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American Society of Clinical Oncology (ASCO): Annual Meeting
Swapping bortezomib for vincristine improves PFS in mantle cell lymphoma
CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.
In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.
The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.
The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.
R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.
Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.
The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m2 was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m2 was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.
A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.
At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).
Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.
However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).
Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).
Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).
Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.
Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.
Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.
The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."
Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.
The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.
CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.
In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.
The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.
The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.
R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.
Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.
The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m2 was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m2 was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.
A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.
At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).
Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.
However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).
Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).
Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).
Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.
Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.
Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.
The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."
Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.
The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.
CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.
In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.
The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.
The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.
R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.
Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.
The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m2 was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m2 was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.
A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.
At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).
Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.
However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).
Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).
Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).
Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.
Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.
Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.
The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."
Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.
The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.
AT THE ASCO ANNUAL MEETING 2014
Key clinical point: Substituting bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.
Major finding: At a median follow-up of 40 months, median progression-free survival was 24.7 months in the bortezomib-containing VR-CAP arm, compared with 14.4 months for R-CHOP, a significant difference.
Data source: Randomized, open-label phase III study in 487 patients with newly diagnosed mantle cell lymphoma.
Disclosures: The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.
Lenalidomide plus R-CHOP tackles thorny DLBCL subtype
CHICAGO – Lenalidomide in combination with R-CHOP chemotherapy induced responses in 98% of patients with newly diagnosed diffuse large B-cell lymphoma in a phase II study.
Among the 60 evaluable patients, 80% had complete responses, and 18% had partial responses.
Moreover, progression-free and overall survival were increased with lenalidomide (Revlimid) in the activated B-cell (ABC) or non–germinal center B-cell (non-GCB) subtype, which is associated with a poor outcome when treated with standard R-CHOP monotherapy.
"It appears the addition of lenalidomide to R-CHOP may ameliorate the negative effect of the non-GCB phenotype on outcome," Dr. Grzegorz Nowakowski said at the annual meeting of the American Society of Clinical Oncology.
About 40% of patients with diffuse large B-cell lymphoma (DLBCL) given R-CHOP every 21 days will relapse or develop refractory disease. For those who do, the response rate for single-agent lenalidomide is about 30%, he said.
The study involved 64 patients with untreated stages II-V CD20-positive DLBCL who received oral lenalidomide 25 mg on days 1-10 with standard-dose R-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) chemotherapy every 21 days for six cycles (R2CHOP).
All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout.
At baseline, 25% of patients were older than age 70 years, 60% had stage IV disease, and 52% were International Prognostic Index high intermediate or high risk.
The DLBCL subtype was germinal-center B-cell (GCB) in 51% and non-GCB in 34%, with 16% unknown.
Efficacy was examined by DLBCL subtype and against a matched case-control cohort of 87 consecutive, contemporary DLBCL cases in the Mayo Clinic Lymphoma Database who were treated with R-CHOP alone.
At 2 years, progression-free survival (PFS) and overall survival rates in the R2CHOP group were 59% and 78%, compared with rates of 52% and 65% in the R-CHOP case-matched controls, said Dr. Nowakowski of the Mayo Clinic, Rochester, Minn.
When the case controls were examined by molecular subtype, there was a significant difference between non-GCB and GCB controls treated with standard R-CHOP alone for progression-free survival (28% vs. 64%; P = .00029) and overall survival (46% vs. 74%; P = .000036).
In contrast, non-GCB and GCB treated with R2CHOP with lenalidomide had similar rates of progression (60% vs. 59%; P = 0.83) and overall survival at 2 years (83% vs. 75%; P = .61), he reported.
Similar results were recently seen in elderly DLBCL patients in the phase II Italian REAL07 trial (Lancet Oncol. 2014 Jun;15:730-7), said Dr. Nowakowski and invited discussant Dr. Andre Goy, chief of lymphoma and chair and director, John Theurer Cancer Center, Hackensack (N.J.) University Medical Center.
Lenalidomide offers "very promising activity with R2CHOP, particularly in the non-GC subtype," Dr. Goy said "These data will need to be confirmed in ongoing randomized studies, but might offer a new platform in combination/maintenance post–R-CHOP, particularly in elderly patients because the ABC percentage increases with age and they tend to have a worse outcome."
Dr. Goy observed that lenalidomide increased the incidence of grade 3 and 4 neutropenia and thrombocytopenia, but this did not translate into more infections, serious adverse events, or treatment delays.
Grade 3 febrile neutropenia developed in six patients, grade 4 sepsis in one, hemorrhage in one, and thrombosis in one, Dr. Nowakowski said. One patient died of perforation/sepsis unrelated to treatment.
The ongoing phase II ECOG 1412 trial is utilizing gene expression profiling of DLBCL subtype in its evaluation of the efficacy of R2CHOP vs. R-CHOP, he said.
The study was supported by Celgene. Dr. Nowakowski reported having no financial disclosures. Dr. Goy reported serving in a consultant or advisory role with Celgene and Pharmacyclics and receiving honoraria from Janssen Oncology and Millennium Pharmaceuticals.
CHICAGO – Lenalidomide in combination with R-CHOP chemotherapy induced responses in 98% of patients with newly diagnosed diffuse large B-cell lymphoma in a phase II study.
Among the 60 evaluable patients, 80% had complete responses, and 18% had partial responses.
Moreover, progression-free and overall survival were increased with lenalidomide (Revlimid) in the activated B-cell (ABC) or non–germinal center B-cell (non-GCB) subtype, which is associated with a poor outcome when treated with standard R-CHOP monotherapy.
"It appears the addition of lenalidomide to R-CHOP may ameliorate the negative effect of the non-GCB phenotype on outcome," Dr. Grzegorz Nowakowski said at the annual meeting of the American Society of Clinical Oncology.
About 40% of patients with diffuse large B-cell lymphoma (DLBCL) given R-CHOP every 21 days will relapse or develop refractory disease. For those who do, the response rate for single-agent lenalidomide is about 30%, he said.
The study involved 64 patients with untreated stages II-V CD20-positive DLBCL who received oral lenalidomide 25 mg on days 1-10 with standard-dose R-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) chemotherapy every 21 days for six cycles (R2CHOP).
All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout.
At baseline, 25% of patients were older than age 70 years, 60% had stage IV disease, and 52% were International Prognostic Index high intermediate or high risk.
The DLBCL subtype was germinal-center B-cell (GCB) in 51% and non-GCB in 34%, with 16% unknown.
Efficacy was examined by DLBCL subtype and against a matched case-control cohort of 87 consecutive, contemporary DLBCL cases in the Mayo Clinic Lymphoma Database who were treated with R-CHOP alone.
At 2 years, progression-free survival (PFS) and overall survival rates in the R2CHOP group were 59% and 78%, compared with rates of 52% and 65% in the R-CHOP case-matched controls, said Dr. Nowakowski of the Mayo Clinic, Rochester, Minn.
When the case controls were examined by molecular subtype, there was a significant difference between non-GCB and GCB controls treated with standard R-CHOP alone for progression-free survival (28% vs. 64%; P = .00029) and overall survival (46% vs. 74%; P = .000036).
In contrast, non-GCB and GCB treated with R2CHOP with lenalidomide had similar rates of progression (60% vs. 59%; P = 0.83) and overall survival at 2 years (83% vs. 75%; P = .61), he reported.
Similar results were recently seen in elderly DLBCL patients in the phase II Italian REAL07 trial (Lancet Oncol. 2014 Jun;15:730-7), said Dr. Nowakowski and invited discussant Dr. Andre Goy, chief of lymphoma and chair and director, John Theurer Cancer Center, Hackensack (N.J.) University Medical Center.
Lenalidomide offers "very promising activity with R2CHOP, particularly in the non-GC subtype," Dr. Goy said "These data will need to be confirmed in ongoing randomized studies, but might offer a new platform in combination/maintenance post–R-CHOP, particularly in elderly patients because the ABC percentage increases with age and they tend to have a worse outcome."
Dr. Goy observed that lenalidomide increased the incidence of grade 3 and 4 neutropenia and thrombocytopenia, but this did not translate into more infections, serious adverse events, or treatment delays.
Grade 3 febrile neutropenia developed in six patients, grade 4 sepsis in one, hemorrhage in one, and thrombosis in one, Dr. Nowakowski said. One patient died of perforation/sepsis unrelated to treatment.
The ongoing phase II ECOG 1412 trial is utilizing gene expression profiling of DLBCL subtype in its evaluation of the efficacy of R2CHOP vs. R-CHOP, he said.
The study was supported by Celgene. Dr. Nowakowski reported having no financial disclosures. Dr. Goy reported serving in a consultant or advisory role with Celgene and Pharmacyclics and receiving honoraria from Janssen Oncology and Millennium Pharmaceuticals.
CHICAGO – Lenalidomide in combination with R-CHOP chemotherapy induced responses in 98% of patients with newly diagnosed diffuse large B-cell lymphoma in a phase II study.
Among the 60 evaluable patients, 80% had complete responses, and 18% had partial responses.
Moreover, progression-free and overall survival were increased with lenalidomide (Revlimid) in the activated B-cell (ABC) or non–germinal center B-cell (non-GCB) subtype, which is associated with a poor outcome when treated with standard R-CHOP monotherapy.
"It appears the addition of lenalidomide to R-CHOP may ameliorate the negative effect of the non-GCB phenotype on outcome," Dr. Grzegorz Nowakowski said at the annual meeting of the American Society of Clinical Oncology.
About 40% of patients with diffuse large B-cell lymphoma (DLBCL) given R-CHOP every 21 days will relapse or develop refractory disease. For those who do, the response rate for single-agent lenalidomide is about 30%, he said.
The study involved 64 patients with untreated stages II-V CD20-positive DLBCL who received oral lenalidomide 25 mg on days 1-10 with standard-dose R-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) chemotherapy every 21 days for six cycles (R2CHOP).
All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout.
At baseline, 25% of patients were older than age 70 years, 60% had stage IV disease, and 52% were International Prognostic Index high intermediate or high risk.
The DLBCL subtype was germinal-center B-cell (GCB) in 51% and non-GCB in 34%, with 16% unknown.
Efficacy was examined by DLBCL subtype and against a matched case-control cohort of 87 consecutive, contemporary DLBCL cases in the Mayo Clinic Lymphoma Database who were treated with R-CHOP alone.
At 2 years, progression-free survival (PFS) and overall survival rates in the R2CHOP group were 59% and 78%, compared with rates of 52% and 65% in the R-CHOP case-matched controls, said Dr. Nowakowski of the Mayo Clinic, Rochester, Minn.
When the case controls were examined by molecular subtype, there was a significant difference between non-GCB and GCB controls treated with standard R-CHOP alone for progression-free survival (28% vs. 64%; P = .00029) and overall survival (46% vs. 74%; P = .000036).
In contrast, non-GCB and GCB treated with R2CHOP with lenalidomide had similar rates of progression (60% vs. 59%; P = 0.83) and overall survival at 2 years (83% vs. 75%; P = .61), he reported.
Similar results were recently seen in elderly DLBCL patients in the phase II Italian REAL07 trial (Lancet Oncol. 2014 Jun;15:730-7), said Dr. Nowakowski and invited discussant Dr. Andre Goy, chief of lymphoma and chair and director, John Theurer Cancer Center, Hackensack (N.J.) University Medical Center.
Lenalidomide offers "very promising activity with R2CHOP, particularly in the non-GC subtype," Dr. Goy said "These data will need to be confirmed in ongoing randomized studies, but might offer a new platform in combination/maintenance post–R-CHOP, particularly in elderly patients because the ABC percentage increases with age and they tend to have a worse outcome."
Dr. Goy observed that lenalidomide increased the incidence of grade 3 and 4 neutropenia and thrombocytopenia, but this did not translate into more infections, serious adverse events, or treatment delays.
Grade 3 febrile neutropenia developed in six patients, grade 4 sepsis in one, hemorrhage in one, and thrombosis in one, Dr. Nowakowski said. One patient died of perforation/sepsis unrelated to treatment.
The ongoing phase II ECOG 1412 trial is utilizing gene expression profiling of DLBCL subtype in its evaluation of the efficacy of R2CHOP vs. R-CHOP, he said.
The study was supported by Celgene. Dr. Nowakowski reported having no financial disclosures. Dr. Goy reported serving in a consultant or advisory role with Celgene and Pharmacyclics and receiving honoraria from Janssen Oncology and Millennium Pharmaceuticals.
AT THE ASCO ANNUAL MEETING 2014
Key clinical point: DLBCL patients with the molecular subtype non-GCB may benefit from the addition of lenalidomide to R-CHOP chemotherapy.
Major finding: Non-GCB and GCB subtypes treated with R-CHOP plus lenalidomide had similar rates of progression (60% vs. 59%; P = .83) and overall survival at 2 years (83% vs. 75%; P = .61)
Data source: A phase II study in 64 newly diagnosed diffuse large B-cell lymphoma patients.
Disclosures: The study was supported by Celgene. Dr. Nowakowski reported having no financial disclosures. Dr. Goy reported serving in a consultant or advisory role with Celgene and Pharmacyclics and receiving honoraria from Janssen Oncology and Millennium Pharmaceuticals.
PET-CT accurately predicts survival of follicular lymphoma patients
CHICAGO – For patients with follicular lymphoma, positron emission tomography–computed tomography performed at the end of induction therapy is strongly predictive of both progression-free and overall survival, a retrospective analysis showed.
The pooled analysis of data on 246 PET-CT scans performed following chemoimmunotherapy in three clinical trials showed that patients with 18-fluorodeoxyglucose (FDG) uptake of 4 or greater on a 5-point scale had a fourfold higher risk for disease progression, compared with patients who became PET negative after induction, reported Dr. Judith Trotman of the University of Sydney (Australia).
At 4.5 years of follow-up, median progression-free survival (PFS) was 16.9 months for patients with a PET uptake of 4 or greater on the 5-point Deauville scale for postinduction response assessment, vs. 74 months for PET-negative patients.
Overall survival at 4.5 years for patients with a higher uptake of FDG PET was 87%, compared with 97% for patients who were PET negative after induction, Dr. Trotman reported at the American Society of Clinical Oncology annual meeting.
"We argue that for the patients who remain PET positive, follicular lymphoma is no longer an indolent histology," Dr. Trotman said.
The study results also showed that conventional CT assessment provides only limited additional value, and that "PET-CT applying the 5-point scale should be the new gold standard for therapeutic response assessment in this lymphoma," she said.
Not so indolent
Although the natural history of follicular lymphoma is a generally indolent course, approximately 15% of patients will die within 5 years of diagnosis, and high-risk scores on the Follicular Lymphoma International Prognostic Index (FLIPI) or its revision (FLIPI2) are not sufficient for predicting which patients are at greatest risk for death, Dr. Trotman said.
Three recent clinical trials reported that positron emission tomography assessment after first-line rituximab-based chemotherapy has good predictive value in patients with high tumor burden follicular lymphoma. Dr. Trotman and his colleagues conducted a pooled analysis of data from the trials with independent review of PET-CT scans to come up with more precise survival estimates and identify the best cutoff for survival using the Deauville scale for response assessment of FDG-avid lymphoma.
The trials were the PRIMA (Primary Rituximab and Maintenance) study of 122 patients, the FOLL05 randomized trial of the Fondazione Italiana Linfomi in 202 patients, and the PET Folliculaire trial in 106 patients.
The Deauville 5-point scale for FDG-avid lymphoma uses the following criteria:
1. No uptake.
2. Uptake less than or equal to mediastinum.
3. Uptake greater than mediastinum but less than or equal to liver.
4. Uptake moderately higher than liver.
5. Uptake markedly higher than liver and/or new lesions.
Dr. Trotman and his colleagues looked at cutoffs of 3 and higher and 4 and higher to see whether they were predictive of prognosis. Reviews of concordance with the trial results, performed by three independent reviewers, showed that a cutoff of 3 or higher had moderate concordance, while a score of 4 or higher had substantial agreement with results.
They then evaluated PET results to see whether they could sharpen the prognostic ability, and found that both cutoffs predicted PFS, but because of the higher concordance score, they chose to focus on the 4+ cutoff.
They found that the hazard ratio (HR) for progression with a score of 4 or greater was 3.9 (P less than .0001), and the hazard ratio for death was 6.7 (P = .0002). Median overall survival in patients with scores of 4 or greater was 79 months, vs. not reached for PET-negative patients.
In multivariate analyses, factors associated with PFS included PET-positive scores of 4 or greater (HR, 3.1; P less than .0001), stable or progressive disease vs. complete responses or complete responses unconfirmed (CR/CRu; HR, 3.7; P = .0013), and partial responses (PRs) vs. CR/CRu (HR, 1.6; P = .04).
Factors associated with OS were PET score and stable/progressive disease vs. CR/CRu (HR, 5.3; P = .05).
"I hope that we can now move on: postinduction PET-CT is a platform for response–adapted therapy, because while achieving PET negativity can better reassure our patients, particularly those otherwise in CRu or PR, the inferior survival of those who remain PET positive compels us to study such PET-response–adapted approaches," Dr. Trotman said.
The invited discussant, Dr. Christopher Flowers of the department of hematology and medical oncology at Emory University, Atlanta, noted that in their analysis, Dr. Trotman and his colleagues included only those scans that were of sufficient quality for central review, and that slightly more than half of all patients had PET scans.
"I think it’s important to try and understand how the PET-available cohort compared to the other clinical trial characteristics of patients to understand whether or not this PET population is a unique population, and [whether] the behavior characteristics may be different from what you might expect from a broader population of patients," he said.
It will be important to see whether the findings will hold up in patients treated with emerging regimens, such as rituximab and bendamustine, and other combinations now in clinical trials, he said.
Dr. Trotman reported having no relevant relationships to disclose. Dr. Flowers disclosed uncompensated consultation from several companies, and receiving research funding from Gilead Sciences, Janssen Pharmaceuticals, Millennium, and Spectrum Pharmaceuticals.
CHICAGO – For patients with follicular lymphoma, positron emission tomography–computed tomography performed at the end of induction therapy is strongly predictive of both progression-free and overall survival, a retrospective analysis showed.
The pooled analysis of data on 246 PET-CT scans performed following chemoimmunotherapy in three clinical trials showed that patients with 18-fluorodeoxyglucose (FDG) uptake of 4 or greater on a 5-point scale had a fourfold higher risk for disease progression, compared with patients who became PET negative after induction, reported Dr. Judith Trotman of the University of Sydney (Australia).
At 4.5 years of follow-up, median progression-free survival (PFS) was 16.9 months for patients with a PET uptake of 4 or greater on the 5-point Deauville scale for postinduction response assessment, vs. 74 months for PET-negative patients.
Overall survival at 4.5 years for patients with a higher uptake of FDG PET was 87%, compared with 97% for patients who were PET negative after induction, Dr. Trotman reported at the American Society of Clinical Oncology annual meeting.
"We argue that for the patients who remain PET positive, follicular lymphoma is no longer an indolent histology," Dr. Trotman said.
The study results also showed that conventional CT assessment provides only limited additional value, and that "PET-CT applying the 5-point scale should be the new gold standard for therapeutic response assessment in this lymphoma," she said.
Not so indolent
Although the natural history of follicular lymphoma is a generally indolent course, approximately 15% of patients will die within 5 years of diagnosis, and high-risk scores on the Follicular Lymphoma International Prognostic Index (FLIPI) or its revision (FLIPI2) are not sufficient for predicting which patients are at greatest risk for death, Dr. Trotman said.
Three recent clinical trials reported that positron emission tomography assessment after first-line rituximab-based chemotherapy has good predictive value in patients with high tumor burden follicular lymphoma. Dr. Trotman and his colleagues conducted a pooled analysis of data from the trials with independent review of PET-CT scans to come up with more precise survival estimates and identify the best cutoff for survival using the Deauville scale for response assessment of FDG-avid lymphoma.
The trials were the PRIMA (Primary Rituximab and Maintenance) study of 122 patients, the FOLL05 randomized trial of the Fondazione Italiana Linfomi in 202 patients, and the PET Folliculaire trial in 106 patients.
The Deauville 5-point scale for FDG-avid lymphoma uses the following criteria:
1. No uptake.
2. Uptake less than or equal to mediastinum.
3. Uptake greater than mediastinum but less than or equal to liver.
4. Uptake moderately higher than liver.
5. Uptake markedly higher than liver and/or new lesions.
Dr. Trotman and his colleagues looked at cutoffs of 3 and higher and 4 and higher to see whether they were predictive of prognosis. Reviews of concordance with the trial results, performed by three independent reviewers, showed that a cutoff of 3 or higher had moderate concordance, while a score of 4 or higher had substantial agreement with results.
They then evaluated PET results to see whether they could sharpen the prognostic ability, and found that both cutoffs predicted PFS, but because of the higher concordance score, they chose to focus on the 4+ cutoff.
They found that the hazard ratio (HR) for progression with a score of 4 or greater was 3.9 (P less than .0001), and the hazard ratio for death was 6.7 (P = .0002). Median overall survival in patients with scores of 4 or greater was 79 months, vs. not reached for PET-negative patients.
In multivariate analyses, factors associated with PFS included PET-positive scores of 4 or greater (HR, 3.1; P less than .0001), stable or progressive disease vs. complete responses or complete responses unconfirmed (CR/CRu; HR, 3.7; P = .0013), and partial responses (PRs) vs. CR/CRu (HR, 1.6; P = .04).
Factors associated with OS were PET score and stable/progressive disease vs. CR/CRu (HR, 5.3; P = .05).
"I hope that we can now move on: postinduction PET-CT is a platform for response–adapted therapy, because while achieving PET negativity can better reassure our patients, particularly those otherwise in CRu or PR, the inferior survival of those who remain PET positive compels us to study such PET-response–adapted approaches," Dr. Trotman said.
The invited discussant, Dr. Christopher Flowers of the department of hematology and medical oncology at Emory University, Atlanta, noted that in their analysis, Dr. Trotman and his colleagues included only those scans that were of sufficient quality for central review, and that slightly more than half of all patients had PET scans.
"I think it’s important to try and understand how the PET-available cohort compared to the other clinical trial characteristics of patients to understand whether or not this PET population is a unique population, and [whether] the behavior characteristics may be different from what you might expect from a broader population of patients," he said.
It will be important to see whether the findings will hold up in patients treated with emerging regimens, such as rituximab and bendamustine, and other combinations now in clinical trials, he said.
Dr. Trotman reported having no relevant relationships to disclose. Dr. Flowers disclosed uncompensated consultation from several companies, and receiving research funding from Gilead Sciences, Janssen Pharmaceuticals, Millennium, and Spectrum Pharmaceuticals.
CHICAGO – For patients with follicular lymphoma, positron emission tomography–computed tomography performed at the end of induction therapy is strongly predictive of both progression-free and overall survival, a retrospective analysis showed.
The pooled analysis of data on 246 PET-CT scans performed following chemoimmunotherapy in three clinical trials showed that patients with 18-fluorodeoxyglucose (FDG) uptake of 4 or greater on a 5-point scale had a fourfold higher risk for disease progression, compared with patients who became PET negative after induction, reported Dr. Judith Trotman of the University of Sydney (Australia).
At 4.5 years of follow-up, median progression-free survival (PFS) was 16.9 months for patients with a PET uptake of 4 or greater on the 5-point Deauville scale for postinduction response assessment, vs. 74 months for PET-negative patients.
Overall survival at 4.5 years for patients with a higher uptake of FDG PET was 87%, compared with 97% for patients who were PET negative after induction, Dr. Trotman reported at the American Society of Clinical Oncology annual meeting.
"We argue that for the patients who remain PET positive, follicular lymphoma is no longer an indolent histology," Dr. Trotman said.
The study results also showed that conventional CT assessment provides only limited additional value, and that "PET-CT applying the 5-point scale should be the new gold standard for therapeutic response assessment in this lymphoma," she said.
Not so indolent
Although the natural history of follicular lymphoma is a generally indolent course, approximately 15% of patients will die within 5 years of diagnosis, and high-risk scores on the Follicular Lymphoma International Prognostic Index (FLIPI) or its revision (FLIPI2) are not sufficient for predicting which patients are at greatest risk for death, Dr. Trotman said.
Three recent clinical trials reported that positron emission tomography assessment after first-line rituximab-based chemotherapy has good predictive value in patients with high tumor burden follicular lymphoma. Dr. Trotman and his colleagues conducted a pooled analysis of data from the trials with independent review of PET-CT scans to come up with more precise survival estimates and identify the best cutoff for survival using the Deauville scale for response assessment of FDG-avid lymphoma.
The trials were the PRIMA (Primary Rituximab and Maintenance) study of 122 patients, the FOLL05 randomized trial of the Fondazione Italiana Linfomi in 202 patients, and the PET Folliculaire trial in 106 patients.
The Deauville 5-point scale for FDG-avid lymphoma uses the following criteria:
1. No uptake.
2. Uptake less than or equal to mediastinum.
3. Uptake greater than mediastinum but less than or equal to liver.
4. Uptake moderately higher than liver.
5. Uptake markedly higher than liver and/or new lesions.
Dr. Trotman and his colleagues looked at cutoffs of 3 and higher and 4 and higher to see whether they were predictive of prognosis. Reviews of concordance with the trial results, performed by three independent reviewers, showed that a cutoff of 3 or higher had moderate concordance, while a score of 4 or higher had substantial agreement with results.
They then evaluated PET results to see whether they could sharpen the prognostic ability, and found that both cutoffs predicted PFS, but because of the higher concordance score, they chose to focus on the 4+ cutoff.
They found that the hazard ratio (HR) for progression with a score of 4 or greater was 3.9 (P less than .0001), and the hazard ratio for death was 6.7 (P = .0002). Median overall survival in patients with scores of 4 or greater was 79 months, vs. not reached for PET-negative patients.
In multivariate analyses, factors associated with PFS included PET-positive scores of 4 or greater (HR, 3.1; P less than .0001), stable or progressive disease vs. complete responses or complete responses unconfirmed (CR/CRu; HR, 3.7; P = .0013), and partial responses (PRs) vs. CR/CRu (HR, 1.6; P = .04).
Factors associated with OS were PET score and stable/progressive disease vs. CR/CRu (HR, 5.3; P = .05).
"I hope that we can now move on: postinduction PET-CT is a platform for response–adapted therapy, because while achieving PET negativity can better reassure our patients, particularly those otherwise in CRu or PR, the inferior survival of those who remain PET positive compels us to study such PET-response–adapted approaches," Dr. Trotman said.
The invited discussant, Dr. Christopher Flowers of the department of hematology and medical oncology at Emory University, Atlanta, noted that in their analysis, Dr. Trotman and his colleagues included only those scans that were of sufficient quality for central review, and that slightly more than half of all patients had PET scans.
"I think it’s important to try and understand how the PET-available cohort compared to the other clinical trial characteristics of patients to understand whether or not this PET population is a unique population, and [whether] the behavior characteristics may be different from what you might expect from a broader population of patients," he said.
It will be important to see whether the findings will hold up in patients treated with emerging regimens, such as rituximab and bendamustine, and other combinations now in clinical trials, he said.
Dr. Trotman reported having no relevant relationships to disclose. Dr. Flowers disclosed uncompensated consultation from several companies, and receiving research funding from Gilead Sciences, Janssen Pharmaceuticals, Millennium, and Spectrum Pharmaceuticals.
AT THE ASCO ANNUAL MEETING 2014
Key clinical point: For patients with follicular lymphoma, a PET-CT performed at the end of induction therapy is predictive of survival.
Major finding: A PET-CT cutoff score of 4 out of 5 on the Deauville lymphoma-response assessment scale was strongly predictive of both progression-free and overall survival of follicular lymphoma.
Data source: A retrospective analysis of prospectively collected data on 246 patients in three clinical trials.
Disclosures: Dr. Trotman reported having no relevant relationships to disclose. Dr. Flowers disclosed uncompensated consultation from several companies, and receiving research funding from Gilead Sciences, Janssen Pharmaceuticals, Millennium, and Spectrum Pharmaceuticals.
Long-term follow-up shows 22% survival rate for advanced GIST
CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.
"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.
In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.
In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.
The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.
As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.
"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.
The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.
An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).
Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.
Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).
An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.
The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).
In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.
"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.
"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.
Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."
"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.
RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.
The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.
CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.
"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.
In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.
In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.
The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.
As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.
"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.
The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.
An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).
Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.
Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).
An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.
The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).
In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.
"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.
"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.
Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."
"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.
RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.
The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.
CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.
"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.
In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.
In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.
The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.
As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.
"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.
The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.
An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).
Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.
Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).
An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.
The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).
In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.
"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.
"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.
Dr. Jon Trent, director of the bone and soft-tissue program at the University of Miami Sylvester Cancer Center, the invited discussant, commented that "molecular subtyping should be required for all GIST patients."
"Most of all, I think we really need a tool other than the current version of RECIST [Response Evaluation Criteria in Solid Tumors], in order to really identify early makers of response and early markers of progression in our GIST patients," he said.
RECIST criteria often fail to provide useful information about early responses to therapy in GIST, he said.
The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.
AT THE ASCO ANNUAL MEETING 2014
Major finding: Ten-year overall survival for patients with metastatic or unresectable gastrointestinal tumors (GIST) treated with imatinib was 22%.
Data source: Long-term follow-up of data on 746 patients enrolled in the randomized phase III SWOG Intergroup S0033 trial.
Disclosures: The study was supported by the National Cancer Institute. Dr. Demetri disclosed serving as a consultant or adviser to ARIAD, Bayer, Novartis, and Pfizer; receiving research funding from Bayer, Novartis, and Pfizer; and receiving other remuneration from Novartis. Dr. Trent disclosed consulting/advising for Ariad, Bayer/Onyx, Novartis, and Pfizer, and receiving honoraria from Pfizer.
VIDEO: ASCO 2014 roundtable on breast cancer research
CHICAGO – The Oncology Report associate editors Dr. William J. Gradishar and Dr. Hope S. Rugo discuss breast cancer research highlights presented at the 2014 annual meeting of the American Association of Clinical Oncology.
Studies discussed include the combined analysis of the SOFT and TEXT trials, looking at ovarian suppression in combination with either an aromatase inhibitor or tamoxifen; ALTTO, looking at the impact of a dual blockade against HER2, and the implications on the use of pCR in research and drug approval; ECOG 5103 adjuvant bevacizumab trial; and POEMS, looking at the possibility of preserving fertility during chemotherapy with the addition of goserelin.
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at the Northwestern University, Chicago. Dr. Hope S. Rugo is a professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – The Oncology Report associate editors Dr. William J. Gradishar and Dr. Hope S. Rugo discuss breast cancer research highlights presented at the 2014 annual meeting of the American Association of Clinical Oncology.
Studies discussed include the combined analysis of the SOFT and TEXT trials, looking at ovarian suppression in combination with either an aromatase inhibitor or tamoxifen; ALTTO, looking at the impact of a dual blockade against HER2, and the implications on the use of pCR in research and drug approval; ECOG 5103 adjuvant bevacizumab trial; and POEMS, looking at the possibility of preserving fertility during chemotherapy with the addition of goserelin.
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at the Northwestern University, Chicago. Dr. Hope S. Rugo is a professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – The Oncology Report associate editors Dr. William J. Gradishar and Dr. Hope S. Rugo discuss breast cancer research highlights presented at the 2014 annual meeting of the American Association of Clinical Oncology.
Studies discussed include the combined analysis of the SOFT and TEXT trials, looking at ovarian suppression in combination with either an aromatase inhibitor or tamoxifen; ALTTO, looking at the impact of a dual blockade against HER2, and the implications on the use of pCR in research and drug approval; ECOG 5103 adjuvant bevacizumab trial; and POEMS, looking at the possibility of preserving fertility during chemotherapy with the addition of goserelin.
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at the Northwestern University, Chicago. Dr. Hope S. Rugo is a professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ASCO ANNUAL MEETING 2014
VIDEO: Drug combo delivers ‘unprecedented’ metastatic melanoma survival
CHICAGO – Pairing the immune checkpoint inhibitors nivolumab and ipilimumab delivered deep and durable responses in patients with advanced metastatic melanoma, producing a 2-year overall survival rate of 79% among 53 patients.
"These are remarkable data even for a trial of this size in metastatic melanoma," noted Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. Sznol discusses the study results, and he outlines how combinations of new agents with older treatments such as interferon and interleukin-2 may be used in the future.
CHICAGO – Pairing the immune checkpoint inhibitors nivolumab and ipilimumab delivered deep and durable responses in patients with advanced metastatic melanoma, producing a 2-year overall survival rate of 79% among 53 patients.
"These are remarkable data even for a trial of this size in metastatic melanoma," noted Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. Sznol discusses the study results, and he outlines how combinations of new agents with older treatments such as interferon and interleukin-2 may be used in the future.
CHICAGO – Pairing the immune checkpoint inhibitors nivolumab and ipilimumab delivered deep and durable responses in patients with advanced metastatic melanoma, producing a 2-year overall survival rate of 79% among 53 patients.
"These are remarkable data even for a trial of this size in metastatic melanoma," noted Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. Sznol discusses the study results, and he outlines how combinations of new agents with older treatments such as interferon and interleukin-2 may be used in the future.
AT THE ASCO ANNUAL MEETING 2014
VIDEO: Advanced melanoma on brink of immunotherapy ‘revolution’
CHICAGO – Advanced melanoma therapy – a field notorious for offering patients few drugs and little chance of survival – may be on the brink of an extraordinary transformation.
"There’s truly a revolution going in the immunotherapy of melanoma," explained Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. O’Day reviews the rapid developments in melanoma treatment options and the shift from a "nuclear bomb" approach to a more-targeted "cruise missile" mindset. He also highlights the parallels between the exceptional advances made in childhood leukemia treatment and new melanoma treatments such as ipilimumab and PD-1 inhibitors, and he discusses the new drugs’ ability to overcome a phenomenon that often defeats chemotherapy: cancer cell resistance.
CHICAGO – Advanced melanoma therapy – a field notorious for offering patients few drugs and little chance of survival – may be on the brink of an extraordinary transformation.
"There’s truly a revolution going in the immunotherapy of melanoma," explained Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. O’Day reviews the rapid developments in melanoma treatment options and the shift from a "nuclear bomb" approach to a more-targeted "cruise missile" mindset. He also highlights the parallels between the exceptional advances made in childhood leukemia treatment and new melanoma treatments such as ipilimumab and PD-1 inhibitors, and he discusses the new drugs’ ability to overcome a phenomenon that often defeats chemotherapy: cancer cell resistance.
CHICAGO – Advanced melanoma therapy – a field notorious for offering patients few drugs and little chance of survival – may be on the brink of an extraordinary transformation.
"There’s truly a revolution going in the immunotherapy of melanoma," explained Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. O’Day reviews the rapid developments in melanoma treatment options and the shift from a "nuclear bomb" approach to a more-targeted "cruise missile" mindset. He also highlights the parallels between the exceptional advances made in childhood leukemia treatment and new melanoma treatments such as ipilimumab and PD-1 inhibitors, and he discusses the new drugs’ ability to overcome a phenomenon that often defeats chemotherapy: cancer cell resistance.
AT THE ASCO ANNUAL MEETING 2014
VIDEO: Pembrolizumab may herald new hope in advanced melanoma
CHICAGO – Results from a phase I study of investigational PD-1 antibody pembrolizumab may point the way toward higher treatment response rates and less toxicity in patients with advanced metastatic melanoma.
Of 411 patients who took pembrolizumab, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. Ribas discussed the study results and explained how PD-1 antibodies help the immune system recognize and mount a more potent T-cell–mediated defense against melanoma.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Results from a phase I study of investigational PD-1 antibody pembrolizumab may point the way toward higher treatment response rates and less toxicity in patients with advanced metastatic melanoma.
Of 411 patients who took pembrolizumab, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. Ribas discussed the study results and explained how PD-1 antibodies help the immune system recognize and mount a more potent T-cell–mediated defense against melanoma.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Results from a phase I study of investigational PD-1 antibody pembrolizumab may point the way toward higher treatment response rates and less toxicity in patients with advanced metastatic melanoma.
Of 411 patients who took pembrolizumab, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles.
In a video interview at the annual meeting of the American Society for Clinical Oncology, Dr. Ribas discussed the study results and explained how PD-1 antibodies help the immune system recognize and mount a more potent T-cell–mediated defense against melanoma.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ASCO ANNUAL MEETING 2014
Mix and match: Chemo, antiangiogenic combos equal in metastatic CRC
CHICAGO – Choose one from column A – FOLFOX or FOLFIRI – and one from column B – cetuximab or bevacizumab – and the outcomes will be virtually identical, say investigators reporting on a phase III trial.
Patients with untreated KRAS wild-type metastatic adenocarcinoma of the colon or rectum who were assigned to either the FOLFOX or FOLFIRI chemotherapy regimens at their doctors’ discretion and were then randomized to receive either cetuximab (Erbitux) or bevacizumab (Avastin) had statistically indistinguishable overall survival rates out to 84 months of follow-up, said Dr. Alan Venook at the annual meeting of the American Society of Clinical Oncology, who is a professor of medical oncology, University of California, San Francisco.
Median overall survival (OS) was 29.0 months in the bevacizumab plus chemotherapy group, and 29.9 months in the cetuximab plus chemotherapy group. Median progression-free survival was 10.8 months and 10.4 months, respectively, Dr. Venook reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
The findings of the CALGB/SWOG 80450 study suggest that any combination of one of the two chemotherapy regimens and one of the two angiogenesis inhibitors can be considered as equally efficacious options for first-line therapy of patients with KRAS wild-type metastatic colorectal cancer.
"Overall survival exceeding 29 months in both arms establishes a new benchmark for treatment of these patients. This was accomplished across a broad clinical trials network and suggests that the results apply in a variety of practice settings," he said.
Dr. Venook noted that a 1992 meta-analysis based on clinical trials conducted in the 1980s showed a median overall survival of 8 months, highlighting the significant progress made in the field over the last 2 decades.
Take your pick
The investigators enrolled patients with KRAS wild-type metastatic CRC (codons 12 and 13) and Eastern Cooperative Oncology Group performance status of 0 or 1 to, at the treating physician’s discretion, either FOLFOX (oxaliplatin, 5-fluoauracil [5-FU] and leucovorin, the mFOLOX6 modification), or to FOLFIRI (irinotecan, 5-FU, and leucovorin). Treatment could be either for palliative intent or as part of a strategy to resect all metastases. Approximately 75% of the patients received FOLFOX, Dr. Venook said.
The patients were then randomized to receive either bevacizumab or cetuximab. The study, which initially enrolled patients without regard to mutational status and included an arm in which patients received both antiangiogenic agents, was amended following accrual of the first 1420 patients to include only patients with wild-type KRAS, and the combination bevacizumab-cetuximab arm was dropped.
For the current, 11th interim analysis, the investigators compared outcomes for 578 patients treated with cetuximab, and 559 treated with bevacizumab.
As noted before, overall survival (OS) in an intention-to-treat population, the primary endpoint was virtually identical when comparing chemotherapy plus cetuximab or bevacizumab. The hazard ratio (HR) for bevacizumab was 0.925 (P = .34).
Similarly, although PFS was .4 months longer in bevacizumab-treated patients, the difference was not significant (HR, 1.04; P = .55).
Likewise, there were no differences looking at either of the antiangiogenics plus FOLFOX (median OS was 30.1 months with cetuximab vs. 26.9 with bevacizumab, HR , .9; P = .09), or FOLFIRI (28.9 months with cetuximab vs. 33.4 months with bevacizumab, HR, 1.2; P = .28).
Median overall survival among patients determined to be disease free after therapy was 66.3 months.
The only marked differences between the combinations came in grade 3 or 4 toxicities, with grade 3 rash seen with cetuximab but not with bevacizumab, and grade 3 or 4 hypertension and gastrointestinal events occurring more frequently with bevacizumab.
There were similar numbers of study withdrawals and deaths on study.
Dr. Venook noted that data on response rates, duration of therapy by dose intensity, and other parameters are pending and will be reported at a later date.
The results show that "for the time being, the cetuximab added to standard chemotherapy, mainly FOLFOX is not superior to bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. Expanded RAS analysis may change this statement in the near future," commented Dr. Josep Tabernero, head of medical oncology at Vall d’Hebron University Hospital in Barcelona, the invited discussant.
"The treatment choice for each patient should consider efficacy, safety, cost, drug availability and some other important parameters," he said.
Dr. Clifford Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, commented that the study may give clinicians the confidence to expand treatment options for patients with metastatic CRC.
"Chemotherapy choice is a choice that is very much market driven in the United States: 75% of patients received FOLFOX. That’s based on sort of a habit as much as anything else, and I hope that this study might raise the other possibility with FOLFIRI," he said at a media briefing earlier in the day.
The study was funded by the National Cancer Institute. Dr. Venook disclosed serving as an uncompensated advisor to several companies including Bristol-Myers Squibb, maker of cetuximab, and Roche/Genetech, maker of bevacizumab. Dr. Tabernero has disclosed serving on advisory boards for Sanofi-Aventis, Pfizer, Roche and Merck. Dr. Hudis served as a data and safety management board chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.
CHICAGO – Choose one from column A – FOLFOX or FOLFIRI – and one from column B – cetuximab or bevacizumab – and the outcomes will be virtually identical, say investigators reporting on a phase III trial.
Patients with untreated KRAS wild-type metastatic adenocarcinoma of the colon or rectum who were assigned to either the FOLFOX or FOLFIRI chemotherapy regimens at their doctors’ discretion and were then randomized to receive either cetuximab (Erbitux) or bevacizumab (Avastin) had statistically indistinguishable overall survival rates out to 84 months of follow-up, said Dr. Alan Venook at the annual meeting of the American Society of Clinical Oncology, who is a professor of medical oncology, University of California, San Francisco.
Median overall survival (OS) was 29.0 months in the bevacizumab plus chemotherapy group, and 29.9 months in the cetuximab plus chemotherapy group. Median progression-free survival was 10.8 months and 10.4 months, respectively, Dr. Venook reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
The findings of the CALGB/SWOG 80450 study suggest that any combination of one of the two chemotherapy regimens and one of the two angiogenesis inhibitors can be considered as equally efficacious options for first-line therapy of patients with KRAS wild-type metastatic colorectal cancer.
"Overall survival exceeding 29 months in both arms establishes a new benchmark for treatment of these patients. This was accomplished across a broad clinical trials network and suggests that the results apply in a variety of practice settings," he said.
Dr. Venook noted that a 1992 meta-analysis based on clinical trials conducted in the 1980s showed a median overall survival of 8 months, highlighting the significant progress made in the field over the last 2 decades.
Take your pick
The investigators enrolled patients with KRAS wild-type metastatic CRC (codons 12 and 13) and Eastern Cooperative Oncology Group performance status of 0 or 1 to, at the treating physician’s discretion, either FOLFOX (oxaliplatin, 5-fluoauracil [5-FU] and leucovorin, the mFOLOX6 modification), or to FOLFIRI (irinotecan, 5-FU, and leucovorin). Treatment could be either for palliative intent or as part of a strategy to resect all metastases. Approximately 75% of the patients received FOLFOX, Dr. Venook said.
The patients were then randomized to receive either bevacizumab or cetuximab. The study, which initially enrolled patients without regard to mutational status and included an arm in which patients received both antiangiogenic agents, was amended following accrual of the first 1420 patients to include only patients with wild-type KRAS, and the combination bevacizumab-cetuximab arm was dropped.
For the current, 11th interim analysis, the investigators compared outcomes for 578 patients treated with cetuximab, and 559 treated with bevacizumab.
As noted before, overall survival (OS) in an intention-to-treat population, the primary endpoint was virtually identical when comparing chemotherapy plus cetuximab or bevacizumab. The hazard ratio (HR) for bevacizumab was 0.925 (P = .34).
Similarly, although PFS was .4 months longer in bevacizumab-treated patients, the difference was not significant (HR, 1.04; P = .55).
Likewise, there were no differences looking at either of the antiangiogenics plus FOLFOX (median OS was 30.1 months with cetuximab vs. 26.9 with bevacizumab, HR , .9; P = .09), or FOLFIRI (28.9 months with cetuximab vs. 33.4 months with bevacizumab, HR, 1.2; P = .28).
Median overall survival among patients determined to be disease free after therapy was 66.3 months.
The only marked differences between the combinations came in grade 3 or 4 toxicities, with grade 3 rash seen with cetuximab but not with bevacizumab, and grade 3 or 4 hypertension and gastrointestinal events occurring more frequently with bevacizumab.
There were similar numbers of study withdrawals and deaths on study.
Dr. Venook noted that data on response rates, duration of therapy by dose intensity, and other parameters are pending and will be reported at a later date.
The results show that "for the time being, the cetuximab added to standard chemotherapy, mainly FOLFOX is not superior to bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. Expanded RAS analysis may change this statement in the near future," commented Dr. Josep Tabernero, head of medical oncology at Vall d’Hebron University Hospital in Barcelona, the invited discussant.
"The treatment choice for each patient should consider efficacy, safety, cost, drug availability and some other important parameters," he said.
Dr. Clifford Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, commented that the study may give clinicians the confidence to expand treatment options for patients with metastatic CRC.
"Chemotherapy choice is a choice that is very much market driven in the United States: 75% of patients received FOLFOX. That’s based on sort of a habit as much as anything else, and I hope that this study might raise the other possibility with FOLFIRI," he said at a media briefing earlier in the day.
The study was funded by the National Cancer Institute. Dr. Venook disclosed serving as an uncompensated advisor to several companies including Bristol-Myers Squibb, maker of cetuximab, and Roche/Genetech, maker of bevacizumab. Dr. Tabernero has disclosed serving on advisory boards for Sanofi-Aventis, Pfizer, Roche and Merck. Dr. Hudis served as a data and safety management board chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.
CHICAGO – Choose one from column A – FOLFOX or FOLFIRI – and one from column B – cetuximab or bevacizumab – and the outcomes will be virtually identical, say investigators reporting on a phase III trial.
Patients with untreated KRAS wild-type metastatic adenocarcinoma of the colon or rectum who were assigned to either the FOLFOX or FOLFIRI chemotherapy regimens at their doctors’ discretion and were then randomized to receive either cetuximab (Erbitux) or bevacizumab (Avastin) had statistically indistinguishable overall survival rates out to 84 months of follow-up, said Dr. Alan Venook at the annual meeting of the American Society of Clinical Oncology, who is a professor of medical oncology, University of California, San Francisco.
Median overall survival (OS) was 29.0 months in the bevacizumab plus chemotherapy group, and 29.9 months in the cetuximab plus chemotherapy group. Median progression-free survival was 10.8 months and 10.4 months, respectively, Dr. Venook reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
The findings of the CALGB/SWOG 80450 study suggest that any combination of one of the two chemotherapy regimens and one of the two angiogenesis inhibitors can be considered as equally efficacious options for first-line therapy of patients with KRAS wild-type metastatic colorectal cancer.
"Overall survival exceeding 29 months in both arms establishes a new benchmark for treatment of these patients. This was accomplished across a broad clinical trials network and suggests that the results apply in a variety of practice settings," he said.
Dr. Venook noted that a 1992 meta-analysis based on clinical trials conducted in the 1980s showed a median overall survival of 8 months, highlighting the significant progress made in the field over the last 2 decades.
Take your pick
The investigators enrolled patients with KRAS wild-type metastatic CRC (codons 12 and 13) and Eastern Cooperative Oncology Group performance status of 0 or 1 to, at the treating physician’s discretion, either FOLFOX (oxaliplatin, 5-fluoauracil [5-FU] and leucovorin, the mFOLOX6 modification), or to FOLFIRI (irinotecan, 5-FU, and leucovorin). Treatment could be either for palliative intent or as part of a strategy to resect all metastases. Approximately 75% of the patients received FOLFOX, Dr. Venook said.
The patients were then randomized to receive either bevacizumab or cetuximab. The study, which initially enrolled patients without regard to mutational status and included an arm in which patients received both antiangiogenic agents, was amended following accrual of the first 1420 patients to include only patients with wild-type KRAS, and the combination bevacizumab-cetuximab arm was dropped.
For the current, 11th interim analysis, the investigators compared outcomes for 578 patients treated with cetuximab, and 559 treated with bevacizumab.
As noted before, overall survival (OS) in an intention-to-treat population, the primary endpoint was virtually identical when comparing chemotherapy plus cetuximab or bevacizumab. The hazard ratio (HR) for bevacizumab was 0.925 (P = .34).
Similarly, although PFS was .4 months longer in bevacizumab-treated patients, the difference was not significant (HR, 1.04; P = .55).
Likewise, there were no differences looking at either of the antiangiogenics plus FOLFOX (median OS was 30.1 months with cetuximab vs. 26.9 with bevacizumab, HR , .9; P = .09), or FOLFIRI (28.9 months with cetuximab vs. 33.4 months with bevacizumab, HR, 1.2; P = .28).
Median overall survival among patients determined to be disease free after therapy was 66.3 months.
The only marked differences between the combinations came in grade 3 or 4 toxicities, with grade 3 rash seen with cetuximab but not with bevacizumab, and grade 3 or 4 hypertension and gastrointestinal events occurring more frequently with bevacizumab.
There were similar numbers of study withdrawals and deaths on study.
Dr. Venook noted that data on response rates, duration of therapy by dose intensity, and other parameters are pending and will be reported at a later date.
The results show that "for the time being, the cetuximab added to standard chemotherapy, mainly FOLFOX is not superior to bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. Expanded RAS analysis may change this statement in the near future," commented Dr. Josep Tabernero, head of medical oncology at Vall d’Hebron University Hospital in Barcelona, the invited discussant.
"The treatment choice for each patient should consider efficacy, safety, cost, drug availability and some other important parameters," he said.
Dr. Clifford Hudis, president of ASCO and chief of the breast cancer service at Memorial Sloan–Kettering Cancer Center in New York, commented that the study may give clinicians the confidence to expand treatment options for patients with metastatic CRC.
"Chemotherapy choice is a choice that is very much market driven in the United States: 75% of patients received FOLFOX. That’s based on sort of a habit as much as anything else, and I hope that this study might raise the other possibility with FOLFIRI," he said at a media briefing earlier in the day.
The study was funded by the National Cancer Institute. Dr. Venook disclosed serving as an uncompensated advisor to several companies including Bristol-Myers Squibb, maker of cetuximab, and Roche/Genetech, maker of bevacizumab. Dr. Tabernero has disclosed serving on advisory boards for Sanofi-Aventis, Pfizer, Roche and Merck. Dr. Hudis served as a data and safety management board chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.
AT THE ASCO ANNUAL MEETING 2014
Key clinical point: Any combination of one of the two chemotherapy regimens (FOLFOX or FOLFIRI) and one of the two angiogenesis inhibitors (cetuximab or bevacizumab) can be considered as equally efficacious options for first-line therapy of patients with KRAS wild type metastatic colorectal cancer.
Major finding: Median overall survival was 29.0 months for patients with metastatic colorectal cancer treated with first-line bevacizumab plus chemotherapy group, and 29.9 months for those treated with cetuximab plus chemotherapy.
Data source: Randomized multicenter U.S. and Canadian trial in 1,137 patients with untreated metastatic colorectal cancer.
Disclosures: The study was funded by the National Cancer Institute. Dr. Venook disclosed serving as an uncompensated advisor to several companies including Bristol-Myers Squibb, maker of cetuximab, and Roche/Genetech, maker of bevacizumab. Dr. Tabernero has disclosed serving on advisory boards for Sanofi-Aventis, Pfizer, Roche, and Merck. Dr. Hudis served as a DSMB chair for Genentech and received research grants from Onyx Pharmaceuticals and Merck.
Pembrolizumab monotherapy posts 6.75-month PFS in stage IV NSCLC
CHICAGO – Monotherapy with the experimental anti-PD-1 antibody pembrolizumab induced durable treatment responses and slowed progression in previously untreated stage IV non–small cell lung cancer in an ongoing phase Ib trial.
The overall response rate was 26% (11 of 42 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 47% (21 of 45 patients) by investigator-assessed, immune-related response criteria (irRC).
Responses are ongoing in 100% of responders by RECIST and 90% of responders by irRC, with the median duration of response not reached after a median of 36 weeks follow-up, Dr. Naiyer Rizvi said at the annual meeting of the American Society of Clinical Oncology.
Responses in the phase I KEYNOTE-001 study are very comparable with response rates of 15%-32% achieved with classic chemotherapy in the first-line setting in phase III studies using gemcitabine plus cisplatin, taxol plus carboplatin, or pemetrexed plus cisplatin, said invited discussant Dr. Julie Brahmer of Johns Hopkins University, Baltimore.
"The key thing [with pembrolizumab] is that these responses are very long lasting," she said.
Moreover, median progression-free survival with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.
"A very early but interesting progression-free survival of 6.75 months is quite intriguing," Dr. Brahmer said.
Enrollment is expected to begin this September in the phase III KEYNOTE-024 study comparing pembrolizumab monotherapy with platinum-based doublet chemotherapy in treatment-naive PD-L1 positive, metastatic non–small cell lung cancer (NSCLC), said Dr. Rizvi, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York.
Study details
Pembrolizumab, previously known as MK-3475, exerts dual ligand (PD-L1 and PD-L2) blockade of the programmed death 1 (PD-1) pathway. It is being investigated in more than 30 different cancers, and it made waves at the ASCO meeting for its treatment of metastatic melanoma.
Dr. Brahmer said that the key questions for the current study are whether PD-L1 sensitivity was the right biomarker to use and what the best cut-off is.
The KEYNOTE-001 study enrolled 84 previously untreated patients with stage IV NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Tumors were classified as PD-L1 positive in 57 patients, using a cut point of at least 1% of tumor cells stained, as measured using a prototype immunohistochemistry assay.
Of these 57 patients, 45 with evaluable imaging at baseline were randomly assigned to pembrolizumab 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Most patients (76%) had nonsquamous histology, and 69% were former smokers.
Patients received a median of nine doses (range 1-23) and spent an average of 154 days on therapy (range 1-400).
Tumor shrinkage by RECIST criteria occurred in 80% of patients with measurable disease and at least one postbaseline scan, Dr. Rizvi said. Activity was observed across dose levels and across the 2- and 3-week schedules.
Nine patients with new tumors would have been considered as having progressive disease and likely taken off therapy if they had been assessed by traditional RECIST criteria rather than irRC, "illustrating that RECIST may not be the best imaging modality to assess patients treated with immunotherapy," he said.
Grade 1-2 treatment-related events occurred in 36 of the 45 patients. The most common events were fatigue in 10 patients, pruritus in 6, and hypothyroidism in 4.
There was one each treatment-related grade 4 blood creatine phosphokinase elevation, grade 3 pericardial effusion, grade 3 pneumonitis, and grade 2 kidney injury, with two events leading to treatment discontinuation.
"Based on these safety data, we feel pembrolizumab is a safe and well-tolerated regimen," Dr. Rizvi said.
An additional 50 patients are being enrolled in the KEYNOTE-001 study, with the total population to be analyzed both with 1% and 45% cut points, he said.
The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.
CHICAGO – Monotherapy with the experimental anti-PD-1 antibody pembrolizumab induced durable treatment responses and slowed progression in previously untreated stage IV non–small cell lung cancer in an ongoing phase Ib trial.
The overall response rate was 26% (11 of 42 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 47% (21 of 45 patients) by investigator-assessed, immune-related response criteria (irRC).
Responses are ongoing in 100% of responders by RECIST and 90% of responders by irRC, with the median duration of response not reached after a median of 36 weeks follow-up, Dr. Naiyer Rizvi said at the annual meeting of the American Society of Clinical Oncology.
Responses in the phase I KEYNOTE-001 study are very comparable with response rates of 15%-32% achieved with classic chemotherapy in the first-line setting in phase III studies using gemcitabine plus cisplatin, taxol plus carboplatin, or pemetrexed plus cisplatin, said invited discussant Dr. Julie Brahmer of Johns Hopkins University, Baltimore.
"The key thing [with pembrolizumab] is that these responses are very long lasting," she said.
Moreover, median progression-free survival with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.
"A very early but interesting progression-free survival of 6.75 months is quite intriguing," Dr. Brahmer said.
Enrollment is expected to begin this September in the phase III KEYNOTE-024 study comparing pembrolizumab monotherapy with platinum-based doublet chemotherapy in treatment-naive PD-L1 positive, metastatic non–small cell lung cancer (NSCLC), said Dr. Rizvi, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York.
Study details
Pembrolizumab, previously known as MK-3475, exerts dual ligand (PD-L1 and PD-L2) blockade of the programmed death 1 (PD-1) pathway. It is being investigated in more than 30 different cancers, and it made waves at the ASCO meeting for its treatment of metastatic melanoma.
Dr. Brahmer said that the key questions for the current study are whether PD-L1 sensitivity was the right biomarker to use and what the best cut-off is.
The KEYNOTE-001 study enrolled 84 previously untreated patients with stage IV NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Tumors were classified as PD-L1 positive in 57 patients, using a cut point of at least 1% of tumor cells stained, as measured using a prototype immunohistochemistry assay.
Of these 57 patients, 45 with evaluable imaging at baseline were randomly assigned to pembrolizumab 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Most patients (76%) had nonsquamous histology, and 69% were former smokers.
Patients received a median of nine doses (range 1-23) and spent an average of 154 days on therapy (range 1-400).
Tumor shrinkage by RECIST criteria occurred in 80% of patients with measurable disease and at least one postbaseline scan, Dr. Rizvi said. Activity was observed across dose levels and across the 2- and 3-week schedules.
Nine patients with new tumors would have been considered as having progressive disease and likely taken off therapy if they had been assessed by traditional RECIST criteria rather than irRC, "illustrating that RECIST may not be the best imaging modality to assess patients treated with immunotherapy," he said.
Grade 1-2 treatment-related events occurred in 36 of the 45 patients. The most common events were fatigue in 10 patients, pruritus in 6, and hypothyroidism in 4.
There was one each treatment-related grade 4 blood creatine phosphokinase elevation, grade 3 pericardial effusion, grade 3 pneumonitis, and grade 2 kidney injury, with two events leading to treatment discontinuation.
"Based on these safety data, we feel pembrolizumab is a safe and well-tolerated regimen," Dr. Rizvi said.
An additional 50 patients are being enrolled in the KEYNOTE-001 study, with the total population to be analyzed both with 1% and 45% cut points, he said.
The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.
CHICAGO – Monotherapy with the experimental anti-PD-1 antibody pembrolizumab induced durable treatment responses and slowed progression in previously untreated stage IV non–small cell lung cancer in an ongoing phase Ib trial.
The overall response rate was 26% (11 of 42 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and 47% (21 of 45 patients) by investigator-assessed, immune-related response criteria (irRC).
Responses are ongoing in 100% of responders by RECIST and 90% of responders by irRC, with the median duration of response not reached after a median of 36 weeks follow-up, Dr. Naiyer Rizvi said at the annual meeting of the American Society of Clinical Oncology.
Responses in the phase I KEYNOTE-001 study are very comparable with response rates of 15%-32% achieved with classic chemotherapy in the first-line setting in phase III studies using gemcitabine plus cisplatin, taxol plus carboplatin, or pemetrexed plus cisplatin, said invited discussant Dr. Julie Brahmer of Johns Hopkins University, Baltimore.
"The key thing [with pembrolizumab] is that these responses are very long lasting," she said.
Moreover, median progression-free survival with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.
"A very early but interesting progression-free survival of 6.75 months is quite intriguing," Dr. Brahmer said.
Enrollment is expected to begin this September in the phase III KEYNOTE-024 study comparing pembrolizumab monotherapy with platinum-based doublet chemotherapy in treatment-naive PD-L1 positive, metastatic non–small cell lung cancer (NSCLC), said Dr. Rizvi, a medical oncologist with Memorial Sloan Kettering Cancer Center in New York.
Study details
Pembrolizumab, previously known as MK-3475, exerts dual ligand (PD-L1 and PD-L2) blockade of the programmed death 1 (PD-1) pathway. It is being investigated in more than 30 different cancers, and it made waves at the ASCO meeting for its treatment of metastatic melanoma.
Dr. Brahmer said that the key questions for the current study are whether PD-L1 sensitivity was the right biomarker to use and what the best cut-off is.
The KEYNOTE-001 study enrolled 84 previously untreated patients with stage IV NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Tumors were classified as PD-L1 positive in 57 patients, using a cut point of at least 1% of tumor cells stained, as measured using a prototype immunohistochemistry assay.
Of these 57 patients, 45 with evaluable imaging at baseline were randomly assigned to pembrolizumab 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Most patients (76%) had nonsquamous histology, and 69% were former smokers.
Patients received a median of nine doses (range 1-23) and spent an average of 154 days on therapy (range 1-400).
Tumor shrinkage by RECIST criteria occurred in 80% of patients with measurable disease and at least one postbaseline scan, Dr. Rizvi said. Activity was observed across dose levels and across the 2- and 3-week schedules.
Nine patients with new tumors would have been considered as having progressive disease and likely taken off therapy if they had been assessed by traditional RECIST criteria rather than irRC, "illustrating that RECIST may not be the best imaging modality to assess patients treated with immunotherapy," he said.
Grade 1-2 treatment-related events occurred in 36 of the 45 patients. The most common events were fatigue in 10 patients, pruritus in 6, and hypothyroidism in 4.
There was one each treatment-related grade 4 blood creatine phosphokinase elevation, grade 3 pericardial effusion, grade 3 pneumonitis, and grade 2 kidney injury, with two events leading to treatment discontinuation.
"Based on these safety data, we feel pembrolizumab is a safe and well-tolerated regimen," Dr. Rizvi said.
An additional 50 patients are being enrolled in the KEYNOTE-001 study, with the total population to be analyzed both with 1% and 45% cut points, he said.
The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.
AT THE ASCO ANNUAL MEETING 2014
Key clinical point: Median progression-free survival with the classic chemotherapy doublets ranged from 4.5 months to 5.3 months but reached 6.75 months by RECIST and 9.25 months by irRC in the interim analysis of pembrolizumab.
Major finding: The overall response rate was 26% by RECIST criteria and 47% by investigator-assessed, immune-related response criteria.
Data source: An ongoing phase 1b study in 45 patients with previously untreated advanced NSCLC.
Disclosures: The study was supported by Merck. Dr. Rizvi reported a consultant or advisory role with Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, MedImmune, and Roche/Genentech.