Patrice Wendling

CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.

Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.

Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.

Lower Dose, Less Toxicity

A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.

Patrice Wendling/IMNG Medical Media

In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.

The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.

Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.

Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.

Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.

Activity and Toxicity Persist at 100 mg

Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.

Patrice Wendling/IMNG Medical Media

Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.

The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.

Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.

Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.

Randomized Trials Started

Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.

Cabozantinib is also being studied in a variety of other cancers, including heavily pretreated, refractory renal cell carcinoma and medullary thyroid cancer.

Exelixis sponsored both trials. Dr. Lee reported no conflicts. Dr. Smith and several of his coauthors reported a consultant/advisory role with and research funding from Exelixis. Dr. Fizazi reported a consultant/advisory role with OncoGenex and Exelixis.

CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.

Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.

Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.

Lower Dose, Less Toxicity

A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.

Patrice Wendling/IMNG Medical Media

In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.

The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.

Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.

Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.

Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.

Activity and Toxicity Persist at 100 mg

Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.

Patrice Wendling/IMNG Medical Media

Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.

The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.

Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.

Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.

Randomized Trials Started

Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.

Cabozantinib is also being studied in a variety of other cancers, including heavily pretreated, refractory renal cell carcinoma and medullary thyroid cancer.

Exelixis sponsored both trials. Dr. Lee reported no conflicts. Dr. Smith and several of his coauthors reported a consultant/advisory role with and research funding from Exelixis. Dr. Fizazi reported a consultant/advisory role with OncoGenex and Exelixis.

CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.

Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.

Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.

Lower Dose, Less Toxicity

A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.

Patrice Wendling/IMNG Medical Media

In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.

The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.

Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.

Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.

Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.

Activity and Toxicity Persist at 100 mg

Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.

Patrice Wendling/IMNG Medical Media

Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.

The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.

Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.

Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.

Randomized Trials Started

Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.

Cabozantinib is also being studied in a variety of other cancers, including heavily pretreated, refractory renal cell carcinoma and medullary thyroid cancer.

Exelixis sponsored both trials. Dr. Lee reported no conflicts. Dr. Smith and several of his coauthors reported a consultant/advisory role with and research funding from Exelixis. Dr. Fizazi reported a consultant/advisory role with OncoGenex and Exelixis.

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

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

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

Patrice Wendling/IMNG Medical Media

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

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

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

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

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

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

Many Asians, Women in International Trial

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

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

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

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

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

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

QoL Better With Afatinib

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

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

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

Acquired Resistance Anticipated

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

Patrice Wendling/IMNG Medical Media

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

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

* This story was updated 6/29/2012.

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

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

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

Patrice Wendling/IMNG Medical Media

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

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

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

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

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

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

Many Asians, Women in International Trial

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

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

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

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

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

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

QoL Better With Afatinib

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

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

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

Acquired Resistance Anticipated

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

Patrice Wendling/IMNG Medical Media

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

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

* This story was updated 6/29/2012.

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

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

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

Patrice Wendling/IMNG Medical Media

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

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

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

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

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

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

Many Asians, Women in International Trial

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

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

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

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

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

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

QoL Better With Afatinib

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

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

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

Acquired Resistance Anticipated

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

Patrice Wendling/IMNG Medical Media

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

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

* This story was updated 6/29/2012.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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