was 27.2 months with prednisone and placebo, but had not been reached in the abiraterone arm at the time of the analysis, with 43% of total events reported. This corresponds to a hazard ratio of 0.75 and P value of .0097 that fell shy of the prespecified significance level of .0008.

No subgroup of patients is driving the overall survival benefit, nor is there a particular group of patients who experienced an unfavorable outcome from treatment with abiraterone relative to the control group, reported Dr. Charles J. Ryan, lead author of a late-breaking abstract presented at the annual meeting of the American Society of Clinical Oncology.

"These data merit consideration as providing a new standard approach in this highly prevalent patient population faced with an unmet medical need," said Dr. Ryan of the University of California, San Francisco.

This is the first trial to show progression and overall survival benefits in this setting. Janssen Research & Development announced it will seek a new indication for abiraterone in chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC) in the second half of 2012.

The combination of abiraterone plus prednisone has already demonstrated an overall survival benefit in patients with prior chemotherapy, leading to its approval in April 2011 for mCRPC that had previously been treated with docetaxel (Taxotere) chemotherapy.

Invited discussant Susan Halabi, Ph.D., a biostatistician at Duke University Medical Center in Durham, N.C., said the trial represents a paradigm shift, but faulted the investigators for stopping the trial before a statistically significant overall survival benefit was seen. Stopping a trial too early may fail to persuade some clinicians to change medical practice, she observed.

COU-AA-302 investigators at 151 sites in 12 countries, including the United States, randomized 546 men to abiraterone at the standard dosage of 1,000 mg daily plus prednisone 5 mg twice daily, and 542 men to the same prednisone dosage plus daily placebo.

At initial diagnosis, 54% of the abiraterone and 50% of the control patients had a Gleason score of 8 or greater. Median prostate-specific antigen (PSA) levels at baseline were 42 ng/mL and 37.7 ng/mL, respectively. The patients’ median age was about 70 years.

After a median follow-up of 22.3 months, the co–primary end point of radiographic progression by blinded central review was reached at a median of 8.3 months in the control arm, but had not been reached in the abiraterone arm (HR, 0.43; P less than .0001). A subset analysis revealed that the benefit of abiraterone on progression-free survival occurred across all subgroups tested, said Dr. Ryan, The investigators also looked at several secondary end points that are hallmarks of disease progression and clinically meaningful to patients over the prolonged natural history of progressive mCRPC, he said.

Abiraterone significantly delayed the time to chemotherapy initiation from 16.8 months with prednisone plus placebo to 25.2 months (HR, 0.58; P less than .0001), to ECOG performance status deterioration from 10.9 months to 12.3 months (HR, 0.82; P = .0053), and to PSA progression from 5.6 months to 11.1 months (HR, 0.49; P less than .0001). Time to opiate use for cancer-related pain was 23.7 months in the control arm, but had not been reached with abiraterone (HR, 0.69; P = .0001).

Subsequent therapy, which can influence both survival and the secondary end points, was reported in 60% of the control arm and 44% of the abiraterone arm, he said. Docetaxel was most commonly used at 53% and 38%, respectively, although abiraterone was subsequently used in 10% of control and 5% of abiraterone patients.

Patients received a median of 15 cycles of abiraterone (range, 1-33 cycles), which is longer than in other trials, but the extended treatment did not lead to any new safety signals, Dr. Ryan said. The abiraterone arm reported more grade 3 and 4 adverse events than did the control arm, notably cardiac events (6% vs. 3%), hypertension (4% vs. 3%) and elevations in alanine aminotransferase (5.4% vs. 0.8%) and aspartate aminotransferase (3% vs. 0.9%). In all, 7% of abiraterone patients discontinued therapy due to an adverse event, compared with 5% of those on prednisone plus placebo.

Ortho Biotech Oncology Research & Development sponsored the study. Dr. Ryan reported no disclosures; his coauthors reported financial relationships with several companies, including Janssen.

CHICAGO – The investigational targeted agent tivozanib was associated with significantly more clinical responses and greater progression-free survival than was sorafenib in a head-to-head comparison among patients with metastatic renal cell carcinoma.

Median progression-free survival for 260 patients randomized to tivozanib was 11.9 months in an independent reviewer analysis, compared with 9.1 months for 257 patients randomized to sorafenib (Nexavar) in an open-label, multicenter phase III clinical trial (P = .042), Dr. Robert Motzer reported at the annual meeting of the American Society of Clinical Oncology.

Dr. Motzer, from the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center in New York City, said data on overall survival, a secondary end point of the trial, would be presented at a later date.

Like sorafenib (Nexavar), tivozanib is a selective tyrosine kinase inhibitor (TKI) with affinity for vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3.

"This study demonstrated that a more potent, selective VEGFR inhibitor with a long half-life achieved superior efficacy, combined with decreased off-target toxicity. Tivozanib should be considered a first-line treatment option for metastatic renal cell carcinoma," Dr. Motzer said.

The invited discussant, Dr. Tim Eisen, a professor of oncology at the University of Cambridge, England, was a coauthor of the study, but he took a more cautious approach. He noted that tivozanib may have looked better than it really is, because the trial pitted a brash young up and comer against a paunchy, aging fighter.

"There are still doubts in my view about the choice of sorafenib, and I would very much like to see comparative data with sunitinib [Sutent] or pazopanib [Votrient] before fully adopting [tivozanib] as a first-line option," he said.

The best responses seen in the study for sorafenib were a 1% complete response rate and 23% partial response, and the progression-free survival values observed were about as good as it gets with sorafenib compared with other studies, Dr. Eisen said, but they stood in contrast to those of the newer agent.

"I think we also need quality of life data, because although the side effect profile is very good as measured in the studies with tivozanib, we don\'t yet know whether that translates into patient preference," he added.

In the TIVO-1 phase III trial, patients with advanced renal cell carcinoma (RCC) with clear cell histology, prior nephrectomy, good performance status (ECOG 0-1), not more than one prior line of therapy, and no prior VEGF or mTOR (mammalian target of rapamycin) inhibitor therapy were assigned to either tivozanib 1.5 mg/day orally for 3 weeks of a 4-week cycle or sorafenib 400 mg orally twice daily continuously. Patients were stratified by geographic region, prior therapies, and number of metastatic lesions.

Independent reviewers determined that tivozanib was associated with a significantly lower risk for disease progress (hazard ratio, 0.797). The investigators were a bit more generous, however, reporting median progression-free survival reached 14.7 months with tivozanib vs. 9.6 months with sorafenib (HR, 0.722; P = .003).

The objective response rates by independent review were 33% and 23%, respectively (P = .014).

There were fewer dose interruptions (18% vs. 35%), dose reductions (12% vs. 43%), and discontinuations (4% vs. 5%) with tivozanib.

Patients on tivozanib had less treatment-emergent grade 3 or 4 diarrhea (2% vs. 6%), palmar plantar erythrodysesthesia (2% vs. 17%), and grade 1-2 alopecia (2% vs. 21%).

In contrast, patients who received the experimental agent had more hypertension (all grade, 44% vs. 34%; grades 3/4, 2% vs. less than 1%), dysphonia (21% vs. 5%), and back pain (14% vs. 7%).

Dr. Motzer noted that the hypertension seen with tivozanib appears to be related to the treatment effect, as higher levels correlated with longer median progression-free survival. Patients with a diastolic blood pressure (BP) reading above 90 mmHg had a median progression-free survival of 18.3 months, compared with 9.1 months for those with a diastolic BP of 90 mmHg or less (HR, 0.553, P =.001). Similarly, patients with systolic BP above 140 mmHg had a median progression-free survival of 16.7 months, compared with 9.0 months for those with normal systolic BP (HR, 0.543, P less than .001).

The study was supported by AVEO Oncology and Astellas Oncology. Dr. Motzer reported receiving research funding from AVEO. Dr. Eisen is a coauthor of the study and has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – The investigational targeted agent tivozanib was associated with significantly more clinical responses and greater progression-free survival than was sorafenib in a head-to-head comparison among patients with metastatic renal cell carcinoma.

Median progression-free survival for 260 patients randomized to tivozanib was 11.9 months in an independent reviewer analysis, compared with 9.1 months for 257 patients randomized to sorafenib (Nexavar) in an open-label, multicenter phase III clinical trial (P = .042), Dr. Robert Motzer reported at the annual meeting of the American Society of Clinical Oncology.

Dr. Motzer, from the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center in New York City, said data on overall survival, a secondary end point of the trial, would be presented at a later date.

Like sorafenib (Nexavar), tivozanib is a selective tyrosine kinase inhibitor (TKI) with affinity for vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3.

"This study demonstrated that a more potent, selective VEGFR inhibitor with a long half-life achieved superior efficacy, combined with decreased off-target toxicity. Tivozanib should be considered a first-line treatment option for metastatic renal cell carcinoma," Dr. Motzer said.

The invited discussant, Dr. Tim Eisen, a professor of oncology at the University of Cambridge, England, was a coauthor of the study, but he took a more cautious approach. He noted that tivozanib may have looked better than it really is, because the trial pitted a brash young up and comer against a paunchy, aging fighter.

"There are still doubts in my view about the choice of sorafenib, and I would very much like to see comparative data with sunitinib [Sutent] or pazopanib [Votrient] before fully adopting [tivozanib] as a first-line option," he said.

The best responses seen in the study for sorafenib were a 1% complete response rate and 23% partial response, and the progression-free survival values observed were about as good as it gets with sorafenib compared with other studies, Dr. Eisen said, but they stood in contrast to those of the newer agent.

"I think we also need quality of life data, because although the side effect profile is very good as measured in the studies with tivozanib, we don\'t yet know whether that translates into patient preference," he added.

In the TIVO-1 phase III trial, patients with advanced renal cell carcinoma (RCC) with clear cell histology, prior nephrectomy, good performance status (ECOG 0-1), not more than one prior line of therapy, and no prior VEGF or mTOR (mammalian target of rapamycin) inhibitor therapy were assigned to either tivozanib 1.5 mg/day orally for 3 weeks of a 4-week cycle or sorafenib 400 mg orally twice daily continuously. Patients were stratified by geographic region, prior therapies, and number of metastatic lesions.

Independent reviewers determined that tivozanib was associated with a significantly lower risk for disease progress (hazard ratio, 0.797). The investigators were a bit more generous, however, reporting median progression-free survival reached 14.7 months with tivozanib vs. 9.6 months with sorafenib (HR, 0.722; P = .003).

The objective response rates by independent review were 33% and 23%, respectively (P = .014).

There were fewer dose interruptions (18% vs. 35%), dose reductions (12% vs. 43%), and discontinuations (4% vs. 5%) with tivozanib.

Patients on tivozanib had less treatment-emergent grade 3 or 4 diarrhea (2% vs. 6%), palmar plantar erythrodysesthesia (2% vs. 17%), and grade 1-2 alopecia (2% vs. 21%).

In contrast, patients who received the experimental agent had more hypertension (all grade, 44% vs. 34%; grades 3/4, 2% vs. less than 1%), dysphonia (21% vs. 5%), and back pain (14% vs. 7%).

Dr. Motzer noted that the hypertension seen with tivozanib appears to be related to the treatment effect, as higher levels correlated with longer median progression-free survival. Patients with a diastolic blood pressure (BP) reading above 90 mmHg had a median progression-free survival of 18.3 months, compared with 9.1 months for those with a diastolic BP of 90 mmHg or less (HR, 0.553, P =.001). Similarly, patients with systolic BP above 140 mmHg had a median progression-free survival of 16.7 months, compared with 9.0 months for those with normal systolic BP (HR, 0.543, P less than .001).

The study was supported by AVEO Oncology and Astellas Oncology. Dr. Motzer reported receiving research funding from AVEO. Dr. Eisen is a coauthor of the study and has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – The investigational targeted agent tivozanib was associated with significantly more clinical responses and greater progression-free survival than was sorafenib in a head-to-head comparison among patients with metastatic renal cell carcinoma.

Median progression-free survival for 260 patients randomized to tivozanib was 11.9 months in an independent reviewer analysis, compared with 9.1 months for 257 patients randomized to sorafenib (Nexavar) in an open-label, multicenter phase III clinical trial (P = .042), Dr. Robert Motzer reported at the annual meeting of the American Society of Clinical Oncology.

Dr. Motzer, from the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center in New York City, said data on overall survival, a secondary end point of the trial, would be presented at a later date.

Like sorafenib (Nexavar), tivozanib is a selective tyrosine kinase inhibitor (TKI) with affinity for vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3.

"This study demonstrated that a more potent, selective VEGFR inhibitor with a long half-life achieved superior efficacy, combined with decreased off-target toxicity. Tivozanib should be considered a first-line treatment option for metastatic renal cell carcinoma," Dr. Motzer said.

The invited discussant, Dr. Tim Eisen, a professor of oncology at the University of Cambridge, England, was a coauthor of the study, but he took a more cautious approach. He noted that tivozanib may have looked better than it really is, because the trial pitted a brash young up and comer against a paunchy, aging fighter.

"There are still doubts in my view about the choice of sorafenib, and I would very much like to see comparative data with sunitinib [Sutent] or pazopanib [Votrient] before fully adopting [tivozanib] as a first-line option," he said.

The best responses seen in the study for sorafenib were a 1% complete response rate and 23% partial response, and the progression-free survival values observed were about as good as it gets with sorafenib compared with other studies, Dr. Eisen said, but they stood in contrast to those of the newer agent.

"I think we also need quality of life data, because although the side effect profile is very good as measured in the studies with tivozanib, we don\'t yet know whether that translates into patient preference," he added.

In the TIVO-1 phase III trial, patients with advanced renal cell carcinoma (RCC) with clear cell histology, prior nephrectomy, good performance status (ECOG 0-1), not more than one prior line of therapy, and no prior VEGF or mTOR (mammalian target of rapamycin) inhibitor therapy were assigned to either tivozanib 1.5 mg/day orally for 3 weeks of a 4-week cycle or sorafenib 400 mg orally twice daily continuously. Patients were stratified by geographic region, prior therapies, and number of metastatic lesions.

Independent reviewers determined that tivozanib was associated with a significantly lower risk for disease progress (hazard ratio, 0.797). The investigators were a bit more generous, however, reporting median progression-free survival reached 14.7 months with tivozanib vs. 9.6 months with sorafenib (HR, 0.722; P = .003).

The objective response rates by independent review were 33% and 23%, respectively (P = .014).

There were fewer dose interruptions (18% vs. 35%), dose reductions (12% vs. 43%), and discontinuations (4% vs. 5%) with tivozanib.

Patients on tivozanib had less treatment-emergent grade 3 or 4 diarrhea (2% vs. 6%), palmar plantar erythrodysesthesia (2% vs. 17%), and grade 1-2 alopecia (2% vs. 21%).

In contrast, patients who received the experimental agent had more hypertension (all grade, 44% vs. 34%; grades 3/4, 2% vs. less than 1%), dysphonia (21% vs. 5%), and back pain (14% vs. 7%).

Dr. Motzer noted that the hypertension seen with tivozanib appears to be related to the treatment effect, as higher levels correlated with longer median progression-free survival. Patients with a diastolic blood pressure (BP) reading above 90 mmHg had a median progression-free survival of 18.3 months, compared with 9.1 months for those with a diastolic BP of 90 mmHg or less (HR, 0.553, P =.001). Similarly, patients with systolic BP above 140 mmHg had a median progression-free survival of 16.7 months, compared with 9.0 months for those with normal systolic BP (HR, 0.543, P less than .001).

The study was supported by AVEO Oncology and Astellas Oncology. Dr. Motzer reported receiving research funding from AVEO. Dr. Eisen is a coauthor of the study and has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – The molecule of the moment – an experimental immunotherapeutic agent known as anti-PD-1 – appears to have encouraging activity against renal cell carcinoma in early clinical studies, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Nine of 33 patients (27%) with metastatic renal cell carcinoma (RCC) in a phase I trial had clinical responses to the agent, officially named BMS-936558, reported Dr. David F. McDermott, a hematologist/oncologist at Beth Israel Deaconess Medical Center in Boston.

The duration of responses ranged from more than 5.6 months to more than 22.3 months. More than half the patients (56%) had not progressed at 24 weeks.

"BMS-936558 can be administered safely in an outpatient setting to pretreated RCC patients, while demonstrating durable clinical benefit. Blockade of the PD-1 pathway may represent an important new target for RCC immunotherapy," Dr. McDermott said.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances antitumor immunity.

When tested in a phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Suzanne Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting. Dr. McDermott presented the results for patients with metastatic RCC in a separate session.

Patients with advanced RCC and other tumor types who had disease progression after 1-5 cycles of systemic therapies received the anti-PD-1 agents at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who had either a complete or partial response or stable disease, or had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

A total of 16 patients with RCC were enrolled at a 10 mg/kg dose of BMS-936558, and 17 were later enrolled at 1 mg/kg. Dr. McDermott presented safety data for those patients and another patient who was not available for an efficacy analysis but had available safety data.

Among patients on the 1-mg/kg dose, four (24%) had a response, with responses lasting from 5.6 to 17.5 months. All of these patients had stable disease for at least 24 weeks, and 47% of the group was progression free at 24 weeks. Median overall survival for this 1-mg/kg group has not been reached, precluding an analysis of overall survival for the entire cohort, "but it’s safe to say that it’s at least going to be 6 months," Dr. McDermottt said.

In the 10-mg/kg group, the overall response rate was 31%; two patients with a persistent reduction in baseline target lesions in the presence of new lesions were not counted as responders in the analysis, he noted.

The responses lasted from 8.4 to 22.3 months, and about two-thirds of the group were progression free at 24 weeks.

"In the RCC patients, this agent was generally tolerable in the outpatient setting, with a safety profile that was similar to the total treated population," Dr. McDermott said.

Grade 3 or 4 adverse events occurred in 6 patients (18%) with RCC.

"I think all in all, the tolerability and the intriguing preliminary efficacy support the ongoing studies of PD-1 blockade in RCC, and I think what makes the pathway especially interesting is whether we can use tumor PDL-1 expression as an upfront selection criterion," commented Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

The trial received support from Bristol-Meyers Squibb and Ono Pharmaceutical Company. Dr. McDermott disclosed having received research funding from BMS, maker of the anti-PD-1 compound, and serving in a consulting or advisory role to the company. Dr Harshman disclosed receiving research funding from BMS.

CHICAGO – The molecule of the moment – an experimental immunotherapeutic agent known as anti-PD-1 – appears to have encouraging activity against renal cell carcinoma in early clinical studies, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Nine of 33 patients (27%) with metastatic renal cell carcinoma (RCC) in a phase I trial had clinical responses to the agent, officially named BMS-936558, reported Dr. David F. McDermott, a hematologist/oncologist at Beth Israel Deaconess Medical Center in Boston.

The duration of responses ranged from more than 5.6 months to more than 22.3 months. More than half the patients (56%) had not progressed at 24 weeks.

"BMS-936558 can be administered safely in an outpatient setting to pretreated RCC patients, while demonstrating durable clinical benefit. Blockade of the PD-1 pathway may represent an important new target for RCC immunotherapy," Dr. McDermott said.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances antitumor immunity.

When tested in a phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Suzanne Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting. Dr. McDermott presented the results for patients with metastatic RCC in a separate session.

Patients with advanced RCC and other tumor types who had disease progression after 1-5 cycles of systemic therapies received the anti-PD-1 agents at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who had either a complete or partial response or stable disease, or had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

A total of 16 patients with RCC were enrolled at a 10 mg/kg dose of BMS-936558, and 17 were later enrolled at 1 mg/kg. Dr. McDermott presented safety data for those patients and another patient who was not available for an efficacy analysis but had available safety data.

Among patients on the 1-mg/kg dose, four (24%) had a response, with responses lasting from 5.6 to 17.5 months. All of these patients had stable disease for at least 24 weeks, and 47% of the group was progression free at 24 weeks. Median overall survival for this 1-mg/kg group has not been reached, precluding an analysis of overall survival for the entire cohort, "but it’s safe to say that it’s at least going to be 6 months," Dr. McDermottt said.

In the 10-mg/kg group, the overall response rate was 31%; two patients with a persistent reduction in baseline target lesions in the presence of new lesions were not counted as responders in the analysis, he noted.

The responses lasted from 8.4 to 22.3 months, and about two-thirds of the group were progression free at 24 weeks.

"In the RCC patients, this agent was generally tolerable in the outpatient setting, with a safety profile that was similar to the total treated population," Dr. McDermott said.

Grade 3 or 4 adverse events occurred in 6 patients (18%) with RCC.

"I think all in all, the tolerability and the intriguing preliminary efficacy support the ongoing studies of PD-1 blockade in RCC, and I think what makes the pathway especially interesting is whether we can use tumor PDL-1 expression as an upfront selection criterion," commented Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

The trial received support from Bristol-Meyers Squibb and Ono Pharmaceutical Company. Dr. McDermott disclosed having received research funding from BMS, maker of the anti-PD-1 compound, and serving in a consulting or advisory role to the company. Dr Harshman disclosed receiving research funding from BMS.

CHICAGO – The molecule of the moment – an experimental immunotherapeutic agent known as anti-PD-1 – appears to have encouraging activity against renal cell carcinoma in early clinical studies, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Nine of 33 patients (27%) with metastatic renal cell carcinoma (RCC) in a phase I trial had clinical responses to the agent, officially named BMS-936558, reported Dr. David F. McDermott, a hematologist/oncologist at Beth Israel Deaconess Medical Center in Boston.

The duration of responses ranged from more than 5.6 months to more than 22.3 months. More than half the patients (56%) had not progressed at 24 weeks.

"BMS-936558 can be administered safely in an outpatient setting to pretreated RCC patients, while demonstrating durable clinical benefit. Blockade of the PD-1 pathway may represent an important new target for RCC immunotherapy," Dr. McDermott said.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances antitumor immunity.

When tested in a phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Suzanne Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting. Dr. McDermott presented the results for patients with metastatic RCC in a separate session.

Patients with advanced RCC and other tumor types who had disease progression after 1-5 cycles of systemic therapies received the anti-PD-1 agents at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who had either a complete or partial response or stable disease, or had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

A total of 16 patients with RCC were enrolled at a 10 mg/kg dose of BMS-936558, and 17 were later enrolled at 1 mg/kg. Dr. McDermott presented safety data for those patients and another patient who was not available for an efficacy analysis but had available safety data.

Among patients on the 1-mg/kg dose, four (24%) had a response, with responses lasting from 5.6 to 17.5 months. All of these patients had stable disease for at least 24 weeks, and 47% of the group was progression free at 24 weeks. Median overall survival for this 1-mg/kg group has not been reached, precluding an analysis of overall survival for the entire cohort, "but it’s safe to say that it’s at least going to be 6 months," Dr. McDermottt said.

In the 10-mg/kg group, the overall response rate was 31%; two patients with a persistent reduction in baseline target lesions in the presence of new lesions were not counted as responders in the analysis, he noted.

The responses lasted from 8.4 to 22.3 months, and about two-thirds of the group were progression free at 24 weeks.

"In the RCC patients, this agent was generally tolerable in the outpatient setting, with a safety profile that was similar to the total treated population," Dr. McDermott said.

Grade 3 or 4 adverse events occurred in 6 patients (18%) with RCC.

"I think all in all, the tolerability and the intriguing preliminary efficacy support the ongoing studies of PD-1 blockade in RCC, and I think what makes the pathway especially interesting is whether we can use tumor PDL-1 expression as an upfront selection criterion," commented Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

The trial received support from Bristol-Meyers Squibb and Ono Pharmaceutical Company. Dr. McDermott disclosed having received research funding from BMS, maker of the anti-PD-1 compound, and serving in a consulting or advisory role to the company. Dr Harshman disclosed receiving research funding from BMS.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

The Food and Drug Administration has prevented at least 50 drug shortages so far this year, mainly as a result of manufacturers giving the agency early warning of impending problems, Dr. Sandra Kweder announced June 4.

Shortages persist, however, especially for key oncology therapies, according to Dr. Kweder, deputy director of the FDA Office of New Drugs, and oncologists who participated in a press briefing at the annual meeting of the American Society of Clinical Oncologists (ASCO) in Chicago.

Since the White House issued an executive order last Oct. 31 encouraging manufacturers to give the FDA "early notification" of potential disruptions, the agency, working with physicians, manufacturers, pharmacists, and others, has been able to avoid more than 150 drug shortages, Dr. Kweder said.

"Early notification by manufacturers of when they are having production difficulties makes a huge difference in our ability to prevent the public from bearing the burden of drug shortages," she said.

"The good news is that the frequency of drug shortages has begun to decline," agreed Dr. Richard Schilsky, chair of the ASCO Government Relations Committee and chief of the hematology/oncology section at the University of Chicago.

However, unpredictability still exists, which means that oncologists are "never sure when a generic is going to go out of supply," said Dr. Schilsky. "That creates a tremendous amount of uncertainty and anxiety for our patients."

Dr. Michael P. Link, ASCO president, said that several commonly used chemotherapy agents remain in short supply, including fluorouracil, nitrogen mustard, and paclitaxel. In addition, although a methotrexate shortage has been addressed, there is now a shortage of sodium bicarbonate, which is needed to give high-dose injections of the drug, said Dr. Link, chief of pediatric hematology/oncology at the Lucile Packard Children’s Hospital at Stanford (Calif.) University.

Shortages often lead to delays in treatment or less-than-desirable substitutions, said Dr. W. Charles Penley, the incoming ASCO Government Relations Committee chair. His practice – Tennessee Oncology in Nashville – is large enough that it generally has been able to locate products in short supply through its purchasing groups. But a leucovorin shortage last summer led him to switch some patients to oral capecitabine (Xeloda).

That drug is more expensive and is not tolerated well by some patients, he said.

And even that product almost went into short supply, Dr. Kweder said. There were some quality control issues that led the agency to temporarily import capecitabine while the manufacturer, Roche, fixed the problem, she said.

Manufacturing and quality control – especially for generic sterile injectables – continue to be behind many shortages, Dr. Kweder said. Sterility has been a consistent problem, with many products found to contain glass particles or metal shavings. She described a zero tolerance policy for such issues with injectables. "No patient should ever be exposed to risks of those sorts," she said.

When asked why generic injectables seem to be having more frequent quality control issues, Dr. Kweder said that the requirements and rules for good manufacturing have not changed over the years, but that the explosion of generic products in the last decade has perhaps put more pressure on manufacturers.

Dr. Schilsky and Dr. Penley said they were hopeful that legislation creating user fees for generic drugmakers would help address the shortage issue. Bills to reauthorize all FDA user fee programs have passed both the House and the Senate; differences are being hashed out in conference right now. The generic user fee – expected to add $1.5 billion to the FDA budget over the next few years – is expected to be retained. Experts expect the president to sign the final bill, said Dr. Schilsky.

The additional funds would give the FDA the ability to cut generic drug review times from the current 24-30 months to about 6-10 months, Dr. Kweder said.

It also would give the agency more resources to eradicate a current backlog of reviews and move more quickly on manufacturing issues, she said.

The legislation includes several additional items on ASCO’s wish list, including a requirement that manufacturers give the FDA early warning of impending shortages. But it does not include any penalties for noncompliance, said Dr. Schilsky.

The Food and Drug Administration has prevented at least 50 drug shortages so far this year, mainly as a result of manufacturers giving the agency early warning of impending problems, Dr. Sandra Kweder announced June 4.

Shortages persist, however, especially for key oncology therapies, according to Dr. Kweder, deputy director of the FDA Office of New Drugs, and oncologists who participated in a press briefing at the annual meeting of the American Society of Clinical Oncologists (ASCO) in Chicago.

Since the White House issued an executive order last Oct. 31 encouraging manufacturers to give the FDA "early notification" of potential disruptions, the agency, working with physicians, manufacturers, pharmacists, and others, has been able to avoid more than 150 drug shortages, Dr. Kweder said.

"Early notification by manufacturers of when they are having production difficulties makes a huge difference in our ability to prevent the public from bearing the burden of drug shortages," she said.

"The good news is that the frequency of drug shortages has begun to decline," agreed Dr. Richard Schilsky, chair of the ASCO Government Relations Committee and chief of the hematology/oncology section at the University of Chicago.

However, unpredictability still exists, which means that oncologists are "never sure when a generic is going to go out of supply," said Dr. Schilsky. "That creates a tremendous amount of uncertainty and anxiety for our patients."

Dr. Michael P. Link, ASCO president, said that several commonly used chemotherapy agents remain in short supply, including fluorouracil, nitrogen mustard, and paclitaxel. In addition, although a methotrexate shortage has been addressed, there is now a shortage of sodium bicarbonate, which is needed to give high-dose injections of the drug, said Dr. Link, chief of pediatric hematology/oncology at the Lucile Packard Children’s Hospital at Stanford (Calif.) University.

Shortages often lead to delays in treatment or less-than-desirable substitutions, said Dr. W. Charles Penley, the incoming ASCO Government Relations Committee chair. His practice – Tennessee Oncology in Nashville – is large enough that it generally has been able to locate products in short supply through its purchasing groups. But a leucovorin shortage last summer led him to switch some patients to oral capecitabine (Xeloda).

That drug is more expensive and is not tolerated well by some patients, he said.

And even that product almost went into short supply, Dr. Kweder said. There were some quality control issues that led the agency to temporarily import capecitabine while the manufacturer, Roche, fixed the problem, she said.

Manufacturing and quality control – especially for generic sterile injectables – continue to be behind many shortages, Dr. Kweder said. Sterility has been a consistent problem, with many products found to contain glass particles or metal shavings. She described a zero tolerance policy for such issues with injectables. "No patient should ever be exposed to risks of those sorts," she said.

When asked why generic injectables seem to be having more frequent quality control issues, Dr. Kweder said that the requirements and rules for good manufacturing have not changed over the years, but that the explosion of generic products in the last decade has perhaps put more pressure on manufacturers.

Dr. Schilsky and Dr. Penley said they were hopeful that legislation creating user fees for generic drugmakers would help address the shortage issue. Bills to reauthorize all FDA user fee programs have passed both the House and the Senate; differences are being hashed out in conference right now. The generic user fee – expected to add $1.5 billion to the FDA budget over the next few years – is expected to be retained. Experts expect the president to sign the final bill, said Dr. Schilsky.

The additional funds would give the FDA the ability to cut generic drug review times from the current 24-30 months to about 6-10 months, Dr. Kweder said.

It also would give the agency more resources to eradicate a current backlog of reviews and move more quickly on manufacturing issues, she said.

The legislation includes several additional items on ASCO’s wish list, including a requirement that manufacturers give the FDA early warning of impending shortages. But it does not include any penalties for noncompliance, said Dr. Schilsky.

The Food and Drug Administration has prevented at least 50 drug shortages so far this year, mainly as a result of manufacturers giving the agency early warning of impending problems, Dr. Sandra Kweder announced June 4.

Shortages persist, however, especially for key oncology therapies, according to Dr. Kweder, deputy director of the FDA Office of New Drugs, and oncologists who participated in a press briefing at the annual meeting of the American Society of Clinical Oncologists (ASCO) in Chicago.

Since the White House issued an executive order last Oct. 31 encouraging manufacturers to give the FDA "early notification" of potential disruptions, the agency, working with physicians, manufacturers, pharmacists, and others, has been able to avoid more than 150 drug shortages, Dr. Kweder said.

"Early notification by manufacturers of when they are having production difficulties makes a huge difference in our ability to prevent the public from bearing the burden of drug shortages," she said.

"The good news is that the frequency of drug shortages has begun to decline," agreed Dr. Richard Schilsky, chair of the ASCO Government Relations Committee and chief of the hematology/oncology section at the University of Chicago.

However, unpredictability still exists, which means that oncologists are "never sure when a generic is going to go out of supply," said Dr. Schilsky. "That creates a tremendous amount of uncertainty and anxiety for our patients."

Dr. Michael P. Link, ASCO president, said that several commonly used chemotherapy agents remain in short supply, including fluorouracil, nitrogen mustard, and paclitaxel. In addition, although a methotrexate shortage has been addressed, there is now a shortage of sodium bicarbonate, which is needed to give high-dose injections of the drug, said Dr. Link, chief of pediatric hematology/oncology at the Lucile Packard Children’s Hospital at Stanford (Calif.) University.

Shortages often lead to delays in treatment or less-than-desirable substitutions, said Dr. W. Charles Penley, the incoming ASCO Government Relations Committee chair. His practice – Tennessee Oncology in Nashville – is large enough that it generally has been able to locate products in short supply through its purchasing groups. But a leucovorin shortage last summer led him to switch some patients to oral capecitabine (Xeloda).

That drug is more expensive and is not tolerated well by some patients, he said.

And even that product almost went into short supply, Dr. Kweder said. There were some quality control issues that led the agency to temporarily import capecitabine while the manufacturer, Roche, fixed the problem, she said.

Manufacturing and quality control – especially for generic sterile injectables – continue to be behind many shortages, Dr. Kweder said. Sterility has been a consistent problem, with many products found to contain glass particles or metal shavings. She described a zero tolerance policy for such issues with injectables. "No patient should ever be exposed to risks of those sorts," she said.

When asked why generic injectables seem to be having more frequent quality control issues, Dr. Kweder said that the requirements and rules for good manufacturing have not changed over the years, but that the explosion of generic products in the last decade has perhaps put more pressure on manufacturers.

Dr. Schilsky and Dr. Penley said they were hopeful that legislation creating user fees for generic drugmakers would help address the shortage issue. Bills to reauthorize all FDA user fee programs have passed both the House and the Senate; differences are being hashed out in conference right now. The generic user fee – expected to add $1.5 billion to the FDA budget over the next few years – is expected to be retained. Experts expect the president to sign the final bill, said Dr. Schilsky.

The additional funds would give the FDA the ability to cut generic drug review times from the current 24-30 months to about 6-10 months, Dr. Kweder said.

It also would give the agency more resources to eradicate a current backlog of reviews and move more quickly on manufacturing issues, she said.

The legislation includes several additional items on ASCO’s wish list, including a requirement that manufacturers give the FDA early warning of impending shortages. But it does not include any penalties for noncompliance, said Dr. Schilsky.

CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."

Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

"The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting," Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

"It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials," he said. "But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor."

Dr. Adams, the moderator, commented, "This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance."

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.

CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."

Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

"The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting," Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

"It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials," he said. "But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor."

Dr. Adams, the moderator, commented, "This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance."

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.

CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."

Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

"The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting," Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

"It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials," he said. "But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor."

Dr. Adams, the moderator, commented, "This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance."

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.

CHICAGO – For patients with resected non–small cell lung cancer bearing epidermal growth factor receptor mutations, daily maintenance with erlotinib was associated with good overall disease-free survival for at least 2 years, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Among 100 patients with NSCLC positive for mutations in the epidermal growth factor receptor (EGFR) who underwent surgery and routine adjuvant chemotherapy or chemoradiotherapy, maintenance with erlotinib (Tarceva) 150 mg daily was associated with a median 2-year disease-free survival of 94%, reported Dr. Joel W. Neal of the Stanford (Calif.) Cancer Institute.

Median overall survival has not been reached, the investigators noted in a poster session.

Only one patient had disease progression while on adjuvant erlotinib, and 10 experienced progression at least 6 months after stopping the drug, suggesting the presence of residual disease that may be sensitive to re-treatment with erlotinib, Dr. Neal said in an interview.

"We’ve encouraged repeat biopsies for patients who have progressed after treatment with adjuvant erlotinib, and of the patients who were biopsied, 6 of 8 had an identical mutation without a known mechanism of resistance," he said.

Five of these patients were evaluable for additional therapy, and all were found to be sensitive to further treatment with erlotinib, Dr. Neal reported.

However, toxicities with erlotinib required dose reductions in some patients, and 6 patients discontinued therapy before the end of the study due to adverse events that included rash, diarrhea, and fatigue.

An oncologist who was not involved in the study commented that he would need to see longer follow-up before he could be convinced of the benefits of adjuvant erlotinib in this population.

"I’m not sure about the toxicity of 2 years of therapy with a TKI [tyrosine kinase inhibitor] in a setting where you’re not quite sure whether you’re improving survival or just disease-free survival," said Dr. Michael J. Purtell, an assistant professor of oncology at Johns Hopkins University in Baltimore, said in an interview.

The investigators designed the study, dubbed SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) to determine whether adjuvant erlotinib could provide a more robust survival benefit to patients than that afforded by conventional adjuvant chemotherapy – typically about 5-10%, they said.

Patients with EGFR mutation–positive, surgically resected stage IA-IIIA NSCLC received 6-9 months of routine adjuvant chemotherapy with or without radiation, and were then continued on oral erlotinib 150 mg daily for up to 2 years. The patients are followed with CT scans every 6 months for 3 years, then once a year for years 4 and 5.

A total of 36 patients were enrolled initially, but the study was later expanded to included 100 patients in all, after initial encouraging results.

The findings thus far suggest that "adjuvant erlotinib has, at least, a cytostatic effect on micrometastatic disease," the investigators wrote.

The study was supported by Genentech. Dr. Neal has received research funding from the company. Dr. Purtell had no relevant disclosures.

CHICAGO – For patients with resected non–small cell lung cancer bearing epidermal growth factor receptor mutations, daily maintenance with erlotinib was associated with good overall disease-free survival for at least 2 years, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Among 100 patients with NSCLC positive for mutations in the epidermal growth factor receptor (EGFR) who underwent surgery and routine adjuvant chemotherapy or chemoradiotherapy, maintenance with erlotinib (Tarceva) 150 mg daily was associated with a median 2-year disease-free survival of 94%, reported Dr. Joel W. Neal of the Stanford (Calif.) Cancer Institute.

Median overall survival has not been reached, the investigators noted in a poster session.

Only one patient had disease progression while on adjuvant erlotinib, and 10 experienced progression at least 6 months after stopping the drug, suggesting the presence of residual disease that may be sensitive to re-treatment with erlotinib, Dr. Neal said in an interview.

"We’ve encouraged repeat biopsies for patients who have progressed after treatment with adjuvant erlotinib, and of the patients who were biopsied, 6 of 8 had an identical mutation without a known mechanism of resistance," he said.

Five of these patients were evaluable for additional therapy, and all were found to be sensitive to further treatment with erlotinib, Dr. Neal reported.

However, toxicities with erlotinib required dose reductions in some patients, and 6 patients discontinued therapy before the end of the study due to adverse events that included rash, diarrhea, and fatigue.

An oncologist who was not involved in the study commented that he would need to see longer follow-up before he could be convinced of the benefits of adjuvant erlotinib in this population.

"I’m not sure about the toxicity of 2 years of therapy with a TKI [tyrosine kinase inhibitor] in a setting where you’re not quite sure whether you’re improving survival or just disease-free survival," said Dr. Michael J. Purtell, an assistant professor of oncology at Johns Hopkins University in Baltimore, said in an interview.

The investigators designed the study, dubbed SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) to determine whether adjuvant erlotinib could provide a more robust survival benefit to patients than that afforded by conventional adjuvant chemotherapy – typically about 5-10%, they said.

Patients with EGFR mutation–positive, surgically resected stage IA-IIIA NSCLC received 6-9 months of routine adjuvant chemotherapy with or without radiation, and were then continued on oral erlotinib 150 mg daily for up to 2 years. The patients are followed with CT scans every 6 months for 3 years, then once a year for years 4 and 5.

A total of 36 patients were enrolled initially, but the study was later expanded to included 100 patients in all, after initial encouraging results.

The findings thus far suggest that "adjuvant erlotinib has, at least, a cytostatic effect on micrometastatic disease," the investigators wrote.

The study was supported by Genentech. Dr. Neal has received research funding from the company. Dr. Purtell had no relevant disclosures.

CHICAGO – For patients with resected non–small cell lung cancer bearing epidermal growth factor receptor mutations, daily maintenance with erlotinib was associated with good overall disease-free survival for at least 2 years, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Among 100 patients with NSCLC positive for mutations in the epidermal growth factor receptor (EGFR) who underwent surgery and routine adjuvant chemotherapy or chemoradiotherapy, maintenance with erlotinib (Tarceva) 150 mg daily was associated with a median 2-year disease-free survival of 94%, reported Dr. Joel W. Neal of the Stanford (Calif.) Cancer Institute.

Median overall survival has not been reached, the investigators noted in a poster session.

Only one patient had disease progression while on adjuvant erlotinib, and 10 experienced progression at least 6 months after stopping the drug, suggesting the presence of residual disease that may be sensitive to re-treatment with erlotinib, Dr. Neal said in an interview.

"We’ve encouraged repeat biopsies for patients who have progressed after treatment with adjuvant erlotinib, and of the patients who were biopsied, 6 of 8 had an identical mutation without a known mechanism of resistance," he said.

Five of these patients were evaluable for additional therapy, and all were found to be sensitive to further treatment with erlotinib, Dr. Neal reported.

However, toxicities with erlotinib required dose reductions in some patients, and 6 patients discontinued therapy before the end of the study due to adverse events that included rash, diarrhea, and fatigue.

An oncologist who was not involved in the study commented that he would need to see longer follow-up before he could be convinced of the benefits of adjuvant erlotinib in this population.

"I’m not sure about the toxicity of 2 years of therapy with a TKI [tyrosine kinase inhibitor] in a setting where you’re not quite sure whether you’re improving survival or just disease-free survival," said Dr. Michael J. Purtell, an assistant professor of oncology at Johns Hopkins University in Baltimore, said in an interview.

The investigators designed the study, dubbed SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) to determine whether adjuvant erlotinib could provide a more robust survival benefit to patients than that afforded by conventional adjuvant chemotherapy – typically about 5-10%, they said.

Patients with EGFR mutation–positive, surgically resected stage IA-IIIA NSCLC received 6-9 months of routine adjuvant chemotherapy with or without radiation, and were then continued on oral erlotinib 150 mg daily for up to 2 years. The patients are followed with CT scans every 6 months for 3 years, then once a year for years 4 and 5.

A total of 36 patients were enrolled initially, but the study was later expanded to included 100 patients in all, after initial encouraging results.

The findings thus far suggest that "adjuvant erlotinib has, at least, a cytostatic effect on micrometastatic disease," the investigators wrote.

The study was supported by Genentech. Dr. Neal has received research funding from the company. Dr. Purtell had no relevant disclosures.