2013 ASCO Annual Meeting

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – Upamostat, an investigational oral inhibitor of urokinase-type plasminogen activator, did not add to the efficacy of capecitabine monotherapy when given as first-line therapy to unselected patients with HER2-negative metastatic breast cancer, based on the results of a phase II trial.

The 132 women studied were assigned evenly to capecitabine monotherapy or to capecitabine plus upamostat. Median progression-free survival, the trial’s primary endpoint, was statistically indistinguishable at about 8 months in each group.

Courtesy Fox Chase Cancer Center

However, upamostat was associated with a 4-month gain in this outcome in the subset of patients who had previously received chemotherapy in the adjuvant or neoadjuvant setting, an unplanned exploratory analysis found.

"Treatment with prior chemotherapy potentially defines a more homogeneous subpopulation in this study. Also, prior chemotherapy could possibly identify a population with more aggressive disease due to higher expression of uPA [urokinase-type plasminogen activator]," said lead author Dr. Lori J. Goldstein of the Fox Chase Cancer Center in Philadelphia. "This would be in line with the treatment effects seen in the group who progressed early after initial diagnosis."

"Future studies with upamostat should target a more homogeneous patient population and incorporate biomarker-specific strategies for patient characterization and selection," Dr. Goldstein recommended.

Adding upamostat to chemotherapy, for nearly 3 years in some cases, was generally safe and well tolerated. The only increase in adverse events was in the incidence of hand-foot syndrome.

"Upamostat can safely be given over extended periods of time. [The study] is also the first proof of activity of an anti-uPA inhibitor in breast cancer therapy," Dr. Goldstein said at the annual meeting of the American Society of Clinical Oncology.

Part of the plasminogen activation system, uPA promotes tumor cell invasion, migration, and proliferation, Dr. Goldstein explained, giving some background to the research.

"As the uPA system is quantitatively more expressed in tumor cells and tumor-associated stromal cells, it is an interesting target for cancer therapy. uPA and PAI-1 [plasminogen activator inhibitor-1] are both ASCO-recommended prognostic and predictive biomarkers for early-stage breast cancer," she said.

Among all the patients enrolled in the trial, median progression-free survival was 8.3 months with the upamostat-capecitabine combination and 7.5 months with capecitabine alone, a nonsignificant difference. The estimated 6-month rates of progression-free survival were 56% and 50%.

Archival tumor specimens were not available for uPA and PAI-1 testing, according to Dr. Goldstein. And testing of serial plasma samples for a variety of biomarkers – uPA, PAI-1, CAIX (a marker associated with poorer prognostic features), and the fibrin degradation product D-dimer – failed to show any differences between groups.

In unplanned exploratory analyses, median progression-free survival among patients who had received prior adjuvant or neoadjuvant chemotherapy was 8.3 months with upamostat-capecitabine combination therapy and 4.3 months with capecitabine monotherapy.

The combination therapy also seemed to have an edge among patients who had experienced their recurrence within 3 years from initial diagnosis (5.6 vs. 2.7 months), Dr. Goldstein reported.

The upamostat-capecitabine group had a higher rate of any-grade hand-foot syndrome (77% vs. 46%), possibly related to a longer duration of treatment, whereas rates of other toxicities were similar.

"The pharmacokinetic analyses demonstrated no drug-drug interactions between upamostat and capecitabine," she noted.

Dr. Goldstein disclosed that she receives research funding from the U.S. Department of Defense and Wilex. The trial was sponsored by Wilex, the maker of upamostat.

CHICAGO – Upamostat, an investigational oral inhibitor of urokinase-type plasminogen activator, did not add to the efficacy of capecitabine monotherapy when given as first-line therapy to unselected patients with HER2-negative metastatic breast cancer, based on the results of a phase II trial.

The 132 women studied were assigned evenly to capecitabine monotherapy or to capecitabine plus upamostat. Median progression-free survival, the trial’s primary endpoint, was statistically indistinguishable at about 8 months in each group.

Courtesy Fox Chase Cancer Center

However, upamostat was associated with a 4-month gain in this outcome in the subset of patients who had previously received chemotherapy in the adjuvant or neoadjuvant setting, an unplanned exploratory analysis found.

"Treatment with prior chemotherapy potentially defines a more homogeneous subpopulation in this study. Also, prior chemotherapy could possibly identify a population with more aggressive disease due to higher expression of uPA [urokinase-type plasminogen activator]," said lead author Dr. Lori J. Goldstein of the Fox Chase Cancer Center in Philadelphia. "This would be in line with the treatment effects seen in the group who progressed early after initial diagnosis."

"Future studies with upamostat should target a more homogeneous patient population and incorporate biomarker-specific strategies for patient characterization and selection," Dr. Goldstein recommended.

Adding upamostat to chemotherapy, for nearly 3 years in some cases, was generally safe and well tolerated. The only increase in adverse events was in the incidence of hand-foot syndrome.

"Upamostat can safely be given over extended periods of time. [The study] is also the first proof of activity of an anti-uPA inhibitor in breast cancer therapy," Dr. Goldstein said at the annual meeting of the American Society of Clinical Oncology.

Part of the plasminogen activation system, uPA promotes tumor cell invasion, migration, and proliferation, Dr. Goldstein explained, giving some background to the research.

"As the uPA system is quantitatively more expressed in tumor cells and tumor-associated stromal cells, it is an interesting target for cancer therapy. uPA and PAI-1 [plasminogen activator inhibitor-1] are both ASCO-recommended prognostic and predictive biomarkers for early-stage breast cancer," she said.

Among all the patients enrolled in the trial, median progression-free survival was 8.3 months with the upamostat-capecitabine combination and 7.5 months with capecitabine alone, a nonsignificant difference. The estimated 6-month rates of progression-free survival were 56% and 50%.

Archival tumor specimens were not available for uPA and PAI-1 testing, according to Dr. Goldstein. And testing of serial plasma samples for a variety of biomarkers – uPA, PAI-1, CAIX (a marker associated with poorer prognostic features), and the fibrin degradation product D-dimer – failed to show any differences between groups.

In unplanned exploratory analyses, median progression-free survival among patients who had received prior adjuvant or neoadjuvant chemotherapy was 8.3 months with upamostat-capecitabine combination therapy and 4.3 months with capecitabine monotherapy.

The combination therapy also seemed to have an edge among patients who had experienced their recurrence within 3 years from initial diagnosis (5.6 vs. 2.7 months), Dr. Goldstein reported.

The upamostat-capecitabine group had a higher rate of any-grade hand-foot syndrome (77% vs. 46%), possibly related to a longer duration of treatment, whereas rates of other toxicities were similar.

"The pharmacokinetic analyses demonstrated no drug-drug interactions between upamostat and capecitabine," she noted.

Dr. Goldstein disclosed that she receives research funding from the U.S. Department of Defense and Wilex. The trial was sponsored by Wilex, the maker of upamostat.

CHICAGO – Upamostat, an investigational oral inhibitor of urokinase-type plasminogen activator, did not add to the efficacy of capecitabine monotherapy when given as first-line therapy to unselected patients with HER2-negative metastatic breast cancer, based on the results of a phase II trial.

The 132 women studied were assigned evenly to capecitabine monotherapy or to capecitabine plus upamostat. Median progression-free survival, the trial’s primary endpoint, was statistically indistinguishable at about 8 months in each group.

Courtesy Fox Chase Cancer Center

However, upamostat was associated with a 4-month gain in this outcome in the subset of patients who had previously received chemotherapy in the adjuvant or neoadjuvant setting, an unplanned exploratory analysis found.

"Treatment with prior chemotherapy potentially defines a more homogeneous subpopulation in this study. Also, prior chemotherapy could possibly identify a population with more aggressive disease due to higher expression of uPA [urokinase-type plasminogen activator]," said lead author Dr. Lori J. Goldstein of the Fox Chase Cancer Center in Philadelphia. "This would be in line with the treatment effects seen in the group who progressed early after initial diagnosis."

"Future studies with upamostat should target a more homogeneous patient population and incorporate biomarker-specific strategies for patient characterization and selection," Dr. Goldstein recommended.

Adding upamostat to chemotherapy, for nearly 3 years in some cases, was generally safe and well tolerated. The only increase in adverse events was in the incidence of hand-foot syndrome.

"Upamostat can safely be given over extended periods of time. [The study] is also the first proof of activity of an anti-uPA inhibitor in breast cancer therapy," Dr. Goldstein said at the annual meeting of the American Society of Clinical Oncology.

Part of the plasminogen activation system, uPA promotes tumor cell invasion, migration, and proliferation, Dr. Goldstein explained, giving some background to the research.

"As the uPA system is quantitatively more expressed in tumor cells and tumor-associated stromal cells, it is an interesting target for cancer therapy. uPA and PAI-1 [plasminogen activator inhibitor-1] are both ASCO-recommended prognostic and predictive biomarkers for early-stage breast cancer," she said.

Among all the patients enrolled in the trial, median progression-free survival was 8.3 months with the upamostat-capecitabine combination and 7.5 months with capecitabine alone, a nonsignificant difference. The estimated 6-month rates of progression-free survival were 56% and 50%.

Archival tumor specimens were not available for uPA and PAI-1 testing, according to Dr. Goldstein. And testing of serial plasma samples for a variety of biomarkers – uPA, PAI-1, CAIX (a marker associated with poorer prognostic features), and the fibrin degradation product D-dimer – failed to show any differences between groups.

In unplanned exploratory analyses, median progression-free survival among patients who had received prior adjuvant or neoadjuvant chemotherapy was 8.3 months with upamostat-capecitabine combination therapy and 4.3 months with capecitabine monotherapy.

The combination therapy also seemed to have an edge among patients who had experienced their recurrence within 3 years from initial diagnosis (5.6 vs. 2.7 months), Dr. Goldstein reported.

The upamostat-capecitabine group had a higher rate of any-grade hand-foot syndrome (77% vs. 46%), possibly related to a longer duration of treatment, whereas rates of other toxicities were similar.

"The pharmacokinetic analyses demonstrated no drug-drug interactions between upamostat and capecitabine," she noted.

Dr. Goldstein disclosed that she receives research funding from the U.S. Department of Defense and Wilex. The trial was sponsored by Wilex, the maker of upamostat.

CHICAGO – Prostate cancer outcomes were predicted by a test that measures the expression of cell cycle progression genes, according to results from a retrospective analysis of prostate tissue samples from five patient cohorts.

The Prolaris test gives each tissue sample a cell cycle progression (CCP) score based on measures of 31 CCP genes, normalized to 15 "housekeeper" genes. A unit change in the test is defined as a doubling in CCP genes. For each unit increase in the test’s score, there was a two- to threefold increase in the risk of disease progression, Dr. Jack M. Cuzick reported at the annual meeting of the American Society of Clinical Oncology.

The CCP signature of Myriad Genetics’ Prolaris test was a highly significant predictor of outcome, said Dr. Cuzick of the Wolfson Institute of Preventive Medicine, London. In all five studies, the hazard ratio per unit change in the CCP score was similar, ranging from 1.89 to 2.92. The findings indicate that the effect size for the CCP score is robust in multiple patient cohorts and diverse clinical settings.

The test provides information for differentiating aggressive and indolent disease beyond that available from clinicopathologic variables, he said. As the natural history of prostate cancer can be variable and difficult to predict, the Prolaris test could help to match treatment more appropriately to each individual’s risk of progression.

In the study that examined the test’s predictive value, five patient groups were evaluated. Formalin-fixed tissue samples were obtained from two English patient cohorts that were conservatively managed (n = 337 and 349), two U.S. patient cohorts that underwent radical prostatectomy (366 men treated at Scott & White Hospital, Temple, Tex.; and 413 men treated at the University of California, San Francisco), and one U.S. cohort that underwent external beam radiation therapy (141 men treated at the Durham, N.C., VA Medical Center).

The cohort of conservatively managed English patients was from the late 1990s and had more than 15 years of follow up. In the 337-patient cohort diagnosed via transurethral resection of the prostate (TURP) and conservatively managed, there were 57 deaths from prostate cancer. In the 349-patient cohort diagnosed via needle biopsy and conservatively managed, there were 90 deaths from prostate cancer.

For each unit increase in the CCP score, the hazard ratio for the cohort diagnosed via TURP was 2.9 and the hazard ratio for those diagnosed via needle biopsy was 2. The CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (P = 6.1 x 10^–22 after diagnosis via TURP, and P = 8.6 x 10^–10 after diagnosis via needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis and was a stronger predictor of disease-specific mortality than other prognostic variables, he said.

In the U.S. prostatectomy cohorts, there were 132 biochemical recurrences (BCRs) in the first cohort and 83 BCRs in the second cohort. With each unit increase in the CCP score, there was a doubling of risk for recurrence. After prostatectomy, the CCP score predicted BCR in univariate analysis (Scott & White: P = 5.6 x 10^–9; University of California: P = 2.23 x 10^–6) and provided additional prognostic information in multivariate analysis (Scott & White: P = 3.3 x 10^–6; University of California: P = 9.5 x10^–5).

After radiation therapy, the CCP score predicted BCR in univariate (P = .0017) and multivariate (P = .034) analysis. In the 141-patient cohort that was diagnosed by needle biopsy and underwent external beam radiation, there were 19 prostate cancer deaths and more than a doubling of risk with each unit increase in CCP score.

CCP scores only modestly correlated with the Gleason score and prostate-specific antigen (PSA) value. The test adds value beyond those measures, Dr. Cuzick said.

CCP scores predict patient outcome in multiple clinical settings, provide independent information beyond clinicopathological variables, and help to further differentiate aggressive from indolent prostate cancer. With low-grade Gleason 6 cancers, the results can aid in telling who is at low risk and who needs aggressive therapy, he concluded.

The study was funded by Myriad Genetics, the maker of the Prolaris test. Dr. Cuzick received honoraria and research support from Myriad.

CHICAGO – Prostate cancer outcomes were predicted by a test that measures the expression of cell cycle progression genes, according to results from a retrospective analysis of prostate tissue samples from five patient cohorts.

The Prolaris test gives each tissue sample a cell cycle progression (CCP) score based on measures of 31 CCP genes, normalized to 15 "housekeeper" genes. A unit change in the test is defined as a doubling in CCP genes. For each unit increase in the test’s score, there was a two- to threefold increase in the risk of disease progression, Dr. Jack M. Cuzick reported at the annual meeting of the American Society of Clinical Oncology.

The CCP signature of Myriad Genetics’ Prolaris test was a highly significant predictor of outcome, said Dr. Cuzick of the Wolfson Institute of Preventive Medicine, London. In all five studies, the hazard ratio per unit change in the CCP score was similar, ranging from 1.89 to 2.92. The findings indicate that the effect size for the CCP score is robust in multiple patient cohorts and diverse clinical settings.

The test provides information for differentiating aggressive and indolent disease beyond that available from clinicopathologic variables, he said. As the natural history of prostate cancer can be variable and difficult to predict, the Prolaris test could help to match treatment more appropriately to each individual’s risk of progression.

In the study that examined the test’s predictive value, five patient groups were evaluated. Formalin-fixed tissue samples were obtained from two English patient cohorts that were conservatively managed (n = 337 and 349), two U.S. patient cohorts that underwent radical prostatectomy (366 men treated at Scott & White Hospital, Temple, Tex.; and 413 men treated at the University of California, San Francisco), and one U.S. cohort that underwent external beam radiation therapy (141 men treated at the Durham, N.C., VA Medical Center).

The cohort of conservatively managed English patients was from the late 1990s and had more than 15 years of follow up. In the 337-patient cohort diagnosed via transurethral resection of the prostate (TURP) and conservatively managed, there were 57 deaths from prostate cancer. In the 349-patient cohort diagnosed via needle biopsy and conservatively managed, there were 90 deaths from prostate cancer.

For each unit increase in the CCP score, the hazard ratio for the cohort diagnosed via TURP was 2.9 and the hazard ratio for those diagnosed via needle biopsy was 2. The CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (P = 6.1 x 10^–22 after diagnosis via TURP, and P = 8.6 x 10^–10 after diagnosis via needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis and was a stronger predictor of disease-specific mortality than other prognostic variables, he said.

In the U.S. prostatectomy cohorts, there were 132 biochemical recurrences (BCRs) in the first cohort and 83 BCRs in the second cohort. With each unit increase in the CCP score, there was a doubling of risk for recurrence. After prostatectomy, the CCP score predicted BCR in univariate analysis (Scott & White: P = 5.6 x 10^–9; University of California: P = 2.23 x 10^–6) and provided additional prognostic information in multivariate analysis (Scott & White: P = 3.3 x 10^–6; University of California: P = 9.5 x10^–5).

After radiation therapy, the CCP score predicted BCR in univariate (P = .0017) and multivariate (P = .034) analysis. In the 141-patient cohort that was diagnosed by needle biopsy and underwent external beam radiation, there were 19 prostate cancer deaths and more than a doubling of risk with each unit increase in CCP score.

CCP scores only modestly correlated with the Gleason score and prostate-specific antigen (PSA) value. The test adds value beyond those measures, Dr. Cuzick said.

CCP scores predict patient outcome in multiple clinical settings, provide independent information beyond clinicopathological variables, and help to further differentiate aggressive from indolent prostate cancer. With low-grade Gleason 6 cancers, the results can aid in telling who is at low risk and who needs aggressive therapy, he concluded.

The study was funded by Myriad Genetics, the maker of the Prolaris test. Dr. Cuzick received honoraria and research support from Myriad.

CHICAGO – Prostate cancer outcomes were predicted by a test that measures the expression of cell cycle progression genes, according to results from a retrospective analysis of prostate tissue samples from five patient cohorts.

The Prolaris test gives each tissue sample a cell cycle progression (CCP) score based on measures of 31 CCP genes, normalized to 15 "housekeeper" genes. A unit change in the test is defined as a doubling in CCP genes. For each unit increase in the test’s score, there was a two- to threefold increase in the risk of disease progression, Dr. Jack M. Cuzick reported at the annual meeting of the American Society of Clinical Oncology.

The CCP signature of Myriad Genetics’ Prolaris test was a highly significant predictor of outcome, said Dr. Cuzick of the Wolfson Institute of Preventive Medicine, London. In all five studies, the hazard ratio per unit change in the CCP score was similar, ranging from 1.89 to 2.92. The findings indicate that the effect size for the CCP score is robust in multiple patient cohorts and diverse clinical settings.

The test provides information for differentiating aggressive and indolent disease beyond that available from clinicopathologic variables, he said. As the natural history of prostate cancer can be variable and difficult to predict, the Prolaris test could help to match treatment more appropriately to each individual’s risk of progression.

In the study that examined the test’s predictive value, five patient groups were evaluated. Formalin-fixed tissue samples were obtained from two English patient cohorts that were conservatively managed (n = 337 and 349), two U.S. patient cohorts that underwent radical prostatectomy (366 men treated at Scott & White Hospital, Temple, Tex.; and 413 men treated at the University of California, San Francisco), and one U.S. cohort that underwent external beam radiation therapy (141 men treated at the Durham, N.C., VA Medical Center).

The cohort of conservatively managed English patients was from the late 1990s and had more than 15 years of follow up. In the 337-patient cohort diagnosed via transurethral resection of the prostate (TURP) and conservatively managed, there were 57 deaths from prostate cancer. In the 349-patient cohort diagnosed via needle biopsy and conservatively managed, there were 90 deaths from prostate cancer.

For each unit increase in the CCP score, the hazard ratio for the cohort diagnosed via TURP was 2.9 and the hazard ratio for those diagnosed via needle biopsy was 2. The CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (P = 6.1 x 10^–22 after diagnosis via TURP, and P = 8.6 x 10^–10 after diagnosis via needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis and was a stronger predictor of disease-specific mortality than other prognostic variables, he said.

In the U.S. prostatectomy cohorts, there were 132 biochemical recurrences (BCRs) in the first cohort and 83 BCRs in the second cohort. With each unit increase in the CCP score, there was a doubling of risk for recurrence. After prostatectomy, the CCP score predicted BCR in univariate analysis (Scott & White: P = 5.6 x 10^–9; University of California: P = 2.23 x 10^–6) and provided additional prognostic information in multivariate analysis (Scott & White: P = 3.3 x 10^–6; University of California: P = 9.5 x10^–5).

After radiation therapy, the CCP score predicted BCR in univariate (P = .0017) and multivariate (P = .034) analysis. In the 141-patient cohort that was diagnosed by needle biopsy and underwent external beam radiation, there were 19 prostate cancer deaths and more than a doubling of risk with each unit increase in CCP score.

CCP scores only modestly correlated with the Gleason score and prostate-specific antigen (PSA) value. The test adds value beyond those measures, Dr. Cuzick said.

CCP scores predict patient outcome in multiple clinical settings, provide independent information beyond clinicopathological variables, and help to further differentiate aggressive from indolent prostate cancer. With low-grade Gleason 6 cancers, the results can aid in telling who is at low risk and who needs aggressive therapy, he concluded.

The study was funded by Myriad Genetics, the maker of the Prolaris test. Dr. Cuzick received honoraria and research support from Myriad.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The combination of pomalidomide and low-dose dexamethasone is superior to high-dose dexamethasone monotherapy for treating patients with relapsed and refractory multiple myeloma, based on updated results from the multicenter, randomized MM-003 trial.

Among the 455 patients studied in the trial, those assigned to the combination therapy had a 52% lower risk of progression or death and a 26% lower risk of death alone when compared with peers assigned to single-agent high-dose dexamethasone.

The two regimens had much the same toxicity profile, although the combination was associated with a higher rate of grade 3/4 hematologic toxicity.

"Pomalidomide in combination with low-dose dexamethasone should be considered as a new standard of care for treatment of relapsed and refractory multiple myeloma patients after treatment with lenalidomide and bortezomib," presenting author Dr. Katja C. Weisel commented at the annual meeting of the American Society of Clinical Oncology.

All of the patients enrolled in the MM-003 trial had received at least two prior therapies and had disease refractory to their last therapy, according to Dr. Weisel, a hematologist-oncologist with the University Hospital Tübingen, Germany. All had experienced a failure of both Millennium’s bortezomib (Velcade) and Celgene’s lenalidomide (Revlimid).

The patients were randomized 2:1 to receive low-dose dexamethasone plus Celgene’s pomalidomide (Pomalyst), an antiangiogenic and immune-modulating agent, or high-dose dexamethasone alone. Patients given pomalidomide or who had a history of deep vein thrombosis were given thromboprophylaxis.

Patients who experienced progression on high-dose dexamethasone entered the companion MM-003C trial, in which they were given pomalidomide.

Initial trial results after a median follow-up of 4 months, which were previously reported, showed there were significantly better progression-free survival and overall survival with the combination. These results led to a recommendation by the trial’s monitoring committee that all patients in the high-dose dexamethasone group be given access to pomalidomide regardless of whether they had progression. In all, half of the patients in that group received pomalidomide after high-dose dexamethasone due to either this recommendation or entry into the companion trial.

In the updated analysis, now with a median follow-up of 10 months, progression-free survival was still significantly better with pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone (4.0 vs. 1.9 months; hazard ratio, 0.48; P less than .001).

Overall survival was also still significantly better with the combination (12.7 vs. 8.1 months; HR, 0.74; P = .028).

"This overall survival benefit was maintained despite a high crossover rate, in 50% of the patients. ... In addition, all patients who were still alive at this time in the high-dose dexamethasone group had received pomalidomide as a salvage treatment," Dr. Weisel noted.

The progression-free survival and overall survival benefits were generally similar across subgroups of patients whose disease was refractory to both lenalidomide and bortezomib, who had received lenalidomide as their last prior therapy, and who had received bortezomib as their last prior therapy.

"The safety profile of pomalidomide is predictable and manageable, and the drug with its oral application is generally well tolerated in this heavily pretreated patient group," Dr. Weisel commented.

The main toxicity with the combination was hematologic toxicity: The rate of grade 3/4 neutropenia was 48% with the combination, compared with 16% with high-dose dexamethasone. The combination group and the high-dose dexamethasone group had essentially the same rates of grade 3/4 deep vein thrombosis and pulmonary embolism (1% and 0%, respectively), peripheral neuropathy (1% and 1%), and discontinuation due to adverse events (9% and 10%).

Dr. Weisel disclosed that she is a consultant to and receives honoraria from Celgene and Janssen.

CHICAGO – The combination of pomalidomide and low-dose dexamethasone is superior to high-dose dexamethasone monotherapy for treating patients with relapsed and refractory multiple myeloma, based on updated results from the multicenter, randomized MM-003 trial.

Among the 455 patients studied in the trial, those assigned to the combination therapy had a 52% lower risk of progression or death and a 26% lower risk of death alone when compared with peers assigned to single-agent high-dose dexamethasone.

The two regimens had much the same toxicity profile, although the combination was associated with a higher rate of grade 3/4 hematologic toxicity.

"Pomalidomide in combination with low-dose dexamethasone should be considered as a new standard of care for treatment of relapsed and refractory multiple myeloma patients after treatment with lenalidomide and bortezomib," presenting author Dr. Katja C. Weisel commented at the annual meeting of the American Society of Clinical Oncology.

All of the patients enrolled in the MM-003 trial had received at least two prior therapies and had disease refractory to their last therapy, according to Dr. Weisel, a hematologist-oncologist with the University Hospital Tübingen, Germany. All had experienced a failure of both Millennium’s bortezomib (Velcade) and Celgene’s lenalidomide (Revlimid).

The patients were randomized 2:1 to receive low-dose dexamethasone plus Celgene’s pomalidomide (Pomalyst), an antiangiogenic and immune-modulating agent, or high-dose dexamethasone alone. Patients given pomalidomide or who had a history of deep vein thrombosis were given thromboprophylaxis.

Patients who experienced progression on high-dose dexamethasone entered the companion MM-003C trial, in which they were given pomalidomide.

Initial trial results after a median follow-up of 4 months, which were previously reported, showed there were significantly better progression-free survival and overall survival with the combination. These results led to a recommendation by the trial’s monitoring committee that all patients in the high-dose dexamethasone group be given access to pomalidomide regardless of whether they had progression. In all, half of the patients in that group received pomalidomide after high-dose dexamethasone due to either this recommendation or entry into the companion trial.

In the updated analysis, now with a median follow-up of 10 months, progression-free survival was still significantly better with pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone (4.0 vs. 1.9 months; hazard ratio, 0.48; P less than .001).

Overall survival was also still significantly better with the combination (12.7 vs. 8.1 months; HR, 0.74; P = .028).

"This overall survival benefit was maintained despite a high crossover rate, in 50% of the patients. ... In addition, all patients who were still alive at this time in the high-dose dexamethasone group had received pomalidomide as a salvage treatment," Dr. Weisel noted.

The progression-free survival and overall survival benefits were generally similar across subgroups of patients whose disease was refractory to both lenalidomide and bortezomib, who had received lenalidomide as their last prior therapy, and who had received bortezomib as their last prior therapy.

"The safety profile of pomalidomide is predictable and manageable, and the drug with its oral application is generally well tolerated in this heavily pretreated patient group," Dr. Weisel commented.

The main toxicity with the combination was hematologic toxicity: The rate of grade 3/4 neutropenia was 48% with the combination, compared with 16% with high-dose dexamethasone. The combination group and the high-dose dexamethasone group had essentially the same rates of grade 3/4 deep vein thrombosis and pulmonary embolism (1% and 0%, respectively), peripheral neuropathy (1% and 1%), and discontinuation due to adverse events (9% and 10%).

Dr. Weisel disclosed that she is a consultant to and receives honoraria from Celgene and Janssen.

CHICAGO – The combination of pomalidomide and low-dose dexamethasone is superior to high-dose dexamethasone monotherapy for treating patients with relapsed and refractory multiple myeloma, based on updated results from the multicenter, randomized MM-003 trial.

Among the 455 patients studied in the trial, those assigned to the combination therapy had a 52% lower risk of progression or death and a 26% lower risk of death alone when compared with peers assigned to single-agent high-dose dexamethasone.

The two regimens had much the same toxicity profile, although the combination was associated with a higher rate of grade 3/4 hematologic toxicity.

"Pomalidomide in combination with low-dose dexamethasone should be considered as a new standard of care for treatment of relapsed and refractory multiple myeloma patients after treatment with lenalidomide and bortezomib," presenting author Dr. Katja C. Weisel commented at the annual meeting of the American Society of Clinical Oncology.

All of the patients enrolled in the MM-003 trial had received at least two prior therapies and had disease refractory to their last therapy, according to Dr. Weisel, a hematologist-oncologist with the University Hospital Tübingen, Germany. All had experienced a failure of both Millennium’s bortezomib (Velcade) and Celgene’s lenalidomide (Revlimid).

The patients were randomized 2:1 to receive low-dose dexamethasone plus Celgene’s pomalidomide (Pomalyst), an antiangiogenic and immune-modulating agent, or high-dose dexamethasone alone. Patients given pomalidomide or who had a history of deep vein thrombosis were given thromboprophylaxis.

Patients who experienced progression on high-dose dexamethasone entered the companion MM-003C trial, in which they were given pomalidomide.

Initial trial results after a median follow-up of 4 months, which were previously reported, showed there were significantly better progression-free survival and overall survival with the combination. These results led to a recommendation by the trial’s monitoring committee that all patients in the high-dose dexamethasone group be given access to pomalidomide regardless of whether they had progression. In all, half of the patients in that group received pomalidomide after high-dose dexamethasone due to either this recommendation or entry into the companion trial.

In the updated analysis, now with a median follow-up of 10 months, progression-free survival was still significantly better with pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone (4.0 vs. 1.9 months; hazard ratio, 0.48; P less than .001).

Overall survival was also still significantly better with the combination (12.7 vs. 8.1 months; HR, 0.74; P = .028).

"This overall survival benefit was maintained despite a high crossover rate, in 50% of the patients. ... In addition, all patients who were still alive at this time in the high-dose dexamethasone group had received pomalidomide as a salvage treatment," Dr. Weisel noted.

The progression-free survival and overall survival benefits were generally similar across subgroups of patients whose disease was refractory to both lenalidomide and bortezomib, who had received lenalidomide as their last prior therapy, and who had received bortezomib as their last prior therapy.

"The safety profile of pomalidomide is predictable and manageable, and the drug with its oral application is generally well tolerated in this heavily pretreated patient group," Dr. Weisel commented.

The main toxicity with the combination was hematologic toxicity: The rate of grade 3/4 neutropenia was 48% with the combination, compared with 16% with high-dose dexamethasone. The combination group and the high-dose dexamethasone group had essentially the same rates of grade 3/4 deep vein thrombosis and pulmonary embolism (1% and 0%, respectively), peripheral neuropathy (1% and 1%), and discontinuation due to adverse events (9% and 10%).

Dr. Weisel disclosed that she is a consultant to and receives honoraria from Celgene and Janssen.

CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.

In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.

"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.

Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.

Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.

The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).

Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.

The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m² on day 1 of cycle one, and 500 mg/m² on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.

The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.

Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.

No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.

The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.

In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).

There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.

Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.

Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.

The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.

CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.

In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.

"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.

Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.

Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.

The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).

Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.

The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m² on day 1 of cycle one, and 500 mg/m² on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.

The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.

Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.

No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.

The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.

In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).

There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.

Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.

Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.

The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.

CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.

In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.

"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.

Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.

Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.

The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).

Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.

The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m² on day 1 of cycle one, and 500 mg/m² on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.

The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.

Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.

No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.

The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.

In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).

There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.

Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.

Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.

The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.

CHICAGO – A combination of docetaxel and nintedanib, a novel inhibitor of multiple tumor growth factors, was associated with a small but significant improvement in progression-free survival in patients with advanced non–small cell lung cancer as compared with docetaxel alone.

In the phase III LUME-Lung I trial in patients with previously treated stage IIIB/IV or recurrent non–-small cell lung cancer (NSCLC), median progression-free survival (PFS) was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (hazard ratio, 0.79; P = .0019), reported Dr. Martin Reck of the department of thoracic oncology at Hospital Grosshansdorf, Germany.

In addition, "we have seen a significant improvement of overall survival in patients with adenocarcinoma," Dr. Reck said at the annual meeting of the American Society of Clinical Oncology.

However, when patients with squamous cell NSCLC were included in the analysis, there was no significant difference in overall survival between the treatment groups, he said.

Nintedanib is an oral kinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-3, platelet-derived growth factor receptors alpha and beta, and the RET tyrosine kinase.

In clinical trials, nintedanib has been delivered safely in combination with various chemotherapy agents, including docetaxel, paclitaxel, platinum comp2ounds, and gemcitabine, and as a single agent had clinical activity in a phase II trial against recurrent NSCLC.

Dr. Reck and his colleagues enrolled 1,314 patients with stage IIIB or IV or recurrent NSCLC after first-line chemotherapy and randomly assigned them in a double-blinded fashion to receive intravenous docetaxel 75 mg/m² on day 1 of a 21-day cycle plus either oral nintedanib 200 mg or placebo twice daily on days 2 through 21 of each cycle. The number of potential docetaxel cycles was unlimited, and docetaxel monotherapy could continue after four cycles of the combination at the investigator’s discretion.

Patients were stratified by performance status, prior bevacizumab (Avastin) use, squamous or nonsquamous histology, and presence or absence of brain metastases.

As of the February 2013 data cutoff, 6 of the 652 patients assigned to the combination and 6 of the 655 assigned to docetaxel/placebo remained on study.

In the intention-to-treat analysis, the trial met its primary endpoint of a centrally reviewed PFS advantage for the combination.

PFS was significantly better both in patients with adenocarcinoma histologies treated with the combination (median 4.0 vs. 2.8 months; HR, 0.77; P = .0193) and with squamous cell carcinomas (2.9 vs. 2.6 months; HR, 0.77; P = .02).

Overall survival did not differ, at a median of 10.1 vs. 9.1 month. Among patients with adenocarcinomas, however, survival was significantly better, at a median of 12.6 vs. 10.3 months, respectively (HR, 0.82; P = .0359). There was also a hint of benefit in patients with adenocarcinomas refractory to prior chemotherapy with a platinum compound (median overall survival, 9.8 vs. 6.3 months; HR, 0.62; P = .0246), although this subanalysis included only 107 patients.

The combination was no better than docetaxel and placebo among patients with squamous cell cancers.

Grade 3 or greater adverse events occurred in 71% of patients on nintedanib/docetaxel, and 64% of controls. In each group, about 22% of patients had adverse events leading to discontinuation of therapy. The most common adverse events were bleeding, thromboembolic events, and hypertension, each of which occurred more frequently with the combination than with docetaxel alone.

The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo.

CHICAGO – A combination of docetaxel and nintedanib, a novel inhibitor of multiple tumor growth factors, was associated with a small but significant improvement in progression-free survival in patients with advanced non–small cell lung cancer as compared with docetaxel alone.

In the phase III LUME-Lung I trial in patients with previously treated stage IIIB/IV or recurrent non–-small cell lung cancer (NSCLC), median progression-free survival (PFS) was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (hazard ratio, 0.79; P = .0019), reported Dr. Martin Reck of the department of thoracic oncology at Hospital Grosshansdorf, Germany.

In addition, "we have seen a significant improvement of overall survival in patients with adenocarcinoma," Dr. Reck said at the annual meeting of the American Society of Clinical Oncology.

However, when patients with squamous cell NSCLC were included in the analysis, there was no significant difference in overall survival between the treatment groups, he said.

Nintedanib is an oral kinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-3, platelet-derived growth factor receptors alpha and beta, and the RET tyrosine kinase.

In clinical trials, nintedanib has been delivered safely in combination with various chemotherapy agents, including docetaxel, paclitaxel, platinum comp2ounds, and gemcitabine, and as a single agent had clinical activity in a phase II trial against recurrent NSCLC.

Dr. Reck and his colleagues enrolled 1,314 patients with stage IIIB or IV or recurrent NSCLC after first-line chemotherapy and randomly assigned them in a double-blinded fashion to receive intravenous docetaxel 75 mg/m² on day 1 of a 21-day cycle plus either oral nintedanib 200 mg or placebo twice daily on days 2 through 21 of each cycle. The number of potential docetaxel cycles was unlimited, and docetaxel monotherapy could continue after four cycles of the combination at the investigator’s discretion.

Patients were stratified by performance status, prior bevacizumab (Avastin) use, squamous or nonsquamous histology, and presence or absence of brain metastases.

As of the February 2013 data cutoff, 6 of the 652 patients assigned to the combination and 6 of the 655 assigned to docetaxel/placebo remained on study.

In the intention-to-treat analysis, the trial met its primary endpoint of a centrally reviewed PFS advantage for the combination.

PFS was significantly better both in patients with adenocarcinoma histologies treated with the combination (median 4.0 vs. 2.8 months; HR, 0.77; P = .0193) and with squamous cell carcinomas (2.9 vs. 2.6 months; HR, 0.77; P = .02).

Overall survival did not differ, at a median of 10.1 vs. 9.1 month. Among patients with adenocarcinomas, however, survival was significantly better, at a median of 12.6 vs. 10.3 months, respectively (HR, 0.82; P = .0359). There was also a hint of benefit in patients with adenocarcinomas refractory to prior chemotherapy with a platinum compound (median overall survival, 9.8 vs. 6.3 months; HR, 0.62; P = .0246), although this subanalysis included only 107 patients.

The combination was no better than docetaxel and placebo among patients with squamous cell cancers.

Grade 3 or greater adverse events occurred in 71% of patients on nintedanib/docetaxel, and 64% of controls. In each group, about 22% of patients had adverse events leading to discontinuation of therapy. The most common adverse events were bleeding, thromboembolic events, and hypertension, each of which occurred more frequently with the combination than with docetaxel alone.

The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo.

CHICAGO – A combination of docetaxel and nintedanib, a novel inhibitor of multiple tumor growth factors, was associated with a small but significant improvement in progression-free survival in patients with advanced non–small cell lung cancer as compared with docetaxel alone.

In the phase III LUME-Lung I trial in patients with previously treated stage IIIB/IV or recurrent non–-small cell lung cancer (NSCLC), median progression-free survival (PFS) was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (hazard ratio, 0.79; P = .0019), reported Dr. Martin Reck of the department of thoracic oncology at Hospital Grosshansdorf, Germany.

In addition, "we have seen a significant improvement of overall survival in patients with adenocarcinoma," Dr. Reck said at the annual meeting of the American Society of Clinical Oncology.

However, when patients with squamous cell NSCLC were included in the analysis, there was no significant difference in overall survival between the treatment groups, he said.

Nintedanib is an oral kinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-3, platelet-derived growth factor receptors alpha and beta, and the RET tyrosine kinase.

In clinical trials, nintedanib has been delivered safely in combination with various chemotherapy agents, including docetaxel, paclitaxel, platinum comp2ounds, and gemcitabine, and as a single agent had clinical activity in a phase II trial against recurrent NSCLC.

Dr. Reck and his colleagues enrolled 1,314 patients with stage IIIB or IV or recurrent NSCLC after first-line chemotherapy and randomly assigned them in a double-blinded fashion to receive intravenous docetaxel 75 mg/m² on day 1 of a 21-day cycle plus either oral nintedanib 200 mg or placebo twice daily on days 2 through 21 of each cycle. The number of potential docetaxel cycles was unlimited, and docetaxel monotherapy could continue after four cycles of the combination at the investigator’s discretion.

Patients were stratified by performance status, prior bevacizumab (Avastin) use, squamous or nonsquamous histology, and presence or absence of brain metastases.

As of the February 2013 data cutoff, 6 of the 652 patients assigned to the combination and 6 of the 655 assigned to docetaxel/placebo remained on study.

In the intention-to-treat analysis, the trial met its primary endpoint of a centrally reviewed PFS advantage for the combination.

PFS was significantly better both in patients with adenocarcinoma histologies treated with the combination (median 4.0 vs. 2.8 months; HR, 0.77; P = .0193) and with squamous cell carcinomas (2.9 vs. 2.6 months; HR, 0.77; P = .02).

Overall survival did not differ, at a median of 10.1 vs. 9.1 month. Among patients with adenocarcinomas, however, survival was significantly better, at a median of 12.6 vs. 10.3 months, respectively (HR, 0.82; P = .0359). There was also a hint of benefit in patients with adenocarcinomas refractory to prior chemotherapy with a platinum compound (median overall survival, 9.8 vs. 6.3 months; HR, 0.62; P = .0246), although this subanalysis included only 107 patients.

The combination was no better than docetaxel and placebo among patients with squamous cell cancers.

Grade 3 or greater adverse events occurred in 71% of patients on nintedanib/docetaxel, and 64% of controls. In each group, about 22% of patients had adverse events leading to discontinuation of therapy. The most common adverse events were bleeding, thromboembolic events, and hypertension, each of which occurred more frequently with the combination than with docetaxel alone.

The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo.