2015 ASCO Annual Meeting

CHICAGO – Nivolumab reduced the risk of death by nearly a third over docetaxel for patients with advanced, refractory nonsquamous non–small cell lung cancer, results of CheckMate 057 showed.

The primary endpoint of median overall survival was 12.2 months for those receiving the PD-1 immune checkpoint inhibitor nivolumab and 9.4 months for those given docetaxel (hazard ratio, 0.73; P = .0015), study author Dr. Luis Paz-Ares reported at the annual meeting of the American Society of Clinical Oncology.

At 1 year, 51% of the nivolumab (Opdivo) group were alive vs. 39% of the docetaxel (Taxotere) group.

The survival advantage was seen across most subgroups, except never smokers and those whose tumors were positive for epidermal growth factor receptor (EGFR) mutations.

The magnitude of the overall survival benefit in patients with PD-L1–positive tumors, however, was “unprecedented in this setting” and ranged from 17.2 months to 19.4 months, Dr. Paz-Ares of the Hospital Universitario Virgen Del Rocio, Seville, Spain, said.

Treatment options for patients with nonsquamous histology who progress following platinum-based doublet chemotherapy are limited. Typical response rates in this context are about 10%, and median overall survival is about 8-10 months, he said.

Discussant Dr. Roy Herbst, chief of medical oncology at Yale Comprehensive Cancer Center in New Haven, Conn., said, “This is a positive randomized phase III trial with a primary endpoint for all comers. The trial sets a new standard for the treatment of previously treated disease … and nivolumab is significantly less toxic than docetaxel.”

Check Mate 057 randomly assigned 292 patients to nivolumab 3 mg/kg every 2 weeks and 290 patients to docetaxel 75 mg/kg every 3 weeks until disease progression or unacceptable toxicity occurred. Patients were stratified by prior maintenance therapy and line of therapy. PD-L1 expression was measured in pretreatment (archival or recent) tumor biopsies.

The objective response rate was significantly higher for patients receiving nivolumab than docetaxel (19% vs. 12%; P = .0246; odds ratio, 1.72), Dr. Paz-Ares said.

Most responses were partial (18% vs. 12%), with only one complete response to nivolumab. The median duration of response was 17.2 months with nivolumab vs. 5.6 months with docetaxel.

Progression-free survival (PFS) was similar between the nivolumab and docetaxel groups (2.3 months vs. 4.2 months; HR, 0.92; P = .39), he said, explaining that progression was more rapid with nivolumab during the first 6 months before slowing to a 1-year PFS rate of 19% vs. 8% for docetaxel.

PD-L1 expression emerged as a significant predictor of objective response rate, PFS, and overall survival, with objective response rates as much as three times higher with nivolumab than docetaxel for patients with high PD-L1 expression, Dr. Paz-Ares said.

Using three predefined cut points of ≥1%, ≥5%, and ≥10% PD-L1 expression, overall survival was 17.2 months, 18.2 months, and 19.4 months with nivolumab vs. 9.0 months, 8.1 months, and 8 months with docetaxel, respectively.

Dr. Herbst described the PD-L1 biomarker as intriguing, but said for now it is only hypothesis generating and should not be used for patient selection. PD-L1 expression was not prospectively stratified in the study, and was not available for 22% of patients, and while it does improve objective response rate, PFS, and overall survival, even patients with less than 1% expression appear to have at least equal activity to that of docetaxel with less toxicity, he noted.

Adverse events of any grade were reported in 69% of patients receiving nivolumab and 88% receiving docetaxel. More importantly, grade 3-4 events occurred in 10% vs. 54%, Dr. Paz-Ares said. The most common events with nivolumab were fatigue, nausea, and decreased appetite.

Notably, the dose intensity delivered was higher for nivolumab than for docetaxel (83% vs. 66%), and 42% of nivolumab patients vs. 50% of docetaxel patients received subsequent systemic therapy, suggesting little influence of further treatment on survival.

In a separate presentation at ASCO, nivolumab reduced the risk of death by 41%, compared with docetaxel, in previously treated advanced squamous NSCLC (HR, 0.59; P = .00025) in the phase III Check Mate 017 study.

Nivolumab received a second indication in March 2015 for use in metastatic squamous NSCLC following failure with platinum-based chemotherapy

Bristol-Myers Squibb sponsored the study. Dr. Paz-Ares reported honoraria from Bristol-Myers Squibb, Roche/Genentech, Lilly, Pfizer, Boehringer, and Clovis. Dr. Herbst reported honoraria from Boehringer Ingelheim, Celgene, Lilly, Merck, NovaRx, and Pfizer; a consulting or advisory role with Biothera, DiaTech Oncology, Koltan Pharmaceuticals, N-of-One, and Quintiles; and research funding from Genentech/Roche and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Nivolumab reduced the risk of death by nearly a third over docetaxel for patients with advanced, refractory nonsquamous non–small cell lung cancer, results of CheckMate 057 showed.

The primary endpoint of median overall survival was 12.2 months for those receiving the PD-1 immune checkpoint inhibitor nivolumab and 9.4 months for those given docetaxel (hazard ratio, 0.73; P = .0015), study author Dr. Luis Paz-Ares reported at the annual meeting of the American Society of Clinical Oncology.

At 1 year, 51% of the nivolumab (Opdivo) group were alive vs. 39% of the docetaxel (Taxotere) group.

The survival advantage was seen across most subgroups, except never smokers and those whose tumors were positive for epidermal growth factor receptor (EGFR) mutations.

The magnitude of the overall survival benefit in patients with PD-L1–positive tumors, however, was “unprecedented in this setting” and ranged from 17.2 months to 19.4 months, Dr. Paz-Ares of the Hospital Universitario Virgen Del Rocio, Seville, Spain, said.

Treatment options for patients with nonsquamous histology who progress following platinum-based doublet chemotherapy are limited. Typical response rates in this context are about 10%, and median overall survival is about 8-10 months, he said.

Discussant Dr. Roy Herbst, chief of medical oncology at Yale Comprehensive Cancer Center in New Haven, Conn., said, “This is a positive randomized phase III trial with a primary endpoint for all comers. The trial sets a new standard for the treatment of previously treated disease … and nivolumab is significantly less toxic than docetaxel.”

Check Mate 057 randomly assigned 292 patients to nivolumab 3 mg/kg every 2 weeks and 290 patients to docetaxel 75 mg/kg every 3 weeks until disease progression or unacceptable toxicity occurred. Patients were stratified by prior maintenance therapy and line of therapy. PD-L1 expression was measured in pretreatment (archival or recent) tumor biopsies.

The objective response rate was significantly higher for patients receiving nivolumab than docetaxel (19% vs. 12%; P = .0246; odds ratio, 1.72), Dr. Paz-Ares said.

Most responses were partial (18% vs. 12%), with only one complete response to nivolumab. The median duration of response was 17.2 months with nivolumab vs. 5.6 months with docetaxel.

Progression-free survival (PFS) was similar between the nivolumab and docetaxel groups (2.3 months vs. 4.2 months; HR, 0.92; P = .39), he said, explaining that progression was more rapid with nivolumab during the first 6 months before slowing to a 1-year PFS rate of 19% vs. 8% for docetaxel.

PD-L1 expression emerged as a significant predictor of objective response rate, PFS, and overall survival, with objective response rates as much as three times higher with nivolumab than docetaxel for patients with high PD-L1 expression, Dr. Paz-Ares said.

Using three predefined cut points of ≥1%, ≥5%, and ≥10% PD-L1 expression, overall survival was 17.2 months, 18.2 months, and 19.4 months with nivolumab vs. 9.0 months, 8.1 months, and 8 months with docetaxel, respectively.

Dr. Herbst described the PD-L1 biomarker as intriguing, but said for now it is only hypothesis generating and should not be used for patient selection. PD-L1 expression was not prospectively stratified in the study, and was not available for 22% of patients, and while it does improve objective response rate, PFS, and overall survival, even patients with less than 1% expression appear to have at least equal activity to that of docetaxel with less toxicity, he noted.

Adverse events of any grade were reported in 69% of patients receiving nivolumab and 88% receiving docetaxel. More importantly, grade 3-4 events occurred in 10% vs. 54%, Dr. Paz-Ares said. The most common events with nivolumab were fatigue, nausea, and decreased appetite.

Notably, the dose intensity delivered was higher for nivolumab than for docetaxel (83% vs. 66%), and 42% of nivolumab patients vs. 50% of docetaxel patients received subsequent systemic therapy, suggesting little influence of further treatment on survival.

In a separate presentation at ASCO, nivolumab reduced the risk of death by 41%, compared with docetaxel, in previously treated advanced squamous NSCLC (HR, 0.59; P = .00025) in the phase III Check Mate 017 study.

Nivolumab received a second indication in March 2015 for use in metastatic squamous NSCLC following failure with platinum-based chemotherapy

Bristol-Myers Squibb sponsored the study. Dr. Paz-Ares reported honoraria from Bristol-Myers Squibb, Roche/Genentech, Lilly, Pfizer, Boehringer, and Clovis. Dr. Herbst reported honoraria from Boehringer Ingelheim, Celgene, Lilly, Merck, NovaRx, and Pfizer; a consulting or advisory role with Biothera, DiaTech Oncology, Koltan Pharmaceuticals, N-of-One, and Quintiles; and research funding from Genentech/Roche and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Nivolumab reduced the risk of death by nearly a third over docetaxel for patients with advanced, refractory nonsquamous non–small cell lung cancer, results of CheckMate 057 showed.

The primary endpoint of median overall survival was 12.2 months for those receiving the PD-1 immune checkpoint inhibitor nivolumab and 9.4 months for those given docetaxel (hazard ratio, 0.73; P = .0015), study author Dr. Luis Paz-Ares reported at the annual meeting of the American Society of Clinical Oncology.

At 1 year, 51% of the nivolumab (Opdivo) group were alive vs. 39% of the docetaxel (Taxotere) group.

The survival advantage was seen across most subgroups, except never smokers and those whose tumors were positive for epidermal growth factor receptor (EGFR) mutations.

The magnitude of the overall survival benefit in patients with PD-L1–positive tumors, however, was “unprecedented in this setting” and ranged from 17.2 months to 19.4 months, Dr. Paz-Ares of the Hospital Universitario Virgen Del Rocio, Seville, Spain, said.

Treatment options for patients with nonsquamous histology who progress following platinum-based doublet chemotherapy are limited. Typical response rates in this context are about 10%, and median overall survival is about 8-10 months, he said.

Discussant Dr. Roy Herbst, chief of medical oncology at Yale Comprehensive Cancer Center in New Haven, Conn., said, “This is a positive randomized phase III trial with a primary endpoint for all comers. The trial sets a new standard for the treatment of previously treated disease … and nivolumab is significantly less toxic than docetaxel.”

Check Mate 057 randomly assigned 292 patients to nivolumab 3 mg/kg every 2 weeks and 290 patients to docetaxel 75 mg/kg every 3 weeks until disease progression or unacceptable toxicity occurred. Patients were stratified by prior maintenance therapy and line of therapy. PD-L1 expression was measured in pretreatment (archival or recent) tumor biopsies.

The objective response rate was significantly higher for patients receiving nivolumab than docetaxel (19% vs. 12%; P = .0246; odds ratio, 1.72), Dr. Paz-Ares said.

Most responses were partial (18% vs. 12%), with only one complete response to nivolumab. The median duration of response was 17.2 months with nivolumab vs. 5.6 months with docetaxel.

Progression-free survival (PFS) was similar between the nivolumab and docetaxel groups (2.3 months vs. 4.2 months; HR, 0.92; P = .39), he said, explaining that progression was more rapid with nivolumab during the first 6 months before slowing to a 1-year PFS rate of 19% vs. 8% for docetaxel.

PD-L1 expression emerged as a significant predictor of objective response rate, PFS, and overall survival, with objective response rates as much as three times higher with nivolumab than docetaxel for patients with high PD-L1 expression, Dr. Paz-Ares said.

Using three predefined cut points of ≥1%, ≥5%, and ≥10% PD-L1 expression, overall survival was 17.2 months, 18.2 months, and 19.4 months with nivolumab vs. 9.0 months, 8.1 months, and 8 months with docetaxel, respectively.

Dr. Herbst described the PD-L1 biomarker as intriguing, but said for now it is only hypothesis generating and should not be used for patient selection. PD-L1 expression was not prospectively stratified in the study, and was not available for 22% of patients, and while it does improve objective response rate, PFS, and overall survival, even patients with less than 1% expression appear to have at least equal activity to that of docetaxel with less toxicity, he noted.

Adverse events of any grade were reported in 69% of patients receiving nivolumab and 88% receiving docetaxel. More importantly, grade 3-4 events occurred in 10% vs. 54%, Dr. Paz-Ares said. The most common events with nivolumab were fatigue, nausea, and decreased appetite.

Notably, the dose intensity delivered was higher for nivolumab than for docetaxel (83% vs. 66%), and 42% of nivolumab patients vs. 50% of docetaxel patients received subsequent systemic therapy, suggesting little influence of further treatment on survival.

In a separate presentation at ASCO, nivolumab reduced the risk of death by 41%, compared with docetaxel, in previously treated advanced squamous NSCLC (HR, 0.59; P = .00025) in the phase III Check Mate 017 study.

Nivolumab received a second indication in March 2015 for use in metastatic squamous NSCLC following failure with platinum-based chemotherapy

Bristol-Myers Squibb sponsored the study. Dr. Paz-Ares reported honoraria from Bristol-Myers Squibb, Roche/Genentech, Lilly, Pfizer, Boehringer, and Clovis. Dr. Herbst reported honoraria from Boehringer Ingelheim, Celgene, Lilly, Merck, NovaRx, and Pfizer; a consulting or advisory role with Biothera, DiaTech Oncology, Koltan Pharmaceuticals, N-of-One, and Quintiles; and research funding from Genentech/Roche and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.

CHICAGO – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.

CHICAGO – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

[email protected]

On Twitter @pwendl

CHICAGO – The largest precision oncology trial ever will use genomic analysis of tumors to match patients with optimal therapies.

In the National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial, patients will undergo biopsy with genomic analysis of their tumors to identify specific molecular abnormalities and then be assigned to the most relevant targeted therapy available, including both currently marketed drugs and investigational agents.

In a video interview, the study’s coprincipal investigator, Dr. Keith T. Flaherty of Massachusetts General Hospital in Boston, described the promises and challenges of translating oceans of data into solid therapeutic responses to difficult-to-treat cancers.

CHICAGO – The largest precision oncology trial ever will use genomic analysis of tumors to match patients with optimal therapies.

In the National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial, patients will undergo biopsy with genomic analysis of their tumors to identify specific molecular abnormalities and then be assigned to the most relevant targeted therapy available, including both currently marketed drugs and investigational agents.

In a video interview, the study’s coprincipal investigator, Dr. Keith T. Flaherty of Massachusetts General Hospital in Boston, described the promises and challenges of translating oceans of data into solid therapeutic responses to difficult-to-treat cancers.

CHICAGO – The largest precision oncology trial ever will use genomic analysis of tumors to match patients with optimal therapies.

In the National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial, patients will undergo biopsy with genomic analysis of their tumors to identify specific molecular abnormalities and then be assigned to the most relevant targeted therapy available, including both currently marketed drugs and investigational agents.

In a video interview, the study’s coprincipal investigator, Dr. Keith T. Flaherty of Massachusetts General Hospital in Boston, described the promises and challenges of translating oceans of data into solid therapeutic responses to difficult-to-treat cancers.

CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.

After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).

The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.

Patrice Wendling/Frontline Medical News

Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.

Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).

The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).

Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”

Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.

There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.

CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.

The impact of PD-L1 expression

As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.

In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.

The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.

“PD-L1 expression is a weak biomarker,” he said.

Greater efficacy, greater toxicity

Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.

Grade 3-4 events were reported in 55% of the combination group, 16.3% of the nivolumab-alone group, and 27.3% of the ipilimumab-alone group. The most common of these events were diarrhea in 2.2% of patients in the nivolumab group, 9.3% of the combination group and 6.1% of the ipilimumab group, colitis (0.6%, 7.7%, 8.7%) and increased alanine aminotransferase levels (1.3%, 8.3%, 1.6%).

“There is no signature adverse event for the combination,” Dr. Wolchok said. “With the use of immune-modulating agents, the majority of grade 3 and 4 select adverse events resolved in all of the groups with the use of established algorithms. However, as we observed in prior studies, most endocrine events did not.”

There was one treatment-related death due to neutropenia in the nivolumab group, one due to cardiac arrest in the ipilimumab group, and none in the combination group.

An expanded access program is available for the combination of nivolumab and ipilimumab through the study sponsor, Bristol-Myers Squibb, Dr. Wolchok noted.

[email protected]

On Twitter@pwendl

CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.

After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).

The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.

Patrice Wendling/Frontline Medical News

Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.

Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).

The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).

Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”

Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.

There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.

CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.

The impact of PD-L1 expression

As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.

In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.

The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.

“PD-L1 expression is a weak biomarker,” he said.

Greater efficacy, greater toxicity

Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.

Grade 3-4 events were reported in 55% of the combination group, 16.3% of the nivolumab-alone group, and 27.3% of the ipilimumab-alone group. The most common of these events were diarrhea in 2.2% of patients in the nivolumab group, 9.3% of the combination group and 6.1% of the ipilimumab group, colitis (0.6%, 7.7%, 8.7%) and increased alanine aminotransferase levels (1.3%, 8.3%, 1.6%).

“There is no signature adverse event for the combination,” Dr. Wolchok said. “With the use of immune-modulating agents, the majority of grade 3 and 4 select adverse events resolved in all of the groups with the use of established algorithms. However, as we observed in prior studies, most endocrine events did not.”

There was one treatment-related death due to neutropenia in the nivolumab group, one due to cardiac arrest in the ipilimumab group, and none in the combination group.

An expanded access program is available for the combination of nivolumab and ipilimumab through the study sponsor, Bristol-Myers Squibb, Dr. Wolchok noted.

[email protected]

On Twitter@pwendl

CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.

After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).

The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.

Patrice Wendling/Frontline Medical News

Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.

Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).

The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).

Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”

Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.

There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.

CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.

The impact of PD-L1 expression

As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.

In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.

The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.

“PD-L1 expression is a weak biomarker,” he said.

Greater efficacy, greater toxicity

Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.

Grade 3-4 events were reported in 55% of the combination group, 16.3% of the nivolumab-alone group, and 27.3% of the ipilimumab-alone group. The most common of these events were diarrhea in 2.2% of patients in the nivolumab group, 9.3% of the combination group and 6.1% of the ipilimumab group, colitis (0.6%, 7.7%, 8.7%) and increased alanine aminotransferase levels (1.3%, 8.3%, 1.6%).

“There is no signature adverse event for the combination,” Dr. Wolchok said. “With the use of immune-modulating agents, the majority of grade 3 and 4 select adverse events resolved in all of the groups with the use of established algorithms. However, as we observed in prior studies, most endocrine events did not.”

There was one treatment-related death due to neutropenia in the nivolumab group, one due to cardiac arrest in the ipilimumab group, and none in the combination group.

An expanded access program is available for the combination of nivolumab and ipilimumab through the study sponsor, Bristol-Myers Squibb, Dr. Wolchok noted.

[email protected]

On Twitter@pwendl

CHICAGO – Combining the immunotherapy antibodies nivolumab and ipilimumab induced more robust responses in untreated advanced melanoma when used together than as single agents, according to phase III results reported at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, Dr. Steven O’Day, whose ipilimumab research rocked ASCO audiences just 5 years ago, gives his insights into the results, what they mean for the future of ipilimumab, and what clinicians may possibly see at ASCO 2016.

The study was sponsored by Bristol-Myers Squibb. The lead investigator, Dr. Jedd D. Wolchok, reported financial relationships with BMS and several other firms.

[email protected]

On Twitter @pwendl

CHICAGO – Combining the immunotherapy antibodies nivolumab and ipilimumab induced more robust responses in untreated advanced melanoma when used together than as single agents, according to phase III results reported at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, Dr. Steven O’Day, whose ipilimumab research rocked ASCO audiences just 5 years ago, gives his insights into the results, what they mean for the future of ipilimumab, and what clinicians may possibly see at ASCO 2016.

The study was sponsored by Bristol-Myers Squibb. The lead investigator, Dr. Jedd D. Wolchok, reported financial relationships with BMS and several other firms.

[email protected]

On Twitter @pwendl

CHICAGO – Combining the immunotherapy antibodies nivolumab and ipilimumab induced more robust responses in untreated advanced melanoma when used together than as single agents, according to phase III results reported at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, Dr. Steven O’Day, whose ipilimumab research rocked ASCO audiences just 5 years ago, gives his insights into the results, what they mean for the future of ipilimumab, and what clinicians may possibly see at ASCO 2016.

The study was sponsored by Bristol-Myers Squibb. The lead investigator, Dr. Jedd D. Wolchok, reported financial relationships with BMS and several other firms.

[email protected]

On Twitter @pwendl

CHICAGO – Decades-old efforts to reduce the intensity of therapies for childhood cancers are paying off, resulting in significant declines in late all-cause mortality among those who survive 5-years after a cancer diagnosis, investigators report.

For patients treated in the 1970s for childhood cancers, the 15-year cumulative mortality rate was 3.1%, compared with 2.4% for those treated in the 80’s, and 1.9% for those treated in the 90’s, reported Dr. Gregory T. Armstrong from St. Jude’s Children’s Research Hospital, Memphis.

Neil Osterweil

“The improvement in cure rate of childhood cancer is really one of the success stories of modern medicine. If you go back to the 1960s, less than 30-40% of children were surviving cancer. Currently, over 82% of children will become 5-year survivors,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

“However, these 5-year survivors, as they move forward, are still at risk for late events and early mortality. As shown previously for these 5-year survivors, even after hitting the 5-year turning point, 18% will be deceased 30 years from diagnosis,” he said.

But efforts to reduce the intensity of therapy without compromising the quality of care appear to be having their effect, as seen in long-term follow-up results from patients in the Childhood Cancer Survivor Study.

The study, initiated in 1994, follows a retrospective cohort of children treated at 31 US and Canadian hospitals from 1970 through 1999 for common childhood malignancies, including leukemias, lymphomas, central nervous system malignancies, Wilms tumor, neuroblastoma, and sarcomas of soft tissues and/or bones.

The investigators looked at follow-up data on 34,033 cohort members who were alive 5 years after diagnosis, and for whom there was detailed information on the cumulative chemotherapy dose exposures and organ-specific radiotherapy dosimetry.

At a median follow-up of 21 years, 3958 (12%) of the cohort had died, and of this group 1618 (41%) were deemed to have died from health-related causes, including late effects of cancer therapy, such as cardiovascular causes (243 deaths), pulmonary problems (136), and second malignancies (751 deaths).

In each category and in all-cause mortality, there were significant reductions in the cumulative incidence of deaths over time. For example: all-cause mortality declined from 12.4% during the 1970-74 era to 6.0 from 1990-94 (P < .001), deaths from second cancers dropped from 1.8% to 1.0% over the same period (P < .001), cardiac-related deaths fell from 0.5% to 0.1% (P = .001), and pulmonary deaths declined from 0.4% to 0.1% (P = .02).

In a multivariable analysis adjusted for age at diagnosis, sex, and diagnosis and follow-up time, each 5-year interval was associated with a significant reduction in deaths from other health related causes (relative risk [RR] 0.86), subsequent neoplasm (RR 0.83), cardiac causes (RR 0.77), and pulmonary disease (RR 0.77). The confidence intervals for all variables indicated statistical significance.

Additionally, when they looked at specific cancers, they saw declines in cardiac mortality for acute lymphoblastic leukemia, Hodgkin’s lymphoma, and Wilms tumor, and a decrease in second malignancies for patients with Wilms tumor.

The reductions in deaths paralleled changes in clinical practice, notably reductions in the use of cranial radiotherapy for patients with acute lymphoblastic leukemia from 86% of patients in the 70s to 22% in the 90s, as well as reductions in abdominal radiation given to children with Wilms tumor (from 77% to 49%, respectively) and in chest radiation given for Hodgkin’s lymphoma (from 96% to 77%).

Dr. Michael P. Link, professor in pediatric cancer at Stanford University School of Medicine, the invited discussant, said the study results provide important lessons for clinicians treating adult as well as childhood cancers. He noted that reductions in the intensity of therapy and limiting exposures results in decreases in late organ toxicity, secondary cancers, and mortality.

“The translation and modification of therapy designed to reduce exposures into clinically significant reductions in all-cause late mortality is a gratifying validation of three decades of refining our therapies to accomplish the same number of cures while lowering the cost of cure,” he said.

The Childhood Cancer Survivor Study is funded by the National Institutes of Health. Dr. Armstrong and Dr. Link reported no relevant disclosures.

CHICAGO – Decades-old efforts to reduce the intensity of therapies for childhood cancers are paying off, resulting in significant declines in late all-cause mortality among those who survive 5-years after a cancer diagnosis, investigators report.

For patients treated in the 1970s for childhood cancers, the 15-year cumulative mortality rate was 3.1%, compared with 2.4% for those treated in the 80’s, and 1.9% for those treated in the 90’s, reported Dr. Gregory T. Armstrong from St. Jude’s Children’s Research Hospital, Memphis.

Neil Osterweil

“The improvement in cure rate of childhood cancer is really one of the success stories of modern medicine. If you go back to the 1960s, less than 30-40% of children were surviving cancer. Currently, over 82% of children will become 5-year survivors,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

“However, these 5-year survivors, as they move forward, are still at risk for late events and early mortality. As shown previously for these 5-year survivors, even after hitting the 5-year turning point, 18% will be deceased 30 years from diagnosis,” he said.

But efforts to reduce the intensity of therapy without compromising the quality of care appear to be having their effect, as seen in long-term follow-up results from patients in the Childhood Cancer Survivor Study.

The study, initiated in 1994, follows a retrospective cohort of children treated at 31 US and Canadian hospitals from 1970 through 1999 for common childhood malignancies, including leukemias, lymphomas, central nervous system malignancies, Wilms tumor, neuroblastoma, and sarcomas of soft tissues and/or bones.

The investigators looked at follow-up data on 34,033 cohort members who were alive 5 years after diagnosis, and for whom there was detailed information on the cumulative chemotherapy dose exposures and organ-specific radiotherapy dosimetry.

At a median follow-up of 21 years, 3958 (12%) of the cohort had died, and of this group 1618 (41%) were deemed to have died from health-related causes, including late effects of cancer therapy, such as cardiovascular causes (243 deaths), pulmonary problems (136), and second malignancies (751 deaths).

In each category and in all-cause mortality, there were significant reductions in the cumulative incidence of deaths over time. For example: all-cause mortality declined from 12.4% during the 1970-74 era to 6.0 from 1990-94 (P < .001), deaths from second cancers dropped from 1.8% to 1.0% over the same period (P < .001), cardiac-related deaths fell from 0.5% to 0.1% (P = .001), and pulmonary deaths declined from 0.4% to 0.1% (P = .02).

In a multivariable analysis adjusted for age at diagnosis, sex, and diagnosis and follow-up time, each 5-year interval was associated with a significant reduction in deaths from other health related causes (relative risk [RR] 0.86), subsequent neoplasm (RR 0.83), cardiac causes (RR 0.77), and pulmonary disease (RR 0.77). The confidence intervals for all variables indicated statistical significance.

Additionally, when they looked at specific cancers, they saw declines in cardiac mortality for acute lymphoblastic leukemia, Hodgkin’s lymphoma, and Wilms tumor, and a decrease in second malignancies for patients with Wilms tumor.

The reductions in deaths paralleled changes in clinical practice, notably reductions in the use of cranial radiotherapy for patients with acute lymphoblastic leukemia from 86% of patients in the 70s to 22% in the 90s, as well as reductions in abdominal radiation given to children with Wilms tumor (from 77% to 49%, respectively) and in chest radiation given for Hodgkin’s lymphoma (from 96% to 77%).

Dr. Michael P. Link, professor in pediatric cancer at Stanford University School of Medicine, the invited discussant, said the study results provide important lessons for clinicians treating adult as well as childhood cancers. He noted that reductions in the intensity of therapy and limiting exposures results in decreases in late organ toxicity, secondary cancers, and mortality.

“The translation and modification of therapy designed to reduce exposures into clinically significant reductions in all-cause late mortality is a gratifying validation of three decades of refining our therapies to accomplish the same number of cures while lowering the cost of cure,” he said.

The Childhood Cancer Survivor Study is funded by the National Institutes of Health. Dr. Armstrong and Dr. Link reported no relevant disclosures.

CHICAGO – Decades-old efforts to reduce the intensity of therapies for childhood cancers are paying off, resulting in significant declines in late all-cause mortality among those who survive 5-years after a cancer diagnosis, investigators report.

For patients treated in the 1970s for childhood cancers, the 15-year cumulative mortality rate was 3.1%, compared with 2.4% for those treated in the 80’s, and 1.9% for those treated in the 90’s, reported Dr. Gregory T. Armstrong from St. Jude’s Children’s Research Hospital, Memphis.

Neil Osterweil

“The improvement in cure rate of childhood cancer is really one of the success stories of modern medicine. If you go back to the 1960s, less than 30-40% of children were surviving cancer. Currently, over 82% of children will become 5-year survivors,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

“However, these 5-year survivors, as they move forward, are still at risk for late events and early mortality. As shown previously for these 5-year survivors, even after hitting the 5-year turning point, 18% will be deceased 30 years from diagnosis,” he said.

But efforts to reduce the intensity of therapy without compromising the quality of care appear to be having their effect, as seen in long-term follow-up results from patients in the Childhood Cancer Survivor Study.

The study, initiated in 1994, follows a retrospective cohort of children treated at 31 US and Canadian hospitals from 1970 through 1999 for common childhood malignancies, including leukemias, lymphomas, central nervous system malignancies, Wilms tumor, neuroblastoma, and sarcomas of soft tissues and/or bones.

The investigators looked at follow-up data on 34,033 cohort members who were alive 5 years after diagnosis, and for whom there was detailed information on the cumulative chemotherapy dose exposures and organ-specific radiotherapy dosimetry.

At a median follow-up of 21 years, 3958 (12%) of the cohort had died, and of this group 1618 (41%) were deemed to have died from health-related causes, including late effects of cancer therapy, such as cardiovascular causes (243 deaths), pulmonary problems (136), and second malignancies (751 deaths).

In each category and in all-cause mortality, there were significant reductions in the cumulative incidence of deaths over time. For example: all-cause mortality declined from 12.4% during the 1970-74 era to 6.0 from 1990-94 (P < .001), deaths from second cancers dropped from 1.8% to 1.0% over the same period (P < .001), cardiac-related deaths fell from 0.5% to 0.1% (P = .001), and pulmonary deaths declined from 0.4% to 0.1% (P = .02).

In a multivariable analysis adjusted for age at diagnosis, sex, and diagnosis and follow-up time, each 5-year interval was associated with a significant reduction in deaths from other health related causes (relative risk [RR] 0.86), subsequent neoplasm (RR 0.83), cardiac causes (RR 0.77), and pulmonary disease (RR 0.77). The confidence intervals for all variables indicated statistical significance.

Additionally, when they looked at specific cancers, they saw declines in cardiac mortality for acute lymphoblastic leukemia, Hodgkin’s lymphoma, and Wilms tumor, and a decrease in second malignancies for patients with Wilms tumor.

The reductions in deaths paralleled changes in clinical practice, notably reductions in the use of cranial radiotherapy for patients with acute lymphoblastic leukemia from 86% of patients in the 70s to 22% in the 90s, as well as reductions in abdominal radiation given to children with Wilms tumor (from 77% to 49%, respectively) and in chest radiation given for Hodgkin’s lymphoma (from 96% to 77%).

Dr. Michael P. Link, professor in pediatric cancer at Stanford University School of Medicine, the invited discussant, said the study results provide important lessons for clinicians treating adult as well as childhood cancers. He noted that reductions in the intensity of therapy and limiting exposures results in decreases in late organ toxicity, secondary cancers, and mortality.

“The translation and modification of therapy designed to reduce exposures into clinically significant reductions in all-cause late mortality is a gratifying validation of three decades of refining our therapies to accomplish the same number of cures while lowering the cost of cure,” he said.

The Childhood Cancer Survivor Study is funded by the National Institutes of Health. Dr. Armstrong and Dr. Link reported no relevant disclosures.