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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.
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.
Overall, I think we’d have to conclude that this is a negative trial. But it actually begs the question as to how certain we are that this drug has no role in breast cancer.
It remains unclear as to whether upamostat hit its target and whether activation of uPA or its naturally occurring inhibitor PAI-1 is even necessary for benefit, as archival tissue was not obtained and, even if it had been, the relevant assays require fresh tissue. So the correlative questions that we all want to answer simply cannot be answered at this time.
The study illustrates the challenges in designing trials of targeted agents. We have hundreds of agents in development. The prevailing wisdom is that many of these agents will only benefit a small minority and that combinations will often be needed. There is a substantial risk of falsely concluding that an agent is inactive depending on the design of the study. And given all of these agents and the expense of developing agents, many drugs will simply not be given a second chance.
Thus, these trials must be carefully designed with consideration of factors such as whether the drug target can be reliably measured, whether power is adequate to assess benefit in relevant subgroups, and what is the best endpoint.
Dr. Eric P. Winer, of the Dana-Farber Cancer Institute in Boston, was the invited discussant of the study. Dr. Farber disclosed that he is a consultant to AstraZeneca, Merrimack, and other companies, and receives research funding from Genentech.
Overall, I think we’d have to conclude that this is a negative trial. But it actually begs the question as to how certain we are that this drug has no role in breast cancer.
It remains unclear as to whether upamostat hit its target and whether activation of uPA or its naturally occurring inhibitor PAI-1 is even necessary for benefit, as archival tissue was not obtained and, even if it had been, the relevant assays require fresh tissue. So the correlative questions that we all want to answer simply cannot be answered at this time.
The study illustrates the challenges in designing trials of targeted agents. We have hundreds of agents in development. The prevailing wisdom is that many of these agents will only benefit a small minority and that combinations will often be needed. There is a substantial risk of falsely concluding that an agent is inactive depending on the design of the study. And given all of these agents and the expense of developing agents, many drugs will simply not be given a second chance.
Thus, these trials must be carefully designed with consideration of factors such as whether the drug target can be reliably measured, whether power is adequate to assess benefit in relevant subgroups, and what is the best endpoint.
Dr. Eric P. Winer, of the Dana-Farber Cancer Institute in Boston, was the invited discussant of the study. Dr. Farber disclosed that he is a consultant to AstraZeneca, Merrimack, and other companies, and receives research funding from Genentech.
Overall, I think we’d have to conclude that this is a negative trial. But it actually begs the question as to how certain we are that this drug has no role in breast cancer.
It remains unclear as to whether upamostat hit its target and whether activation of uPA or its naturally occurring inhibitor PAI-1 is even necessary for benefit, as archival tissue was not obtained and, even if it had been, the relevant assays require fresh tissue. So the correlative questions that we all want to answer simply cannot be answered at this time.
The study illustrates the challenges in designing trials of targeted agents. We have hundreds of agents in development. The prevailing wisdom is that many of these agents will only benefit a small minority and that combinations will often be needed. There is a substantial risk of falsely concluding that an agent is inactive depending on the design of the study. And given all of these agents and the expense of developing agents, many drugs will simply not be given a second chance.
Thus, these trials must be carefully designed with consideration of factors such as whether the drug target can be reliably measured, whether power is adequate to assess benefit in relevant subgroups, and what is the best endpoint.
Dr. Eric P. Winer, of the Dana-Farber Cancer Institute in Boston, was the invited discussant of the study. Dr. Farber disclosed that he is a consultant to AstraZeneca, Merrimack, and other companies, and receives research funding from Genentech.
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.
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.
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.
AT THE ASCO ANNUAL MEETING 2013
Major finding: Adding upamostat vs. placebo did not significantly prolong progression-free survival in the entire trial population (8.3 vs. 7.5 months), but there was a suggestion of benefit in the subset previously given chemotherapy (8.3 vs. 4.3 months).
Data source: A randomized double-blind phase II trial comparing upamostat plus capecitabine vs. capecitabine alone as first-line therapy among 132 patients with HER2-negative metastatic breast cancer
Disclosures: 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.
