User login
Len plus anti-CD19 Mab MOR208 active against advanced DLBCL
LUGANO, SWITZERLAND – Combining lenalidomide (Revlimid) with an anti-CD19 monoclonal antibody labeled MOR208 showed promising activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were ineligible for stem cell transplant and had poor prognosis, early interim results from a clinical study indicate.
Among 34 patients evaluable for response, the preliminary objective response rate (ORR) was 56%, including complete responses in 32% of patients, reported Gilles Salles, MD, PhD, of the University of Lyon, France.
MOR208 is a humanized anti-CD19 monoclonal antibody with the Fc-antibody region enhanced to improve cytotoxicity. Its mechanisms of action include natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct cytotoxicity.
In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro, Dr. Salles said.
In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.
In an ongoing phase II, open-label study, Dr. Salles and his colleagues are enrolling transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.
Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other NHL histological subtypes, or central nervous system lymphoma involvement are excluded.
Patients receive MOR208 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally is delivered on days 1-21 of each cycle. Patients who have stable disease or better at the end of 12 cycles can be maintained on MOR208 at the same dose on days 1 and 15.
As of the data cutoff on March 6, 2017, 44 patients had been enrolled, and 34 were evaluable for response. The median patient age was 73 years (range, 47-82 years).
At the time of the data presentation, ORR, the primary endpoint, was 56%, consisting of 32% complete responses (11 patients), 24% partial responses (8), 12% stable disease (4), and 32% of patients who either had disease progression or had not yet had a postbaseline response assessment.
The median time to response was 1.8 months, with a median time to complete response of 3.4 months. Of 19 responders, 16 continue to have a response, including 10 of 11 patients with complete responses.
The most common grade 3 or 4 hematologic toxicities were neutropenia, anemia, and thrombocytopenia. Nonhematologic toxicities of any grade included rashes in 20% of patients, pyrexia in 16%, diarrhea in 16%, asthenia in 14%, and pneumonia, bronchitis, and nausea in 11% each.
There were no reported infusion-related reactions with the antibody. In all, 27% of patients required a lenalidomide dose reduction – to 20 mg/day in 20% of patients and to 15 mg/day in 7%.
Study accrual, follow-up of patients on therapy, investigations of cell origin, and subgroup analyses are ongoing.
MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor/consultant to many of the same companies.
LUGANO, SWITZERLAND – Combining lenalidomide (Revlimid) with an anti-CD19 monoclonal antibody labeled MOR208 showed promising activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were ineligible for stem cell transplant and had poor prognosis, early interim results from a clinical study indicate.
Among 34 patients evaluable for response, the preliminary objective response rate (ORR) was 56%, including complete responses in 32% of patients, reported Gilles Salles, MD, PhD, of the University of Lyon, France.
MOR208 is a humanized anti-CD19 monoclonal antibody with the Fc-antibody region enhanced to improve cytotoxicity. Its mechanisms of action include natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct cytotoxicity.
In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro, Dr. Salles said.
In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.
In an ongoing phase II, open-label study, Dr. Salles and his colleagues are enrolling transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.
Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other NHL histological subtypes, or central nervous system lymphoma involvement are excluded.
Patients receive MOR208 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally is delivered on days 1-21 of each cycle. Patients who have stable disease or better at the end of 12 cycles can be maintained on MOR208 at the same dose on days 1 and 15.
As of the data cutoff on March 6, 2017, 44 patients had been enrolled, and 34 were evaluable for response. The median patient age was 73 years (range, 47-82 years).
At the time of the data presentation, ORR, the primary endpoint, was 56%, consisting of 32% complete responses (11 patients), 24% partial responses (8), 12% stable disease (4), and 32% of patients who either had disease progression or had not yet had a postbaseline response assessment.
The median time to response was 1.8 months, with a median time to complete response of 3.4 months. Of 19 responders, 16 continue to have a response, including 10 of 11 patients with complete responses.
The most common grade 3 or 4 hematologic toxicities were neutropenia, anemia, and thrombocytopenia. Nonhematologic toxicities of any grade included rashes in 20% of patients, pyrexia in 16%, diarrhea in 16%, asthenia in 14%, and pneumonia, bronchitis, and nausea in 11% each.
There were no reported infusion-related reactions with the antibody. In all, 27% of patients required a lenalidomide dose reduction – to 20 mg/day in 20% of patients and to 15 mg/day in 7%.
Study accrual, follow-up of patients on therapy, investigations of cell origin, and subgroup analyses are ongoing.
MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor/consultant to many of the same companies.
LUGANO, SWITZERLAND – Combining lenalidomide (Revlimid) with an anti-CD19 monoclonal antibody labeled MOR208 showed promising activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were ineligible for stem cell transplant and had poor prognosis, early interim results from a clinical study indicate.
Among 34 patients evaluable for response, the preliminary objective response rate (ORR) was 56%, including complete responses in 32% of patients, reported Gilles Salles, MD, PhD, of the University of Lyon, France.
MOR208 is a humanized anti-CD19 monoclonal antibody with the Fc-antibody region enhanced to improve cytotoxicity. Its mechanisms of action include natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct cytotoxicity.
In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro, Dr. Salles said.
In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.
In an ongoing phase II, open-label study, Dr. Salles and his colleagues are enrolling transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.
Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other NHL histological subtypes, or central nervous system lymphoma involvement are excluded.
Patients receive MOR208 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally is delivered on days 1-21 of each cycle. Patients who have stable disease or better at the end of 12 cycles can be maintained on MOR208 at the same dose on days 1 and 15.
As of the data cutoff on March 6, 2017, 44 patients had been enrolled, and 34 were evaluable for response. The median patient age was 73 years (range, 47-82 years).
At the time of the data presentation, ORR, the primary endpoint, was 56%, consisting of 32% complete responses (11 patients), 24% partial responses (8), 12% stable disease (4), and 32% of patients who either had disease progression or had not yet had a postbaseline response assessment.
The median time to response was 1.8 months, with a median time to complete response of 3.4 months. Of 19 responders, 16 continue to have a response, including 10 of 11 patients with complete responses.
The most common grade 3 or 4 hematologic toxicities were neutropenia, anemia, and thrombocytopenia. Nonhematologic toxicities of any grade included rashes in 20% of patients, pyrexia in 16%, diarrhea in 16%, asthenia in 14%, and pneumonia, bronchitis, and nausea in 11% each.
There were no reported infusion-related reactions with the antibody. In all, 27% of patients required a lenalidomide dose reduction – to 20 mg/day in 20% of patients and to 15 mg/day in 7%.
Study accrual, follow-up of patients on therapy, investigations of cell origin, and subgroup analyses are ongoing.
MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor/consultant to many of the same companies.
AT 14-ICML
Key clinical point: A combination of the anti-CD19 monoclonal antibody MOR208 and the immunomodulator lenalidomide has shown good activity against relapsed/refractory diffuse large B-cell lymphoma.
Major finding: The preliminary objective response rate was 56%, including 32% complete responses.
Data source: An ongoing open-label phase II study with 44 patients out of a planned 80 enrolled.
Disclosures: MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor or consultant to many of the same companies.
Hitting BTK, PI3K pays off in B-cell malignancies
LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.
One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).
“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.
In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.
Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.
All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.
For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.
Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.
One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.
The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.
The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.
The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.
The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.
One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).
“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.
In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.
Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.
All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.
For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.
Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.
One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.
The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.
The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.
The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.
The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.
One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).
“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.
In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.
Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.
All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.
For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.
Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.
One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.
The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.
The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.
The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.
The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
AT 14-ICML
Key clinical point:
Major finding: The objective response rate to the combination was 94% in 18 patients with chronic lymphocytic leukemia and 79% in 14 patients with mantle cell lymphoma.
Data source: A phase I/IB dose-escalation study.
Disclosures: The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
Novel CAR T cells drive high objective response rate in multiple myeloma
CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.
“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”
Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.
B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.
In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.
Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.
No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.
One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.
The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.
Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).
The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.
The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.
The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.
“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”
Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.
B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.
In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.
Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.
No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.
One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.
The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.
Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).
The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.
The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.
The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
CHICAGO – CARs just keep getting better: In an early clinical trial, a chimeric antigen receptor (CAR) T-cell construct targeting B-cell maturation protein induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
“In our current trials we have observed revolutionary, quick, and durable remissions in patients with multiple myeloma,” said Wanhong Zhao, MD, of the Second Affiliated Hospital of Xi’an (China) Jiaotong University.
“I think what you’re seeing here is the expansion of immunotherapy to cancers that really are refractory to chemotherapy and how immunotherapy is now providing hope to a lot of patients with cancers that were not really responding to our standard chemotherapies,” commented ASCO expert Michael S. Sabel, MD, of the University of Michigan, Ann Arbor. “What I also think is really fascinating about this and similar forms of research is that you are now seeing the merger of immunotherapy with personalized medicine.”
Current CAR T-cell technologies targeting CD19 or a similar antigen have shown efficacy against acute lymphoblastic leukemia and some forms of lymphoma, but it has been difficult to identify a suitable target in multiple myeloma.
B-cell maturation antigen (BCMA) was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.
Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA.
In the study by Dr. Zhao and his colleagues, 19 patients had been followed for more than 4 months before the data cutoff in January 2017. Four months is the minimum established by the International Myeloma Working Group for efficacy assessment.
Of the 19 patients, 14 had achieved a stringent complete response (sCR), 4 had very good partial responses, and 1 had a partial response, for an objective response rate of 100%.
No patients who achieved an sCR have had relapses, and all five patients who have been in follow-up for more than a year have maintained their sCRs and are free of minimal residual disease, Dr. Zhao reported.
One patient with a very good partial response had disease progression, with recurrence of an extramedullary lesion that had previously disappeared.
The most common adverse event was cytokine release syndrome, which occurred in 85% of patients, but the condition was transient and manageable in a majority, Dr. Zhao said.
Two patients developed grade 3 cytokine release syndrome and were treated with tocilizumab (Actemra).
The investigators plan to enroll a total of 100 patients from participating hospitals in China and are planning a U.S. trial for launch in early 2018.
The investigators hope to look at BCMA CAR-T cell therapy in the frontline for patients with newly diagnosed multiple myeloma.
The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
AT THE 2017 ASCO ANNUAL MEETING
Key clinical point: All of 19 patients treated with the CAR T-cell construct targeting B-cell maturation antigen had an objective response.
Major finding: Of 35 patients with relapsed/refractory multiple myeloma treated with BCMA, 33 had remissions.
Data source: A prospective single-arm study of 35 patients, with enrollment planned for 100.
Disclosures: The study was funded by Legend Biotech. Coauthor Fran (Xiaohu) Fan, MD, PhD, is employed by the company. Dr. Zhao did not report disclosures. Dr. Sabel had no disclosures relevant to the study.
T-DMI doesn’t wow in HER2-overexpressing NSCLC
CHICAGO –Beyond its role in advanced breast cancer, the antibody-drug conjugate ado-trastuzumab-emtansine (T-DM1; Kadcyla) showed modest activity in some patients with metastatic non–small cell lung cancer (mNSCLC) overexpressing the human epidermal growth factor-2 (HER2) receptor, investigators reported.
In an ongoing phase II study, 4 of 20 patients with mNSCLC whose tumors expressed the highest levels of HER2 had partial responses. In contrast, none of the 20 patients with tumors overexpressing HER2 at lower levels had responses, reported Thomas E. Stinchcombe, MD, of Duke University, Durham, N.C.
Previous studies have shown that HER2 overexpression by immunohistochemistry (IHC) is associated with poor prognosis in patients with NSCLC, but in contrast to breast and gastric cancers, HER2 overexpression in NSCLC is not always accompanied by HER2 amplifications.
“HER2 amplifications and HER2 mutations are generally mutually exclusive in NSCLC. Given the known mechanism of action of T-DM1, HER2 overexpression was chosen as an inclusion criterion for this study,” Dr. Stinchcombe said.
They enrolled patients with HER2-overexpressing mNSCLC who had disease progression following platinum-based chemotherapy. The patients were assigned to one of two 20-patient cohorts based on IHC2+ (10% or more of cells stained with 2+ intensity), or IHC3+ (10% or more of cells stained with 3+intensity).
For the primary endpoint of treatment response none of the patients in the IHC2+ cohort had objective responses by Response Evaluation Criteria in Solid Tumors (RECIST), although eight patients in this cohort had stable disease, including one patient who remained in stable disease status on treatment out to 21 months at last follow-up.
In the IHC3+ cohort, four patients had partial responses, for an objective response rate of 20%. The median duration of response was 7.3 months. Two patients in this cohort had stable disease.
Median PFS was similar between the cohorts, at 2.6 months for IHC2+ and 2.7 months for IHC3+. The respective median OS durations were 12.2 and 12.1 months.
The safety profile of T-DM1 in this population was similar to that seen in breast cancer. There were two grade 3 serious adverse events: one infusion-related hypersensitivity reaction, and one case of thrombocytopenia. There were 10 grade 3 events of any kind, 1 grade 4 event, and 1 treatment withdrawal due to a grade 2 infusion reaction.
“I think it’s honestly a little hard to tell from this study, which is very small, whether there is really a role of [HER2] overexpression in actually driving oncogenesis and being a target for T-DM1,” she said.
Dr. Stinchcombe reported institutional research funding from Hoffmann-LaRoche, which sponsored the trial, and several coauthors are employees of the company.
CHICAGO –Beyond its role in advanced breast cancer, the antibody-drug conjugate ado-trastuzumab-emtansine (T-DM1; Kadcyla) showed modest activity in some patients with metastatic non–small cell lung cancer (mNSCLC) overexpressing the human epidermal growth factor-2 (HER2) receptor, investigators reported.
In an ongoing phase II study, 4 of 20 patients with mNSCLC whose tumors expressed the highest levels of HER2 had partial responses. In contrast, none of the 20 patients with tumors overexpressing HER2 at lower levels had responses, reported Thomas E. Stinchcombe, MD, of Duke University, Durham, N.C.
Previous studies have shown that HER2 overexpression by immunohistochemistry (IHC) is associated with poor prognosis in patients with NSCLC, but in contrast to breast and gastric cancers, HER2 overexpression in NSCLC is not always accompanied by HER2 amplifications.
“HER2 amplifications and HER2 mutations are generally mutually exclusive in NSCLC. Given the known mechanism of action of T-DM1, HER2 overexpression was chosen as an inclusion criterion for this study,” Dr. Stinchcombe said.
They enrolled patients with HER2-overexpressing mNSCLC who had disease progression following platinum-based chemotherapy. The patients were assigned to one of two 20-patient cohorts based on IHC2+ (10% or more of cells stained with 2+ intensity), or IHC3+ (10% or more of cells stained with 3+intensity).
For the primary endpoint of treatment response none of the patients in the IHC2+ cohort had objective responses by Response Evaluation Criteria in Solid Tumors (RECIST), although eight patients in this cohort had stable disease, including one patient who remained in stable disease status on treatment out to 21 months at last follow-up.
In the IHC3+ cohort, four patients had partial responses, for an objective response rate of 20%. The median duration of response was 7.3 months. Two patients in this cohort had stable disease.
Median PFS was similar between the cohorts, at 2.6 months for IHC2+ and 2.7 months for IHC3+. The respective median OS durations were 12.2 and 12.1 months.
The safety profile of T-DM1 in this population was similar to that seen in breast cancer. There were two grade 3 serious adverse events: one infusion-related hypersensitivity reaction, and one case of thrombocytopenia. There were 10 grade 3 events of any kind, 1 grade 4 event, and 1 treatment withdrawal due to a grade 2 infusion reaction.
“I think it’s honestly a little hard to tell from this study, which is very small, whether there is really a role of [HER2] overexpression in actually driving oncogenesis and being a target for T-DM1,” she said.
Dr. Stinchcombe reported institutional research funding from Hoffmann-LaRoche, which sponsored the trial, and several coauthors are employees of the company.
CHICAGO –Beyond its role in advanced breast cancer, the antibody-drug conjugate ado-trastuzumab-emtansine (T-DM1; Kadcyla) showed modest activity in some patients with metastatic non–small cell lung cancer (mNSCLC) overexpressing the human epidermal growth factor-2 (HER2) receptor, investigators reported.
In an ongoing phase II study, 4 of 20 patients with mNSCLC whose tumors expressed the highest levels of HER2 had partial responses. In contrast, none of the 20 patients with tumors overexpressing HER2 at lower levels had responses, reported Thomas E. Stinchcombe, MD, of Duke University, Durham, N.C.
Previous studies have shown that HER2 overexpression by immunohistochemistry (IHC) is associated with poor prognosis in patients with NSCLC, but in contrast to breast and gastric cancers, HER2 overexpression in NSCLC is not always accompanied by HER2 amplifications.
“HER2 amplifications and HER2 mutations are generally mutually exclusive in NSCLC. Given the known mechanism of action of T-DM1, HER2 overexpression was chosen as an inclusion criterion for this study,” Dr. Stinchcombe said.
They enrolled patients with HER2-overexpressing mNSCLC who had disease progression following platinum-based chemotherapy. The patients were assigned to one of two 20-patient cohorts based on IHC2+ (10% or more of cells stained with 2+ intensity), or IHC3+ (10% or more of cells stained with 3+intensity).
For the primary endpoint of treatment response none of the patients in the IHC2+ cohort had objective responses by Response Evaluation Criteria in Solid Tumors (RECIST), although eight patients in this cohort had stable disease, including one patient who remained in stable disease status on treatment out to 21 months at last follow-up.
In the IHC3+ cohort, four patients had partial responses, for an objective response rate of 20%. The median duration of response was 7.3 months. Two patients in this cohort had stable disease.
Median PFS was similar between the cohorts, at 2.6 months for IHC2+ and 2.7 months for IHC3+. The respective median OS durations were 12.2 and 12.1 months.
The safety profile of T-DM1 in this population was similar to that seen in breast cancer. There were two grade 3 serious adverse events: one infusion-related hypersensitivity reaction, and one case of thrombocytopenia. There were 10 grade 3 events of any kind, 1 grade 4 event, and 1 treatment withdrawal due to a grade 2 infusion reaction.
“I think it’s honestly a little hard to tell from this study, which is very small, whether there is really a role of [HER2] overexpression in actually driving oncogenesis and being a target for T-DM1,” she said.
Dr. Stinchcombe reported institutional research funding from Hoffmann-LaRoche, which sponsored the trial, and several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: Some non–small cell lung cancer (NSCLC) tumors overexpress HER2, suggesting the use of T-DM1, an anti-HER2 antibody drug conjugate.
Major finding: Four of 20 patients with HER2-overexpressing NSCLC has partial responses to T-DM1 therapy.
Data source: Open-label prospective trial of 40 patients with NSCLC positive for HER2.
Disclosures: Dr. Stinchcombe reported institutional research funding from Hoffmann-LaRoche, which sponsored the trial, and several coauthors are employees of the company.
Alectinib in ALK+ NSCLC is a watershed moment
CHICAGO – In what’s being hailed as practice-changing findings, the anaplastic lymphoma kinase inhibitor alectinib (Alecensa) was associated with more than doubled progression-free survival (PFS), compared with crizotinib (Xalkori), the current standard of care, in patients with treatment-naive non–small cell lung cancer (NSCLC) positive for ALK.
Additionally, in the global, phase III trial, alectinib was associated with a significantly lower risk of progression to CNS metastases, a common complication of advanced ALK+ NSCLC, reported Alice T. Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, on behalf of investigators in the ALEX trial.
“I view this as a watershed moment for the treatment of ALK mutant–positive lung cancer,” commented ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
Unlike other head-to-head studies of similar drugs that frequently show only incremental benefit, the ALEX results showed a dramatic difference in outcomes for patients treated with alectinib, he said.
By comparison, the median PFS difference between chemotherapy and crizotinib in the PROFILE 1014 in patients with ALK-positive NSCLC trial was 10.9 vs. 7.0 months, Dr. Heymach pointed out.
The ALEX investigators enrolled 303 patients with untreated ALK-positive NSCLC confirmed by a central immunohistochemistry lab and randomly assigned them to treatment with either oral alectinib 600 mg twice daily or crizotinib 250 mg b.i.d.
At the primary data cutoff in February 2017, median PFS, the primary endpoint, was 11.1 months for patients treated with crizotinib, versus not reached for those treated with alectinib, translating into a hazard ratio for alectinib of 0.47 (P less than .0001).
Based on an independent review, the median PFS was determined to be 10.4 months for crizotinib, vs. 25.7 months with alectinib (HR, 0.50; P not shown).
The cumulative incidence of CNS progression, a secondary endpoint, was 41.4% in the crizotinib arm, vs. 9.41% in the alectinib arm (cause-specific HR, 0.16; P not shown).
In each arm, 97% of patients had any adverse event, and the incidence of serious adverse events was similar between the arms, at 29% for crizotinib and 28% for alectinib.
Adverse events leading to treatment discontinuation, dose reduction, or dose interruption were more frequent with crizotinib.
In the question and answer portion of the briefing, Dr. Shaw was asked whether crizotinib still had a role in this population.
“Going forward, I think that it’s pretty clear, if you have a newly diagnosed patient with metastatic ALK-positive lung cancer, that likely alectinib would be the preferred first choice,” she said.
The ALEX trial is supported by Roche. Dr. Shaw disclosed consulting or an advisory role with the company, and multiple coauthors disclosed similar relationships.
CHICAGO – In what’s being hailed as practice-changing findings, the anaplastic lymphoma kinase inhibitor alectinib (Alecensa) was associated with more than doubled progression-free survival (PFS), compared with crizotinib (Xalkori), the current standard of care, in patients with treatment-naive non–small cell lung cancer (NSCLC) positive for ALK.
Additionally, in the global, phase III trial, alectinib was associated with a significantly lower risk of progression to CNS metastases, a common complication of advanced ALK+ NSCLC, reported Alice T. Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, on behalf of investigators in the ALEX trial.
“I view this as a watershed moment for the treatment of ALK mutant–positive lung cancer,” commented ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
Unlike other head-to-head studies of similar drugs that frequently show only incremental benefit, the ALEX results showed a dramatic difference in outcomes for patients treated with alectinib, he said.
By comparison, the median PFS difference between chemotherapy and crizotinib in the PROFILE 1014 in patients with ALK-positive NSCLC trial was 10.9 vs. 7.0 months, Dr. Heymach pointed out.
The ALEX investigators enrolled 303 patients with untreated ALK-positive NSCLC confirmed by a central immunohistochemistry lab and randomly assigned them to treatment with either oral alectinib 600 mg twice daily or crizotinib 250 mg b.i.d.
At the primary data cutoff in February 2017, median PFS, the primary endpoint, was 11.1 months for patients treated with crizotinib, versus not reached for those treated with alectinib, translating into a hazard ratio for alectinib of 0.47 (P less than .0001).
Based on an independent review, the median PFS was determined to be 10.4 months for crizotinib, vs. 25.7 months with alectinib (HR, 0.50; P not shown).
The cumulative incidence of CNS progression, a secondary endpoint, was 41.4% in the crizotinib arm, vs. 9.41% in the alectinib arm (cause-specific HR, 0.16; P not shown).
In each arm, 97% of patients had any adverse event, and the incidence of serious adverse events was similar between the arms, at 29% for crizotinib and 28% for alectinib.
Adverse events leading to treatment discontinuation, dose reduction, or dose interruption were more frequent with crizotinib.
In the question and answer portion of the briefing, Dr. Shaw was asked whether crizotinib still had a role in this population.
“Going forward, I think that it’s pretty clear, if you have a newly diagnosed patient with metastatic ALK-positive lung cancer, that likely alectinib would be the preferred first choice,” she said.
The ALEX trial is supported by Roche. Dr. Shaw disclosed consulting or an advisory role with the company, and multiple coauthors disclosed similar relationships.
CHICAGO – In what’s being hailed as practice-changing findings, the anaplastic lymphoma kinase inhibitor alectinib (Alecensa) was associated with more than doubled progression-free survival (PFS), compared with crizotinib (Xalkori), the current standard of care, in patients with treatment-naive non–small cell lung cancer (NSCLC) positive for ALK.
Additionally, in the global, phase III trial, alectinib was associated with a significantly lower risk of progression to CNS metastases, a common complication of advanced ALK+ NSCLC, reported Alice T. Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, on behalf of investigators in the ALEX trial.
“I view this as a watershed moment for the treatment of ALK mutant–positive lung cancer,” commented ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
Unlike other head-to-head studies of similar drugs that frequently show only incremental benefit, the ALEX results showed a dramatic difference in outcomes for patients treated with alectinib, he said.
By comparison, the median PFS difference between chemotherapy and crizotinib in the PROFILE 1014 in patients with ALK-positive NSCLC trial was 10.9 vs. 7.0 months, Dr. Heymach pointed out.
The ALEX investigators enrolled 303 patients with untreated ALK-positive NSCLC confirmed by a central immunohistochemistry lab and randomly assigned them to treatment with either oral alectinib 600 mg twice daily or crizotinib 250 mg b.i.d.
At the primary data cutoff in February 2017, median PFS, the primary endpoint, was 11.1 months for patients treated with crizotinib, versus not reached for those treated with alectinib, translating into a hazard ratio for alectinib of 0.47 (P less than .0001).
Based on an independent review, the median PFS was determined to be 10.4 months for crizotinib, vs. 25.7 months with alectinib (HR, 0.50; P not shown).
The cumulative incidence of CNS progression, a secondary endpoint, was 41.4% in the crizotinib arm, vs. 9.41% in the alectinib arm (cause-specific HR, 0.16; P not shown).
In each arm, 97% of patients had any adverse event, and the incidence of serious adverse events was similar between the arms, at 29% for crizotinib and 28% for alectinib.
Adverse events leading to treatment discontinuation, dose reduction, or dose interruption were more frequent with crizotinib.
In the question and answer portion of the briefing, Dr. Shaw was asked whether crizotinib still had a role in this population.
“Going forward, I think that it’s pretty clear, if you have a newly diagnosed patient with metastatic ALK-positive lung cancer, that likely alectinib would be the preferred first choice,” she said.
The ALEX trial is supported by Roche. Dr. Shaw disclosed consulting or an advisory role with the company, and multiple coauthors disclosed similar relationships.
AT ASCO 2017
Key clinical point: Alectinib was associated with more than double the progression-free survival of standard of care crizotinib in patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase.
Major finding: Median PFS by independent review was 10.4 months with crizotinib vs. 25.7 months with alectinib.
Data source: The ALEX trial, a phase III trial of 303 patients with ALK-positive NSCLC.
Disclosures: The ALEX trial is supported by Roche. Dr. Shaw disclosed consulting or an advisory role with the company, and multiple coauthors disclosed similar relationships
VIDEO: Alectinib doubles PFS and then some over crizotinib in ALK+ NSCLC
CHICAGO – The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.
The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.
The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.
The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: Combined immunotherapy strategy shows promise in advanced solid tumors
CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.
BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.
BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.
BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
Immune-agonist combo has activity against several tumor types
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: A combination of a GITR-agonist and anti-PD-1 agent was safe and produced partial responses in patients with heavily pretreated advanced cancers.
Major finding: Two patients with cancers that had progression on a PD-1 inhibitor had durable partial responses.
Data source: A phase I/IIa dose-finding and safety study of BMS986156 alone or in combination with nivolumab (Opdivo).
Disclosures: The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising for several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
Test goes wide and deep to detect free tumor DNA in blood
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
AT ASCO 2017
Key clinical point: High-intensity sequencing of plasma samples appears capable of detecting actionable tumor mutations in a large proportion of samples.
Major finding: In 89% of patients with advanced cancers, genetic variants were identified in both tumor samples and circulating free DNA testing.
Data source: Prospective study of tissue and plasma samples from 124 patients with non–small cell lung cancer or metastatic breast and prostate cancers.
Disclosures: The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
Interventions ease cancer-related stress, depression
CHICAGO – Clinicians have gotten much better in recent decades at helping patients cope with physical side effects from cancer care, but mental health interventions aimed at easing stress and fear are often absent or, at best, an afterthought.
As three new studies show, however, early psychological interventions can both improve the quality of life for patients with cancer and enhance clinical outcomes.
For example, an online stress management program dubbed STREAM, developed jointly by oncologists and psychologists, was associated with significantly better quality of life and lower levels of distress for patients 2 months after a new cancer diagnosis, compared with controls who had not yet used it, reported Viviane Hess, MD, a medical oncologist at the University Hospital of Basel (Switzerland).
“From randomized controlled trials, we know that cognitive behavioral therapies are effective in mediating distress. However, the majority of cancer patients lack psychological support, due to both barriers on the patients’ side and lack of resources on the providers’ side,” she said at a briefing at the annual meeting of the American Society of Clinical Oncology.
Other studies presented in the briefing show that psychological interventions can significantly reduce patient anxieties about the possibility of cancer recurrence and help relieve depressive symptoms for at least 6 months among patients with advanced cancers.
STREAM
Dr. Hess and her colleagues conducted a prospective, wait-list controlled trial for patients who had started therapy for a newly diagnosed cancer within the past 12 weeks. The patients were randomized to either immediate use of an online psychological intervention or to a delayed start.
The investigators chose a web-based intervention because a majority of patients with cancer already use the Internet for information, and because Internet interventions can overcome barriers of time and distance, with results comparable to those seen with face-to-face interventions, Dr. Hess said.
The intervention consisted of eight weekly sessions based on approaches used in cognitive behavioral therapy, with focus on bodily reactions to stress, cognitive stress reduction, feelings, and social interactions. Each of the eight sessions focused on a single topic. Patients were given written and audio information about each topic and then were asked to perform exercises and complete questionnaires.
For this “minimal contact” intervention, psychologists based in Basel reviewed each patient’s progress weekly and gave written feedback personalized for that patient via a secure online portal.
In all, 129 patients were randomized (65 to the intervention and 64 controls). The majority were women treated with curative intent for early-stage breast cancer. Patients newly diagnosed with lung, ovarian, and gastrointestinal cancers, as well as melanoma and lymphoma, also were included.
Patients in both the active intervention and control groups were assessed at baseline and at 2 months with three quality-of-life measures: the FACIT-F (Functional Assessment of Chronic Illness Therapy Fatigue subscale), DT (Distress Thermometer), and HADS (Hospital Anxiety and Depression Scale).
At 2 months, the mean FACIT-F score for patients in both the intervention and control groups increased, indicating an improved quality of life, but the change was significantly greater for patients in the intervention group (mean 8.59 points vs. controls; P = .0032). There was also a significant decrease in the DT scale from 6 points at baseline to 4 points at 2 months among patients randomized to the intervention, but no change among controls. There were no significant differences in either anxiety or depression between the groups, however.
“Most oncologists, particularly when we’re meeting patients for the first time and starting on curative intent therapy, it is assumed there is a level of distress … but we assume that that level of distress will fall naturally as we start them on therapy,” commented ASCO expert Don S. Dizon, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study.
“What Dr. Hess is showing is that not only do they have distress, but it’s significant distress,” he said, adding that the study shows that online tools can be effective at providing support, and that the ease of access can help patients who might otherwise never meet with a mental health professional.
Recurrence fears assuaged
In a separate study, investigators from Australia reported results of a randomized phase II trial showing that an intervention called Conquer Fear was effective at lowering fear of recurrence among patients with successfully treated stage I-III breast, colorectal, or melanoma cancers who reported a high level of fear of recurrence.
“Fear of cancer recurrence is associated with poorer quality of life, greater distress, lack of planning for the future, avoidance or excessive use of screening, and greater health care utilization,” said Jane MacNeil Beith, MD, PhD, a medical oncologist at the University of Sydney.
Dr. Beith and her colleagues randomly assigned 222 patients to either the Conquer Fear intervention or relaxation training (control group).
Patients assigned to the control group received five 1-hour individual, face-to-face relaxation sessions over 10 weeks. The sessions included muscle relaxation, meditative relaxation, and visualization and quick relaxation techniques taught by trained study instructors. Patients in each group received instructions for home-based relaxation techniques.
The Conquer Fear intervention is intended to help patients with values clarification, detached mindfulness (focusing on the moment), attention training, meta-cognitive therapy (worry or not worry), and a behavioral contract to ensure appropriate follow-up.
They measured fear of recurrence using the validated 42-item Fear of Cancer Recurrence Inventory (FCRI), which scores fear on a scale of 0-168, with higher scores indicating higher levels of fear, Dr. Beith said.
The mean baseline FCRI scores were 82.7 for patients assigned to the intervention and 85.7 in controls.
Participants in both groups had improvement of all outcomes, but patients in the active intervention group had significantly lower FCRI total scores at the end of the intervention and at 3 and 6 months of follow-up. The severity of fear of recurrence was also lower among patients in the intervention group immediately afterward and at 3 months, but not at 6 months, she reported.
“I applaud Dr. Beith for her trial, particularly because we as oncologists have only about 15 minutes with our patients, and the assessments for our patients, even in follow-up, for the most part concentrate on cancer-related outcomes, because that’s what our patients want to know. They want to know if they’re fine, or they want to know, is their cancer back,” Dr. Dizon commented.
The study demonstrates fear of recurrence is real, but that there are also interventions that can help patients reduce those fears, he said.
CALM
In a third study, Gary Rodin, MD, from the department of supportive care at Princess Margaret Cancer Centre in Toronto, and his colleagues reported that a brief psychological intervention with the acronym CALM (for Managing Cancer and Living Meaningfully) was associated with a “clinically meaningful” reduction in depressive symptoms in patients with advanced cancer.
Patients in CALM receive three to six individual sessions delivered over 3-6 months. The program helps patients cope with symptom management and improve communications with health care providers, understand changes in themselves and their relations with others, find a personal sense of meaning and purpose, and learn to live with thoughts of the future and mortality, Dr. Rodin explained.
In a clinical trial, 52% of the 151 patients randomized to the intervention had clinically important reductions in depressive symptoms at 3 months, compared with 33% of controls assigned to usual care. At 6 months, the respective reductions in depressive symptoms were 64% vs. 35%.
The intervention also was effective at preventing depression among 137 patients without depressive symptoms at baseline. In this group, 13% of patients who received the CALM intervention had depressive symptoms at 3 months, compared with 30% of controls.
In addition, patients who received CALM support at both 3 and 6 months said they were better prepared for the end of life, reported that they had greater opportunity to talk about their concerns for the future, were less frightened, and said they had greater ability to express and manage their feelings. At 6 months these effects were strengthened, and the CALM group also felt more able to understand their cancer experience, deal with changes in relationships as a result of cancer, explore ways of communicating with their health care team and family, and clarify their values and beliefs.
“The intervention addresses both the practical problems that people face, and there are many – How do I manage my pain? My symptoms? – but also the profound problems and issues that people face – What is the meaning of my life? – when having a terminal diagnosis, for instance,” he said.
The investigators are currently establishing a global network to train health professionals in the delivery of CALM, and to evaluate the program’s effectiveness in different clinical settings and cultures, he said.
The STREAM study was institutionally supported. Dr. Hess disclosed travel and accommodations from CSL Behring. The Conquer Fear study was funded by Cancer Australia, beyondBlue, and the Australian National Breast Cancer Foundation. Dr. Beith reported no relevant disclosures. The CALM study was supported by the Canadian Institute of Health Research. Dr. Rodin reported no relevant disclosures.
CHICAGO – Clinicians have gotten much better in recent decades at helping patients cope with physical side effects from cancer care, but mental health interventions aimed at easing stress and fear are often absent or, at best, an afterthought.
As three new studies show, however, early psychological interventions can both improve the quality of life for patients with cancer and enhance clinical outcomes.
For example, an online stress management program dubbed STREAM, developed jointly by oncologists and psychologists, was associated with significantly better quality of life and lower levels of distress for patients 2 months after a new cancer diagnosis, compared with controls who had not yet used it, reported Viviane Hess, MD, a medical oncologist at the University Hospital of Basel (Switzerland).
“From randomized controlled trials, we know that cognitive behavioral therapies are effective in mediating distress. However, the majority of cancer patients lack psychological support, due to both barriers on the patients’ side and lack of resources on the providers’ side,” she said at a briefing at the annual meeting of the American Society of Clinical Oncology.
Other studies presented in the briefing show that psychological interventions can significantly reduce patient anxieties about the possibility of cancer recurrence and help relieve depressive symptoms for at least 6 months among patients with advanced cancers.
STREAM
Dr. Hess and her colleagues conducted a prospective, wait-list controlled trial for patients who had started therapy for a newly diagnosed cancer within the past 12 weeks. The patients were randomized to either immediate use of an online psychological intervention or to a delayed start.
The investigators chose a web-based intervention because a majority of patients with cancer already use the Internet for information, and because Internet interventions can overcome barriers of time and distance, with results comparable to those seen with face-to-face interventions, Dr. Hess said.
The intervention consisted of eight weekly sessions based on approaches used in cognitive behavioral therapy, with focus on bodily reactions to stress, cognitive stress reduction, feelings, and social interactions. Each of the eight sessions focused on a single topic. Patients were given written and audio information about each topic and then were asked to perform exercises and complete questionnaires.
For this “minimal contact” intervention, psychologists based in Basel reviewed each patient’s progress weekly and gave written feedback personalized for that patient via a secure online portal.
In all, 129 patients were randomized (65 to the intervention and 64 controls). The majority were women treated with curative intent for early-stage breast cancer. Patients newly diagnosed with lung, ovarian, and gastrointestinal cancers, as well as melanoma and lymphoma, also were included.
Patients in both the active intervention and control groups were assessed at baseline and at 2 months with three quality-of-life measures: the FACIT-F (Functional Assessment of Chronic Illness Therapy Fatigue subscale), DT (Distress Thermometer), and HADS (Hospital Anxiety and Depression Scale).
At 2 months, the mean FACIT-F score for patients in both the intervention and control groups increased, indicating an improved quality of life, but the change was significantly greater for patients in the intervention group (mean 8.59 points vs. controls; P = .0032). There was also a significant decrease in the DT scale from 6 points at baseline to 4 points at 2 months among patients randomized to the intervention, but no change among controls. There were no significant differences in either anxiety or depression between the groups, however.
“Most oncologists, particularly when we’re meeting patients for the first time and starting on curative intent therapy, it is assumed there is a level of distress … but we assume that that level of distress will fall naturally as we start them on therapy,” commented ASCO expert Don S. Dizon, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study.
“What Dr. Hess is showing is that not only do they have distress, but it’s significant distress,” he said, adding that the study shows that online tools can be effective at providing support, and that the ease of access can help patients who might otherwise never meet with a mental health professional.
Recurrence fears assuaged
In a separate study, investigators from Australia reported results of a randomized phase II trial showing that an intervention called Conquer Fear was effective at lowering fear of recurrence among patients with successfully treated stage I-III breast, colorectal, or melanoma cancers who reported a high level of fear of recurrence.
“Fear of cancer recurrence is associated with poorer quality of life, greater distress, lack of planning for the future, avoidance or excessive use of screening, and greater health care utilization,” said Jane MacNeil Beith, MD, PhD, a medical oncologist at the University of Sydney.
Dr. Beith and her colleagues randomly assigned 222 patients to either the Conquer Fear intervention or relaxation training (control group).
Patients assigned to the control group received five 1-hour individual, face-to-face relaxation sessions over 10 weeks. The sessions included muscle relaxation, meditative relaxation, and visualization and quick relaxation techniques taught by trained study instructors. Patients in each group received instructions for home-based relaxation techniques.
The Conquer Fear intervention is intended to help patients with values clarification, detached mindfulness (focusing on the moment), attention training, meta-cognitive therapy (worry or not worry), and a behavioral contract to ensure appropriate follow-up.
They measured fear of recurrence using the validated 42-item Fear of Cancer Recurrence Inventory (FCRI), which scores fear on a scale of 0-168, with higher scores indicating higher levels of fear, Dr. Beith said.
The mean baseline FCRI scores were 82.7 for patients assigned to the intervention and 85.7 in controls.
Participants in both groups had improvement of all outcomes, but patients in the active intervention group had significantly lower FCRI total scores at the end of the intervention and at 3 and 6 months of follow-up. The severity of fear of recurrence was also lower among patients in the intervention group immediately afterward and at 3 months, but not at 6 months, she reported.
“I applaud Dr. Beith for her trial, particularly because we as oncologists have only about 15 minutes with our patients, and the assessments for our patients, even in follow-up, for the most part concentrate on cancer-related outcomes, because that’s what our patients want to know. They want to know if they’re fine, or they want to know, is their cancer back,” Dr. Dizon commented.
The study demonstrates fear of recurrence is real, but that there are also interventions that can help patients reduce those fears, he said.
CALM
In a third study, Gary Rodin, MD, from the department of supportive care at Princess Margaret Cancer Centre in Toronto, and his colleagues reported that a brief psychological intervention with the acronym CALM (for Managing Cancer and Living Meaningfully) was associated with a “clinically meaningful” reduction in depressive symptoms in patients with advanced cancer.
Patients in CALM receive three to six individual sessions delivered over 3-6 months. The program helps patients cope with symptom management and improve communications with health care providers, understand changes in themselves and their relations with others, find a personal sense of meaning and purpose, and learn to live with thoughts of the future and mortality, Dr. Rodin explained.
In a clinical trial, 52% of the 151 patients randomized to the intervention had clinically important reductions in depressive symptoms at 3 months, compared with 33% of controls assigned to usual care. At 6 months, the respective reductions in depressive symptoms were 64% vs. 35%.
The intervention also was effective at preventing depression among 137 patients without depressive symptoms at baseline. In this group, 13% of patients who received the CALM intervention had depressive symptoms at 3 months, compared with 30% of controls.
In addition, patients who received CALM support at both 3 and 6 months said they were better prepared for the end of life, reported that they had greater opportunity to talk about their concerns for the future, were less frightened, and said they had greater ability to express and manage their feelings. At 6 months these effects were strengthened, and the CALM group also felt more able to understand their cancer experience, deal with changes in relationships as a result of cancer, explore ways of communicating with their health care team and family, and clarify their values and beliefs.
“The intervention addresses both the practical problems that people face, and there are many – How do I manage my pain? My symptoms? – but also the profound problems and issues that people face – What is the meaning of my life? – when having a terminal diagnosis, for instance,” he said.
The investigators are currently establishing a global network to train health professionals in the delivery of CALM, and to evaluate the program’s effectiveness in different clinical settings and cultures, he said.
The STREAM study was institutionally supported. Dr. Hess disclosed travel and accommodations from CSL Behring. The Conquer Fear study was funded by Cancer Australia, beyondBlue, and the Australian National Breast Cancer Foundation. Dr. Beith reported no relevant disclosures. The CALM study was supported by the Canadian Institute of Health Research. Dr. Rodin reported no relevant disclosures.
CHICAGO – Clinicians have gotten much better in recent decades at helping patients cope with physical side effects from cancer care, but mental health interventions aimed at easing stress and fear are often absent or, at best, an afterthought.
As three new studies show, however, early psychological interventions can both improve the quality of life for patients with cancer and enhance clinical outcomes.
For example, an online stress management program dubbed STREAM, developed jointly by oncologists and psychologists, was associated with significantly better quality of life and lower levels of distress for patients 2 months after a new cancer diagnosis, compared with controls who had not yet used it, reported Viviane Hess, MD, a medical oncologist at the University Hospital of Basel (Switzerland).
“From randomized controlled trials, we know that cognitive behavioral therapies are effective in mediating distress. However, the majority of cancer patients lack psychological support, due to both barriers on the patients’ side and lack of resources on the providers’ side,” she said at a briefing at the annual meeting of the American Society of Clinical Oncology.
Other studies presented in the briefing show that psychological interventions can significantly reduce patient anxieties about the possibility of cancer recurrence and help relieve depressive symptoms for at least 6 months among patients with advanced cancers.
STREAM
Dr. Hess and her colleagues conducted a prospective, wait-list controlled trial for patients who had started therapy for a newly diagnosed cancer within the past 12 weeks. The patients were randomized to either immediate use of an online psychological intervention or to a delayed start.
The investigators chose a web-based intervention because a majority of patients with cancer already use the Internet for information, and because Internet interventions can overcome barriers of time and distance, with results comparable to those seen with face-to-face interventions, Dr. Hess said.
The intervention consisted of eight weekly sessions based on approaches used in cognitive behavioral therapy, with focus on bodily reactions to stress, cognitive stress reduction, feelings, and social interactions. Each of the eight sessions focused on a single topic. Patients were given written and audio information about each topic and then were asked to perform exercises and complete questionnaires.
For this “minimal contact” intervention, psychologists based in Basel reviewed each patient’s progress weekly and gave written feedback personalized for that patient via a secure online portal.
In all, 129 patients were randomized (65 to the intervention and 64 controls). The majority were women treated with curative intent for early-stage breast cancer. Patients newly diagnosed with lung, ovarian, and gastrointestinal cancers, as well as melanoma and lymphoma, also were included.
Patients in both the active intervention and control groups were assessed at baseline and at 2 months with three quality-of-life measures: the FACIT-F (Functional Assessment of Chronic Illness Therapy Fatigue subscale), DT (Distress Thermometer), and HADS (Hospital Anxiety and Depression Scale).
At 2 months, the mean FACIT-F score for patients in both the intervention and control groups increased, indicating an improved quality of life, but the change was significantly greater for patients in the intervention group (mean 8.59 points vs. controls; P = .0032). There was also a significant decrease in the DT scale from 6 points at baseline to 4 points at 2 months among patients randomized to the intervention, but no change among controls. There were no significant differences in either anxiety or depression between the groups, however.
“Most oncologists, particularly when we’re meeting patients for the first time and starting on curative intent therapy, it is assumed there is a level of distress … but we assume that that level of distress will fall naturally as we start them on therapy,” commented ASCO expert Don S. Dizon, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study.
“What Dr. Hess is showing is that not only do they have distress, but it’s significant distress,” he said, adding that the study shows that online tools can be effective at providing support, and that the ease of access can help patients who might otherwise never meet with a mental health professional.
Recurrence fears assuaged
In a separate study, investigators from Australia reported results of a randomized phase II trial showing that an intervention called Conquer Fear was effective at lowering fear of recurrence among patients with successfully treated stage I-III breast, colorectal, or melanoma cancers who reported a high level of fear of recurrence.
“Fear of cancer recurrence is associated with poorer quality of life, greater distress, lack of planning for the future, avoidance or excessive use of screening, and greater health care utilization,” said Jane MacNeil Beith, MD, PhD, a medical oncologist at the University of Sydney.
Dr. Beith and her colleagues randomly assigned 222 patients to either the Conquer Fear intervention or relaxation training (control group).
Patients assigned to the control group received five 1-hour individual, face-to-face relaxation sessions over 10 weeks. The sessions included muscle relaxation, meditative relaxation, and visualization and quick relaxation techniques taught by trained study instructors. Patients in each group received instructions for home-based relaxation techniques.
The Conquer Fear intervention is intended to help patients with values clarification, detached mindfulness (focusing on the moment), attention training, meta-cognitive therapy (worry or not worry), and a behavioral contract to ensure appropriate follow-up.
They measured fear of recurrence using the validated 42-item Fear of Cancer Recurrence Inventory (FCRI), which scores fear on a scale of 0-168, with higher scores indicating higher levels of fear, Dr. Beith said.
The mean baseline FCRI scores were 82.7 for patients assigned to the intervention and 85.7 in controls.
Participants in both groups had improvement of all outcomes, but patients in the active intervention group had significantly lower FCRI total scores at the end of the intervention and at 3 and 6 months of follow-up. The severity of fear of recurrence was also lower among patients in the intervention group immediately afterward and at 3 months, but not at 6 months, she reported.
“I applaud Dr. Beith for her trial, particularly because we as oncologists have only about 15 minutes with our patients, and the assessments for our patients, even in follow-up, for the most part concentrate on cancer-related outcomes, because that’s what our patients want to know. They want to know if they’re fine, or they want to know, is their cancer back,” Dr. Dizon commented.
The study demonstrates fear of recurrence is real, but that there are also interventions that can help patients reduce those fears, he said.
CALM
In a third study, Gary Rodin, MD, from the department of supportive care at Princess Margaret Cancer Centre in Toronto, and his colleagues reported that a brief psychological intervention with the acronym CALM (for Managing Cancer and Living Meaningfully) was associated with a “clinically meaningful” reduction in depressive symptoms in patients with advanced cancer.
Patients in CALM receive three to six individual sessions delivered over 3-6 months. The program helps patients cope with symptom management and improve communications with health care providers, understand changes in themselves and their relations with others, find a personal sense of meaning and purpose, and learn to live with thoughts of the future and mortality, Dr. Rodin explained.
In a clinical trial, 52% of the 151 patients randomized to the intervention had clinically important reductions in depressive symptoms at 3 months, compared with 33% of controls assigned to usual care. At 6 months, the respective reductions in depressive symptoms were 64% vs. 35%.
The intervention also was effective at preventing depression among 137 patients without depressive symptoms at baseline. In this group, 13% of patients who received the CALM intervention had depressive symptoms at 3 months, compared with 30% of controls.
In addition, patients who received CALM support at both 3 and 6 months said they were better prepared for the end of life, reported that they had greater opportunity to talk about their concerns for the future, were less frightened, and said they had greater ability to express and manage their feelings. At 6 months these effects were strengthened, and the CALM group also felt more able to understand their cancer experience, deal with changes in relationships as a result of cancer, explore ways of communicating with their health care team and family, and clarify their values and beliefs.
“The intervention addresses both the practical problems that people face, and there are many – How do I manage my pain? My symptoms? – but also the profound problems and issues that people face – What is the meaning of my life? – when having a terminal diagnosis, for instance,” he said.
The investigators are currently establishing a global network to train health professionals in the delivery of CALM, and to evaluate the program’s effectiveness in different clinical settings and cultures, he said.
The STREAM study was institutionally supported. Dr. Hess disclosed travel and accommodations from CSL Behring. The Conquer Fear study was funded by Cancer Australia, beyondBlue, and the Australian National Breast Cancer Foundation. Dr. Beith reported no relevant disclosures. The CALM study was supported by the Canadian Institute of Health Research. Dr. Rodin reported no relevant disclosures.
AT ASCO 2017
Key clinical point: Oncologists and patients may focus on only the clinical aspects of care while overlooking cancer-associated distress, anxiety, or fear.
Major finding: Each of three psychological interventions was effective at reducing mental health symptoms in patients with cancer.
Data source: Randomized trials of interventions aimed at relieving mental health symptoms associated with a new cancer diagnoses, fear of cancer recurrence, and advanced or metastatic disease.
Disclosures: The STREAM study was institutionally supported. Dr. Hess disclosed travel and accommodations from CSL Behring. The Conquer Fear study was funded by Cancer Australia, beyondBlue, and the Australian National Breast Cancer Foundation. Dr. Beith reported no relevant disclosures. The CALM study was supported by the Canadian Institute of Health Research. Dr. Rodin reported no relevant disclosures.