Neil Osterweil

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.

Neil Osterweil/MDedge News

Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.

The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.

“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.

Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.

Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.

To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.

The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.

Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.

Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.

At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.

All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.

“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.

Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.

Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.

At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.

Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.

In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).

“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.

The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.

SOURCE: Short NJ et al. ASH 2019, Abstract 283.

ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.

Neil Osterweil/MDedge News

Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.

The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.

“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.

Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.

Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.

To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.

The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.

Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.

Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.

At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.

All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.

“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.

Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.

Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.

At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.

Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.

In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).

“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.

The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.

SOURCE: Short NJ et al. ASH 2019, Abstract 283.

ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.

Neil Osterweil/MDedge News

Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported Nicholas J. Short, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.

The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.

“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.

Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.

Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.

To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.

The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.

Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.

Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.

At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.

All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.

“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.

Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.

Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.

At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.

Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.

In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).

“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.

The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.

SOURCE: Short NJ et al. ASH 2019, Abstract 283.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

Adding intraoperative radiotherapy to the standard of care for patients with newly diagnosed glioblastoma appear to offer improved local control and survival, compared with those of historical controls without major adverse events, according to authors of a pooled analysis.

Among 51 patients who underwent tumor resection followed by intraoperative radiotherapy (IORT), standard adjuvant chemoradiotherapy, and chemotherapy maintenance, the estimated 2-year overall survival (OS) rate was 38.7%, compared with 26.5% at 2 years for patients who had received external beam radiotherapy (EBRT) and concomitant plus adjuvant temozolomide in a multinational phase 3 trial, reported Gustavo Sarria, MD, from University Medical Center Mannheim (Germany) and colleagues.

The median local progression-free survival (L-PFS) at a median follow-up of 18 months was 16 months, and the median distant PFS (D-PFS) was 30 months, indicating effective delay of tumor recurrence in a substantial proportion of patients.

“Intraoperative radiotherapy does not require extra radiation to travel through healthy tissue as compared to EBRT, thus allowing for local dose escalation at the site of most likely recurrence,” they wrote in Radiotherapy and Oncology.

The investigators performed a retrospective analysis of data on a total of 51 patients with a median age of 55 years who were treated with IORT and standard of care at five centers in Germany, Perum, and China. The patients all underwent brain surgery followed by a single IORT application at doses ranging from 10 to 40 Gy, with low-energy (50-kV) x-rays.

Following surgery, all patients received 60-Gy intensity-modulated or volumetric-modulated arc (IMRT-VMAT) EBRT and concomitant temozolomide chemotherapy followed by maintenance temozolomide.

At a median follow-up of 18 months the median OS was 18 months, median overall PFS was 11.4 months, median L-PFS (new lesions 1 cm or less from the tumor cavity border) was 16 months, and median D-PFS (new lesions more than 1 cm from the tumor cavity border) was 30 months.

The estimated Kaplan-Meier 1-, 2-, and 3-year OS rates were 79.5%, 38.7%, and 25.6%, respectively. The estimated median PFS over the same time points was 46.2%, 29.4%, and 5.9. The 1-, 2-, and 3-year estimated L-PFS was 60.9%, 37.9%, and 12.6%, and D-FPS rates were 76.7%, 65.0%, and 39.0% respectively.

In slightly more than one-third of the cases (35.3%), the first progression occurred locally. Grade 1 radionecrosis occurred in 7.8% of patients, and 17.6% had grade 3 radionecrosis. There were no grade 4 toxicities reported, and no treatment-related deaths.

The investigators noted that IORT added to standard of care is being tested against standard care alone in a multinational phase 3 randomized trial (NCT02685605).

The authors did not receive outside funding for the study. Dr. Sarria reported Grants from Carl Zeiss Meditec outside the submitted work.

SOURCE: Sarria G et al. J Rad Oncol. 2019 Oct 16. doi: 10.1016/j.radonc.2019.09.023.

Adding intraoperative radiotherapy to the standard of care for patients with newly diagnosed glioblastoma appear to offer improved local control and survival, compared with those of historical controls without major adverse events, according to authors of a pooled analysis.

Among 51 patients who underwent tumor resection followed by intraoperative radiotherapy (IORT), standard adjuvant chemoradiotherapy, and chemotherapy maintenance, the estimated 2-year overall survival (OS) rate was 38.7%, compared with 26.5% at 2 years for patients who had received external beam radiotherapy (EBRT) and concomitant plus adjuvant temozolomide in a multinational phase 3 trial, reported Gustavo Sarria, MD, from University Medical Center Mannheim (Germany) and colleagues.

The median local progression-free survival (L-PFS) at a median follow-up of 18 months was 16 months, and the median distant PFS (D-PFS) was 30 months, indicating effective delay of tumor recurrence in a substantial proportion of patients.

“Intraoperative radiotherapy does not require extra radiation to travel through healthy tissue as compared to EBRT, thus allowing for local dose escalation at the site of most likely recurrence,” they wrote in Radiotherapy and Oncology.

The investigators performed a retrospective analysis of data on a total of 51 patients with a median age of 55 years who were treated with IORT and standard of care at five centers in Germany, Perum, and China. The patients all underwent brain surgery followed by a single IORT application at doses ranging from 10 to 40 Gy, with low-energy (50-kV) x-rays.

Following surgery, all patients received 60-Gy intensity-modulated or volumetric-modulated arc (IMRT-VMAT) EBRT and concomitant temozolomide chemotherapy followed by maintenance temozolomide.

At a median follow-up of 18 months the median OS was 18 months, median overall PFS was 11.4 months, median L-PFS (new lesions 1 cm or less from the tumor cavity border) was 16 months, and median D-PFS (new lesions more than 1 cm from the tumor cavity border) was 30 months.

The estimated Kaplan-Meier 1-, 2-, and 3-year OS rates were 79.5%, 38.7%, and 25.6%, respectively. The estimated median PFS over the same time points was 46.2%, 29.4%, and 5.9. The 1-, 2-, and 3-year estimated L-PFS was 60.9%, 37.9%, and 12.6%, and D-FPS rates were 76.7%, 65.0%, and 39.0% respectively.

In slightly more than one-third of the cases (35.3%), the first progression occurred locally. Grade 1 radionecrosis occurred in 7.8% of patients, and 17.6% had grade 3 radionecrosis. There were no grade 4 toxicities reported, and no treatment-related deaths.

The investigators noted that IORT added to standard of care is being tested against standard care alone in a multinational phase 3 randomized trial (NCT02685605).

The authors did not receive outside funding for the study. Dr. Sarria reported Grants from Carl Zeiss Meditec outside the submitted work.

SOURCE: Sarria G et al. J Rad Oncol. 2019 Oct 16. doi: 10.1016/j.radonc.2019.09.023.

Adding intraoperative radiotherapy to the standard of care for patients with newly diagnosed glioblastoma appear to offer improved local control and survival, compared with those of historical controls without major adverse events, according to authors of a pooled analysis.

Among 51 patients who underwent tumor resection followed by intraoperative radiotherapy (IORT), standard adjuvant chemoradiotherapy, and chemotherapy maintenance, the estimated 2-year overall survival (OS) rate was 38.7%, compared with 26.5% at 2 years for patients who had received external beam radiotherapy (EBRT) and concomitant plus adjuvant temozolomide in a multinational phase 3 trial, reported Gustavo Sarria, MD, from University Medical Center Mannheim (Germany) and colleagues.

The median local progression-free survival (L-PFS) at a median follow-up of 18 months was 16 months, and the median distant PFS (D-PFS) was 30 months, indicating effective delay of tumor recurrence in a substantial proportion of patients.

“Intraoperative radiotherapy does not require extra radiation to travel through healthy tissue as compared to EBRT, thus allowing for local dose escalation at the site of most likely recurrence,” they wrote in Radiotherapy and Oncology.

The investigators performed a retrospective analysis of data on a total of 51 patients with a median age of 55 years who were treated with IORT and standard of care at five centers in Germany, Perum, and China. The patients all underwent brain surgery followed by a single IORT application at doses ranging from 10 to 40 Gy, with low-energy (50-kV) x-rays.

Following surgery, all patients received 60-Gy intensity-modulated or volumetric-modulated arc (IMRT-VMAT) EBRT and concomitant temozolomide chemotherapy followed by maintenance temozolomide.

At a median follow-up of 18 months the median OS was 18 months, median overall PFS was 11.4 months, median L-PFS (new lesions 1 cm or less from the tumor cavity border) was 16 months, and median D-PFS (new lesions more than 1 cm from the tumor cavity border) was 30 months.

The estimated Kaplan-Meier 1-, 2-, and 3-year OS rates were 79.5%, 38.7%, and 25.6%, respectively. The estimated median PFS over the same time points was 46.2%, 29.4%, and 5.9. The 1-, 2-, and 3-year estimated L-PFS was 60.9%, 37.9%, and 12.6%, and D-FPS rates were 76.7%, 65.0%, and 39.0% respectively.

In slightly more than one-third of the cases (35.3%), the first progression occurred locally. Grade 1 radionecrosis occurred in 7.8% of patients, and 17.6% had grade 3 radionecrosis. There were no grade 4 toxicities reported, and no treatment-related deaths.

The investigators noted that IORT added to standard of care is being tested against standard care alone in a multinational phase 3 randomized trial (NCT02685605).

The authors did not receive outside funding for the study. Dr. Sarria reported Grants from Carl Zeiss Meditec outside the submitted work.

SOURCE: Sarria G et al. J Rad Oncol. 2019 Oct 16. doi: 10.1016/j.radonc.2019.09.023.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.

Neil Osterweil/MDedge News

Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.

“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.

The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.

Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).

After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.

At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.

When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:

• Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
• Stage IIB: 56.2% versus 48.4%, difference 7.8%.
• Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
• Stage IIIB: 48.6% versus 23.1%, difference 25.6%.

The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.

There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).

pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).

Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).

The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).

“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.

Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.

“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”

“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.

The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.

SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.

SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.

Neil Osterweil/MDedge News

Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.

“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.

The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.

Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).

After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.

At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.

When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:

• Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
• Stage IIB: 56.2% versus 48.4%, difference 7.8%.
• Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
• Stage IIIB: 48.6% versus 23.1%, difference 25.6%.

The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.

There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).

pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).

Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).

The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).

“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.

Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.

“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”

“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.

The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.

SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.

SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.

Neil Osterweil/MDedge News

Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.

“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.

The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.

Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).

After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.

At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.

When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:

• Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
• Stage IIB: 56.2% versus 48.4%, difference 7.8%.
• Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
• Stage IIIB: 48.6% versus 23.1%, difference 25.6%.

The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.

There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).

pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).

Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).

The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).

“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.

Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.

“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”

“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.

The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.

SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

ORLANDO – An investigational selective inhibitor of the complement pathway, sutimlimab, induced rapid and sustained benefits in patients with cold agglutinin disease, a rare autoimmune hemolytic anemia with no currently approved effective therapies.

Neil Osterweil/MDedge News

Among 24 patients with cold agglutinin disease who received at least one dose of sutimlimab in a phase 3 trial, 20 had a mean increase in hemoglobin of at least 1 g/dL, and 17 remained transfusion free from weeks 5 to 26 following sutimlimab infusion.

“Sutimlimab has the potential to change treatment practices for patients with this disease,” said lead author Alexander Röth, MD, from the University of Duisburg-Essen (Germany), at a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Mean total bilirubin rapidly normalized within 1-3 weeks of infusion of sutimlimab, and patients had a mean improvement of 11 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (FACIT-F), indicating a substantial improvement in their quality of life, Dr. Röth said.

Cold agglutinin disease is an acquired hemolytic anemia with an underlying lymphoproliferative disorder. The estimated prevalence of the disease is 16 per 1 million persons. The disease is characterized by hemolysis driven by activation of the complement pathway, leading to opsonization of erythrocytes (coating of erythrocytes with particles that facilitate phagocytosis and other immune reactions), extravascular hemolysis (primarily in the liver), intravascular hemolysis, and anemia.

Patients experience severe fatigue and poor quality of life, as well as increased risk for thrombosis and mortality, compared with matched cohorts.

Sutimlimab is a humanized monoclonal antibody that blocks the C1s component of the classical complement pathway, thereby stopping pathway activation while leaving alternative lectin pathways intact.

Dr. Röth presented results of the phase 3, open-label Cardinal study. Patients with cold agglutinin disease with baseline hemoglobin of 10 g/dL or less, active hemolysis signaled by total bilirubin levels above normal, and at least one blood transfusion within the past 6 months were eligible for the study. Patients with secondary cold agglutinin syndrome or rituximab therapy within the last 3 months or combination therapies within the last 6 months were excluded.

Sutimlimab was delivered intravenously at a dose of 6.5 g for patients under 75 kg in weight and 7.5 g for those 75 kg and over at day 0 and 7, then every 2 weeks thereafter.

A total of 24 patients with a mean age of 71 years were enrolled. Of the 24 patients, 15 (62.5%) were women.

The patients had received a mean of 3.2 transfusions (range 1-19) in the previous 6 months, and 15 had received one or more prior targeted therapies for the disease within the last 5 years. The mean baseline hemoglobin level was 8.6 (range 4.9-11.1) g/dL.

Hemoglobin levels increased rapidly after the first infusion, with a mean increase of 1.2 g/dL at the end of week 1, and 2.3 g/dL after week 3.

The estimated mean increase at treatment assessment (an average of weeks 23, 25, and 26) – the primary endpoint – was 2.6 g/dL, exceeding the prespecified increase of at least 2 g/dL. Normalization of hemoglobin to 12 g/dL or greater was an alternative primary endpoint. The trial met the primary endpoint, with 13 of 24 patients (54.2%) achieving either of the two prespecified events.

The mean overall hemoglobin level was maintained above 11 g/dL after week 3. Of the 24 patients, 20 had hemoglobin increases of 1 g/dL or greater.

Mean total bilirubin, a marker of hemolysis, dropped markedly within hours of infusion and was normalized by week 3.

As noted before, patient quality of life, as measured by the FACIT-F scale, improved by a mean of 11 points from a mean baseline of 32 out of 52 points.

All but two patients had one or more treatment-emergent adverse events, and seven of these patients had a serious treatment-related event, although none of the serious events were thought to be related to sutimlimab. One patient with liver cancer died from causes deemed unrelated to the drug. There were no meningococcal infections.

All 22 patients who completed the 26 weeks of therapy continued on an extended safety phase of the study.

The study results demonstrate that targeting the complement pathways is an novel and effective approach to managing cold agglutinin disease, Dr. Röth concluded.

Neil Osterweil/MDedge News

In a press briefing the day before the presentation, moderator Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School, Baltimore, who treats patients with cold agglutinin disease, said that the results “are very exciting.”

“These patients are very difficult to treat and there really is no approved drug,” he said. “Right now, we usually use [rituximab] first line, but only half of those patients respond, and usually it only lasts for 6 months or so, so this is a welcome addition.”

Sutimlimab was granted Breakthrough Therapy designation by the Food and Drug Administration, and Orphan Drug status by the FDA, European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.

The study was supported by Sanofi. Dr. Röth reported financial relationships with Sanofi and other companies.

SOURCE: Röth A et al. ASH 2019, Abstract LBA-2.

SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.

The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.

“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.

Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.

Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.

“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.

Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.

Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.

In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.

The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
 

Study details

DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.

As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.

ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.

The median time to response was 1.6 month, and the median duration of response was 14.8 months.

The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.

Interstitial lung disease

After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.

A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.

In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.

The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.

However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.

“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.

The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.

SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.

SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.

The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.

“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.

Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.

Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.

“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.

Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.

Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.

In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.

The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
 

Study details

DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.

As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.

ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.

The median time to response was 1.6 month, and the median duration of response was 14.8 months.

The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.

Interstitial lung disease

After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.

A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.

In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.

The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.

However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.

“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.

The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.

SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.

SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.

The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.

“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.

Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.

Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.

“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.

Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.

Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.

In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.

The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
 

Study details

DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.

As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.

ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.

The median time to response was 1.6 month, and the median duration of response was 14.8 months.

The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.

Interstitial lung disease

After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.

A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.

In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.

The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.

However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.

“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.

The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.

SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.