2011 ASCO Annual Meeting

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Carboplatin or cisplatin monotherapy has significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer, according to Dr. Steven J. Isakoff.

The overall response rate to therapy with one of the platinum compounds was 30.2% – 4.7% complete responses and 25.6% partial responses, Dr. Isakoff of Massachusetts General Hospital cancer center, Boston, and his colleagues in the Translational Breast Cancer Research Consortium found.

Subgroup analyses of the multicenter single-arm trial suggested a higher response rate with cisplatin (37%) than with carboplatin (23%), but this was not a head-to-head study, and the results should be interpreted with caution because physicians were allowed to choose one of the two agents at their own discretion, which could introduce bias into the results, Dr. Isakoff said at the meeting.

The drugs were generally well tolerated with manageable toxicities; some patients have received as many as 23 cycles, he said in an interview.

The investigators also looked at the utility of two members of the p53 family of oncogenic transcription factors, p63 and p73, for predicting response to platinum agents in triple-negative breast cancer (tumors lacking receptors for estrogen, progesterone, or HER2/neu that are targeted by other forms of therapy).

"As information about the activity of platinum in BRCA carriers has become recognized, people are thinking about it more in triple-negative breast cancer," Dr. Isakoff said. "We still don’t know whether triple-negative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy, and I think it’s going to take some of the randomized studies that are going on now in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there’s something special about triple negative and platinum."

The TBCRC009 study enrolled 86 patients with triple-negative breast cancer. The patients were assigned on the treating physician’s choice to receive either cisplatin at 75mg/m² IV every 3 weeks, or carboplatin to an area under the curve of 6 every 3 weeks.

In addition to the overall response rates noted here, the authors calculated a clinical benefit rate (a combination of complete and partial response and stable disease) of 34%.

Median progression-free survival (PFS) was 89 days. Thirty-three percent of patients had a PFS of less than 6 weeks, and another 33% had a PFS longer than 6 months. Among responders, a median PFS was 242 days. Responders had a median of nine chemotherapy cycles.

In subgroup analyses, platinum compounds were associated with a 33% response rate when used as first-line agents, and 17% when used in the second line. Only 17 patients received platinum as a second-line therapy, however.

The patients generally tolerated the drugs well. There was one case each of grade 4 neutropenia and hypertension. Grade 3 events included nine cases of fatigue, six of neutropenia, five of anemia, and four of hyponatremia.

"In general, it was well tolerated. We didn’t see unexpected toxicities with platinum, and we modified things with dose reductions as appropriate. It was not a common event to come off therapy due to toxicity," Dr. Isakoff said.

The investigators continue to collect data to determine whether p63/p73 expression can be a biomarker for response to platinum agents. The authors are also conducting BRCA mutation, molecular subtype, and circulating tumor cell analyses.

"This study was well designed with prospective powering for the p63/p73 correlative end point," said Dr. Stephen K.L. Chia of the British Columbia Cancer Agency and the University of British Columbia, in Vancouver, the invited discussant.

The rationale for investigating p63/p73 as a predictive biomarker is sound because these markers can be found in about 35%-40% of triple-negative breast cancers, he said. Questions that need to be addressed include whether there is a change in expression of the markers in metastatic relapse, and whether the heterogeneous group of triple-negative breast cancers can be further refined through molecular subtyping.

The study was funded by the AVON Foundation, Breast Cancer Research Foundation, Susan D. Komen for the Cure, Golfers Against Cancer, the Tracey Davis Breast Cancer Research Fund, and investigator awards from the NCI-AVON Partners for Progress, Harvard-MIT, and the Dana-Farber/Harvard Cancer Center. The authors said they had no other relevant financial disclosures.

CHICAGO – Carboplatin or cisplatin monotherapy has significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer, according to Dr. Steven J. Isakoff.

The overall response rate to therapy with one of the platinum compounds was 30.2% – 4.7% complete responses and 25.6% partial responses, Dr. Isakoff of Massachusetts General Hospital cancer center, Boston, and his colleagues in the Translational Breast Cancer Research Consortium found.

Subgroup analyses of the multicenter single-arm trial suggested a higher response rate with cisplatin (37%) than with carboplatin (23%), but this was not a head-to-head study, and the results should be interpreted with caution because physicians were allowed to choose one of the two agents at their own discretion, which could introduce bias into the results, Dr. Isakoff said at the meeting.

The drugs were generally well tolerated with manageable toxicities; some patients have received as many as 23 cycles, he said in an interview.

The investigators also looked at the utility of two members of the p53 family of oncogenic transcription factors, p63 and p73, for predicting response to platinum agents in triple-negative breast cancer (tumors lacking receptors for estrogen, progesterone, or HER2/neu that are targeted by other forms of therapy).

"As information about the activity of platinum in BRCA carriers has become recognized, people are thinking about it more in triple-negative breast cancer," Dr. Isakoff said. "We still don’t know whether triple-negative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy, and I think it’s going to take some of the randomized studies that are going on now in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there’s something special about triple negative and platinum."

The TBCRC009 study enrolled 86 patients with triple-negative breast cancer. The patients were assigned on the treating physician’s choice to receive either cisplatin at 75mg/m² IV every 3 weeks, or carboplatin to an area under the curve of 6 every 3 weeks.

In addition to the overall response rates noted here, the authors calculated a clinical benefit rate (a combination of complete and partial response and stable disease) of 34%.

Median progression-free survival (PFS) was 89 days. Thirty-three percent of patients had a PFS of less than 6 weeks, and another 33% had a PFS longer than 6 months. Among responders, a median PFS was 242 days. Responders had a median of nine chemotherapy cycles.

In subgroup analyses, platinum compounds were associated with a 33% response rate when used as first-line agents, and 17% when used in the second line. Only 17 patients received platinum as a second-line therapy, however.

The patients generally tolerated the drugs well. There was one case each of grade 4 neutropenia and hypertension. Grade 3 events included nine cases of fatigue, six of neutropenia, five of anemia, and four of hyponatremia.

"In general, it was well tolerated. We didn’t see unexpected toxicities with platinum, and we modified things with dose reductions as appropriate. It was not a common event to come off therapy due to toxicity," Dr. Isakoff said.

The investigators continue to collect data to determine whether p63/p73 expression can be a biomarker for response to platinum agents. The authors are also conducting BRCA mutation, molecular subtype, and circulating tumor cell analyses.

"This study was well designed with prospective powering for the p63/p73 correlative end point," said Dr. Stephen K.L. Chia of the British Columbia Cancer Agency and the University of British Columbia, in Vancouver, the invited discussant.

The rationale for investigating p63/p73 as a predictive biomarker is sound because these markers can be found in about 35%-40% of triple-negative breast cancers, he said. Questions that need to be addressed include whether there is a change in expression of the markers in metastatic relapse, and whether the heterogeneous group of triple-negative breast cancers can be further refined through molecular subtyping.

The study was funded by the AVON Foundation, Breast Cancer Research Foundation, Susan D. Komen for the Cure, Golfers Against Cancer, the Tracey Davis Breast Cancer Research Fund, and investigator awards from the NCI-AVON Partners for Progress, Harvard-MIT, and the Dana-Farber/Harvard Cancer Center. The authors said they had no other relevant financial disclosures.

CHICAGO – Carboplatin or cisplatin monotherapy has significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer, according to Dr. Steven J. Isakoff.

The overall response rate to therapy with one of the platinum compounds was 30.2% – 4.7% complete responses and 25.6% partial responses, Dr. Isakoff of Massachusetts General Hospital cancer center, Boston, and his colleagues in the Translational Breast Cancer Research Consortium found.

Subgroup analyses of the multicenter single-arm trial suggested a higher response rate with cisplatin (37%) than with carboplatin (23%), but this was not a head-to-head study, and the results should be interpreted with caution because physicians were allowed to choose one of the two agents at their own discretion, which could introduce bias into the results, Dr. Isakoff said at the meeting.

The drugs were generally well tolerated with manageable toxicities; some patients have received as many as 23 cycles, he said in an interview.

The investigators also looked at the utility of two members of the p53 family of oncogenic transcription factors, p63 and p73, for predicting response to platinum agents in triple-negative breast cancer (tumors lacking receptors for estrogen, progesterone, or HER2/neu that are targeted by other forms of therapy).

"As information about the activity of platinum in BRCA carriers has become recognized, people are thinking about it more in triple-negative breast cancer," Dr. Isakoff said. "We still don’t know whether triple-negative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy, and I think it’s going to take some of the randomized studies that are going on now in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there’s something special about triple negative and platinum."

The TBCRC009 study enrolled 86 patients with triple-negative breast cancer. The patients were assigned on the treating physician’s choice to receive either cisplatin at 75mg/m² IV every 3 weeks, or carboplatin to an area under the curve of 6 every 3 weeks.

In addition to the overall response rates noted here, the authors calculated a clinical benefit rate (a combination of complete and partial response and stable disease) of 34%.

Median progression-free survival (PFS) was 89 days. Thirty-three percent of patients had a PFS of less than 6 weeks, and another 33% had a PFS longer than 6 months. Among responders, a median PFS was 242 days. Responders had a median of nine chemotherapy cycles.

In subgroup analyses, platinum compounds were associated with a 33% response rate when used as first-line agents, and 17% when used in the second line. Only 17 patients received platinum as a second-line therapy, however.

The patients generally tolerated the drugs well. There was one case each of grade 4 neutropenia and hypertension. Grade 3 events included nine cases of fatigue, six of neutropenia, five of anemia, and four of hyponatremia.

"In general, it was well tolerated. We didn’t see unexpected toxicities with platinum, and we modified things with dose reductions as appropriate. It was not a common event to come off therapy due to toxicity," Dr. Isakoff said.

The investigators continue to collect data to determine whether p63/p73 expression can be a biomarker for response to platinum agents. The authors are also conducting BRCA mutation, molecular subtype, and circulating tumor cell analyses.

"This study was well designed with prospective powering for the p63/p73 correlative end point," said Dr. Stephen K.L. Chia of the British Columbia Cancer Agency and the University of British Columbia, in Vancouver, the invited discussant.

The rationale for investigating p63/p73 as a predictive biomarker is sound because these markers can be found in about 35%-40% of triple-negative breast cancers, he said. Questions that need to be addressed include whether there is a change in expression of the markers in metastatic relapse, and whether the heterogeneous group of triple-negative breast cancers can be further refined through molecular subtyping.

The study was funded by the AVON Foundation, Breast Cancer Research Foundation, Susan D. Komen for the Cure, Golfers Against Cancer, the Tracey Davis Breast Cancer Research Fund, and investigator awards from the NCI-AVON Partners for Progress, Harvard-MIT, and the Dana-Farber/Harvard Cancer Center. The authors said they had no other relevant financial disclosures.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don't want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor's effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don't want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor's effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.

CHICAGO – The combination of two oral drugs that target selected molecules in the mitogen-activated protein kinase signaling pathway appears to be safe and active in patients with melanoma, a phase I trial found. The finding was reported at the annual meeting of the American Society of Clinical Oncology.

Among patients with BRAF-mutated melanoma who had not previously received an agent targeting that molecule, the combination of an investigational BRAF inhibitor (GSK436) and an investigational MEK inhibitor (GSK212) achieved a response rate of 50%-77%.

Both drugs could be used in their full monotherapy doses when combined. And the combination was well tolerated; indeed, certain adverse effects that were seen with each drug when used alone (such as a rash with MEK inhibitor monotherapy) were less common when they were used together.

"The clinical activity in BRAF V600–mutant melanoma is definitely compelling," commented lead investigator Dr. Jeffrey R. Infante, a medical oncologist and director of drug development at the Sarah Cannon Research Institute in Nashville, Tenn. "But like everyone in the audience, I think, we are anxiously awaiting the long-term durability" data. "This combination could have potential implications in multiple tumor types outside of melanoma and have broader impacts in oncology," he added.

"I am really impressed by these data," said discussant Dr. Reinhard Dummer of the University Hospital Zurich. In particular, although the trial was not designed to assess responses and the follow-up is still short, some of the patients had complete remissions, he noted.

"I have to admit, I never thought that we could have complete remissions with kinase inhibitors, so I hope that they will continue," he said. "With this in mind, I think we can reset our goals for melanoma research: We don't want to go for progression-free survival in the future, but we should go for cure."

The reduced rate of the inflammatory rash with the combination was "very surprising," given that the rash is likely a stress response resulting from the MEK inhibitor's effect on the MAP [mitogen-activated protein] kinase pathway in the skin, Dr. Dummer said. "How can it happen that this rash is reduced in the combination with the BRAF inhibitor? This is completely not understandable for me. Cutaneous biologists will have a lot of fun to study this model."

Both drugs, which are manufactured by GlaxoSmithKline, have previously shown activity as single agents in patients who have melanoma with BRAF V600 gene mutations, which are found in about half of cases. "The goal was to ... give [the drugs] together and really hope to get a profound synergy in combination in pathway inhibition," explained Dr. Infante.

Patients were eligible for the trial if they had melanoma or another cancer with a V600 mutation in the BRAF gene. Those who had stable brain metastases after surgery or radiosurgery could enroll.

Patients having certain eye conditions were excluded because of previously identified, related issues associated with MEK inhibitor therapy. But there was no limit on the number of prior therapies.

In part A of the study, the investigators tested for drug-drug interactions. In part B, they performed dose escalation, assessed safety and activity, and enrolled expansion cohorts of patients, such as those who had previously received a BRAF inhibitor.

Among the eight patients in part A, there was no effect of the MEK inhibitor when given daily on the pharmacokinetics of single doses of the BRAF inhibitor, Dr. Infante reported.

Of the 109 patients in part B, fully 93% had melanoma and 91% specifically had the V600E BRAF mutation. The majority (54%) had received at least two prior lines of systemic anticancer therapy.

Dose-escalation results showed that both drugs could be given in combination at their full monotherapy doses (150 mg twice daily of the BRAF inhibitor and 2 mg once daily of the MEK inhibitor), largely without dose-limiting toxicities.

Only one dose-limiting toxicity was seen with the full dose of each drug. The patient developed a neutrophilic panniculitis, manifesting as painful red nodules on the thorax and extremities, in association with fever and chills. It resolved with discontinuation of the drugs and steroid therapy.

Across the dose combinations, 79% of patients experienced an adverse event and 19% experienced a grade 3 or higher adverse event, most often neutropenia, leukopenia, diarrhea, and fever. There was no clear association with doses, according to Dr. Infante.

In a finding as yet without explanation, certain adverse events that had been seen previously with each drug when they were given alone were actually less common when they were combined. Specifically, rash occurred in 25% of patients, whereas historically it has been seen in 75%-80% of those given the MEK inhibitor alone. And squamous cell carcinoma and other hyperproliferative skin lesions were seen in roughly 1%, whereas they have been seen in 7%-15% of those given the BRAF inhibitor alone.

Among the 71 patients with melanoma who had not previously received a BRAF inhibitor, the rate of unconfirmed objective response (complete or partial response) ranged from 50% to 77%, depending on the dose combination. Five patients had complete responses. For comparison, the response rate in BRAF-mutated melanoma has been 63% with the BRAF inhibitor alone and 40% with the MEK inhibitor alone.

Additionally, the rate of disease control (complete response, partial response, or stable disease) ranged from 95% to 100%, Dr. Infante reported. And the large majority of patients (83%) are still receiving combination therapy.

Analyses among the 24 patients with melanoma who had previously received a BRAF inhibitor showed that about half had a reduction in tumor size. There was no clear difference according to the duration of the earlier BRAF inhibitor therapy.

The investigators are now conducting a phase II trial in which 150 patients with V600E- or V600K-mutant melanoma are being randomly assigned to therapy with the BRAF inhibitor alone or in combination with the MEK inhibitor at two dose levels.

Dr. Dummer, the discussant, noted that obtaining biopsies is "very crucial" to understanding how such novel antimelanoma therapies are working. "Our patients, when you explain this to them, they will agree to sequential biopsies," he commented. "And I encourage all of you to participate in trials with a very strong translational research" component.

Dr. Infante reported that he is an unpaid consultant to GlaxoSmithKline, and that several coauthors are GSK employees. Dr. Dummer reported that he is a consultant to Bristol-Myers Squibb, Merck, Novartis, and Roche, and receives honoraria from Bristol-Myers Squibb.