2012 ASCO Annual Meeting

CHICAGO – The investigational tyrosine kinase inhibitor cabozantinib showed "encouraging" activity against metastatic, treatment-refractory renal cell carcinoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Cabozantinib was associated with a 28% objective response rate and a median progression-free survival of 14.7 months, among 25 patients with metastatic renal cell carcinoma, one-third of whom had been treated with at least four prior systemic therapies. Median overall survival had not been reached at a median 14.7 months of follow-up in the drug-drug interaction study, said Dr. Toni K. Choueiri, director of the kidney cancer center at the Dana-Farber Cancer Institute in Boston.

One patient with symptomatic metastatic bone lesions had partial resolution of the lesions on a bone scan, and was able to substantially reduce narcotic use by 7 weeks and continue on a reduced dose through week 25. A second patient with bone metastases and pain at baseline had complete resolution of pain by 4 weeks, and has remained pain free for more than 90 weeks on study, Dr. Choueiri said.

"The safety profile was somewhat similar to other TKIs [tyrosine kinase inhibitors], with manageable adverse events, with an extended treatment period over 600-plus days," he said.

Cabozantinib, also known as XL184, is a small-molecule inhibitor of the c-MET and vascular endothelial growth factor (VEGF) receptor 2 pathways. Up to 25% of patients with renal cell carcinoma have disease that is refractory to anti-VEGF therapies, but may be susceptible to cabozantinib, with its ability to overcome resistance to VEGF through blockage of the c-MET kinase pathway.

In addition, nearly one-third of patients develop metastases to bone, which are generally resistant to existing therapies and are prognostic of poor survival; hence the rationale for testing cabozantinib in this population, Dr. Choueiri said.

A total of 25 patients with metastatic kidney cancer in whom prior therapies had failed received cabozantinib at a dose of 140 mg daily with a single dose of rosiglitazone (Avandia) as part of a phase I study to test drug-drug interactions.

Most of the patients (22) had previously received anti-VEGF therapy, 15 had received therapy directed against mTOR (mammalian target of rapamycin), 13 had received anti-VEGF and anti-mTOR agents in combination, 5 had received cytokine therapy, and 3 had undergone chemotherapy. Four patients had bone metastases.

At last follow-up, 7 patients remained on study and 18 had discontinued, 8 for progressive disease, 6 for adverse events, and 4 at the patient’s request.

Of the 21 patients evaluable for a postbaseline RECIST assessment, 7 had a confirmed partial response, 13 had stable disease, and 1 had disease progression. A total of 18 patients met the criteria for disease control (partial responses plus stable disease) at 16 weeks.

The median duration of response is not yet estimable, Dr. Choueiri said. Of the 21 patients with one or more postbaseline scans, 19 had some degree of tumor regression, ranging from about a 5% shrinkage to a decline of more than 60%.

The most frequently occurring grade 3 or 4 adverse events were fatigue in four patients, diarrhea in three, hypophosphatemia in nine, and hyponatremia in five. There were no drug-related deaths.

Investigators are planning an evaluation of cabozantinib at a dose of 60 mg daily as first-line therapy for renal cell carcinoma, Dr. Choueiri said.

"I think overall [with] cabozantinib, it is rational to think of it as a synergistic approach to VEGF and c-MET blockade," said Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

She noted that while cabozantinib has "intriguing preliminary efficacy," the toxicities – primarily fatigue, diarrhea, and nausea – were similar to those seen in trials of the drug for prostate cancer, and required discontinuations in nearly one-fourth of patients.

"A big question will be whether a lower dose can achieve the same efficacy," she said.

The study was funded by Exelixis, maker of cabozantinib. Dr. Choueiri has received research funding from the company. Dr. Harshman has received research funding from Bristol-Myers Squibb.

CHICAGO – The investigational tyrosine kinase inhibitor cabozantinib showed "encouraging" activity against metastatic, treatment-refractory renal cell carcinoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Cabozantinib was associated with a 28% objective response rate and a median progression-free survival of 14.7 months, among 25 patients with metastatic renal cell carcinoma, one-third of whom had been treated with at least four prior systemic therapies. Median overall survival had not been reached at a median 14.7 months of follow-up in the drug-drug interaction study, said Dr. Toni K. Choueiri, director of the kidney cancer center at the Dana-Farber Cancer Institute in Boston.

One patient with symptomatic metastatic bone lesions had partial resolution of the lesions on a bone scan, and was able to substantially reduce narcotic use by 7 weeks and continue on a reduced dose through week 25. A second patient with bone metastases and pain at baseline had complete resolution of pain by 4 weeks, and has remained pain free for more than 90 weeks on study, Dr. Choueiri said.

"The safety profile was somewhat similar to other TKIs [tyrosine kinase inhibitors], with manageable adverse events, with an extended treatment period over 600-plus days," he said.

Cabozantinib, also known as XL184, is a small-molecule inhibitor of the c-MET and vascular endothelial growth factor (VEGF) receptor 2 pathways. Up to 25% of patients with renal cell carcinoma have disease that is refractory to anti-VEGF therapies, but may be susceptible to cabozantinib, with its ability to overcome resistance to VEGF through blockage of the c-MET kinase pathway.

In addition, nearly one-third of patients develop metastases to bone, which are generally resistant to existing therapies and are prognostic of poor survival; hence the rationale for testing cabozantinib in this population, Dr. Choueiri said.

A total of 25 patients with metastatic kidney cancer in whom prior therapies had failed received cabozantinib at a dose of 140 mg daily with a single dose of rosiglitazone (Avandia) as part of a phase I study to test drug-drug interactions.

Most of the patients (22) had previously received anti-VEGF therapy, 15 had received therapy directed against mTOR (mammalian target of rapamycin), 13 had received anti-VEGF and anti-mTOR agents in combination, 5 had received cytokine therapy, and 3 had undergone chemotherapy. Four patients had bone metastases.

At last follow-up, 7 patients remained on study and 18 had discontinued, 8 for progressive disease, 6 for adverse events, and 4 at the patient’s request.

Of the 21 patients evaluable for a postbaseline RECIST assessment, 7 had a confirmed partial response, 13 had stable disease, and 1 had disease progression. A total of 18 patients met the criteria for disease control (partial responses plus stable disease) at 16 weeks.

The median duration of response is not yet estimable, Dr. Choueiri said. Of the 21 patients with one or more postbaseline scans, 19 had some degree of tumor regression, ranging from about a 5% shrinkage to a decline of more than 60%.

The most frequently occurring grade 3 or 4 adverse events were fatigue in four patients, diarrhea in three, hypophosphatemia in nine, and hyponatremia in five. There were no drug-related deaths.

Investigators are planning an evaluation of cabozantinib at a dose of 60 mg daily as first-line therapy for renal cell carcinoma, Dr. Choueiri said.

"I think overall [with] cabozantinib, it is rational to think of it as a synergistic approach to VEGF and c-MET blockade," said Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

She noted that while cabozantinib has "intriguing preliminary efficacy," the toxicities – primarily fatigue, diarrhea, and nausea – were similar to those seen in trials of the drug for prostate cancer, and required discontinuations in nearly one-fourth of patients.

"A big question will be whether a lower dose can achieve the same efficacy," she said.

The study was funded by Exelixis, maker of cabozantinib. Dr. Choueiri has received research funding from the company. Dr. Harshman has received research funding from Bristol-Myers Squibb.

CHICAGO – The investigational tyrosine kinase inhibitor cabozantinib showed "encouraging" activity against metastatic, treatment-refractory renal cell carcinoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

Cabozantinib was associated with a 28% objective response rate and a median progression-free survival of 14.7 months, among 25 patients with metastatic renal cell carcinoma, one-third of whom had been treated with at least four prior systemic therapies. Median overall survival had not been reached at a median 14.7 months of follow-up in the drug-drug interaction study, said Dr. Toni K. Choueiri, director of the kidney cancer center at the Dana-Farber Cancer Institute in Boston.

One patient with symptomatic metastatic bone lesions had partial resolution of the lesions on a bone scan, and was able to substantially reduce narcotic use by 7 weeks and continue on a reduced dose through week 25. A second patient with bone metastases and pain at baseline had complete resolution of pain by 4 weeks, and has remained pain free for more than 90 weeks on study, Dr. Choueiri said.

"The safety profile was somewhat similar to other TKIs [tyrosine kinase inhibitors], with manageable adverse events, with an extended treatment period over 600-plus days," he said.

Cabozantinib, also known as XL184, is a small-molecule inhibitor of the c-MET and vascular endothelial growth factor (VEGF) receptor 2 pathways. Up to 25% of patients with renal cell carcinoma have disease that is refractory to anti-VEGF therapies, but may be susceptible to cabozantinib, with its ability to overcome resistance to VEGF through blockage of the c-MET kinase pathway.

In addition, nearly one-third of patients develop metastases to bone, which are generally resistant to existing therapies and are prognostic of poor survival; hence the rationale for testing cabozantinib in this population, Dr. Choueiri said.

A total of 25 patients with metastatic kidney cancer in whom prior therapies had failed received cabozantinib at a dose of 140 mg daily with a single dose of rosiglitazone (Avandia) as part of a phase I study to test drug-drug interactions.

Most of the patients (22) had previously received anti-VEGF therapy, 15 had received therapy directed against mTOR (mammalian target of rapamycin), 13 had received anti-VEGF and anti-mTOR agents in combination, 5 had received cytokine therapy, and 3 had undergone chemotherapy. Four patients had bone metastases.

At last follow-up, 7 patients remained on study and 18 had discontinued, 8 for progressive disease, 6 for adverse events, and 4 at the patient’s request.

Of the 21 patients evaluable for a postbaseline RECIST assessment, 7 had a confirmed partial response, 13 had stable disease, and 1 had disease progression. A total of 18 patients met the criteria for disease control (partial responses plus stable disease) at 16 weeks.

The median duration of response is not yet estimable, Dr. Choueiri said. Of the 21 patients with one or more postbaseline scans, 19 had some degree of tumor regression, ranging from about a 5% shrinkage to a decline of more than 60%.

The most frequently occurring grade 3 or 4 adverse events were fatigue in four patients, diarrhea in three, hypophosphatemia in nine, and hyponatremia in five. There were no drug-related deaths.

Investigators are planning an evaluation of cabozantinib at a dose of 60 mg daily as first-line therapy for renal cell carcinoma, Dr. Choueiri said.

"I think overall [with] cabozantinib, it is rational to think of it as a synergistic approach to VEGF and c-MET blockade," said Dr. Lauren C. Harshman, an oncologist at Stanford (Calif.) University. Dr. Harshman was the invited discussant but was not involved in the study.

She noted that while cabozantinib has "intriguing preliminary efficacy," the toxicities – primarily fatigue, diarrhea, and nausea – were similar to those seen in trials of the drug for prostate cancer, and required discontinuations in nearly one-fourth of patients.

"A big question will be whether a lower dose can achieve the same efficacy," she said.

The study was funded by Exelixis, maker of cabozantinib. Dr. Choueiri has received research funding from the company. Dr. Harshman has received research funding from Bristol-Myers Squibb.

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.

An exploratory analysis favored whole pelvic vs. prostate-only radiation for overall survival (HR, 0.90; P = .57) and DSS (HR, 0.65; P = .15), but Dr. Mason called this finding hypothesis generating.

He remarked that combined ADT plus RT is enshrined in the European Association of Urology and National Comprehensive Cancer Network guidelines, "but that uptake is uncertain, and we have concerns as to whether this has been taken up as much as it should have been."

Dr. Small agreed with the authors’ conclusion that ADT and RT should be offered to all men with locally advanced prostate cancer suitable for RT, but said the absolute difference in 10-year overall-survival is modest, at 6%. Because accrual took place 10 years ago, the results also cannot be fully extrapolated to the increasingly common high-risk patients seen in the United States, who tend to be at a high grade and lower stage.

He pointed out that the combination arm had a 5% absolute increase in deaths because of secondary malignancies, which warrants exploration. "It makes you wonder what the radiation is doing here," he added.

Still, Dr. Small commended the authors for persevering with what he described as a tough study to do with a nonradiation arm. "This study is a demonstration of the power of the cooperative groups, and in an era of shrinking resources, points out that undersourcing the cooperative groups – as has been advocated by some – is shortsighted," he said.

Atrasentan Flops Again

Dr. David I. Quinn had the unenviable task of delivering the final word on atrasentan (Xinlay) as a prostate cancer therapy. The selective endothelin blocker failed as monotherapy in two previous phase III trials, and was so ineffective in combination with docetaxel that the phase III Southwest Oncology Group S0421 trial in advanced castration-resistant disease was halted early last year.

A new post hoc analysis from S0421 identified an 8-month survival benefit with atrasentan in a distinct subset of poor-prognosis patients with skeletal metastases and four bone metabolism biomarkers (median, 13 months vs. 5 months; P = .02).

Still, the drug proved futile when compared with docetaxel plus placebo in the entire cohort for time to progression (median, 9 months for both; HR, 1.03; P = .71) and overall survival (median, 18 months for both; HR, 1.04; P = .61). The 2-year progression-free survival was 18% in both groups, and overall survival rates were 37% and 38%, respectively.

"Endothelin blockade with currently available drugs such as atrasentan and zibotentan, which has three negative studies, is now a failed experiment," said Dr. Quinn, coleader of genitourinary medical oncology at the University of Southern California, Los Angeles. "It has been superseded by osteoblast-targeted therapy that actually works, like radium-223."

Dr. Parker reported consulting or advising for Algeta and receiving honoraria from Bayer; his coauthors reported financial relationships including employment with Algeta, which initiated the ALSYMPCA trial. Dr. Saad reported consulting or advising for and receiving honorarium and research funding from Amgen. Dr. Mason reported no disclosures. Dr. Quinn reported financial relationships with several firms. SWOG S0421 was supported by the Eastern Cooperative Oncology Group and Cancer and Leukemia Group B. Dr. Small reported consulting or advising for Dendreon and receiving research funding from Genzyme and Sanofi.

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.

An exploratory analysis favored whole pelvic vs. prostate-only radiation for overall survival (HR, 0.90; P = .57) and DSS (HR, 0.65; P = .15), but Dr. Mason called this finding hypothesis generating.

He remarked that combined ADT plus RT is enshrined in the European Association of Urology and National Comprehensive Cancer Network guidelines, "but that uptake is uncertain, and we have concerns as to whether this has been taken up as much as it should have been."

Dr. Small agreed with the authors’ conclusion that ADT and RT should be offered to all men with locally advanced prostate cancer suitable for RT, but said the absolute difference in 10-year overall-survival is modest, at 6%. Because accrual took place 10 years ago, the results also cannot be fully extrapolated to the increasingly common high-risk patients seen in the United States, who tend to be at a high grade and lower stage.

He pointed out that the combination arm had a 5% absolute increase in deaths because of secondary malignancies, which warrants exploration. "It makes you wonder what the radiation is doing here," he added.

Still, Dr. Small commended the authors for persevering with what he described as a tough study to do with a nonradiation arm. "This study is a demonstration of the power of the cooperative groups, and in an era of shrinking resources, points out that undersourcing the cooperative groups – as has been advocated by some – is shortsighted," he said.

Atrasentan Flops Again

Dr. David I. Quinn had the unenviable task of delivering the final word on atrasentan (Xinlay) as a prostate cancer therapy. The selective endothelin blocker failed as monotherapy in two previous phase III trials, and was so ineffective in combination with docetaxel that the phase III Southwest Oncology Group S0421 trial in advanced castration-resistant disease was halted early last year.

A new post hoc analysis from S0421 identified an 8-month survival benefit with atrasentan in a distinct subset of poor-prognosis patients with skeletal metastases and four bone metabolism biomarkers (median, 13 months vs. 5 months; P = .02).

Still, the drug proved futile when compared with docetaxel plus placebo in the entire cohort for time to progression (median, 9 months for both; HR, 1.03; P = .71) and overall survival (median, 18 months for both; HR, 1.04; P = .61). The 2-year progression-free survival was 18% in both groups, and overall survival rates were 37% and 38%, respectively.

"Endothelin blockade with currently available drugs such as atrasentan and zibotentan, which has three negative studies, is now a failed experiment," said Dr. Quinn, coleader of genitourinary medical oncology at the University of Southern California, Los Angeles. "It has been superseded by osteoblast-targeted therapy that actually works, like radium-223."

Dr. Parker reported consulting or advising for Algeta and receiving honoraria from Bayer; his coauthors reported financial relationships including employment with Algeta, which initiated the ALSYMPCA trial. Dr. Saad reported consulting or advising for and receiving honorarium and research funding from Amgen. Dr. Mason reported no disclosures. Dr. Quinn reported financial relationships with several firms. SWOG S0421 was supported by the Eastern Cooperative Oncology Group and Cancer and Leukemia Group B. Dr. Small reported consulting or advising for Dendreon and receiving research funding from Genzyme and Sanofi.

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.

An exploratory analysis favored whole pelvic vs. prostate-only radiation for overall survival (HR, 0.90; P = .57) and DSS (HR, 0.65; P = .15), but Dr. Mason called this finding hypothesis generating.

He remarked that combined ADT plus RT is enshrined in the European Association of Urology and National Comprehensive Cancer Network guidelines, "but that uptake is uncertain, and we have concerns as to whether this has been taken up as much as it should have been."

Dr. Small agreed with the authors’ conclusion that ADT and RT should be offered to all men with locally advanced prostate cancer suitable for RT, but said the absolute difference in 10-year overall-survival is modest, at 6%. Because accrual took place 10 years ago, the results also cannot be fully extrapolated to the increasingly common high-risk patients seen in the United States, who tend to be at a high grade and lower stage.

He pointed out that the combination arm had a 5% absolute increase in deaths because of secondary malignancies, which warrants exploration. "It makes you wonder what the radiation is doing here," he added.

Still, Dr. Small commended the authors for persevering with what he described as a tough study to do with a nonradiation arm. "This study is a demonstration of the power of the cooperative groups, and in an era of shrinking resources, points out that undersourcing the cooperative groups – as has been advocated by some – is shortsighted," he said.

Atrasentan Flops Again

Dr. David I. Quinn had the unenviable task of delivering the final word on atrasentan (Xinlay) as a prostate cancer therapy. The selective endothelin blocker failed as monotherapy in two previous phase III trials, and was so ineffective in combination with docetaxel that the phase III Southwest Oncology Group S0421 trial in advanced castration-resistant disease was halted early last year.

A new post hoc analysis from S0421 identified an 8-month survival benefit with atrasentan in a distinct subset of poor-prognosis patients with skeletal metastases and four bone metabolism biomarkers (median, 13 months vs. 5 months; P = .02).

Still, the drug proved futile when compared with docetaxel plus placebo in the entire cohort for time to progression (median, 9 months for both; HR, 1.03; P = .71) and overall survival (median, 18 months for both; HR, 1.04; P = .61). The 2-year progression-free survival was 18% in both groups, and overall survival rates were 37% and 38%, respectively.

"Endothelin blockade with currently available drugs such as atrasentan and zibotentan, which has three negative studies, is now a failed experiment," said Dr. Quinn, coleader of genitourinary medical oncology at the University of Southern California, Los Angeles. "It has been superseded by osteoblast-targeted therapy that actually works, like radium-223."

Dr. Parker reported consulting or advising for Algeta and receiving honoraria from Bayer; his coauthors reported financial relationships including employment with Algeta, which initiated the ALSYMPCA trial. Dr. Saad reported consulting or advising for and receiving honorarium and research funding from Amgen. Dr. Mason reported no disclosures. Dr. Quinn reported financial relationships with several firms. SWOG S0421 was supported by the Eastern Cooperative Oncology Group and Cancer and Leukemia Group B. Dr. Small reported consulting or advising for Dendreon and receiving research funding from Genzyme and Sanofi.

CHICAGO – An experimental therapy is closing in on a new target in metastatic castration-resistant prostate cancer: heat shock protein 27.

OGX-427 is a second-generation antisense oligonucleotide that is designed to reduce production of heat shock protein 27 (Hsp27), a cell-survival protein that is highly expressed in many cancers including prostate and associated with poorer prognosis. Hsp27 increases after castration therapy as a stress survival response and has been shown to be highly overexpressed in castration-resistant prostate cancer tissues, Dr. Kim N. Chi explained at the annual meeting of the American Society of Clinical Oncology.

In phase I studies, OGX-427 decreased tumor markers in patients with prostate and ovarian cancer and measurable disease by more than 15% in roughly one-third of patients. The drug has a prolonged half-life of about 10 days, but no dose-limiting toxicities were identified. Mostly the adverse events were dose-dependent, grade 1-2 infusion reactions, said Dr. Chi, chair of the genitourinary group and medical director of clinical trials at the Vancouver (British Columbia) Prostate Centre–BC Cancer Agency.

The goal of the current phase II trial was to improve the 12-week progression-free rate in chemotherapy naive men with metastatic castration-resistant prostate cancer. Patients were randomized to twice-daily prednisone 5 mg alone or with OGX-427 600 mg IV in three loading doses in the first week followed by 1,000 mg weekly for up to 24 weeks for patients with a best response of stable disease or continuously for responders.

The current analysis includes 42 of the 72 planned patients. Because of the frequent use of corticosteroids to manage infusion reactions, the control arm was added to isolate out the effect of OGX-427, he said.

The 22 patients in the OGX-427 arm were slightly younger than the 20 controls were (median 66 years vs. 72 years), but the OGX-427 arm had more patients with lung metastases (14% vs. 0%), elevated lactate dehydrogenase (36% vs. 15), elevated alkaline phosphatase (32% vs. 10%), prior prednisone therapy (23% vs. 15%) and 5 or more circulating tumor cells/7.5 mL of blood (96% vs. 90%), Dr. Chi pointed out.

Median treatment duration was 24 weeks with OGX-427 and 14 weeks with prednisone alone. In all, 93% of controls came off treatment because of disease progression vs. only 31% on OGX-427, although 25% also did so because of adverse events.

At 12 weeks, 71% of patients on OGX-427 were progression free, compared with 40% on prednisone alone, he said.

A prostate-specific antigen decline of 50% or more occurred in 50% and 20%, respectively.

The objective response rate was 44%, including one complete response and three partial responses, among nine evaluable OGX-427 patients vs. 0% among 12 evaluable controls.

Sixty percent of OGX-427 patients have had either a decrease of more than 5 circulating tumor cells/7.5 mL or maintained a less 5 cell/7.5 mL count, compared with 41% of controls having a similar decline.

Treatment-related events have been predominantly infusion related and were described as a flulike illness that occurs mainly in the first couple of infusions and includes grade 1/2 chills (55%), diarrhea (41%), nausea (32%), flushing (23%), vomiting (23%) and pyrexia (18%).

"Patients tend to build tolerance and they [events] are brief and self-limited," Dr. Chi said.

Grade 3/4 lymphopenia was more common with OGX-427 at 18% vs. 10% among controls but did not result in any infectious sequelae.

"These preliminary data identify Hsp27 as a novel therapeutic target and supports continued evaluation of OGX-427 for patients with castration-resistant prostate cancer," he concluded.

Discussant Dr. Karim Fizazi, with Institut Gustave Roussy, Villejuif, France, said he was surprised by the "quite-high" adverse event rates for chills, nausea, and diarrhea, but that fortunately they were mostly grade 1 and 2. He said the biological background for targeting Hsp27 is very strong and called the preliminary evidence of clinical activity exciting.

"If these data are confirmed, which I don’t really doubt they will, what will be the phase III development path for such IV [intravenous] weekly drug infusions in the context of all the drugs we now have in prostate cancer?" he asked.

The current trial is ongoing, with a phase II trial of OGX-427 plus abiraterone (Zytiga) in castration-resistant prostate cancer to be initiated later this year, according to OncoGenex Pharmaceuticals. The company is also developing the targeted anticlusterin molecule OGX-001 to be evaluated later this year in two phase III trials in castration-resistant disease.

Dr. Chi reports research funding from OncoGenex Pharmaceuticals, which is developing OGX-427. Dr. Fizazi reports a consultant or advisory role with OncoGenex and Exelixis.

CHICAGO – An experimental therapy is closing in on a new target in metastatic castration-resistant prostate cancer: heat shock protein 27.

OGX-427 is a second-generation antisense oligonucleotide that is designed to reduce production of heat shock protein 27 (Hsp27), a cell-survival protein that is highly expressed in many cancers including prostate and associated with poorer prognosis. Hsp27 increases after castration therapy as a stress survival response and has been shown to be highly overexpressed in castration-resistant prostate cancer tissues, Dr. Kim N. Chi explained at the annual meeting of the American Society of Clinical Oncology.

In phase I studies, OGX-427 decreased tumor markers in patients with prostate and ovarian cancer and measurable disease by more than 15% in roughly one-third of patients. The drug has a prolonged half-life of about 10 days, but no dose-limiting toxicities were identified. Mostly the adverse events were dose-dependent, grade 1-2 infusion reactions, said Dr. Chi, chair of the genitourinary group and medical director of clinical trials at the Vancouver (British Columbia) Prostate Centre–BC Cancer Agency.

The goal of the current phase II trial was to improve the 12-week progression-free rate in chemotherapy naive men with metastatic castration-resistant prostate cancer. Patients were randomized to twice-daily prednisone 5 mg alone or with OGX-427 600 mg IV in three loading doses in the first week followed by 1,000 mg weekly for up to 24 weeks for patients with a best response of stable disease or continuously for responders.

The current analysis includes 42 of the 72 planned patients. Because of the frequent use of corticosteroids to manage infusion reactions, the control arm was added to isolate out the effect of OGX-427, he said.

The 22 patients in the OGX-427 arm were slightly younger than the 20 controls were (median 66 years vs. 72 years), but the OGX-427 arm had more patients with lung metastases (14% vs. 0%), elevated lactate dehydrogenase (36% vs. 15), elevated alkaline phosphatase (32% vs. 10%), prior prednisone therapy (23% vs. 15%) and 5 or more circulating tumor cells/7.5 mL of blood (96% vs. 90%), Dr. Chi pointed out.

Median treatment duration was 24 weeks with OGX-427 and 14 weeks with prednisone alone. In all, 93% of controls came off treatment because of disease progression vs. only 31% on OGX-427, although 25% also did so because of adverse events.

At 12 weeks, 71% of patients on OGX-427 were progression free, compared with 40% on prednisone alone, he said.

A prostate-specific antigen decline of 50% or more occurred in 50% and 20%, respectively.

The objective response rate was 44%, including one complete response and three partial responses, among nine evaluable OGX-427 patients vs. 0% among 12 evaluable controls.

Sixty percent of OGX-427 patients have had either a decrease of more than 5 circulating tumor cells/7.5 mL or maintained a less 5 cell/7.5 mL count, compared with 41% of controls having a similar decline.

Treatment-related events have been predominantly infusion related and were described as a flulike illness that occurs mainly in the first couple of infusions and includes grade 1/2 chills (55%), diarrhea (41%), nausea (32%), flushing (23%), vomiting (23%) and pyrexia (18%).

"Patients tend to build tolerance and they [events] are brief and self-limited," Dr. Chi said.

Grade 3/4 lymphopenia was more common with OGX-427 at 18% vs. 10% among controls but did not result in any infectious sequelae.

"These preliminary data identify Hsp27 as a novel therapeutic target and supports continued evaluation of OGX-427 for patients with castration-resistant prostate cancer," he concluded.

Discussant Dr. Karim Fizazi, with Institut Gustave Roussy, Villejuif, France, said he was surprised by the "quite-high" adverse event rates for chills, nausea, and diarrhea, but that fortunately they were mostly grade 1 and 2. He said the biological background for targeting Hsp27 is very strong and called the preliminary evidence of clinical activity exciting.

"If these data are confirmed, which I don’t really doubt they will, what will be the phase III development path for such IV [intravenous] weekly drug infusions in the context of all the drugs we now have in prostate cancer?" he asked.

The current trial is ongoing, with a phase II trial of OGX-427 plus abiraterone (Zytiga) in castration-resistant prostate cancer to be initiated later this year, according to OncoGenex Pharmaceuticals. The company is also developing the targeted anticlusterin molecule OGX-001 to be evaluated later this year in two phase III trials in castration-resistant disease.

Dr. Chi reports research funding from OncoGenex Pharmaceuticals, which is developing OGX-427. Dr. Fizazi reports a consultant or advisory role with OncoGenex and Exelixis.

CHICAGO – An experimental therapy is closing in on a new target in metastatic castration-resistant prostate cancer: heat shock protein 27.

OGX-427 is a second-generation antisense oligonucleotide that is designed to reduce production of heat shock protein 27 (Hsp27), a cell-survival protein that is highly expressed in many cancers including prostate and associated with poorer prognosis. Hsp27 increases after castration therapy as a stress survival response and has been shown to be highly overexpressed in castration-resistant prostate cancer tissues, Dr. Kim N. Chi explained at the annual meeting of the American Society of Clinical Oncology.

In phase I studies, OGX-427 decreased tumor markers in patients with prostate and ovarian cancer and measurable disease by more than 15% in roughly one-third of patients. The drug has a prolonged half-life of about 10 days, but no dose-limiting toxicities were identified. Mostly the adverse events were dose-dependent, grade 1-2 infusion reactions, said Dr. Chi, chair of the genitourinary group and medical director of clinical trials at the Vancouver (British Columbia) Prostate Centre–BC Cancer Agency.

The goal of the current phase II trial was to improve the 12-week progression-free rate in chemotherapy naive men with metastatic castration-resistant prostate cancer. Patients were randomized to twice-daily prednisone 5 mg alone or with OGX-427 600 mg IV in three loading doses in the first week followed by 1,000 mg weekly for up to 24 weeks for patients with a best response of stable disease or continuously for responders.

The current analysis includes 42 of the 72 planned patients. Because of the frequent use of corticosteroids to manage infusion reactions, the control arm was added to isolate out the effect of OGX-427, he said.

The 22 patients in the OGX-427 arm were slightly younger than the 20 controls were (median 66 years vs. 72 years), but the OGX-427 arm had more patients with lung metastases (14% vs. 0%), elevated lactate dehydrogenase (36% vs. 15), elevated alkaline phosphatase (32% vs. 10%), prior prednisone therapy (23% vs. 15%) and 5 or more circulating tumor cells/7.5 mL of blood (96% vs. 90%), Dr. Chi pointed out.

Median treatment duration was 24 weeks with OGX-427 and 14 weeks with prednisone alone. In all, 93% of controls came off treatment because of disease progression vs. only 31% on OGX-427, although 25% also did so because of adverse events.

At 12 weeks, 71% of patients on OGX-427 were progression free, compared with 40% on prednisone alone, he said.

A prostate-specific antigen decline of 50% or more occurred in 50% and 20%, respectively.

The objective response rate was 44%, including one complete response and three partial responses, among nine evaluable OGX-427 patients vs. 0% among 12 evaluable controls.

Sixty percent of OGX-427 patients have had either a decrease of more than 5 circulating tumor cells/7.5 mL or maintained a less 5 cell/7.5 mL count, compared with 41% of controls having a similar decline.

Treatment-related events have been predominantly infusion related and were described as a flulike illness that occurs mainly in the first couple of infusions and includes grade 1/2 chills (55%), diarrhea (41%), nausea (32%), flushing (23%), vomiting (23%) and pyrexia (18%).

"Patients tend to build tolerance and they [events] are brief and self-limited," Dr. Chi said.

Grade 3/4 lymphopenia was more common with OGX-427 at 18% vs. 10% among controls but did not result in any infectious sequelae.

"These preliminary data identify Hsp27 as a novel therapeutic target and supports continued evaluation of OGX-427 for patients with castration-resistant prostate cancer," he concluded.

Discussant Dr. Karim Fizazi, with Institut Gustave Roussy, Villejuif, France, said he was surprised by the "quite-high" adverse event rates for chills, nausea, and diarrhea, but that fortunately they were mostly grade 1 and 2. He said the biological background for targeting Hsp27 is very strong and called the preliminary evidence of clinical activity exciting.

"If these data are confirmed, which I don’t really doubt they will, what will be the phase III development path for such IV [intravenous] weekly drug infusions in the context of all the drugs we now have in prostate cancer?" he asked.

The current trial is ongoing, with a phase II trial of OGX-427 plus abiraterone (Zytiga) in castration-resistant prostate cancer to be initiated later this year, according to OncoGenex Pharmaceuticals. The company is also developing the targeted anticlusterin molecule OGX-001 to be evaluated later this year in two phase III trials in castration-resistant disease.

Dr. Chi reports research funding from OncoGenex Pharmaceuticals, which is developing OGX-427. Dr. Fizazi reports a consultant or advisory role with OncoGenex and Exelixis.

CHICAGO – Coupling carboplatin chemotherapy with pemetrexed significantly improved survival in the subset of hard-to-treat patients with advanced non–small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.

Progression-free survival increased from a median of 3.0 months to 5.9 months (hazard ratio, 0.46; P less than .001), and overall survival from 5.6 months to 9.1 months (HR, 0.57; P = .001) with the addition of carboplatin to pemetrexed (Alimta), according to final results of a phase III trial.

Patrice Wendling/IMNG Medical Media

This represents a 43% reduction in the risk of death, with 43% of patients on the combination alive at 12 months vs. 18% on single-agent pemetrexed. None of the patients had received prior chemotherapy.

The results can be generalized to patients of all histologic subtypes who have an ECOG performance status of 2, Dr. Rogerio Lilenbaum said at the annual meeting of the American Society of Clinical Oncology.

"Although carboplatin plus pemetrexed may be a particularly suitable regimen in this population because of its safety profile, we do not think these results are unique to this regimen or nonsquamous patients," he said.

"Given the magnitude of the benefit seen in this study, and the immediate applicability of these data to clinical practice, we urge the appropriate organizations to revise their guidelines, which to this date, by and large, still recommend single-agent therapy for these patients."

Patients with non–small cell lung cancer (NSCLC) and an ECOG performance status (PS) of 2 are ambulatory and can care for themselves, but are unable to work. The optimal management strategy for these patients remains unresolved in the wake of mixed results from several phase III trials, including the IFCT-0501 (Intergroupe Francophone de Cancerologie Thoracique 1501) trial of carboplatin and paclitaxel vs. vinorelbine or gemcitabine (Gemzar) monotherapy (Lancet 2011;378:1079-88) and the U.S. Oncology trial of gemcitabine plus carboplatin vs. gemcitabine (J. Clin. Oncol. 2009;27:5808-15).

In contrast, the current results were so robust that one audience member asked whether they were "contaminated" with better–performance status patients.

Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan in Ann Arbor, said the results clearly demonstrate – as other trials have suggested – that two-drug regimens can improve response rate and survival, and should be an option in PS 2 patients.

He applauded the investigators for choosing a tolerable regimen and avoiding the "cult of cisplatin," but went on to say that PS 2 denotes a very heterogeneous population. Thus, single-agent therapy should remain an option for very elderly patients, those with excessive comorbidities, and those who do not tolerate a two-drug therapy.

He faulted the team for not providing quality-of-life data, and said that "supportive care with a focus on palliation of symptoms is imperative for all patients, because quality of life is really key."

Median Follow-Up Was 6 Months

Investigators at eight centers in Brazil and one in the United States stratified 203 chemotherapy-naive patients with stage IIIB or IV advanced non–small cell lung cancer by stage, age, and weight loss, and then randomly assigned them to pemetrexed 500 mg/m² or the same pemetrexed dose plus carboplatin AUC (area under the curve) 5 every 3 weeks for 4 cycles. All patients received folic acid, vitamin B₁₂ and dexamethasone. The protocol was amended in May 2009 to exclude patients with squamous cell histology for which pemetrexed is not indicated.

Median follow-up was 6.1 months in all patients. Their median age was 65 years, 95% had stage IV disease, two-thirds were former smokers, and 81% had adenocarcinoma histology. Squamous cell histology was slightly imbalanced at 11% of the single-agent and 3% of the pemetrexed/carboplatin arm, but the difference was not significant. The median number of cycles was four in both arms.

The overall response rate was 24% with the combination vs. 10.5% with pemetrexed alone (P less than .029), despite the fact that 33.3% and 23.3% of patients, respectively, did not reach the point of a formal response assessment, said Dr. Lilenbaum, chair of solid tumor oncology at the Cleveland Clinic Florida in Weston.

Analysis Redone to Exclude Squamous Cell

The investigators repeated the survival analysis excluding patients with squamous cell or unknown histology, and the hazard ratios were nearly identical to the intent-to-treat population for both progression-free and overall survival (HR, 0.45 and 0.59, respectively).

Subgroup analyses revealed a significant reduction in the risk of death with pemetrexed plus carboplatin in elderly patients (HR, 0.49; P less than .015) and never smokers (HR, 0.47; P less than .035), he said.

The use of second-line therapy was similar, at 31% in the pemetrexed arm and 29.5% in the combination arm. Docetaxel was most commonly used among the pemetrexed-plus-carboplatin patients (30% vs. 19%), whereas carboplatin was more common in the single-agent pemetrexed arm (31% vs. 15%).

Toxicity was mild, although the combination arm had slightly more grade 3/4 anemia (11.7% vs. 3.9%) and neutropenia (5.8% vs. 1%). Nonhematologic toxicity was largely absent. Dyspnea was present with combination and single-agent therapy (5.8% vs. 10.8%), but "was likely due to underlying disease."

There were four treatment-related deaths in the combination arm from renal failure, sepsis, pneumonia, and thrombocytopenia and none in the single-agent pemetrexed arm (P = .121), Dr. Lilenbaum reported.

Dr. Lilenbaum reported research funding from Eli Lilly, and a coauthor reported serving as a consultant or advisor for Lilly. Dr. Kalemkerian reported research funding from Lilly.

CHICAGO – Coupling carboplatin chemotherapy with pemetrexed significantly improved survival in the subset of hard-to-treat patients with advanced non–small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.

Progression-free survival increased from a median of 3.0 months to 5.9 months (hazard ratio, 0.46; P less than .001), and overall survival from 5.6 months to 9.1 months (HR, 0.57; P = .001) with the addition of carboplatin to pemetrexed (Alimta), according to final results of a phase III trial.

Patrice Wendling/IMNG Medical Media

This represents a 43% reduction in the risk of death, with 43% of patients on the combination alive at 12 months vs. 18% on single-agent pemetrexed. None of the patients had received prior chemotherapy.

The results can be generalized to patients of all histologic subtypes who have an ECOG performance status of 2, Dr. Rogerio Lilenbaum said at the annual meeting of the American Society of Clinical Oncology.

"Although carboplatin plus pemetrexed may be a particularly suitable regimen in this population because of its safety profile, we do not think these results are unique to this regimen or nonsquamous patients," he said.

"Given the magnitude of the benefit seen in this study, and the immediate applicability of these data to clinical practice, we urge the appropriate organizations to revise their guidelines, which to this date, by and large, still recommend single-agent therapy for these patients."

Patients with non–small cell lung cancer (NSCLC) and an ECOG performance status (PS) of 2 are ambulatory and can care for themselves, but are unable to work. The optimal management strategy for these patients remains unresolved in the wake of mixed results from several phase III trials, including the IFCT-0501 (Intergroupe Francophone de Cancerologie Thoracique 1501) trial of carboplatin and paclitaxel vs. vinorelbine or gemcitabine (Gemzar) monotherapy (Lancet 2011;378:1079-88) and the U.S. Oncology trial of gemcitabine plus carboplatin vs. gemcitabine (J. Clin. Oncol. 2009;27:5808-15).

In contrast, the current results were so robust that one audience member asked whether they were "contaminated" with better–performance status patients.

Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan in Ann Arbor, said the results clearly demonstrate – as other trials have suggested – that two-drug regimens can improve response rate and survival, and should be an option in PS 2 patients.

He applauded the investigators for choosing a tolerable regimen and avoiding the "cult of cisplatin," but went on to say that PS 2 denotes a very heterogeneous population. Thus, single-agent therapy should remain an option for very elderly patients, those with excessive comorbidities, and those who do not tolerate a two-drug therapy.

He faulted the team for not providing quality-of-life data, and said that "supportive care with a focus on palliation of symptoms is imperative for all patients, because quality of life is really key."

Median Follow-Up Was 6 Months

Investigators at eight centers in Brazil and one in the United States stratified 203 chemotherapy-naive patients with stage IIIB or IV advanced non–small cell lung cancer by stage, age, and weight loss, and then randomly assigned them to pemetrexed 500 mg/m² or the same pemetrexed dose plus carboplatin AUC (area under the curve) 5 every 3 weeks for 4 cycles. All patients received folic acid, vitamin B₁₂ and dexamethasone. The protocol was amended in May 2009 to exclude patients with squamous cell histology for which pemetrexed is not indicated.

Median follow-up was 6.1 months in all patients. Their median age was 65 years, 95% had stage IV disease, two-thirds were former smokers, and 81% had adenocarcinoma histology. Squamous cell histology was slightly imbalanced at 11% of the single-agent and 3% of the pemetrexed/carboplatin arm, but the difference was not significant. The median number of cycles was four in both arms.

The overall response rate was 24% with the combination vs. 10.5% with pemetrexed alone (P less than .029), despite the fact that 33.3% and 23.3% of patients, respectively, did not reach the point of a formal response assessment, said Dr. Lilenbaum, chair of solid tumor oncology at the Cleveland Clinic Florida in Weston.

Analysis Redone to Exclude Squamous Cell

The investigators repeated the survival analysis excluding patients with squamous cell or unknown histology, and the hazard ratios were nearly identical to the intent-to-treat population for both progression-free and overall survival (HR, 0.45 and 0.59, respectively).

Subgroup analyses revealed a significant reduction in the risk of death with pemetrexed plus carboplatin in elderly patients (HR, 0.49; P less than .015) and never smokers (HR, 0.47; P less than .035), he said.

The use of second-line therapy was similar, at 31% in the pemetrexed arm and 29.5% in the combination arm. Docetaxel was most commonly used among the pemetrexed-plus-carboplatin patients (30% vs. 19%), whereas carboplatin was more common in the single-agent pemetrexed arm (31% vs. 15%).

Toxicity was mild, although the combination arm had slightly more grade 3/4 anemia (11.7% vs. 3.9%) and neutropenia (5.8% vs. 1%). Nonhematologic toxicity was largely absent. Dyspnea was present with combination and single-agent therapy (5.8% vs. 10.8%), but "was likely due to underlying disease."

There were four treatment-related deaths in the combination arm from renal failure, sepsis, pneumonia, and thrombocytopenia and none in the single-agent pemetrexed arm (P = .121), Dr. Lilenbaum reported.

Dr. Lilenbaum reported research funding from Eli Lilly, and a coauthor reported serving as a consultant or advisor for Lilly. Dr. Kalemkerian reported research funding from Lilly.

CHICAGO – Coupling carboplatin chemotherapy with pemetrexed significantly improved survival in the subset of hard-to-treat patients with advanced non–small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.

Progression-free survival increased from a median of 3.0 months to 5.9 months (hazard ratio, 0.46; P less than .001), and overall survival from 5.6 months to 9.1 months (HR, 0.57; P = .001) with the addition of carboplatin to pemetrexed (Alimta), according to final results of a phase III trial.

Patrice Wendling/IMNG Medical Media

This represents a 43% reduction in the risk of death, with 43% of patients on the combination alive at 12 months vs. 18% on single-agent pemetrexed. None of the patients had received prior chemotherapy.

The results can be generalized to patients of all histologic subtypes who have an ECOG performance status of 2, Dr. Rogerio Lilenbaum said at the annual meeting of the American Society of Clinical Oncology.

"Although carboplatin plus pemetrexed may be a particularly suitable regimen in this population because of its safety profile, we do not think these results are unique to this regimen or nonsquamous patients," he said.

"Given the magnitude of the benefit seen in this study, and the immediate applicability of these data to clinical practice, we urge the appropriate organizations to revise their guidelines, which to this date, by and large, still recommend single-agent therapy for these patients."

Patients with non–small cell lung cancer (NSCLC) and an ECOG performance status (PS) of 2 are ambulatory and can care for themselves, but are unable to work. The optimal management strategy for these patients remains unresolved in the wake of mixed results from several phase III trials, including the IFCT-0501 (Intergroupe Francophone de Cancerologie Thoracique 1501) trial of carboplatin and paclitaxel vs. vinorelbine or gemcitabine (Gemzar) monotherapy (Lancet 2011;378:1079-88) and the U.S. Oncology trial of gemcitabine plus carboplatin vs. gemcitabine (J. Clin. Oncol. 2009;27:5808-15).

In contrast, the current results were so robust that one audience member asked whether they were "contaminated" with better–performance status patients.

Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan in Ann Arbor, said the results clearly demonstrate – as other trials have suggested – that two-drug regimens can improve response rate and survival, and should be an option in PS 2 patients.

He applauded the investigators for choosing a tolerable regimen and avoiding the "cult of cisplatin," but went on to say that PS 2 denotes a very heterogeneous population. Thus, single-agent therapy should remain an option for very elderly patients, those with excessive comorbidities, and those who do not tolerate a two-drug therapy.

He faulted the team for not providing quality-of-life data, and said that "supportive care with a focus on palliation of symptoms is imperative for all patients, because quality of life is really key."

Median Follow-Up Was 6 Months

Investigators at eight centers in Brazil and one in the United States stratified 203 chemotherapy-naive patients with stage IIIB or IV advanced non–small cell lung cancer by stage, age, and weight loss, and then randomly assigned them to pemetrexed 500 mg/m² or the same pemetrexed dose plus carboplatin AUC (area under the curve) 5 every 3 weeks for 4 cycles. All patients received folic acid, vitamin B₁₂ and dexamethasone. The protocol was amended in May 2009 to exclude patients with squamous cell histology for which pemetrexed is not indicated.

Median follow-up was 6.1 months in all patients. Their median age was 65 years, 95% had stage IV disease, two-thirds were former smokers, and 81% had adenocarcinoma histology. Squamous cell histology was slightly imbalanced at 11% of the single-agent and 3% of the pemetrexed/carboplatin arm, but the difference was not significant. The median number of cycles was four in both arms.

The overall response rate was 24% with the combination vs. 10.5% with pemetrexed alone (P less than .029), despite the fact that 33.3% and 23.3% of patients, respectively, did not reach the point of a formal response assessment, said Dr. Lilenbaum, chair of solid tumor oncology at the Cleveland Clinic Florida in Weston.

Analysis Redone to Exclude Squamous Cell

The investigators repeated the survival analysis excluding patients with squamous cell or unknown histology, and the hazard ratios were nearly identical to the intent-to-treat population for both progression-free and overall survival (HR, 0.45 and 0.59, respectively).

Subgroup analyses revealed a significant reduction in the risk of death with pemetrexed plus carboplatin in elderly patients (HR, 0.49; P less than .015) and never smokers (HR, 0.47; P less than .035), he said.

The use of second-line therapy was similar, at 31% in the pemetrexed arm and 29.5% in the combination arm. Docetaxel was most commonly used among the pemetrexed-plus-carboplatin patients (30% vs. 19%), whereas carboplatin was more common in the single-agent pemetrexed arm (31% vs. 15%).

Toxicity was mild, although the combination arm had slightly more grade 3/4 anemia (11.7% vs. 3.9%) and neutropenia (5.8% vs. 1%). Nonhematologic toxicity was largely absent. Dyspnea was present with combination and single-agent therapy (5.8% vs. 10.8%), but "was likely due to underlying disease."

There were four treatment-related deaths in the combination arm from renal failure, sepsis, pneumonia, and thrombocytopenia and none in the single-agent pemetrexed arm (P = .121), Dr. Lilenbaum reported.

Dr. Lilenbaum reported research funding from Eli Lilly, and a coauthor reported serving as a consultant or advisor for Lilly. Dr. Kalemkerian reported research funding from Lilly.

CHICAGO – Second-line treatment with docetaxel led to significantly better outcomes than with erlotinib in a head-to-head comparison among patients whose non–small cell lung cancer did not have a mutation in the epidermal growth factor receptor.

Progression-free survival, response, and disease control rates all favored docetaxel (Taxotere) in the phase III TAILOR (Tarceva Italian Lung Optimization Trial) study, investigators reported. "TAILOR does not support the use of erlotinib over docetaxel in patients with EGFR wild type," Dr. Marina C. Garassino said at the annual meeting of the American Society of Clinical Oncology.

TAILOR is the only prospective trial to select patients with non–small cell lung cancer (NSCLC) carrying the epidermal growth factor receptor (EGFR) in its wild-type form for a direct comparison of docetaxel with erlotinib (Tarceva), a tyrosine kinase inhibitor (TKI) targeting EGFR. TKIs are well established in the treatment of patients harboring EGFR mutations, but their role continues to be debated in EGFR wild type, which accounts for about 85%-90% of NSCLC cases.

Investigators randomized 222 patients who had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-2 and had advanced or recurrent disease after prior treatment with a platinum-based doublet. They were assigned to erlotinib 150 mg daily or to either of two doses of docetaxel: 75 mg/m² on day 1 every 21 days, or 35 mg/m² on days 1, 8 and 15 every 28 days until disease progression or unacceptable toxicity. Three patients were not included in the intent-to-treat analysis because of major protocol violations, according to the late-breaking abstract.

About three-fourths of the patients had adenocarcinoma histology, were current or ex-smokers, and carried wild-type KRAS. EGFR and KRAS mutational status was determined by a central lab and was cross-validated in two independent labs. The patients’ median age was about 66 years.

The investigators noted the following findings:

• The median time to progression was 3.4 months with docetaxel and 2.4 months with erlotinib (hazard ratio, 0.69; P = .014). At 6 months, 29% of patients who were given docetaxel were free of progression, compared with 17% on erlotinib, said Dr. Garassino of the medical oncology department at Fatebenefratelli and Ophthalmic Hospital in Milan.

• The disease control rate (defined as complete and partial responses and stable disease) was doubled in the docetaxel arm at 41.5% vs. 22.8% in the erlotinib arm (P = .007).

• Responses in the erlotinib arm were "rare and almost unseen" (2.2% vs. 14%; P = .004), she said. No erlotinib patients had a complete response, whereas 4.3% did with docetaxel. During a discussion of the study, this finding was questioned as being unusual for single-agent docetaxel in second-line use. Although no independent review was conducted, Dr. Garassino replied that the data were trustworthy.

A progression-free survival subgroup analysis favored docetaxel over erlotinib, regardless of age, sex, performance status, and smoking status, although the interactions were not statistically significant. Patients with and without KRAS mutations also benefited from docetaxel (HR, 0.84 and 0.65, respectively; P = .237), with median progression-free survival also similar in these patients at 2.6 months and 2.4 months (HR, 0.91; P = .558).

KRAS mutation does not seem to be a predictive or prognostic factor in second line, said Dr. Garassino, who remarked that a possible negative predictive and prognostic role has been suggested for KRAS.

Overall survival, the study’s primary end point, will be evaluated after the required 199 deaths have occurred.

Toxicity was as expected, with treatment-related adverse events leading to dose modifications in 22% of the docetaxel and 29% of the erlotinib arms. Data on rash have not been analyzed for correlation with progression or response.

Five randomized trials have compared chemotherapy vs. EGFR TKIs in previously treated NSCLC patients, but they were all were conducted in unselected patients, and only two trials reported outcomes by EGFR mutational status for a minority of patients in unplanned analyses. The hazard ratio for progression-free survival in TAILOR is consistent with the retrospective analyses from the recent TITAN (Lancet Oncology 2012;13:300-8) and INTEREST (Lancet 2008;372:1809-18) trials, suggesting benefit of chemotherapy over EGFR TKIs in EGFR wild-type patients, said discussant Benjamin Solomon, Ph.D.

"Although we await the survival data, in the second-line setting, as we know already in the first-line [setting], outcomes are better with chemotherapy (docetaxel) than EGFR TKIs, (erlotinib) in patients with EGFR wild-type non–small cell lung cancer," said Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.

The one caveat, he added, is that EGFR wild-type patients are not a homogeneous population, and thus clinicians should still test for ALK gene rearrangements and other potentially actionable genetic alterations.

Attendee Dr. Steven Vogl, an oncologist who practices in the Bronx, New York, asked whether the conclusion from the current results is "that docetaxel is not a very good drug and that erlotinib is a terrible drug and we shouldn’t give it to these nonmutated patients anymore?"

After a slight pause, Dr. Garassino responded, "I think that you are right," to a round of laughter and applause.

TAILOR was sponsored by Agenzia Italiana del Farmaco. Dr. Garassino and her coauthors reported no disclosures. Dr. Solomon reported an advisory or consultant role with AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer and Roche.

CHICAGO – Second-line treatment with docetaxel led to significantly better outcomes than with erlotinib in a head-to-head comparison among patients whose non–small cell lung cancer did not have a mutation in the epidermal growth factor receptor.

Progression-free survival, response, and disease control rates all favored docetaxel (Taxotere) in the phase III TAILOR (Tarceva Italian Lung Optimization Trial) study, investigators reported. "TAILOR does not support the use of erlotinib over docetaxel in patients with EGFR wild type," Dr. Marina C. Garassino said at the annual meeting of the American Society of Clinical Oncology.

TAILOR is the only prospective trial to select patients with non–small cell lung cancer (NSCLC) carrying the epidermal growth factor receptor (EGFR) in its wild-type form for a direct comparison of docetaxel with erlotinib (Tarceva), a tyrosine kinase inhibitor (TKI) targeting EGFR. TKIs are well established in the treatment of patients harboring EGFR mutations, but their role continues to be debated in EGFR wild type, which accounts for about 85%-90% of NSCLC cases.

Investigators randomized 222 patients who had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-2 and had advanced or recurrent disease after prior treatment with a platinum-based doublet. They were assigned to erlotinib 150 mg daily or to either of two doses of docetaxel: 75 mg/m² on day 1 every 21 days, or 35 mg/m² on days 1, 8 and 15 every 28 days until disease progression or unacceptable toxicity. Three patients were not included in the intent-to-treat analysis because of major protocol violations, according to the late-breaking abstract.

About three-fourths of the patients had adenocarcinoma histology, were current or ex-smokers, and carried wild-type KRAS. EGFR and KRAS mutational status was determined by a central lab and was cross-validated in two independent labs. The patients’ median age was about 66 years.

The investigators noted the following findings:

• The median time to progression was 3.4 months with docetaxel and 2.4 months with erlotinib (hazard ratio, 0.69; P = .014). At 6 months, 29% of patients who were given docetaxel were free of progression, compared with 17% on erlotinib, said Dr. Garassino of the medical oncology department at Fatebenefratelli and Ophthalmic Hospital in Milan.

• The disease control rate (defined as complete and partial responses and stable disease) was doubled in the docetaxel arm at 41.5% vs. 22.8% in the erlotinib arm (P = .007).

• Responses in the erlotinib arm were "rare and almost unseen" (2.2% vs. 14%; P = .004), she said. No erlotinib patients had a complete response, whereas 4.3% did with docetaxel. During a discussion of the study, this finding was questioned as being unusual for single-agent docetaxel in second-line use. Although no independent review was conducted, Dr. Garassino replied that the data were trustworthy.

A progression-free survival subgroup analysis favored docetaxel over erlotinib, regardless of age, sex, performance status, and smoking status, although the interactions were not statistically significant. Patients with and without KRAS mutations also benefited from docetaxel (HR, 0.84 and 0.65, respectively; P = .237), with median progression-free survival also similar in these patients at 2.6 months and 2.4 months (HR, 0.91; P = .558).

KRAS mutation does not seem to be a predictive or prognostic factor in second line, said Dr. Garassino, who remarked that a possible negative predictive and prognostic role has been suggested for KRAS.

Overall survival, the study’s primary end point, will be evaluated after the required 199 deaths have occurred.

Toxicity was as expected, with treatment-related adverse events leading to dose modifications in 22% of the docetaxel and 29% of the erlotinib arms. Data on rash have not been analyzed for correlation with progression or response.

Five randomized trials have compared chemotherapy vs. EGFR TKIs in previously treated NSCLC patients, but they were all were conducted in unselected patients, and only two trials reported outcomes by EGFR mutational status for a minority of patients in unplanned analyses. The hazard ratio for progression-free survival in TAILOR is consistent with the retrospective analyses from the recent TITAN (Lancet Oncology 2012;13:300-8) and INTEREST (Lancet 2008;372:1809-18) trials, suggesting benefit of chemotherapy over EGFR TKIs in EGFR wild-type patients, said discussant Benjamin Solomon, Ph.D.

"Although we await the survival data, in the second-line setting, as we know already in the first-line [setting], outcomes are better with chemotherapy (docetaxel) than EGFR TKIs, (erlotinib) in patients with EGFR wild-type non–small cell lung cancer," said Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.

The one caveat, he added, is that EGFR wild-type patients are not a homogeneous population, and thus clinicians should still test for ALK gene rearrangements and other potentially actionable genetic alterations.

Attendee Dr. Steven Vogl, an oncologist who practices in the Bronx, New York, asked whether the conclusion from the current results is "that docetaxel is not a very good drug and that erlotinib is a terrible drug and we shouldn’t give it to these nonmutated patients anymore?"

After a slight pause, Dr. Garassino responded, "I think that you are right," to a round of laughter and applause.

TAILOR was sponsored by Agenzia Italiana del Farmaco. Dr. Garassino and her coauthors reported no disclosures. Dr. Solomon reported an advisory or consultant role with AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer and Roche.

CHICAGO – Second-line treatment with docetaxel led to significantly better outcomes than with erlotinib in a head-to-head comparison among patients whose non–small cell lung cancer did not have a mutation in the epidermal growth factor receptor.

Progression-free survival, response, and disease control rates all favored docetaxel (Taxotere) in the phase III TAILOR (Tarceva Italian Lung Optimization Trial) study, investigators reported. "TAILOR does not support the use of erlotinib over docetaxel in patients with EGFR wild type," Dr. Marina C. Garassino said at the annual meeting of the American Society of Clinical Oncology.

TAILOR is the only prospective trial to select patients with non–small cell lung cancer (NSCLC) carrying the epidermal growth factor receptor (EGFR) in its wild-type form for a direct comparison of docetaxel with erlotinib (Tarceva), a tyrosine kinase inhibitor (TKI) targeting EGFR. TKIs are well established in the treatment of patients harboring EGFR mutations, but their role continues to be debated in EGFR wild type, which accounts for about 85%-90% of NSCLC cases.

Investigators randomized 222 patients who had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-2 and had advanced or recurrent disease after prior treatment with a platinum-based doublet. They were assigned to erlotinib 150 mg daily or to either of two doses of docetaxel: 75 mg/m² on day 1 every 21 days, or 35 mg/m² on days 1, 8 and 15 every 28 days until disease progression or unacceptable toxicity. Three patients were not included in the intent-to-treat analysis because of major protocol violations, according to the late-breaking abstract.

About three-fourths of the patients had adenocarcinoma histology, were current or ex-smokers, and carried wild-type KRAS. EGFR and KRAS mutational status was determined by a central lab and was cross-validated in two independent labs. The patients’ median age was about 66 years.

The investigators noted the following findings:

• The median time to progression was 3.4 months with docetaxel and 2.4 months with erlotinib (hazard ratio, 0.69; P = .014). At 6 months, 29% of patients who were given docetaxel were free of progression, compared with 17% on erlotinib, said Dr. Garassino of the medical oncology department at Fatebenefratelli and Ophthalmic Hospital in Milan.

• The disease control rate (defined as complete and partial responses and stable disease) was doubled in the docetaxel arm at 41.5% vs. 22.8% in the erlotinib arm (P = .007).

• Responses in the erlotinib arm were "rare and almost unseen" (2.2% vs. 14%; P = .004), she said. No erlotinib patients had a complete response, whereas 4.3% did with docetaxel. During a discussion of the study, this finding was questioned as being unusual for single-agent docetaxel in second-line use. Although no independent review was conducted, Dr. Garassino replied that the data were trustworthy.

A progression-free survival subgroup analysis favored docetaxel over erlotinib, regardless of age, sex, performance status, and smoking status, although the interactions were not statistically significant. Patients with and without KRAS mutations also benefited from docetaxel (HR, 0.84 and 0.65, respectively; P = .237), with median progression-free survival also similar in these patients at 2.6 months and 2.4 months (HR, 0.91; P = .558).

KRAS mutation does not seem to be a predictive or prognostic factor in second line, said Dr. Garassino, who remarked that a possible negative predictive and prognostic role has been suggested for KRAS.

Overall survival, the study’s primary end point, will be evaluated after the required 199 deaths have occurred.

Toxicity was as expected, with treatment-related adverse events leading to dose modifications in 22% of the docetaxel and 29% of the erlotinib arms. Data on rash have not been analyzed for correlation with progression or response.

Five randomized trials have compared chemotherapy vs. EGFR TKIs in previously treated NSCLC patients, but they were all were conducted in unselected patients, and only two trials reported outcomes by EGFR mutational status for a minority of patients in unplanned analyses. The hazard ratio for progression-free survival in TAILOR is consistent with the retrospective analyses from the recent TITAN (Lancet Oncology 2012;13:300-8) and INTEREST (Lancet 2008;372:1809-18) trials, suggesting benefit of chemotherapy over EGFR TKIs in EGFR wild-type patients, said discussant Benjamin Solomon, Ph.D.

"Although we await the survival data, in the second-line setting, as we know already in the first-line [setting], outcomes are better with chemotherapy (docetaxel) than EGFR TKIs, (erlotinib) in patients with EGFR wild-type non–small cell lung cancer," said Dr. Solomon of the lung cancer service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria.

The one caveat, he added, is that EGFR wild-type patients are not a homogeneous population, and thus clinicians should still test for ALK gene rearrangements and other potentially actionable genetic alterations.

Attendee Dr. Steven Vogl, an oncologist who practices in the Bronx, New York, asked whether the conclusion from the current results is "that docetaxel is not a very good drug and that erlotinib is a terrible drug and we shouldn’t give it to these nonmutated patients anymore?"

After a slight pause, Dr. Garassino responded, "I think that you are right," to a round of laughter and applause.

TAILOR was sponsored by Agenzia Italiana del Farmaco. Dr. Garassino and her coauthors reported no disclosures. Dr. Solomon reported an advisory or consultant role with AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer and Roche.

CHICAGO – The oral investigational MEK inhibitor selumetinib has crossed a clinical hurdle in the treatment of KRAS-mutated non–small cell lung cancer, but it was not without a cost in terms of toxicity.

When compared with docetaxel alone in a phase II trial of 87 patients with locally advanced or metastatic disease, second-line treatment with selumetinib plus docetaxel significantly improved all secondary outcomes:

• Progression-free survival went from 2.1 months to 5.3 months (hazard ratio, 0.58; 1-sided P value = .013).

• Response rate went from 0% to 37.2% (two-sided mid P value less than .0001).

• The percent alive and progression free at 6 months rose from 15.8% to 37.1% (one-sided P = .0158).

• The change in tumor size at 12 weeks favored selumetinib by –26% (one-sided P = .004).

The primary end point of overall survival was increased as well from 5.2 months to 9.4 months with selumetinib plus docetaxel, albeit not significantly (HR, 0.80; 1-sided P = .206).

"This is the first prospective study to demonstrate a clinical benefit for patients with KRAS-mutant non-small cell lung cancer or even perhaps for KRAS-mutant patients of any cancer," lead author Dr. Pasi Jänne said at the meeting.

The results were met with enthusiasm because KRAS is the most frequently mutated oncogene in non–small cell lung cancer outside Asia, but currently there is no targeted therapy for this subset of patients. In addition, these patients fail to derive the same benefit from chemotherapy and do not respond to epidermal growth factor receptor (EFGR) targeted therapies.

Selumetinib is a selective inhibitor of MEK 1/2, a critical downstream effector protein of KRAS signaling. When used as monotherapy, it has shown clinical activity in second-/third-line NSCLC, but was not superior to pemetrexed (J. Thorac. Oncol. 2010;5:1630-6).

Invited discussant Dr. Joel Neal of Stanford (Calif.) University also heralded selumetinib plus docetaxel as the first clinically validated strategy for KRAS-mutant NSCLC, but called the toxicity significant.

"The ideal targeted therapy is probably a little less toxic and maybe potentially even more effective," he said.

Four of the 44 patients (9%) treated with selumetinib plus docetaxel died as the result of a serious adverse event, and 21, or 47.7% were hospitalized from an adverse event.

Adverse events led to dose reductions of selumetinib in 34% of patients and dose interruptions in 45.5%.

Grade 3/4 peripheral edema (2.3%), dermatitis acneiform (6.8%) and febrile neutropenia (18.2%) were all increased in selumetinib patients, and were absent in controls.

Some disease-related adverse events were improved with the addition of selumetinib, said Dr. Jänne of the Dana Farber Cancer Institute in Boston. Grade 3/4 decreased appetite was absent in patients treated with the combination vs. 2.4% of controls) and there was less fatigue of all grades (27.3% vs. 33.3%) or grade 3/4 (0% vs. 7.1%).

Dr. Neal pointed out that the response rate in unselected second- or third-line non–small cell lung cancer trials is generally 9%, and ranges from 57% to 70% when targeted agents such as erlotinib (Tarceva) and crizotinib (Xalkori) are used against the correct molecular alteration.

"This trial falls somewhere in between, which is still very impressive," he said.

The 5.3 month progression-free survival with selumetinib also falls between the 2-3 months reported in unselected trials and the 9 months or better in selected trials.

Selumetinib’s overall survival time of 9.4 months surpasses that of 7-8 months in unselected trials, but falls short of the astounding overall survival times of roughly 24 months for crizotinib in patients with an anaplastic lymphoma kinase (ALK) rearrangement and 27 months for erlotinib in those with an EGFR mutation.

As for whether KRAS is truly an actionable target in non–small cell lung cancer, Dr. Neal said it probably depends on the agent.

"With selumetinib and docetaxel, I’d say probably; this looks very promising," he said.

The answer was a more equivocal "possibly" for other targeted therapies such as the selective MET inhibitor tivantinib plus erlotinib or the investigational MEK inhibitor GSK 1120212.

Both men observed that the clinical activity of selumetinib plus docetaxel could be affected by dosing order (Br. J. Cancer 2012;106:858-66) and other passenger mutations such as p53, which was recently shown in a mouse model to be more sensitive to the combination than the LKB1 mutation (Nature 2012;483:613-7).

Patients in the phase II trial were randomized to docetaxel 75 mg/m² administered every 21 days plus twice-daily selumetinib 75 mg or placebo. The selumetinib arm received a median of five cycles and the control arm, four cycles.

The safety analysis was based on 44 selumetinib and 43 controls, and the efficacy analysis on 43 and 40 patients, respectively.

The majority of patients, or 88%, were current or former smokers, roughly half had a WHO performance status 0, and 82% had adenocarcinoma histology. Their median age was 59 years.

The study was sponsored by AstraZeneca. Dr. Jänne reported a consultant/advisory role with AstraZeneca; several of his coauthors reported financial relationships with firms including employment or stock ownership with AstraZeneca. Dr. Neal reported research funding from Genentech.

CHICAGO – The oral investigational MEK inhibitor selumetinib has crossed a clinical hurdle in the treatment of KRAS-mutated non–small cell lung cancer, but it was not without a cost in terms of toxicity.

When compared with docetaxel alone in a phase II trial of 87 patients with locally advanced or metastatic disease, second-line treatment with selumetinib plus docetaxel significantly improved all secondary outcomes:

• Progression-free survival went from 2.1 months to 5.3 months (hazard ratio, 0.58; 1-sided P value = .013).

• Response rate went from 0% to 37.2% (two-sided mid P value less than .0001).

• The percent alive and progression free at 6 months rose from 15.8% to 37.1% (one-sided P = .0158).

• The change in tumor size at 12 weeks favored selumetinib by –26% (one-sided P = .004).

The primary end point of overall survival was increased as well from 5.2 months to 9.4 months with selumetinib plus docetaxel, albeit not significantly (HR, 0.80; 1-sided P = .206).

"This is the first prospective study to demonstrate a clinical benefit for patients with KRAS-mutant non-small cell lung cancer or even perhaps for KRAS-mutant patients of any cancer," lead author Dr. Pasi Jänne said at the meeting.

The results were met with enthusiasm because KRAS is the most frequently mutated oncogene in non–small cell lung cancer outside Asia, but currently there is no targeted therapy for this subset of patients. In addition, these patients fail to derive the same benefit from chemotherapy and do not respond to epidermal growth factor receptor (EFGR) targeted therapies.

Selumetinib is a selective inhibitor of MEK 1/2, a critical downstream effector protein of KRAS signaling. When used as monotherapy, it has shown clinical activity in second-/third-line NSCLC, but was not superior to pemetrexed (J. Thorac. Oncol. 2010;5:1630-6).

Invited discussant Dr. Joel Neal of Stanford (Calif.) University also heralded selumetinib plus docetaxel as the first clinically validated strategy for KRAS-mutant NSCLC, but called the toxicity significant.

"The ideal targeted therapy is probably a little less toxic and maybe potentially even more effective," he said.

Four of the 44 patients (9%) treated with selumetinib plus docetaxel died as the result of a serious adverse event, and 21, or 47.7% were hospitalized from an adverse event.

Adverse events led to dose reductions of selumetinib in 34% of patients and dose interruptions in 45.5%.

Grade 3/4 peripheral edema (2.3%), dermatitis acneiform (6.8%) and febrile neutropenia (18.2%) were all increased in selumetinib patients, and were absent in controls.

Some disease-related adverse events were improved with the addition of selumetinib, said Dr. Jänne of the Dana Farber Cancer Institute in Boston. Grade 3/4 decreased appetite was absent in patients treated with the combination vs. 2.4% of controls) and there was less fatigue of all grades (27.3% vs. 33.3%) or grade 3/4 (0% vs. 7.1%).

Dr. Neal pointed out that the response rate in unselected second- or third-line non–small cell lung cancer trials is generally 9%, and ranges from 57% to 70% when targeted agents such as erlotinib (Tarceva) and crizotinib (Xalkori) are used against the correct molecular alteration.

"This trial falls somewhere in between, which is still very impressive," he said.

The 5.3 month progression-free survival with selumetinib also falls between the 2-3 months reported in unselected trials and the 9 months or better in selected trials.

Selumetinib’s overall survival time of 9.4 months surpasses that of 7-8 months in unselected trials, but falls short of the astounding overall survival times of roughly 24 months for crizotinib in patients with an anaplastic lymphoma kinase (ALK) rearrangement and 27 months for erlotinib in those with an EGFR mutation.

As for whether KRAS is truly an actionable target in non–small cell lung cancer, Dr. Neal said it probably depends on the agent.

"With selumetinib and docetaxel, I’d say probably; this looks very promising," he said.

The answer was a more equivocal "possibly" for other targeted therapies such as the selective MET inhibitor tivantinib plus erlotinib or the investigational MEK inhibitor GSK 1120212.

Both men observed that the clinical activity of selumetinib plus docetaxel could be affected by dosing order (Br. J. Cancer 2012;106:858-66) and other passenger mutations such as p53, which was recently shown in a mouse model to be more sensitive to the combination than the LKB1 mutation (Nature 2012;483:613-7).

Patients in the phase II trial were randomized to docetaxel 75 mg/m² administered every 21 days plus twice-daily selumetinib 75 mg or placebo. The selumetinib arm received a median of five cycles and the control arm, four cycles.

The safety analysis was based on 44 selumetinib and 43 controls, and the efficacy analysis on 43 and 40 patients, respectively.

The majority of patients, or 88%, were current or former smokers, roughly half had a WHO performance status 0, and 82% had adenocarcinoma histology. Their median age was 59 years.

The study was sponsored by AstraZeneca. Dr. Jänne reported a consultant/advisory role with AstraZeneca; several of his coauthors reported financial relationships with firms including employment or stock ownership with AstraZeneca. Dr. Neal reported research funding from Genentech.

CHICAGO – The oral investigational MEK inhibitor selumetinib has crossed a clinical hurdle in the treatment of KRAS-mutated non–small cell lung cancer, but it was not without a cost in terms of toxicity.

When compared with docetaxel alone in a phase II trial of 87 patients with locally advanced or metastatic disease, second-line treatment with selumetinib plus docetaxel significantly improved all secondary outcomes:

• Progression-free survival went from 2.1 months to 5.3 months (hazard ratio, 0.58; 1-sided P value = .013).

• Response rate went from 0% to 37.2% (two-sided mid P value less than .0001).

• The percent alive and progression free at 6 months rose from 15.8% to 37.1% (one-sided P = .0158).

• The change in tumor size at 12 weeks favored selumetinib by –26% (one-sided P = .004).

The primary end point of overall survival was increased as well from 5.2 months to 9.4 months with selumetinib plus docetaxel, albeit not significantly (HR, 0.80; 1-sided P = .206).

"This is the first prospective study to demonstrate a clinical benefit for patients with KRAS-mutant non-small cell lung cancer or even perhaps for KRAS-mutant patients of any cancer," lead author Dr. Pasi Jänne said at the meeting.

The results were met with enthusiasm because KRAS is the most frequently mutated oncogene in non–small cell lung cancer outside Asia, but currently there is no targeted therapy for this subset of patients. In addition, these patients fail to derive the same benefit from chemotherapy and do not respond to epidermal growth factor receptor (EFGR) targeted therapies.

Selumetinib is a selective inhibitor of MEK 1/2, a critical downstream effector protein of KRAS signaling. When used as monotherapy, it has shown clinical activity in second-/third-line NSCLC, but was not superior to pemetrexed (J. Thorac. Oncol. 2010;5:1630-6).

Invited discussant Dr. Joel Neal of Stanford (Calif.) University also heralded selumetinib plus docetaxel as the first clinically validated strategy for KRAS-mutant NSCLC, but called the toxicity significant.

"The ideal targeted therapy is probably a little less toxic and maybe potentially even more effective," he said.

Four of the 44 patients (9%) treated with selumetinib plus docetaxel died as the result of a serious adverse event, and 21, or 47.7% were hospitalized from an adverse event.

Adverse events led to dose reductions of selumetinib in 34% of patients and dose interruptions in 45.5%.

Grade 3/4 peripheral edema (2.3%), dermatitis acneiform (6.8%) and febrile neutropenia (18.2%) were all increased in selumetinib patients, and were absent in controls.

Some disease-related adverse events were improved with the addition of selumetinib, said Dr. Jänne of the Dana Farber Cancer Institute in Boston. Grade 3/4 decreased appetite was absent in patients treated with the combination vs. 2.4% of controls) and there was less fatigue of all grades (27.3% vs. 33.3%) or grade 3/4 (0% vs. 7.1%).

Dr. Neal pointed out that the response rate in unselected second- or third-line non–small cell lung cancer trials is generally 9%, and ranges from 57% to 70% when targeted agents such as erlotinib (Tarceva) and crizotinib (Xalkori) are used against the correct molecular alteration.

"This trial falls somewhere in between, which is still very impressive," he said.

The 5.3 month progression-free survival with selumetinib also falls between the 2-3 months reported in unselected trials and the 9 months or better in selected trials.

Selumetinib’s overall survival time of 9.4 months surpasses that of 7-8 months in unselected trials, but falls short of the astounding overall survival times of roughly 24 months for crizotinib in patients with an anaplastic lymphoma kinase (ALK) rearrangement and 27 months for erlotinib in those with an EGFR mutation.

As for whether KRAS is truly an actionable target in non–small cell lung cancer, Dr. Neal said it probably depends on the agent.

"With selumetinib and docetaxel, I’d say probably; this looks very promising," he said.

The answer was a more equivocal "possibly" for other targeted therapies such as the selective MET inhibitor tivantinib plus erlotinib or the investigational MEK inhibitor GSK 1120212.

Both men observed that the clinical activity of selumetinib plus docetaxel could be affected by dosing order (Br. J. Cancer 2012;106:858-66) and other passenger mutations such as p53, which was recently shown in a mouse model to be more sensitive to the combination than the LKB1 mutation (Nature 2012;483:613-7).

Patients in the phase II trial were randomized to docetaxel 75 mg/m² administered every 21 days plus twice-daily selumetinib 75 mg or placebo. The selumetinib arm received a median of five cycles and the control arm, four cycles.

The safety analysis was based on 44 selumetinib and 43 controls, and the efficacy analysis on 43 and 40 patients, respectively.

The majority of patients, or 88%, were current or former smokers, roughly half had a WHO performance status 0, and 82% had adenocarcinoma histology. Their median age was 59 years.

The study was sponsored by AstraZeneca. Dr. Jänne reported a consultant/advisory role with AstraZeneca; several of his coauthors reported financial relationships with firms including employment or stock ownership with AstraZeneca. Dr. Neal reported research funding from Genentech.

CHICAGO – Cancer survivors with chemotherapy-induced peripheral neuropathy may be headed for a fall, researchers cautioned at the annual meeting of the American Society of Clinical Oncology.

About 12% of patients with chemotherapy-induced peripheral neuropathy (CIPN) had at least one fall, and nearly 60% experienced some kind of physical problem related to CIPN, reported Dr. Supriya Mohile of the department of hematology/oncology at the University of Rochester (N.Y.).

"We should in our clinics longitudinally evaluate patients not only for toxicities from neuropathy, but also for physical functioning and falls," she said.

Dr. Mohile urged providing patients with balance and mobility training throughout chemotherapy and minimizing fall risk by recommending assistive devices and home-safety evaluations and modifications as necessary.

She and her colleagues evaluated 421 patients who had reported baseline data as part of a randomized phase III trial for a topical cream. The patients had completed chemotherapy and had self-reported CIPN of 4 or greater on an 11-point scale. The patients were not on significant medications for either pain or neuropathy, and those with other possible causes of neuropathy, such as diabetes, were excluded.

They found that about one-third of patients had a CIPN-related problem such as difficulty stooping, walking for one-fourth of a mile, or performing tasks requiring heavy lifting.

Additionally, more than 25% reported a functional loss, limiting their ability to shop, manage money, walk across a room, do light housework, or bathe themselves.

Comparing 260 patients who reported falls or physical problems with 161 who did not, the investigators identified pain, sensory neuropathy, and motor neuropathy as toxicities independently associated with falls and/or physical problems (P less than .001 for all three comparisons).

In a multivariate analysis controlling for age, sex, race, ethnicity, marital status, education, history of taxane exposure, previous surgery and radiation, pain, and sensory neuropathy, the investigators found that breast cancer (odds ratio, 2.776; P = .045) and motor neuropathy (OR, 1.138; P = .006) were independently associated with falls. Factors associated with having a physical performance problem were previous surgery (OR, 2.536; P = .013) and motor neuropathy (OR, 1.325; P less than .001).

Functional losses were more likely to occur among Hispanics (OR, 5.318; P = –.048), patients with any physical performance problem (OR, 4.942; P less than .001), and those with motor neuropathy (OR, 1.191; P = .0001).

The study was limited by the heterogeneity of the cancer sample, its cross-sectional design that precludes determination of causality or of a temporal relationship between chemotherapy and neuropathies, and self-report of CIPN toxicities, Dr. Mohile said.

Commenting on the study, Dr. Charles L. Loprinzi, emeritus chair of the division of medical oncology at the Mayo Clinic in Rochester, Minn., said that it supports earlier findings of a relationship between epidermal nerve fiber loss and deficits in sensory and motor function leading, and that "it makes sense" that such losses would lead to functional losses.*

The study was funded by grants from the National Cancer Institute. Dr. Mohile reported no relevant disclosures. Dr. Loprinzi disclosed receiving research funding from Abbott, Amgen, Bristol-Myers Squibb, Eisai, Novartis, Ortho Biotech, Pfizer, Roche, and Sanofi.

* Dr. Loprinzi's title was corrected on June 18, 2012.

CHICAGO – Cancer survivors with chemotherapy-induced peripheral neuropathy may be headed for a fall, researchers cautioned at the annual meeting of the American Society of Clinical Oncology.

About 12% of patients with chemotherapy-induced peripheral neuropathy (CIPN) had at least one fall, and nearly 60% experienced some kind of physical problem related to CIPN, reported Dr. Supriya Mohile of the department of hematology/oncology at the University of Rochester (N.Y.).

"We should in our clinics longitudinally evaluate patients not only for toxicities from neuropathy, but also for physical functioning and falls," she said.

Dr. Mohile urged providing patients with balance and mobility training throughout chemotherapy and minimizing fall risk by recommending assistive devices and home-safety evaluations and modifications as necessary.

She and her colleagues evaluated 421 patients who had reported baseline data as part of a randomized phase III trial for a topical cream. The patients had completed chemotherapy and had self-reported CIPN of 4 or greater on an 11-point scale. The patients were not on significant medications for either pain or neuropathy, and those with other possible causes of neuropathy, such as diabetes, were excluded.

They found that about one-third of patients had a CIPN-related problem such as difficulty stooping, walking for one-fourth of a mile, or performing tasks requiring heavy lifting.

Additionally, more than 25% reported a functional loss, limiting their ability to shop, manage money, walk across a room, do light housework, or bathe themselves.

Comparing 260 patients who reported falls or physical problems with 161 who did not, the investigators identified pain, sensory neuropathy, and motor neuropathy as toxicities independently associated with falls and/or physical problems (P less than .001 for all three comparisons).

In a multivariate analysis controlling for age, sex, race, ethnicity, marital status, education, history of taxane exposure, previous surgery and radiation, pain, and sensory neuropathy, the investigators found that breast cancer (odds ratio, 2.776; P = .045) and motor neuropathy (OR, 1.138; P = .006) were independently associated with falls. Factors associated with having a physical performance problem were previous surgery (OR, 2.536; P = .013) and motor neuropathy (OR, 1.325; P less than .001).

Functional losses were more likely to occur among Hispanics (OR, 5.318; P = –.048), patients with any physical performance problem (OR, 4.942; P less than .001), and those with motor neuropathy (OR, 1.191; P = .0001).

The study was limited by the heterogeneity of the cancer sample, its cross-sectional design that precludes determination of causality or of a temporal relationship between chemotherapy and neuropathies, and self-report of CIPN toxicities, Dr. Mohile said.

Commenting on the study, Dr. Charles L. Loprinzi, emeritus chair of the division of medical oncology at the Mayo Clinic in Rochester, Minn., said that it supports earlier findings of a relationship between epidermal nerve fiber loss and deficits in sensory and motor function leading, and that "it makes sense" that such losses would lead to functional losses.*

The study was funded by grants from the National Cancer Institute. Dr. Mohile reported no relevant disclosures. Dr. Loprinzi disclosed receiving research funding from Abbott, Amgen, Bristol-Myers Squibb, Eisai, Novartis, Ortho Biotech, Pfizer, Roche, and Sanofi.

* Dr. Loprinzi's title was corrected on June 18, 2012.

CHICAGO – Cancer survivors with chemotherapy-induced peripheral neuropathy may be headed for a fall, researchers cautioned at the annual meeting of the American Society of Clinical Oncology.

About 12% of patients with chemotherapy-induced peripheral neuropathy (CIPN) had at least one fall, and nearly 60% experienced some kind of physical problem related to CIPN, reported Dr. Supriya Mohile of the department of hematology/oncology at the University of Rochester (N.Y.).

"We should in our clinics longitudinally evaluate patients not only for toxicities from neuropathy, but also for physical functioning and falls," she said.

Dr. Mohile urged providing patients with balance and mobility training throughout chemotherapy and minimizing fall risk by recommending assistive devices and home-safety evaluations and modifications as necessary.

She and her colleagues evaluated 421 patients who had reported baseline data as part of a randomized phase III trial for a topical cream. The patients had completed chemotherapy and had self-reported CIPN of 4 or greater on an 11-point scale. The patients were not on significant medications for either pain or neuropathy, and those with other possible causes of neuropathy, such as diabetes, were excluded.

They found that about one-third of patients had a CIPN-related problem such as difficulty stooping, walking for one-fourth of a mile, or performing tasks requiring heavy lifting.

Additionally, more than 25% reported a functional loss, limiting their ability to shop, manage money, walk across a room, do light housework, or bathe themselves.

Comparing 260 patients who reported falls or physical problems with 161 who did not, the investigators identified pain, sensory neuropathy, and motor neuropathy as toxicities independently associated with falls and/or physical problems (P less than .001 for all three comparisons).

In a multivariate analysis controlling for age, sex, race, ethnicity, marital status, education, history of taxane exposure, previous surgery and radiation, pain, and sensory neuropathy, the investigators found that breast cancer (odds ratio, 2.776; P = .045) and motor neuropathy (OR, 1.138; P = .006) were independently associated with falls. Factors associated with having a physical performance problem were previous surgery (OR, 2.536; P = .013) and motor neuropathy (OR, 1.325; P less than .001).

Functional losses were more likely to occur among Hispanics (OR, 5.318; P = –.048), patients with any physical performance problem (OR, 4.942; P less than .001), and those with motor neuropathy (OR, 1.191; P = .0001).

The study was limited by the heterogeneity of the cancer sample, its cross-sectional design that precludes determination of causality or of a temporal relationship between chemotherapy and neuropathies, and self-report of CIPN toxicities, Dr. Mohile said.

Commenting on the study, Dr. Charles L. Loprinzi, emeritus chair of the division of medical oncology at the Mayo Clinic in Rochester, Minn., said that it supports earlier findings of a relationship between epidermal nerve fiber loss and deficits in sensory and motor function leading, and that "it makes sense" that such losses would lead to functional losses.*

The study was funded by grants from the National Cancer Institute. Dr. Mohile reported no relevant disclosures. Dr. Loprinzi disclosed receiving research funding from Abbott, Amgen, Bristol-Myers Squibb, Eisai, Novartis, Ortho Biotech, Pfizer, Roche, and Sanofi.

* Dr. Loprinzi's title was corrected on June 18, 2012.

CHICAGO – Final results of the phase III PARAMOUNT trial support continued use of pemetrexed after pemetrexed-plus-cisplatin induction therapy for advanced, nonsquamous non-small cell lung cancer.

More patients on pemetrexed (Alimta) maintenance were alive at 1 year (58% vs. 45% of the control group) and 2 years (32% vs. 21%), investigators reported. With nearly all patients off study treatment, median overall survival from randomization was 13.9 months with pemetrexed maintenance plus best supportive care (BSC) vs. 11.0 months with BSC plus placebo.

This translates into a 22% reduction in the risk of death (HR, 0.78; log-rank P = .0195). An analysis of overall survival from the start of induction yielded the same risk reduction with the median reaching 16.9 months in patients maintained on pemetrexed vs. 14.0 months in the control group (HR 0.78; log-rank P = .0191).

Patrice Wendling/IMNG Medical Media

The benefit of pemetrexed maintenance was consistent across all subgroups, including patients with a complete or partial response (HR 0.81) and those with stable disease (HR 0.76) after induction therapy, Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

"This is the first study to show that continuation maintenance had a clear impact on the natural course of the disease in advanced non–small cell lung cancer, including an improvement in [progression-free survival] and [overall survival], and may support a change in the treatment paradigm in this clinical setting," said Dr. Paz-Ares of University Hospital Virgen del Rocio in Seville, Spain.

"I think we should share with our patients the information about the role of maintenance treatment, but it doesn’t mean that every single patient should be treated in this way," he said.

At last year’s ASCO meeting, the investigators reported that pemetrexed maintenance significantly reduced the study’s primary end point, the risk of disease progression (HR 0.62). Results were subsequently published in Lancet Oncology (Lancet Oncol. 2012;13:247-55).

The overall survival data were not mature at the time, leaving some clinicians to question the overall efficacy of pemetrexed maintenance and whether the delay in progression was enough to justify the potential increased toxicity with continued therapy.

Patrice Wendling/IMNG Medical Media

Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan Comprehensive Cancer Center in Ann Arbor, said the strength of the trial was the selection of a tolerable maintenance drug, although chronic fatigue with pemetrexed maintenance can be bothersome and quality of life appears similar with placebo. He also pointed out that pemetrexed and placebo patients received a median of four cycles, suggesting that most patients do not benefit.

Everyone Received Pemetrexed Induction

In the PARAMOUNT trial, 939 chemotherapy-naive patients with advanced nonsquamous NSCLC, at least one measurable lesion, and an ECOG performance status of 0 or 1 received four cycles of induction pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1 of a 21-day cycle. The 539 patients who responded were then stratified by disease stage, performance status, and induction response and randomly assigned to maintenance with pemetrexed 500 mg/m² every 21 days plus BSC or to BSC and placebo. All patients received folic acid and vitamin B₁₂.

The median age was 61 years, about 90% of patients had stage IV disease, 86%-89% had adenocarcinoma histology, and 42%-44% had a complete or partial response to induction therapy. The mean number of maintenance cycles was 7.9 (range 1-44) for the 359 pemetrexed patients and 5 cycles for the 180 placebo patients (range 1-38).

Median follow-up for all patients was 12.5 months, and reached 24.3 months among all patients still alive.

Reassessment of progression-free survival at the time of the final analysis once again favored pemetrexed (HR 0.60), confirming the robustness of the results, Dr. Paz-Ares said of the late-breaking abstract.

The pemetrexed maintenance arm had more grade 3/4 events than did the placebo arm, notably fatigue (4.7% vs. 1.1%), anemia (6.4% vs. 0.6%), and neutropenia (5.8% vs. 0%).

Most Treated After Stopping Maintenance

In all, 64% of the pemetrexed arm and 72% of the placebo arm received postdiscontinuation therapy, mainly erlotinib (Tarceva) (40% of the pemetrexed arm and 43% of the control group). Only docetaxel (Taxotere) usage differed significantly between arms (32% vs. 43%; P = .013), he said.

During a discussion of the study, an attendee asked whether the estimate of the benefit of pemetrexed would be more credible if the study had mandated an established second-line treatment for controls.

Dr. Paz-Ares said the percentage of patients receiving second- and third-line treatment is in the high range compared with other trials and exceeds what occurs in normal practice. He called the 72% of controls receiving postdiscontinuation therapy "quite remarkable," and said he interprets the 64% of pemetrexed patients receiving additional therapy as proof these patients are "not losing any further chance of having second or third-line treatment."

Several attendees questioned the use of four rather than six cycles of induction therapy, suggesting that patients may have been undertreated. Dr. Paz-Ares said that even in trials that mandate six cycles, patients typically receive a median of four or five cycles at maximum, and that one additional cycle likely would not have impacted overall survival.

"The whole thing here is that we have very few drugs that are active in non–small cell lung cancer and we have to be able to squeeze most of the benefit from each of them, and this is why I’m really in favor of this maintenance kind of treatment," he added.

PARAMOUNT was supported by Eli Lilly. Dr. Paz-Ares reported a consultant/advisory role with, and honoraria from, Bayer, Lilly, Pfizer, and Roche. His coauthors include employees of Eli Lilly. Dr. Kalemkerian reported research funding from Lilly.

CHICAGO – Final results of the phase III PARAMOUNT trial support continued use of pemetrexed after pemetrexed-plus-cisplatin induction therapy for advanced, nonsquamous non-small cell lung cancer.

More patients on pemetrexed (Alimta) maintenance were alive at 1 year (58% vs. 45% of the control group) and 2 years (32% vs. 21%), investigators reported. With nearly all patients off study treatment, median overall survival from randomization was 13.9 months with pemetrexed maintenance plus best supportive care (BSC) vs. 11.0 months with BSC plus placebo.

This translates into a 22% reduction in the risk of death (HR, 0.78; log-rank P = .0195). An analysis of overall survival from the start of induction yielded the same risk reduction with the median reaching 16.9 months in patients maintained on pemetrexed vs. 14.0 months in the control group (HR 0.78; log-rank P = .0191).

Patrice Wendling/IMNG Medical Media

The benefit of pemetrexed maintenance was consistent across all subgroups, including patients with a complete or partial response (HR 0.81) and those with stable disease (HR 0.76) after induction therapy, Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

"This is the first study to show that continuation maintenance had a clear impact on the natural course of the disease in advanced non–small cell lung cancer, including an improvement in [progression-free survival] and [overall survival], and may support a change in the treatment paradigm in this clinical setting," said Dr. Paz-Ares of University Hospital Virgen del Rocio in Seville, Spain.

"I think we should share with our patients the information about the role of maintenance treatment, but it doesn’t mean that every single patient should be treated in this way," he said.

At last year’s ASCO meeting, the investigators reported that pemetrexed maintenance significantly reduced the study’s primary end point, the risk of disease progression (HR 0.62). Results were subsequently published in Lancet Oncology (Lancet Oncol. 2012;13:247-55).

The overall survival data were not mature at the time, leaving some clinicians to question the overall efficacy of pemetrexed maintenance and whether the delay in progression was enough to justify the potential increased toxicity with continued therapy.

Patrice Wendling/IMNG Medical Media

Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan Comprehensive Cancer Center in Ann Arbor, said the strength of the trial was the selection of a tolerable maintenance drug, although chronic fatigue with pemetrexed maintenance can be bothersome and quality of life appears similar with placebo. He also pointed out that pemetrexed and placebo patients received a median of four cycles, suggesting that most patients do not benefit.

Everyone Received Pemetrexed Induction

In the PARAMOUNT trial, 939 chemotherapy-naive patients with advanced nonsquamous NSCLC, at least one measurable lesion, and an ECOG performance status of 0 or 1 received four cycles of induction pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1 of a 21-day cycle. The 539 patients who responded were then stratified by disease stage, performance status, and induction response and randomly assigned to maintenance with pemetrexed 500 mg/m² every 21 days plus BSC or to BSC and placebo. All patients received folic acid and vitamin B₁₂.

The median age was 61 years, about 90% of patients had stage IV disease, 86%-89% had adenocarcinoma histology, and 42%-44% had a complete or partial response to induction therapy. The mean number of maintenance cycles was 7.9 (range 1-44) for the 359 pemetrexed patients and 5 cycles for the 180 placebo patients (range 1-38).

Median follow-up for all patients was 12.5 months, and reached 24.3 months among all patients still alive.

Reassessment of progression-free survival at the time of the final analysis once again favored pemetrexed (HR 0.60), confirming the robustness of the results, Dr. Paz-Ares said of the late-breaking abstract.

The pemetrexed maintenance arm had more grade 3/4 events than did the placebo arm, notably fatigue (4.7% vs. 1.1%), anemia (6.4% vs. 0.6%), and neutropenia (5.8% vs. 0%).

Most Treated After Stopping Maintenance

In all, 64% of the pemetrexed arm and 72% of the placebo arm received postdiscontinuation therapy, mainly erlotinib (Tarceva) (40% of the pemetrexed arm and 43% of the control group). Only docetaxel (Taxotere) usage differed significantly between arms (32% vs. 43%; P = .013), he said.

During a discussion of the study, an attendee asked whether the estimate of the benefit of pemetrexed would be more credible if the study had mandated an established second-line treatment for controls.

Dr. Paz-Ares said the percentage of patients receiving second- and third-line treatment is in the high range compared with other trials and exceeds what occurs in normal practice. He called the 72% of controls receiving postdiscontinuation therapy "quite remarkable," and said he interprets the 64% of pemetrexed patients receiving additional therapy as proof these patients are "not losing any further chance of having second or third-line treatment."

Several attendees questioned the use of four rather than six cycles of induction therapy, suggesting that patients may have been undertreated. Dr. Paz-Ares said that even in trials that mandate six cycles, patients typically receive a median of four or five cycles at maximum, and that one additional cycle likely would not have impacted overall survival.

"The whole thing here is that we have very few drugs that are active in non–small cell lung cancer and we have to be able to squeeze most of the benefit from each of them, and this is why I’m really in favor of this maintenance kind of treatment," he added.

PARAMOUNT was supported by Eli Lilly. Dr. Paz-Ares reported a consultant/advisory role with, and honoraria from, Bayer, Lilly, Pfizer, and Roche. His coauthors include employees of Eli Lilly. Dr. Kalemkerian reported research funding from Lilly.

CHICAGO – Final results of the phase III PARAMOUNT trial support continued use of pemetrexed after pemetrexed-plus-cisplatin induction therapy for advanced, nonsquamous non-small cell lung cancer.

More patients on pemetrexed (Alimta) maintenance were alive at 1 year (58% vs. 45% of the control group) and 2 years (32% vs. 21%), investigators reported. With nearly all patients off study treatment, median overall survival from randomization was 13.9 months with pemetrexed maintenance plus best supportive care (BSC) vs. 11.0 months with BSC plus placebo.

This translates into a 22% reduction in the risk of death (HR, 0.78; log-rank P = .0195). An analysis of overall survival from the start of induction yielded the same risk reduction with the median reaching 16.9 months in patients maintained on pemetrexed vs. 14.0 months in the control group (HR 0.78; log-rank P = .0191).

Patrice Wendling/IMNG Medical Media

The benefit of pemetrexed maintenance was consistent across all subgroups, including patients with a complete or partial response (HR 0.81) and those with stable disease (HR 0.76) after induction therapy, Dr. Luis Paz-Ares said at the annual meeting of the American Society of Clinical Oncology.

"This is the first study to show that continuation maintenance had a clear impact on the natural course of the disease in advanced non–small cell lung cancer, including an improvement in [progression-free survival] and [overall survival], and may support a change in the treatment paradigm in this clinical setting," said Dr. Paz-Ares of University Hospital Virgen del Rocio in Seville, Spain.

"I think we should share with our patients the information about the role of maintenance treatment, but it doesn’t mean that every single patient should be treated in this way," he said.

At last year’s ASCO meeting, the investigators reported that pemetrexed maintenance significantly reduced the study’s primary end point, the risk of disease progression (HR 0.62). Results were subsequently published in Lancet Oncology (Lancet Oncol. 2012;13:247-55).

The overall survival data were not mature at the time, leaving some clinicians to question the overall efficacy of pemetrexed maintenance and whether the delay in progression was enough to justify the potential increased toxicity with continued therapy.

Patrice Wendling/IMNG Medical Media

Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan Comprehensive Cancer Center in Ann Arbor, said the strength of the trial was the selection of a tolerable maintenance drug, although chronic fatigue with pemetrexed maintenance can be bothersome and quality of life appears similar with placebo. He also pointed out that pemetrexed and placebo patients received a median of four cycles, suggesting that most patients do not benefit.

Everyone Received Pemetrexed Induction

In the PARAMOUNT trial, 939 chemotherapy-naive patients with advanced nonsquamous NSCLC, at least one measurable lesion, and an ECOG performance status of 0 or 1 received four cycles of induction pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1 of a 21-day cycle. The 539 patients who responded were then stratified by disease stage, performance status, and induction response and randomly assigned to maintenance with pemetrexed 500 mg/m² every 21 days plus BSC or to BSC and placebo. All patients received folic acid and vitamin B₁₂.

The median age was 61 years, about 90% of patients had stage IV disease, 86%-89% had adenocarcinoma histology, and 42%-44% had a complete or partial response to induction therapy. The mean number of maintenance cycles was 7.9 (range 1-44) for the 359 pemetrexed patients and 5 cycles for the 180 placebo patients (range 1-38).

Median follow-up for all patients was 12.5 months, and reached 24.3 months among all patients still alive.

Reassessment of progression-free survival at the time of the final analysis once again favored pemetrexed (HR 0.60), confirming the robustness of the results, Dr. Paz-Ares said of the late-breaking abstract.

The pemetrexed maintenance arm had more grade 3/4 events than did the placebo arm, notably fatigue (4.7% vs. 1.1%), anemia (6.4% vs. 0.6%), and neutropenia (5.8% vs. 0%).

Most Treated After Stopping Maintenance

In all, 64% of the pemetrexed arm and 72% of the placebo arm received postdiscontinuation therapy, mainly erlotinib (Tarceva) (40% of the pemetrexed arm and 43% of the control group). Only docetaxel (Taxotere) usage differed significantly between arms (32% vs. 43%; P = .013), he said.

During a discussion of the study, an attendee asked whether the estimate of the benefit of pemetrexed would be more credible if the study had mandated an established second-line treatment for controls.

Dr. Paz-Ares said the percentage of patients receiving second- and third-line treatment is in the high range compared with other trials and exceeds what occurs in normal practice. He called the 72% of controls receiving postdiscontinuation therapy "quite remarkable," and said he interprets the 64% of pemetrexed patients receiving additional therapy as proof these patients are "not losing any further chance of having second or third-line treatment."

Several attendees questioned the use of four rather than six cycles of induction therapy, suggesting that patients may have been undertreated. Dr. Paz-Ares said that even in trials that mandate six cycles, patients typically receive a median of four or five cycles at maximum, and that one additional cycle likely would not have impacted overall survival.

"The whole thing here is that we have very few drugs that are active in non–small cell lung cancer and we have to be able to squeeze most of the benefit from each of them, and this is why I’m really in favor of this maintenance kind of treatment," he added.

PARAMOUNT was supported by Eli Lilly. Dr. Paz-Ares reported a consultant/advisory role with, and honoraria from, Bayer, Lilly, Pfizer, and Roche. His coauthors include employees of Eli Lilly. Dr. Kalemkerian reported research funding from Lilly.

CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.

Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).

"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.

"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.

Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.

"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.

Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.

GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.

The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).

Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.

The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.

Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.

Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.

"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.

Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.

Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.

"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."

Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.

The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.

CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.

Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).

"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.

"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.

Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.

"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.

Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.

GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.

The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).

Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.

The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.

Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.

Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.

"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.

Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.

Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.

"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."

Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.

The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.

CHICAGO – Regorafenib, an investigational tyrosine kinase inhibitor, dramatically delayed disease progression among patients with treatment-refractory metastatic gastrointestinal stromal tumor in a phase III trial.

Median progression-free survival reached 4.8 months with regorafenib vs. 0.9 months for placebo in the GRID (GIST–Regorafenib in Disease) study (hazard ratio, 0.27; P less than .0001).

"Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care," said Dr. George D. Demetri, who presented the results at the annual meeting of the American Society of Clinical Oncology.

"It is immaterial whether patients in this study were on third line, fourth line, or greater line, the hazard ratios were quite similar – [showing] a significant robust effect regardless of the number of prior inhibitors that these patients had been exposed to," added Dr. Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

GIST, the most common sarcoma subtype, until fairly recently had no known treatment. The advent of imatinib (Gleevec) and later sunitinib (Sutent) changed the disease from one that was essentially untreatable into one that has two Food & Drug Administration–approved treatment options; with median survival increasing from 3-6 months to 5 years or more. Within just a few years of therapy, however, 90% of tumors can become resistant to the anticancer effects of both approved agents.

Regorafenib is a multitarget tyrosine kinase inhibitor (TKI), which has a high affinity for two mutated, activated kinases – KIT and platelet-derived growth factor receptor – that act as the main biological drivers of GIST, Dr. Demetri explained.

"GIST is truly addicted to KIT," he said during a press briefing. Regorafenib also targets vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, RET, BRAF, and the fibroblast growth factor receptor 1.

Preclinical and early-phase clinical trials have shown regorafenib has a range of anticancer activity, including a recently published phase II trial in which it was given to patients with advanced GIST after imatinib or sunitinib failure (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.39.9394]). These promising results, released at last year’s ASCO annual meeting, prompted the phase III, double-blind, placebo-controlled GRID trial.

GRID was a "unique academic/industrial collaboration" undertaken in 17 countries across North America, Europe, and Asia-Pacific that took just 7 months from initiation to complete patient accrual. A total of 236 patients with metastatic, unresectable GIST intolerant to or progressing despite treatment with imatinib and sunitinib were screened, with 199 randomized (2:1) to regorafenib (160 mg/day) or placebo plus best supportive care.

The median age of patients was 58 years, with 75% of regorafenib-treated patients receiving two prior lines of therapy (imatinib and sunitinib only), and 59% receiving more than two prior treatments (imatinib, sunitinib, and others). Regorafenib-treated patients also had been exposed to were nilotinib (Tasigna, 21.8%), other TKIs (1.5%), mTOR inhibitors (2.3%), and cytotoxic chemotherapy (9.8%).

Active treatment or placebo was given in 4-week cycles, with 3 weeks on, and 1 week off treatment until disease progression. After disease progression, treatment was unblinded and placebo-treated patients could cross over to active treatment and receive open-label regorafenib until the next disease progression. Patients could also continue regorafenib if the clinician felt that this was of benefit. At the next progression, however, treatment was stopped.

The primary end point was progression-free survival, which clearly favored regorafenib over placebo. Exploratory analysis suggested regorafenib is effective in all molecular subtypes of GIST, including those with exon 9 and exon 11 mutations in KIT.

Important secondary end points were disease control and overall response rates. The disease control at 12 weeks or more was 52.6% for regorafenib and 9.1% for placebo, while overall response rates were 4.5% vs. 1.5%.

Dr. Demetri noted that another important secondary end point, overall survival would be confounded if the drug worked – and indeed 85% of placebo-patients crossed over to receive regorafenib. This was an intentional part of the study design, he said.

"The hazard ratio [0.77] for overall survival trended in favor of the patients who got started on regorafenib, there was a 23% decrease in the risk of death, but that was not statistically significant," Dr. Demetri said. Median overall survival has not currently been reached for either study arm.

Grade 3 drug-related side effects included those commonly associated with multitargeting TKIs or other cancer therapies, with hypertension (22.7%), hand-foot syndrome (19.7%), diarrhea (5.3%), fatigue (2.3%), mucositis (1.5%), and alopecia (1.5%) reported, as well as a few others including nausea, constipation, and myalgia.

Discussing the trial’s findings, Grant McArthur, Ph.D., of the Peter MacCallum Cancer Center in East Melbourne, Australia, said it was a very important study.

"Regorafenib is a very interesting inhibitor that is certainly worthwhile investigating in gastrointestinal stromal tumors," he said. "Clearly, this is a positive study and there’s no doubt that regorafenib is a viable third-line treatment option now for our patients."

Dr. McArthur added, however: "Best supportive care as the comparator is one standard of care. The alternative standard of care is continuation of a KIT tyrosine kinase inhibitor," which could perhaps be further investigated.

The GRID trial was sponsored by Bayer HealthCare AG. Dr. Demetri disclosed ties with Bayer, Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, and Roche/Genentech. Dr. McArthur disclosed ties with Bristol-Myers-Squibb, GlaxoSmithKline, Millennium, Novartis, Pfizer, and Roche/Genentech.

CHICAGO – The investigational antibody-drug conjugate inotuzumab ozogamicin delivered weekly produced a high objective response rate in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia, investigators reported.*

"Inotuzumab ozogamicin is very active in relapsed/refractory ALL. We’re reporting an objective response rate of 52%, most likely the highest activity for a single agent in this setting," said Dr. Elias Jabbour of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, a cytotoxic antibiotic. The investigators recently reported that the compound, delivered at a dose of 1.8 mg/m² IV over 1 hour once monthly, was associated with a 57% overall response rate in 49 patients, but with a dose-limiting toxicity of thrombocytopenia (Lancet Oncol. 2012;13:403-11).

The current study was designed to see whether lower but more frequent doses might offer better anti-ALL activity and have a better safety profile, as suggested by preclinical studies. Dr. Jabbour presented the results at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled adults and children with relapsed/refractory CD22-positive ALL and treated them with inotuzumab 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; they repeated the cycle every 3-4 weeks for up to eight cycles.

Of the 27 patients available for analysis, 10 had a failed first remission lasting less than 12 months and one had a remission of more than 12 months’ duration. Six patients had undergone two salvage regimens and 10 had received at least three. Two patients had previously undergone an allogeneic stem cell transplant.

Three of the patients had a complete remission (CR), defined as the disappearance of all clinical and/or radiologic evidence of disease, a neutrophil count greater than 1.0 × 10⁹/L, a platelet count greater than 100 × 10⁹/L, and normal marrow differential with less than 5% blasts. Eight patients had complete remission except for platelet recovery (CRp) and three had a complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), Dr. Jabbour said.

Eleven patients had disease resistant to the therapy and two died within 4 weeks of treatment.

Among patients evaluable for cytogenetic response, there were responses in two of two patients with a complete remission, in five of six patients with a CRp, and in two of two with a CRi. Of 14 patients evaluable for minimal residual disease (MRD), three of three with a CR were MRD negative, as were seven of eight with a CRp and one of three with a CRi. In all, 11 of the 27 patients in the analysis were MRD negative, he reported.

Median progression-free survival and median duration of response were 5 months each. Median overall survival was 7 months and did not differ significantly when patients were censored at the time of transplant. Median overall survival in this study compared favorably with that of the once-monthly dosing schedule (5 months).

Adverse events included infusion-related fever (grade 1/2 in three patients and grade 3/4 in four) and hypotension (grade 1/2 in one patient). There was one case of grade 1/2 bilirubin elevation, six grade 1/2 liver enzyme elevations, and two grade 3/4 enzyme elevations. All of the liver changes were reversible.

Prognostic factors for worse outcome were three or more salvage regimens and Philadelphia chromosome positivity.

Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant, commented that intozumab has "impressive" single-agent activity in relapsed/refractory ALL, and that it appears to be safe before allogenic transplant. It remains to be seen whether the agent may have efficacy when combined with chemotherapy or other monoclonal antibodies in the relapsed and front-line settings, or activity when used as a single agent up front, he said.

Dr. Jabbour disclosed ties with Pfizer, which funded the study. Dr. Medeiros disclosed ties with Milennium, Celgene, and Novartis.

*This paragraph was revised June 19, 2012.

CHICAGO – The investigational antibody-drug conjugate inotuzumab ozogamicin delivered weekly produced a high objective response rate in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia, investigators reported.*

"Inotuzumab ozogamicin is very active in relapsed/refractory ALL. We’re reporting an objective response rate of 52%, most likely the highest activity for a single agent in this setting," said Dr. Elias Jabbour of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, a cytotoxic antibiotic. The investigators recently reported that the compound, delivered at a dose of 1.8 mg/m² IV over 1 hour once monthly, was associated with a 57% overall response rate in 49 patients, but with a dose-limiting toxicity of thrombocytopenia (Lancet Oncol. 2012;13:403-11).

The current study was designed to see whether lower but more frequent doses might offer better anti-ALL activity and have a better safety profile, as suggested by preclinical studies. Dr. Jabbour presented the results at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled adults and children with relapsed/refractory CD22-positive ALL and treated them with inotuzumab 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; they repeated the cycle every 3-4 weeks for up to eight cycles.

Of the 27 patients available for analysis, 10 had a failed first remission lasting less than 12 months and one had a remission of more than 12 months’ duration. Six patients had undergone two salvage regimens and 10 had received at least three. Two patients had previously undergone an allogeneic stem cell transplant.

Three of the patients had a complete remission (CR), defined as the disappearance of all clinical and/or radiologic evidence of disease, a neutrophil count greater than 1.0 × 10⁹/L, a platelet count greater than 100 × 10⁹/L, and normal marrow differential with less than 5% blasts. Eight patients had complete remission except for platelet recovery (CRp) and three had a complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), Dr. Jabbour said.

Eleven patients had disease resistant to the therapy and two died within 4 weeks of treatment.

Among patients evaluable for cytogenetic response, there were responses in two of two patients with a complete remission, in five of six patients with a CRp, and in two of two with a CRi. Of 14 patients evaluable for minimal residual disease (MRD), three of three with a CR were MRD negative, as were seven of eight with a CRp and one of three with a CRi. In all, 11 of the 27 patients in the analysis were MRD negative, he reported.

Median progression-free survival and median duration of response were 5 months each. Median overall survival was 7 months and did not differ significantly when patients were censored at the time of transplant. Median overall survival in this study compared favorably with that of the once-monthly dosing schedule (5 months).

Adverse events included infusion-related fever (grade 1/2 in three patients and grade 3/4 in four) and hypotension (grade 1/2 in one patient). There was one case of grade 1/2 bilirubin elevation, six grade 1/2 liver enzyme elevations, and two grade 3/4 enzyme elevations. All of the liver changes were reversible.

Prognostic factors for worse outcome were three or more salvage regimens and Philadelphia chromosome positivity.

Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant, commented that intozumab has "impressive" single-agent activity in relapsed/refractory ALL, and that it appears to be safe before allogenic transplant. It remains to be seen whether the agent may have efficacy when combined with chemotherapy or other monoclonal antibodies in the relapsed and front-line settings, or activity when used as a single agent up front, he said.

Dr. Jabbour disclosed ties with Pfizer, which funded the study. Dr. Medeiros disclosed ties with Milennium, Celgene, and Novartis.

*This paragraph was revised June 19, 2012.

CHICAGO – The investigational antibody-drug conjugate inotuzumab ozogamicin delivered weekly produced a high objective response rate in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia, investigators reported.*

"Inotuzumab ozogamicin is very active in relapsed/refractory ALL. We’re reporting an objective response rate of 52%, most likely the highest activity for a single agent in this setting," said Dr. Elias Jabbour of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, a cytotoxic antibiotic. The investigators recently reported that the compound, delivered at a dose of 1.8 mg/m² IV over 1 hour once monthly, was associated with a 57% overall response rate in 49 patients, but with a dose-limiting toxicity of thrombocytopenia (Lancet Oncol. 2012;13:403-11).

The current study was designed to see whether lower but more frequent doses might offer better anti-ALL activity and have a better safety profile, as suggested by preclinical studies. Dr. Jabbour presented the results at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled adults and children with relapsed/refractory CD22-positive ALL and treated them with inotuzumab 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; they repeated the cycle every 3-4 weeks for up to eight cycles.

Of the 27 patients available for analysis, 10 had a failed first remission lasting less than 12 months and one had a remission of more than 12 months’ duration. Six patients had undergone two salvage regimens and 10 had received at least three. Two patients had previously undergone an allogeneic stem cell transplant.

Three of the patients had a complete remission (CR), defined as the disappearance of all clinical and/or radiologic evidence of disease, a neutrophil count greater than 1.0 × 10⁹/L, a platelet count greater than 100 × 10⁹/L, and normal marrow differential with less than 5% blasts. Eight patients had complete remission except for platelet recovery (CRp) and three had a complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), Dr. Jabbour said.

Eleven patients had disease resistant to the therapy and two died within 4 weeks of treatment.

Among patients evaluable for cytogenetic response, there were responses in two of two patients with a complete remission, in five of six patients with a CRp, and in two of two with a CRi. Of 14 patients evaluable for minimal residual disease (MRD), three of three with a CR were MRD negative, as were seven of eight with a CRp and one of three with a CRi. In all, 11 of the 27 patients in the analysis were MRD negative, he reported.

Median progression-free survival and median duration of response were 5 months each. Median overall survival was 7 months and did not differ significantly when patients were censored at the time of transplant. Median overall survival in this study compared favorably with that of the once-monthly dosing schedule (5 months).

Adverse events included infusion-related fever (grade 1/2 in three patients and grade 3/4 in four) and hypotension (grade 1/2 in one patient). There was one case of grade 1/2 bilirubin elevation, six grade 1/2 liver enzyme elevations, and two grade 3/4 enzyme elevations. All of the liver changes were reversible.

Prognostic factors for worse outcome were three or more salvage regimens and Philadelphia chromosome positivity.

Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant, commented that intozumab has "impressive" single-agent activity in relapsed/refractory ALL, and that it appears to be safe before allogenic transplant. It remains to be seen whether the agent may have efficacy when combined with chemotherapy or other monoclonal antibodies in the relapsed and front-line settings, or activity when used as a single agent up front, he said.

Dr. Jabbour disclosed ties with Pfizer, which funded the study. Dr. Medeiros disclosed ties with Milennium, Celgene, and Novartis.

*This paragraph was revised June 19, 2012.