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Export protein inhibitor shows activity against refractory myeloma
Think of it as a biological nuclear export ban: A combination of the nuclear export protein inhibitor selinexor and dexamethasone was associated with relatively good objective response rates and clinical benefit rates among some patients with relapsed or refractory multiple myeloma (MM).
In the dose-expansion portion of a phase 1 dose-finding trial, the objective response rate (ORR) among 12 patients treated with selinexor 45 mg/m2 and 20 mg dexamethasone twice weekly was 50%, and the clinical benefit rate – a composite of complete responses, very good partial responses, partial responses and minimal responses – was 58%, reported Christine Chen, MD, of Princess Margaret Cancer Centre in Toronto, and her colleagues.
“Selinexor is an oral agent with a completely novel mechanism of action and anti-MM activity in combination with dexamethasone that could provide a new option for patients suffering from this incurable disease,” wrote Dr. Chen and her colleagues. The report was published in Blood.
Selinexor is a selective oral inhibitor of the cellular nuclear export protein exportin 1 (XPO1). Inhibition of this protein causes tumor suppressor proteins to accumulate in the nuclei of malignant cells, leading to programmed cell death (apoptosis) of malignant cells, but with minimal effects on normal cells.
The study, performed in centers in Canada, the United States, and Denmark, was designed primarily to identify the recommended dose of oral selinexor for phase 2 trials, with or without corticosteroids.
A total of 84 patients were enrolled, including 22 with MM and 3 with Waldenstrom macroglobulinemia in the dose-escalation phase, and 59 with MM in the dose expansion phase.
In the dose-expansion phase, patients were treated with one of two dosing schemes: either selinexor at a dose of 45 or 60 mg/m2 plus dexamethasone 20 mg twice weekly in 28-day cycles, or selinexor in a 40 mg or 60 mg flat dose without corticosteroids in 21-day cycles.
As a single agent, selinexor showed minimal activity, with an ORR of 4%, and clinical benefit rate of 21% in 57 patients.
Among 12 patients assigned to the 45 mg/m2 selinexor dose plus dexamethasone, the ORR was 50%, consisting of one complete response and five partial responses. In addition, one patient at this dose level had a minimal response, three had stable disease, one had disease progression, and one was withdrawn from the study before disease assessment, with no evidence of progression.
There were no objective responses in the 60-mg/m2 selinexor dose group.
Among all 84 patients enrolled, the ORR with selinexor alone or in combination was 10%, and the clinical benefit rate was 25%. Of the patients with Waldenstrom macroglobulinemia, one had a partial response and one had a minimal response.
In the safety analysis, which included all patients who received at least one dose of selinexor, the most common grade 3 or 4 adverse events included thrombocytopenia in 45% of patients, hyponatremia in 26% of patients, and anemia and neutropenia in 23% each.
The most common nonhematologic adverse events – primarily grade 1 or 2 – included nausea, fatigue, anorexia, vomiting, and weight loss and diarrhea.
The combination of selinexor and dexamethasone is currently being investigated in the phase 2 Selinexor Treatment of Refractory Myeloma study, in combination with standard multiple myeloma therapies in the STOMP trial (Selinexor and Backbone Treatments of Multiple Myeloma Patients), and with bortezomib in the BOSTON trial (Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma).
Dr. Chen reported no conflicts of interest. Her coauthors reported financial ties to Karyopharm Therapeutics, which funded the study.
hematologynews@frontlinemedcom.com
SOURCE: Chen C et al. Blood. 2018;131(8):855-63.
Think of it as a biological nuclear export ban: A combination of the nuclear export protein inhibitor selinexor and dexamethasone was associated with relatively good objective response rates and clinical benefit rates among some patients with relapsed or refractory multiple myeloma (MM).
In the dose-expansion portion of a phase 1 dose-finding trial, the objective response rate (ORR) among 12 patients treated with selinexor 45 mg/m2 and 20 mg dexamethasone twice weekly was 50%, and the clinical benefit rate – a composite of complete responses, very good partial responses, partial responses and minimal responses – was 58%, reported Christine Chen, MD, of Princess Margaret Cancer Centre in Toronto, and her colleagues.
“Selinexor is an oral agent with a completely novel mechanism of action and anti-MM activity in combination with dexamethasone that could provide a new option for patients suffering from this incurable disease,” wrote Dr. Chen and her colleagues. The report was published in Blood.
Selinexor is a selective oral inhibitor of the cellular nuclear export protein exportin 1 (XPO1). Inhibition of this protein causes tumor suppressor proteins to accumulate in the nuclei of malignant cells, leading to programmed cell death (apoptosis) of malignant cells, but with minimal effects on normal cells.
The study, performed in centers in Canada, the United States, and Denmark, was designed primarily to identify the recommended dose of oral selinexor for phase 2 trials, with or without corticosteroids.
A total of 84 patients were enrolled, including 22 with MM and 3 with Waldenstrom macroglobulinemia in the dose-escalation phase, and 59 with MM in the dose expansion phase.
In the dose-expansion phase, patients were treated with one of two dosing schemes: either selinexor at a dose of 45 or 60 mg/m2 plus dexamethasone 20 mg twice weekly in 28-day cycles, or selinexor in a 40 mg or 60 mg flat dose without corticosteroids in 21-day cycles.
As a single agent, selinexor showed minimal activity, with an ORR of 4%, and clinical benefit rate of 21% in 57 patients.
Among 12 patients assigned to the 45 mg/m2 selinexor dose plus dexamethasone, the ORR was 50%, consisting of one complete response and five partial responses. In addition, one patient at this dose level had a minimal response, three had stable disease, one had disease progression, and one was withdrawn from the study before disease assessment, with no evidence of progression.
There were no objective responses in the 60-mg/m2 selinexor dose group.
Among all 84 patients enrolled, the ORR with selinexor alone or in combination was 10%, and the clinical benefit rate was 25%. Of the patients with Waldenstrom macroglobulinemia, one had a partial response and one had a minimal response.
In the safety analysis, which included all patients who received at least one dose of selinexor, the most common grade 3 or 4 adverse events included thrombocytopenia in 45% of patients, hyponatremia in 26% of patients, and anemia and neutropenia in 23% each.
The most common nonhematologic adverse events – primarily grade 1 or 2 – included nausea, fatigue, anorexia, vomiting, and weight loss and diarrhea.
The combination of selinexor and dexamethasone is currently being investigated in the phase 2 Selinexor Treatment of Refractory Myeloma study, in combination with standard multiple myeloma therapies in the STOMP trial (Selinexor and Backbone Treatments of Multiple Myeloma Patients), and with bortezomib in the BOSTON trial (Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma).
Dr. Chen reported no conflicts of interest. Her coauthors reported financial ties to Karyopharm Therapeutics, which funded the study.
hematologynews@frontlinemedcom.com
SOURCE: Chen C et al. Blood. 2018;131(8):855-63.
Think of it as a biological nuclear export ban: A combination of the nuclear export protein inhibitor selinexor and dexamethasone was associated with relatively good objective response rates and clinical benefit rates among some patients with relapsed or refractory multiple myeloma (MM).
In the dose-expansion portion of a phase 1 dose-finding trial, the objective response rate (ORR) among 12 patients treated with selinexor 45 mg/m2 and 20 mg dexamethasone twice weekly was 50%, and the clinical benefit rate – a composite of complete responses, very good partial responses, partial responses and minimal responses – was 58%, reported Christine Chen, MD, of Princess Margaret Cancer Centre in Toronto, and her colleagues.
“Selinexor is an oral agent with a completely novel mechanism of action and anti-MM activity in combination with dexamethasone that could provide a new option for patients suffering from this incurable disease,” wrote Dr. Chen and her colleagues. The report was published in Blood.
Selinexor is a selective oral inhibitor of the cellular nuclear export protein exportin 1 (XPO1). Inhibition of this protein causes tumor suppressor proteins to accumulate in the nuclei of malignant cells, leading to programmed cell death (apoptosis) of malignant cells, but with minimal effects on normal cells.
The study, performed in centers in Canada, the United States, and Denmark, was designed primarily to identify the recommended dose of oral selinexor for phase 2 trials, with or without corticosteroids.
A total of 84 patients were enrolled, including 22 with MM and 3 with Waldenstrom macroglobulinemia in the dose-escalation phase, and 59 with MM in the dose expansion phase.
In the dose-expansion phase, patients were treated with one of two dosing schemes: either selinexor at a dose of 45 or 60 mg/m2 plus dexamethasone 20 mg twice weekly in 28-day cycles, or selinexor in a 40 mg or 60 mg flat dose without corticosteroids in 21-day cycles.
As a single agent, selinexor showed minimal activity, with an ORR of 4%, and clinical benefit rate of 21% in 57 patients.
Among 12 patients assigned to the 45 mg/m2 selinexor dose plus dexamethasone, the ORR was 50%, consisting of one complete response and five partial responses. In addition, one patient at this dose level had a minimal response, three had stable disease, one had disease progression, and one was withdrawn from the study before disease assessment, with no evidence of progression.
There were no objective responses in the 60-mg/m2 selinexor dose group.
Among all 84 patients enrolled, the ORR with selinexor alone or in combination was 10%, and the clinical benefit rate was 25%. Of the patients with Waldenstrom macroglobulinemia, one had a partial response and one had a minimal response.
In the safety analysis, which included all patients who received at least one dose of selinexor, the most common grade 3 or 4 adverse events included thrombocytopenia in 45% of patients, hyponatremia in 26% of patients, and anemia and neutropenia in 23% each.
The most common nonhematologic adverse events – primarily grade 1 or 2 – included nausea, fatigue, anorexia, vomiting, and weight loss and diarrhea.
The combination of selinexor and dexamethasone is currently being investigated in the phase 2 Selinexor Treatment of Refractory Myeloma study, in combination with standard multiple myeloma therapies in the STOMP trial (Selinexor and Backbone Treatments of Multiple Myeloma Patients), and with bortezomib in the BOSTON trial (Bortezomib, Selinexor and Dexamethasone in Patients with Multiple Myeloma).
Dr. Chen reported no conflicts of interest. Her coauthors reported financial ties to Karyopharm Therapeutics, which funded the study.
hematologynews@frontlinemedcom.com
SOURCE: Chen C et al. Blood. 2018;131(8):855-63.
FROM BLOOD
Key clinical point:
Major finding: The objective response rate among 12 patients with multiple myeloma treated at a dose of 45 mg/m2 selinexor and 20 mg dexamethasone was 50%.
Data source: Phase 1 dose-escalation and expansion study of 81 patients with relapsed or refractory multiple myeloma and three patients with Waldenstrom macroglobulinemia.
Disclosures: Dr. Chen reported no conflicts of interest. Her coauthors reported financial ties to Karyopharm Therapeutics, which funded the study.
Source: Chen C et al. Blood. 2018;131(8):855-63.
Mycosis fungoides increases risk for second cancers
LA JOLLA, CALIF. – Patients with mycosis fungoides are at increased risk for developing other cancers and should be screened for second primary and hematologic malignancies, results of a cancer registry survey suggest.
A study of data on 6,196 patients included in 18 population-based cancer registries comprising the SEER-18 (Surveillance, Epidemiology, and End Results 18) database who were diagnosed and followed from 2000 to 2014 showed that 514 (8.3%) developed second cancers, compared with the 70.8 secondary malignancies that would be expected in the general population. This difference translated into a standardized incidence ratio (SIR) of 7.3, reported Amrita Goyal, MD, and Aleksandr Lazaryan, MD, PhD, of the University of Minnesota, Minneapolis.
Patients with MF have a 500% greater risk for developing a second solid malignancy and a 2700% greater likelihood of developing a second hematologic malignancy, she said.
The investigators hypothesized that MF predisposes patients to second malignancies because of its immunocompromising effects.
Dr. Goyal said that, although the SEER data set does not include information on disease stage for all patients, when they looked at a separate cohort of 173 University of Minnesota patients with MF, they saw that patients with higher-stage MF were significantly more likely to develop secondary malignancies than patients with lower-stage disease.
The investigators looked at the actual and expected cancer incidence rates for the SEER-18 population sample, and used data on age, sex, race, and calendar year to generate incidence estimates for the general population.
They found that 514 patients in the SEER-18 population developed a total of 170 second primary hematologic malignancies, for a SIR of 27.4, compared with the general population. The most common hematologic cancers were Hodgkin lymphoma (SIR 69.8) and non-Hodgkin lymphoma (SIR 46.5), and other second hematologic malignancies included multiple myeloma (SIR 4.5), chronic lymphocytic leukemia (SIR 9.1). and acute leukemias (SIR 8.1).
The most frequently occurring second solid tumors included cancers of the nose, nasal cavity, and middle ear (SIR 30.4); thyroid (SIR 16.1); brain (SIR 15.1); and breast (SIR 8.0).
Other solid tumors with an approximately 400%-500% higher incidence included cancers of the prostate, bladder, colon, and kidneys.
Dr. Goyal and Dr. Lazaryan recommend development of targeted cancer screening strategies for patients with MF.
The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Goyal A et al. TCLF 2018 Abstract EP18_2.
LA JOLLA, CALIF. – Patients with mycosis fungoides are at increased risk for developing other cancers and should be screened for second primary and hematologic malignancies, results of a cancer registry survey suggest.
A study of data on 6,196 patients included in 18 population-based cancer registries comprising the SEER-18 (Surveillance, Epidemiology, and End Results 18) database who were diagnosed and followed from 2000 to 2014 showed that 514 (8.3%) developed second cancers, compared with the 70.8 secondary malignancies that would be expected in the general population. This difference translated into a standardized incidence ratio (SIR) of 7.3, reported Amrita Goyal, MD, and Aleksandr Lazaryan, MD, PhD, of the University of Minnesota, Minneapolis.
Patients with MF have a 500% greater risk for developing a second solid malignancy and a 2700% greater likelihood of developing a second hematologic malignancy, she said.
The investigators hypothesized that MF predisposes patients to second malignancies because of its immunocompromising effects.
Dr. Goyal said that, although the SEER data set does not include information on disease stage for all patients, when they looked at a separate cohort of 173 University of Minnesota patients with MF, they saw that patients with higher-stage MF were significantly more likely to develop secondary malignancies than patients with lower-stage disease.
The investigators looked at the actual and expected cancer incidence rates for the SEER-18 population sample, and used data on age, sex, race, and calendar year to generate incidence estimates for the general population.
They found that 514 patients in the SEER-18 population developed a total of 170 second primary hematologic malignancies, for a SIR of 27.4, compared with the general population. The most common hematologic cancers were Hodgkin lymphoma (SIR 69.8) and non-Hodgkin lymphoma (SIR 46.5), and other second hematologic malignancies included multiple myeloma (SIR 4.5), chronic lymphocytic leukemia (SIR 9.1). and acute leukemias (SIR 8.1).
The most frequently occurring second solid tumors included cancers of the nose, nasal cavity, and middle ear (SIR 30.4); thyroid (SIR 16.1); brain (SIR 15.1); and breast (SIR 8.0).
Other solid tumors with an approximately 400%-500% higher incidence included cancers of the prostate, bladder, colon, and kidneys.
Dr. Goyal and Dr. Lazaryan recommend development of targeted cancer screening strategies for patients with MF.
The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Goyal A et al. TCLF 2018 Abstract EP18_2.
LA JOLLA, CALIF. – Patients with mycosis fungoides are at increased risk for developing other cancers and should be screened for second primary and hematologic malignancies, results of a cancer registry survey suggest.
A study of data on 6,196 patients included in 18 population-based cancer registries comprising the SEER-18 (Surveillance, Epidemiology, and End Results 18) database who were diagnosed and followed from 2000 to 2014 showed that 514 (8.3%) developed second cancers, compared with the 70.8 secondary malignancies that would be expected in the general population. This difference translated into a standardized incidence ratio (SIR) of 7.3, reported Amrita Goyal, MD, and Aleksandr Lazaryan, MD, PhD, of the University of Minnesota, Minneapolis.
Patients with MF have a 500% greater risk for developing a second solid malignancy and a 2700% greater likelihood of developing a second hematologic malignancy, she said.
The investigators hypothesized that MF predisposes patients to second malignancies because of its immunocompromising effects.
Dr. Goyal said that, although the SEER data set does not include information on disease stage for all patients, when they looked at a separate cohort of 173 University of Minnesota patients with MF, they saw that patients with higher-stage MF were significantly more likely to develop secondary malignancies than patients with lower-stage disease.
The investigators looked at the actual and expected cancer incidence rates for the SEER-18 population sample, and used data on age, sex, race, and calendar year to generate incidence estimates for the general population.
They found that 514 patients in the SEER-18 population developed a total of 170 second primary hematologic malignancies, for a SIR of 27.4, compared with the general population. The most common hematologic cancers were Hodgkin lymphoma (SIR 69.8) and non-Hodgkin lymphoma (SIR 46.5), and other second hematologic malignancies included multiple myeloma (SIR 4.5), chronic lymphocytic leukemia (SIR 9.1). and acute leukemias (SIR 8.1).
The most frequently occurring second solid tumors included cancers of the nose, nasal cavity, and middle ear (SIR 30.4); thyroid (SIR 16.1); brain (SIR 15.1); and breast (SIR 8.0).
Other solid tumors with an approximately 400%-500% higher incidence included cancers of the prostate, bladder, colon, and kidneys.
Dr. Goyal and Dr. Lazaryan recommend development of targeted cancer screening strategies for patients with MF.
The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Goyal A et al. TCLF 2018 Abstract EP18_2.
REPORTING FROM TCLF 2018
Key clinical point:
Major finding: Patients with MF have a 730% greater likelihood of developing a second primary hematologic malignancy.
Study details: A retrospective review of data on 6,196 patients in the SEER-18 database.
Disclosures: The study was funded in part by an American Society of Hematology HONORS grant. The researchers reported having no conflicts of interest.
Source: Goyal A et al. TCLF 2018 Abstract EP18_2.
Basiliximab/BEAM may improve post-ASCT outcomes in PTCL
LA JOLLA, CALIF. – Combining a radio-labeled, anti-CD25, monoclonal antibody with BEAM chemotherapy appears to be an effective and safe conditioning regimen prior to autologous stem cell transplant in patients with peripheral T-cell lymphoma (PTCL), investigators report.
In a phase 1 trial, median progression-free survival (PFS) was 10.6 months for patients treated with the yttrium-90–labeled, chimeric, anti-CD25 antibody basiliximab (Simulect) at one of three dose levels plus standard dose BEAM (carmustine, etoposide, cytarabine, and melphalan), said Jasmine Zain, MD, of the City of Hope Medical Center in Duarte, Calif.
There have been no significant cases of delayed transplant engraftment or unexpected increases in either mucositis or infectious complications, she said at the annual T-cell Lymphoma Forum.
“With standard conditioning, I think the best outcome we have seen is that at 5 years we have about 45% to 50% event-free survival, depending on the histology,” she said. “So we’re hoping we will surpass that.”
The first patient to receive a transplant in the study was treated in July 2015, and since most relapses in this patient population tend to occur within 2 years of transplant, the investigators expect that they will get a better idea of the results in the near future, Dr. Zain said.
PTCL generally has a poor prognosis, and many centers have turned to high-dose therapy followed by autologous stem cell transplant as a consolidation strategy for patients who are in their first or subsequent complete remissions, as well as for patients with relapsed or refractory disease.
“We in this field consider autologous stem cell transplant to be not curative for PTCL. It is true that some patients will achieve long-term remission and even long-term survival,” she said. ”But overall, even with long-term data, it seems like most patients will eventually relapse.”
The goal of the ongoing study is to determine whether adding basiliximab to BEAM could improve outcomes in the long run.
Unlike ibritumomab tiuxetan (Zevalin) – an yttrium-90–labeled antibody that’s been combined with rituximab to target CD20 in relapsed or refractory low-grade follicular B-cell non-Hodgkin lymphoma – basiliximab is targeted to CD25, which is preferentially expressed on T cells.
Basiliximab has been shown to inhibit growth of human anaplastic large cell lymphoma (ALCL) tumors and improve survival in mice bearing human tumor xenografts.
Because the beta particles that basiliximab emits cannot be detected on conventional scans, the antibody is also labeled with an indium-111 radiotracer for purposes of tracking.
At the time of Dr. Zain’s presentation, 13 patients ranging from 19 to 77 years of age were enrolled in the phase 1 trial. The patients were assigned to receive basiliximab at a dose of either 0.4, 0.5, or 0.6 mCi/kg in combination with standard dose BEAM.
The first patient treated had delayed engraftment of platelets; all subsequent patients had engraftment as expected.
There were no grade 3 or 4 toxicities at any dose level and no treatment-related mortality. The most frequent toxicity was grade 2 stomatitis, which occurred in three patients each in the 0.4 and 0.6 miC/kg levels and in four patients at the 0.5 miC/kg level of basiliximab. There were no dose-limiting toxicities.
As of the data cutoff, three patients have experienced relapses, and two of those patients died from disease progression. The times from transplant to relapse were 301 days and 218 days in the two patients who died, and it was 108 days in the third patient.
Dose expansion is continuing in the study, with an additional seven patients scheduled for treatment at the 0.6 miC/kg dose, Dr. Zain said.
Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center and the National Cancer Institute. The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Zain J et al. TCLF 2018.
LA JOLLA, CALIF. – Combining a radio-labeled, anti-CD25, monoclonal antibody with BEAM chemotherapy appears to be an effective and safe conditioning regimen prior to autologous stem cell transplant in patients with peripheral T-cell lymphoma (PTCL), investigators report.
In a phase 1 trial, median progression-free survival (PFS) was 10.6 months for patients treated with the yttrium-90–labeled, chimeric, anti-CD25 antibody basiliximab (Simulect) at one of three dose levels plus standard dose BEAM (carmustine, etoposide, cytarabine, and melphalan), said Jasmine Zain, MD, of the City of Hope Medical Center in Duarte, Calif.
There have been no significant cases of delayed transplant engraftment or unexpected increases in either mucositis or infectious complications, she said at the annual T-cell Lymphoma Forum.
“With standard conditioning, I think the best outcome we have seen is that at 5 years we have about 45% to 50% event-free survival, depending on the histology,” she said. “So we’re hoping we will surpass that.”
The first patient to receive a transplant in the study was treated in July 2015, and since most relapses in this patient population tend to occur within 2 years of transplant, the investigators expect that they will get a better idea of the results in the near future, Dr. Zain said.
PTCL generally has a poor prognosis, and many centers have turned to high-dose therapy followed by autologous stem cell transplant as a consolidation strategy for patients who are in their first or subsequent complete remissions, as well as for patients with relapsed or refractory disease.
“We in this field consider autologous stem cell transplant to be not curative for PTCL. It is true that some patients will achieve long-term remission and even long-term survival,” she said. ”But overall, even with long-term data, it seems like most patients will eventually relapse.”
The goal of the ongoing study is to determine whether adding basiliximab to BEAM could improve outcomes in the long run.
Unlike ibritumomab tiuxetan (Zevalin) – an yttrium-90–labeled antibody that’s been combined with rituximab to target CD20 in relapsed or refractory low-grade follicular B-cell non-Hodgkin lymphoma – basiliximab is targeted to CD25, which is preferentially expressed on T cells.
Basiliximab has been shown to inhibit growth of human anaplastic large cell lymphoma (ALCL) tumors and improve survival in mice bearing human tumor xenografts.
Because the beta particles that basiliximab emits cannot be detected on conventional scans, the antibody is also labeled with an indium-111 radiotracer for purposes of tracking.
At the time of Dr. Zain’s presentation, 13 patients ranging from 19 to 77 years of age were enrolled in the phase 1 trial. The patients were assigned to receive basiliximab at a dose of either 0.4, 0.5, or 0.6 mCi/kg in combination with standard dose BEAM.
The first patient treated had delayed engraftment of platelets; all subsequent patients had engraftment as expected.
There were no grade 3 or 4 toxicities at any dose level and no treatment-related mortality. The most frequent toxicity was grade 2 stomatitis, which occurred in three patients each in the 0.4 and 0.6 miC/kg levels and in four patients at the 0.5 miC/kg level of basiliximab. There were no dose-limiting toxicities.
As of the data cutoff, three patients have experienced relapses, and two of those patients died from disease progression. The times from transplant to relapse were 301 days and 218 days in the two patients who died, and it was 108 days in the third patient.
Dose expansion is continuing in the study, with an additional seven patients scheduled for treatment at the 0.6 miC/kg dose, Dr. Zain said.
Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center and the National Cancer Institute. The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Zain J et al. TCLF 2018.
LA JOLLA, CALIF. – Combining a radio-labeled, anti-CD25, monoclonal antibody with BEAM chemotherapy appears to be an effective and safe conditioning regimen prior to autologous stem cell transplant in patients with peripheral T-cell lymphoma (PTCL), investigators report.
In a phase 1 trial, median progression-free survival (PFS) was 10.6 months for patients treated with the yttrium-90–labeled, chimeric, anti-CD25 antibody basiliximab (Simulect) at one of three dose levels plus standard dose BEAM (carmustine, etoposide, cytarabine, and melphalan), said Jasmine Zain, MD, of the City of Hope Medical Center in Duarte, Calif.
There have been no significant cases of delayed transplant engraftment or unexpected increases in either mucositis or infectious complications, she said at the annual T-cell Lymphoma Forum.
“With standard conditioning, I think the best outcome we have seen is that at 5 years we have about 45% to 50% event-free survival, depending on the histology,” she said. “So we’re hoping we will surpass that.”
The first patient to receive a transplant in the study was treated in July 2015, and since most relapses in this patient population tend to occur within 2 years of transplant, the investigators expect that they will get a better idea of the results in the near future, Dr. Zain said.
PTCL generally has a poor prognosis, and many centers have turned to high-dose therapy followed by autologous stem cell transplant as a consolidation strategy for patients who are in their first or subsequent complete remissions, as well as for patients with relapsed or refractory disease.
“We in this field consider autologous stem cell transplant to be not curative for PTCL. It is true that some patients will achieve long-term remission and even long-term survival,” she said. ”But overall, even with long-term data, it seems like most patients will eventually relapse.”
The goal of the ongoing study is to determine whether adding basiliximab to BEAM could improve outcomes in the long run.
Unlike ibritumomab tiuxetan (Zevalin) – an yttrium-90–labeled antibody that’s been combined with rituximab to target CD20 in relapsed or refractory low-grade follicular B-cell non-Hodgkin lymphoma – basiliximab is targeted to CD25, which is preferentially expressed on T cells.
Basiliximab has been shown to inhibit growth of human anaplastic large cell lymphoma (ALCL) tumors and improve survival in mice bearing human tumor xenografts.
Because the beta particles that basiliximab emits cannot be detected on conventional scans, the antibody is also labeled with an indium-111 radiotracer for purposes of tracking.
At the time of Dr. Zain’s presentation, 13 patients ranging from 19 to 77 years of age were enrolled in the phase 1 trial. The patients were assigned to receive basiliximab at a dose of either 0.4, 0.5, or 0.6 mCi/kg in combination with standard dose BEAM.
The first patient treated had delayed engraftment of platelets; all subsequent patients had engraftment as expected.
There were no grade 3 or 4 toxicities at any dose level and no treatment-related mortality. The most frequent toxicity was grade 2 stomatitis, which occurred in three patients each in the 0.4 and 0.6 miC/kg levels and in four patients at the 0.5 miC/kg level of basiliximab. There were no dose-limiting toxicities.
As of the data cutoff, three patients have experienced relapses, and two of those patients died from disease progression. The times from transplant to relapse were 301 days and 218 days in the two patients who died, and it was 108 days in the third patient.
Dose expansion is continuing in the study, with an additional seven patients scheduled for treatment at the 0.6 miC/kg dose, Dr. Zain said.
Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center and the National Cancer Institute. The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
hematologynews@frontlinemedcom.com
SOURCE: Zain J et al. TCLF 2018.
REPORTING FROM TLCF 2018
Key clinical point:
Major finding: Median progression-free survival posttransplant was 10.6 months.
Study details: A phase 1, dose-finding trial in 13 patients with PTCL.
Disclosures: Dr. Zain did not report information on conflicts of interest. The study is supported by City of Hope Medical Center, Duarte, Calif., and the National Cancer Institute.
Source: Zain J et al. TLCF 2018.
Axitinib/pembrolizumab combo safe, effective against mRCC
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
FROM THE LANCET ONCOLOGY
Key clinical point: A combination of axitinib and pembrolizumab was tolerable and showed activity against advanced/metastatic renal cell carcinoma.
Major finding: At a median of 20.4 months of follow-up, the overall response rate was 73%.
Study details: Open-label phase 1b dose-finding trial and expansion in 52 patients with advanced RCC.
Disclosures: Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
Source: Atkins MB et al. Lancet Oncol 2018 Feb 10. doi: 10.1016/S1470-2045(18)30081-0.
Denosumab on par with zoledronic acid for multiple myeloma bone disease
Denosumab was noninferior to zoledronic acid at delaying skeletal-related events in patients with newly diagnosed multiple myeloma and one or more lytic bone lesions, according to findings from an international randomized trial.
In a phase 3 double-blind, double-dummy, controlled trial, patients were randomly assigned to receive either subcutaneous denosumab or intravenous zoledronic acid, plus the investigator’s choice of first-line antimyeloma therapy. The primary endpoint of noninferiority of denosumab at preventing time to first skeletal-related event, compared with zoledronic acid, was met, reported Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center, Boston, and colleagues.
Median progression-free survival, an exploratory endpoint, was significantly longer with denosumab – 46.1 months vs. 35.4 months – translating into a hazard ratio of 0.82 (P = .036) for progression on denosumab. There was no difference in overall survival, however.
Denosumab is a monoclonal antibody that binds to and inactivates receptor activator of nuclear factor kappa-B ligand, a promoter of osteoclast formation, activation, and survival. Zoledronic acid is a bisphosphonate that may have antimyeloma effects, the investigators noted.
“The greater progression-free survival with denosumab than with zoledronic acid is compelling in view of the previous preclinical and clinical evidence supporting an anti-RANKL[receptor factor kappa-B ligand]–mediated, antimyeloma effect. These results, in combination with the improved renal adverse event profile, support denosumab as an additional option to the standard of care for patients with multiple myeloma,” the investigators wrote in The Lancet Oncology.
The trial included 1,718 patients age 18 and older treated at 259 centers in 29 countries. All patients had newly diagnosed multiple myeloma with at least one documented lytic bone lesion. The patients were randomly assigned to denosumab or zoledronic acid, and were stratified by intent to undergo autologous stem cell transplant, antimyeloma therapy regimen, stage according to the International Staging System, previous skeletal-related events, and region.
As noted, the trial met the primary endpoint of noninferiority of denosumab, with a hazard ratio for time to first skeletal-related event vs. zoledronic acid of 0.98 (P = .010).
The safety analysis, which included all patients who were randomized and received at least one dose of study medication (850 on denosumab and 852 on zoledronic acid) showed that the agents were associated with similar incidences of neutropenia, thrombocytopenia, anemia, febrile neutropenia, and pneumonia. The incidence of renal toxicity, however, was lower with denosumab than with zoledronic acid (10% vs. 17%, respectively), whereas hypocalcemia was higher with denosumab (17% vs. 12%). There were no significant differences in the incidence of osteonecrosis of the jaw, a common problem with osteoclast inhibitors.
There was one treatment-related death, a case of cardiac arrest in a patient treated with zoledronic acid.
The investigators noted that the study was limited by a lack of response data, and by the fact that patients with creatinine clearance less than 30 mL/minute were not enrolled because of study blinding and the product label of zoledronic acid.
The study was sponsored by Amgen. Dr. Raje and multiple coauthors disclosed personal fees from Amgen and other companies. Three of the coauthors are current or former Amgen employees.
SOURCE: Raje NS et al. Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30072-X.
The study by Dr. Raje and colleagues is the largest placebo-controlled study ever done in patients with myeloma, but there are still many questions about how to move forward with this treatment. For instance, since only patients with myeloma-related bone disease at diagnosis were enrolled, the benefit of denosumab in patients without bone disease is uncertain. Additionally, the study did not show a survival benefit for denosumab over zoledronic acid.
Cost is also a factor, as denosumab is a higher priced treatment and requires continuous therapy. New treatment options, such as anti-CD38 monoclonal antibodies, are also available. It’s unclear how denosumab adds value in the context of these new therapies.
Meletios A. Dimopoulos, MD, and Efstathios Kastritis, MD, are with the department of clinical therapeutics at the National and Kapodistrian University of Athens, Greece. Dr. Dimopoulos had received honoraria from Celgene, Amgen, Takeda, Janssen, and Novartis. Dr. Kastritis has received honoraria from Janssen, Amgen, Prothena, Takeda, and Genesis Pharma. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30075-5).
The study by Dr. Raje and colleagues is the largest placebo-controlled study ever done in patients with myeloma, but there are still many questions about how to move forward with this treatment. For instance, since only patients with myeloma-related bone disease at diagnosis were enrolled, the benefit of denosumab in patients without bone disease is uncertain. Additionally, the study did not show a survival benefit for denosumab over zoledronic acid.
Cost is also a factor, as denosumab is a higher priced treatment and requires continuous therapy. New treatment options, such as anti-CD38 monoclonal antibodies, are also available. It’s unclear how denosumab adds value in the context of these new therapies.
Meletios A. Dimopoulos, MD, and Efstathios Kastritis, MD, are with the department of clinical therapeutics at the National and Kapodistrian University of Athens, Greece. Dr. Dimopoulos had received honoraria from Celgene, Amgen, Takeda, Janssen, and Novartis. Dr. Kastritis has received honoraria from Janssen, Amgen, Prothena, Takeda, and Genesis Pharma. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30075-5).
The study by Dr. Raje and colleagues is the largest placebo-controlled study ever done in patients with myeloma, but there are still many questions about how to move forward with this treatment. For instance, since only patients with myeloma-related bone disease at diagnosis were enrolled, the benefit of denosumab in patients without bone disease is uncertain. Additionally, the study did not show a survival benefit for denosumab over zoledronic acid.
Cost is also a factor, as denosumab is a higher priced treatment and requires continuous therapy. New treatment options, such as anti-CD38 monoclonal antibodies, are also available. It’s unclear how denosumab adds value in the context of these new therapies.
Meletios A. Dimopoulos, MD, and Efstathios Kastritis, MD, are with the department of clinical therapeutics at the National and Kapodistrian University of Athens, Greece. Dr. Dimopoulos had received honoraria from Celgene, Amgen, Takeda, Janssen, and Novartis. Dr. Kastritis has received honoraria from Janssen, Amgen, Prothena, Takeda, and Genesis Pharma. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30075-5).
Denosumab was noninferior to zoledronic acid at delaying skeletal-related events in patients with newly diagnosed multiple myeloma and one or more lytic bone lesions, according to findings from an international randomized trial.
In a phase 3 double-blind, double-dummy, controlled trial, patients were randomly assigned to receive either subcutaneous denosumab or intravenous zoledronic acid, plus the investigator’s choice of first-line antimyeloma therapy. The primary endpoint of noninferiority of denosumab at preventing time to first skeletal-related event, compared with zoledronic acid, was met, reported Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center, Boston, and colleagues.
Median progression-free survival, an exploratory endpoint, was significantly longer with denosumab – 46.1 months vs. 35.4 months – translating into a hazard ratio of 0.82 (P = .036) for progression on denosumab. There was no difference in overall survival, however.
Denosumab is a monoclonal antibody that binds to and inactivates receptor activator of nuclear factor kappa-B ligand, a promoter of osteoclast formation, activation, and survival. Zoledronic acid is a bisphosphonate that may have antimyeloma effects, the investigators noted.
“The greater progression-free survival with denosumab than with zoledronic acid is compelling in view of the previous preclinical and clinical evidence supporting an anti-RANKL[receptor factor kappa-B ligand]–mediated, antimyeloma effect. These results, in combination with the improved renal adverse event profile, support denosumab as an additional option to the standard of care for patients with multiple myeloma,” the investigators wrote in The Lancet Oncology.
The trial included 1,718 patients age 18 and older treated at 259 centers in 29 countries. All patients had newly diagnosed multiple myeloma with at least one documented lytic bone lesion. The patients were randomly assigned to denosumab or zoledronic acid, and were stratified by intent to undergo autologous stem cell transplant, antimyeloma therapy regimen, stage according to the International Staging System, previous skeletal-related events, and region.
As noted, the trial met the primary endpoint of noninferiority of denosumab, with a hazard ratio for time to first skeletal-related event vs. zoledronic acid of 0.98 (P = .010).
The safety analysis, which included all patients who were randomized and received at least one dose of study medication (850 on denosumab and 852 on zoledronic acid) showed that the agents were associated with similar incidences of neutropenia, thrombocytopenia, anemia, febrile neutropenia, and pneumonia. The incidence of renal toxicity, however, was lower with denosumab than with zoledronic acid (10% vs. 17%, respectively), whereas hypocalcemia was higher with denosumab (17% vs. 12%). There were no significant differences in the incidence of osteonecrosis of the jaw, a common problem with osteoclast inhibitors.
There was one treatment-related death, a case of cardiac arrest in a patient treated with zoledronic acid.
The investigators noted that the study was limited by a lack of response data, and by the fact that patients with creatinine clearance less than 30 mL/minute were not enrolled because of study blinding and the product label of zoledronic acid.
The study was sponsored by Amgen. Dr. Raje and multiple coauthors disclosed personal fees from Amgen and other companies. Three of the coauthors are current or former Amgen employees.
SOURCE: Raje NS et al. Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30072-X.
Denosumab was noninferior to zoledronic acid at delaying skeletal-related events in patients with newly diagnosed multiple myeloma and one or more lytic bone lesions, according to findings from an international randomized trial.
In a phase 3 double-blind, double-dummy, controlled trial, patients were randomly assigned to receive either subcutaneous denosumab or intravenous zoledronic acid, plus the investigator’s choice of first-line antimyeloma therapy. The primary endpoint of noninferiority of denosumab at preventing time to first skeletal-related event, compared with zoledronic acid, was met, reported Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center, Boston, and colleagues.
Median progression-free survival, an exploratory endpoint, was significantly longer with denosumab – 46.1 months vs. 35.4 months – translating into a hazard ratio of 0.82 (P = .036) for progression on denosumab. There was no difference in overall survival, however.
Denosumab is a monoclonal antibody that binds to and inactivates receptor activator of nuclear factor kappa-B ligand, a promoter of osteoclast formation, activation, and survival. Zoledronic acid is a bisphosphonate that may have antimyeloma effects, the investigators noted.
“The greater progression-free survival with denosumab than with zoledronic acid is compelling in view of the previous preclinical and clinical evidence supporting an anti-RANKL[receptor factor kappa-B ligand]–mediated, antimyeloma effect. These results, in combination with the improved renal adverse event profile, support denosumab as an additional option to the standard of care for patients with multiple myeloma,” the investigators wrote in The Lancet Oncology.
The trial included 1,718 patients age 18 and older treated at 259 centers in 29 countries. All patients had newly diagnosed multiple myeloma with at least one documented lytic bone lesion. The patients were randomly assigned to denosumab or zoledronic acid, and were stratified by intent to undergo autologous stem cell transplant, antimyeloma therapy regimen, stage according to the International Staging System, previous skeletal-related events, and region.
As noted, the trial met the primary endpoint of noninferiority of denosumab, with a hazard ratio for time to first skeletal-related event vs. zoledronic acid of 0.98 (P = .010).
The safety analysis, which included all patients who were randomized and received at least one dose of study medication (850 on denosumab and 852 on zoledronic acid) showed that the agents were associated with similar incidences of neutropenia, thrombocytopenia, anemia, febrile neutropenia, and pneumonia. The incidence of renal toxicity, however, was lower with denosumab than with zoledronic acid (10% vs. 17%, respectively), whereas hypocalcemia was higher with denosumab (17% vs. 12%). There were no significant differences in the incidence of osteonecrosis of the jaw, a common problem with osteoclast inhibitors.
There was one treatment-related death, a case of cardiac arrest in a patient treated with zoledronic acid.
The investigators noted that the study was limited by a lack of response data, and by the fact that patients with creatinine clearance less than 30 mL/minute were not enrolled because of study blinding and the product label of zoledronic acid.
The study was sponsored by Amgen. Dr. Raje and multiple coauthors disclosed personal fees from Amgen and other companies. Three of the coauthors are current or former Amgen employees.
SOURCE: Raje NS et al. Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30072-X.
FROM LANCET ONCOLOGY
Key clinical point: Denosumab was noninferior to zoledronic acid for time to skeletal-related events in patients with multiple myeloma with bone involvement.
Major finding: The hazard ratio for noninferiority of denosumab was 0.98 (P = .010).
Data source: A phase 3 randomized double-blind, double-dummy, controlled trial in 1,718 patients with newly diagnosed multiple myeloma with one or more lytic bone lesions.
Disclosures: The study was sponsored by Amgen. Dr. Raje and multiple coauthors disclosed personal fees from Amgen and other companies. Three of the coauthors are current or former Amgen employees.
Source: Raje NS et al. Lancet Oncol. 2018 Feb 8. doi: 10.1016/S1470-2045(18)30072-X.
A view from the bridge to transplant for PTCL
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
Getting hematologic cancer drugs on the fast track
LA JOLLA, CALIF. – The words “rapid approval” and “Food and Drug Administration” rarely appear in the same sentence. But despite that perception, the pace of hematologic drug development has been accelerating over the last several years, according to an agency staffer.
“FDA is committed toward the expedited development of safe and effective therapies for serious and life-threatening diseases,” R. Angelo de Claro, MD, of the FDA’s Office of Hematology and Oncology Products said at the annual T-cell Lymphoma Forum. Dr. de Claro outlined his agency’s efforts to accelerate approval of drugs for treatment of T-cell malignancies.
Hematologic drug bonanza
In 2017 alone, the FDA approved 17 agents for new or expanded indications for hematologic malignancies, including brentuximab vedotin (Adcetris) for anaplastic large cell lymphoma (ALCL) and CD30-positive mycosis fungoides (MF).
Approval was based on a 56% objective response rate for brentuximab vedotin versus 12% for physician’s choice in a phase 3 trial (ALCANZA) of 131 patients with mycosis fungoides or primary cutaneous ALCL. All patients had received one prior systemic therapy and were randomized (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene.
Dr. de Claro noted that in the ALCANZA trial, patients were required to have one or more biopsy samples with at least 10% CD30 expression, but among 184 patients with MF screened for the trial, 32% were ineligible because of less than 10% CD30 expression. The FDA therefore requested additional efficacy data for patients with MF with less than 10% CD30 expression and accepted data from two investigator-sponsored trials showing that 35 patients with MF expressing CD30 on 1%-9% of cells had a 31% overall response rate, whereas two patients with no CD30 expression did not have responses.
Who minds the store
Hematology products are under the aegis of the FDA’s Oncology Center of Excellence. Oversight includes benign hematology products, as well as products for hematologic cancers and hematologic support. Hematology and oncology toxicology is monitored by pharmacologists and toxicologists in a separate division, he explained.
“The Oncology Center of Excellence was formally launched in 2017 as part of the 21st century CURES Act. The mission of the Oncology Center of Excellence is to achieve patient-centered regulatory decision making through innovation and collaboration,” he said.
Getting the nod
To get approved, a new therapy requires “substantial” evidence of efficacy and safety. Regular approvals are based on either direct measures of clinical benefits – how a patient “feels, functions, or survives” – or a measure of the effect of a drug on an established surrogate endpoint.
For an accelerated approval, developers must be able to show evidence on either a surrogate or intermediate clinical endpoint that the agent is reasonably likely to offer a benefit and be a meaningful improvement over available therapies. Postapproval trials may be needed to verify the proposed benefits.
FDA accelerated approval programs include:
- Fast track. The pathway requires nonclinical or clinical data demonstrating the potential for addressing an unmet need.
- Breakthrough therapy. This pathway requires preliminary clinical evidence demonstrating substantial improvement over existing available therapies.
- Priority review. These are agents that, if approved, would provide significant improvements in safety or effectiveness.
- Accelerated approval. The drug must demonstrate an effect on an “endpoint reasonably likely to predict clinical benefit over available therapies.”
Dr. de Claro is employed by the FDA. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The words “rapid approval” and “Food and Drug Administration” rarely appear in the same sentence. But despite that perception, the pace of hematologic drug development has been accelerating over the last several years, according to an agency staffer.
“FDA is committed toward the expedited development of safe and effective therapies for serious and life-threatening diseases,” R. Angelo de Claro, MD, of the FDA’s Office of Hematology and Oncology Products said at the annual T-cell Lymphoma Forum. Dr. de Claro outlined his agency’s efforts to accelerate approval of drugs for treatment of T-cell malignancies.
Hematologic drug bonanza
In 2017 alone, the FDA approved 17 agents for new or expanded indications for hematologic malignancies, including brentuximab vedotin (Adcetris) for anaplastic large cell lymphoma (ALCL) and CD30-positive mycosis fungoides (MF).
Approval was based on a 56% objective response rate for brentuximab vedotin versus 12% for physician’s choice in a phase 3 trial (ALCANZA) of 131 patients with mycosis fungoides or primary cutaneous ALCL. All patients had received one prior systemic therapy and were randomized (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene.
Dr. de Claro noted that in the ALCANZA trial, patients were required to have one or more biopsy samples with at least 10% CD30 expression, but among 184 patients with MF screened for the trial, 32% were ineligible because of less than 10% CD30 expression. The FDA therefore requested additional efficacy data for patients with MF with less than 10% CD30 expression and accepted data from two investigator-sponsored trials showing that 35 patients with MF expressing CD30 on 1%-9% of cells had a 31% overall response rate, whereas two patients with no CD30 expression did not have responses.
Who minds the store
Hematology products are under the aegis of the FDA’s Oncology Center of Excellence. Oversight includes benign hematology products, as well as products for hematologic cancers and hematologic support. Hematology and oncology toxicology is monitored by pharmacologists and toxicologists in a separate division, he explained.
“The Oncology Center of Excellence was formally launched in 2017 as part of the 21st century CURES Act. The mission of the Oncology Center of Excellence is to achieve patient-centered regulatory decision making through innovation and collaboration,” he said.
Getting the nod
To get approved, a new therapy requires “substantial” evidence of efficacy and safety. Regular approvals are based on either direct measures of clinical benefits – how a patient “feels, functions, or survives” – or a measure of the effect of a drug on an established surrogate endpoint.
For an accelerated approval, developers must be able to show evidence on either a surrogate or intermediate clinical endpoint that the agent is reasonably likely to offer a benefit and be a meaningful improvement over available therapies. Postapproval trials may be needed to verify the proposed benefits.
FDA accelerated approval programs include:
- Fast track. The pathway requires nonclinical or clinical data demonstrating the potential for addressing an unmet need.
- Breakthrough therapy. This pathway requires preliminary clinical evidence demonstrating substantial improvement over existing available therapies.
- Priority review. These are agents that, if approved, would provide significant improvements in safety or effectiveness.
- Accelerated approval. The drug must demonstrate an effect on an “endpoint reasonably likely to predict clinical benefit over available therapies.”
Dr. de Claro is employed by the FDA. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – The words “rapid approval” and “Food and Drug Administration” rarely appear in the same sentence. But despite that perception, the pace of hematologic drug development has been accelerating over the last several years, according to an agency staffer.
“FDA is committed toward the expedited development of safe and effective therapies for serious and life-threatening diseases,” R. Angelo de Claro, MD, of the FDA’s Office of Hematology and Oncology Products said at the annual T-cell Lymphoma Forum. Dr. de Claro outlined his agency’s efforts to accelerate approval of drugs for treatment of T-cell malignancies.
Hematologic drug bonanza
In 2017 alone, the FDA approved 17 agents for new or expanded indications for hematologic malignancies, including brentuximab vedotin (Adcetris) for anaplastic large cell lymphoma (ALCL) and CD30-positive mycosis fungoides (MF).
Approval was based on a 56% objective response rate for brentuximab vedotin versus 12% for physician’s choice in a phase 3 trial (ALCANZA) of 131 patients with mycosis fungoides or primary cutaneous ALCL. All patients had received one prior systemic therapy and were randomized (1:1) to receive either brentuximab vedotin or the physician’s choice of methotrexate or bexarotene.
Dr. de Claro noted that in the ALCANZA trial, patients were required to have one or more biopsy samples with at least 10% CD30 expression, but among 184 patients with MF screened for the trial, 32% were ineligible because of less than 10% CD30 expression. The FDA therefore requested additional efficacy data for patients with MF with less than 10% CD30 expression and accepted data from two investigator-sponsored trials showing that 35 patients with MF expressing CD30 on 1%-9% of cells had a 31% overall response rate, whereas two patients with no CD30 expression did not have responses.
Who minds the store
Hematology products are under the aegis of the FDA’s Oncology Center of Excellence. Oversight includes benign hematology products, as well as products for hematologic cancers and hematologic support. Hematology and oncology toxicology is monitored by pharmacologists and toxicologists in a separate division, he explained.
“The Oncology Center of Excellence was formally launched in 2017 as part of the 21st century CURES Act. The mission of the Oncology Center of Excellence is to achieve patient-centered regulatory decision making through innovation and collaboration,” he said.
Getting the nod
To get approved, a new therapy requires “substantial” evidence of efficacy and safety. Regular approvals are based on either direct measures of clinical benefits – how a patient “feels, functions, or survives” – or a measure of the effect of a drug on an established surrogate endpoint.
For an accelerated approval, developers must be able to show evidence on either a surrogate or intermediate clinical endpoint that the agent is reasonably likely to offer a benefit and be a meaningful improvement over available therapies. Postapproval trials may be needed to verify the proposed benefits.
FDA accelerated approval programs include:
- Fast track. The pathway requires nonclinical or clinical data demonstrating the potential for addressing an unmet need.
- Breakthrough therapy. This pathway requires preliminary clinical evidence demonstrating substantial improvement over existing available therapies.
- Priority review. These are agents that, if approved, would provide significant improvements in safety or effectiveness.
- Accelerated approval. The drug must demonstrate an effect on an “endpoint reasonably likely to predict clinical benefit over available therapies.”
Dr. de Claro is employed by the FDA. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
T-cell lymphoma therapies on the horizon
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
VIP an unwelcome contributor to eosinophilic esophagitis
Vasoactive intestinal peptide (VIP) appears to play an important role in the pathology of eosinophilic esophagitis (EoE) by recruiting mast cells and eosinophils that contribute to EoE’s hallmark symptoms of dysphagia and esophageal dysmotility, investigators reported in the February issue of Cellular and Molecular Gastroenterology and Hepatology.
Blocking one of three VIP receptors – chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2) – could reduce eosinophil infiltration and mast cell numbers in the esophagus, wrote Alok K. Verma, PhD, a postodoctoral fellow at Tulane University in New Orleans, and his colleagues.
“We suggest that inhibiting the VIP–CRTH2 axis may ameliorate the dysphagia, stricture, and motility dysfunction of chronic EoE,” they wrote in a research letter to Cellular and Molecular Gastroenterology and Hepatology.
Several cytokines and chemokines, notably interleukin-5 and eotaxin-3, have been fingered as suspects in eosinophil infiltration, but whether chemokines other than eotaxin play a role has not been well documented, the investigators noted.
They hypothesized that VIP may be a chemoattractant that draws eosinophils into perineural areas of the muscular mucosa of the esophagus.
To test this idea, they looked at VIP-expression in samples from patients both with and without EoE and found that VIP expression was low among controls (without EoE); they also found that eosinophils were seen to accumulate near VIP-expressing nerve cells in biopsy samples from patients with EoE.
When they performed in vitro studies of VIP binding and immunologic functions, they found that eosinophils primarily express the CRTH2 receptor rather than the vasoactive intestinal peptide receptor 1 (VPAC-1) or VPAC-2.
They also demonstrated that VIP’s effects on eosinophil motility was similar to that of eotaxin and that, when they pretreated eosinophils with a CRTH2 inhibitor, esoinophil motility was hampered.
The investigators next looked at biopsy specimens from patients with EoE and found that eosinophils that express CRTH2 accumulated in the epithelial mucosa.
To see whether (as they and other researchers had suspected) VIP and its interaction with the CRTH2 receptor might play a role in mast cell recruitment, they performed immunofluorescence analyses and confirmed the presence of the CRTH2 receptor on tryptase-positive mast cells in the esophageal mucosa of patients with EoE.
“These findings suggest that, similar to eosinophils, mast cells accumulate via interaction of the CRTH2 receptor with neutrally derived VIP,” they wrote.
Finally, to see whether a reduction in peak eosinophil levels in patients with EoE with a CRTH2 antagonist – as seen in prior studies – could also ameliorate the negative effects of mast cells on esophageal function, they looked at the effects of CRTH2 inhibition in a mouse model of human EoE.
They found that, in the mice treated with a CRTH2 blocker, each segment of the esophagus had significant reductions in both eosinophil infiltration and mast cell numbers (P less than .05 for each).
The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.
SOURCE: Verma AK et al. Cell Mol Gastroenterol Hepatol. 2018;5[1]:99-100.e7.
The rapid increase in the incidence of pediatric and adult eosinophilic esophagitis (EoE) draws immediate attention to the importance of studying the mechanisms underlying this detrimental condition. The lack of preventive or curative therapies for EoE further underscores the importance of research that addresses gaps in our understanding of how eosinophilic inflammation of the esophagus is regulated on the molecular and cellular level. EoE is classified as an allergic immune disorder of the gastrointestinal tract and is characterized by eosinophil-rich, chronic Th2-type inflammation of the esophagus.
In this recent publication, the laboratory of Anil Mishra, PhD, showed that vasoactive intestinal peptide (VIP) serves as a potent chemoattractant for eosinophils and promotes accumulation of these innate immune cells adjacent to nerve cells in the muscular mucosa. Increased VIP expression was documented in EoE patients when compared to controls, and the authors identified the chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTH2) as a main binding receptor for VIP. Interestingly, CRTH2 was not only found to be expressed on eosinophils but also on tissue mast cells – another innate immune cell type that significantly contributes to the inflammatory tissue infiltrate in EoE patients. Based on the human findings, the authors tested whether VIP plays a major role in recruiting eosinophils and mast cells to the inflamed esophagus and whether CRTH2 blockade can modulate experimental EoE. Indeed, EoE pathology improved in animals that were treated with a CRTH2 antagonist.
In conclusion, these observations suggest that inhibiting the VIP-CRTH2 axis may serve as a therapeutic intervention pathway to ameliorate innate tissue inflammation in EoE patients.
Edda Fiebiger, PhD, is in the department of pediatrics in the division of gastroenterology, hepatology and nutrition at Boston Children’s Hospital, as well as in the department of medicine at Harvard Medical School, also in Boston. She had no disclosures.
The rapid increase in the incidence of pediatric and adult eosinophilic esophagitis (EoE) draws immediate attention to the importance of studying the mechanisms underlying this detrimental condition. The lack of preventive or curative therapies for EoE further underscores the importance of research that addresses gaps in our understanding of how eosinophilic inflammation of the esophagus is regulated on the molecular and cellular level. EoE is classified as an allergic immune disorder of the gastrointestinal tract and is characterized by eosinophil-rich, chronic Th2-type inflammation of the esophagus.
In this recent publication, the laboratory of Anil Mishra, PhD, showed that vasoactive intestinal peptide (VIP) serves as a potent chemoattractant for eosinophils and promotes accumulation of these innate immune cells adjacent to nerve cells in the muscular mucosa. Increased VIP expression was documented in EoE patients when compared to controls, and the authors identified the chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTH2) as a main binding receptor for VIP. Interestingly, CRTH2 was not only found to be expressed on eosinophils but also on tissue mast cells – another innate immune cell type that significantly contributes to the inflammatory tissue infiltrate in EoE patients. Based on the human findings, the authors tested whether VIP plays a major role in recruiting eosinophils and mast cells to the inflamed esophagus and whether CRTH2 blockade can modulate experimental EoE. Indeed, EoE pathology improved in animals that were treated with a CRTH2 antagonist.
In conclusion, these observations suggest that inhibiting the VIP-CRTH2 axis may serve as a therapeutic intervention pathway to ameliorate innate tissue inflammation in EoE patients.
Edda Fiebiger, PhD, is in the department of pediatrics in the division of gastroenterology, hepatology and nutrition at Boston Children’s Hospital, as well as in the department of medicine at Harvard Medical School, also in Boston. She had no disclosures.
The rapid increase in the incidence of pediatric and adult eosinophilic esophagitis (EoE) draws immediate attention to the importance of studying the mechanisms underlying this detrimental condition. The lack of preventive or curative therapies for EoE further underscores the importance of research that addresses gaps in our understanding of how eosinophilic inflammation of the esophagus is regulated on the molecular and cellular level. EoE is classified as an allergic immune disorder of the gastrointestinal tract and is characterized by eosinophil-rich, chronic Th2-type inflammation of the esophagus.
In this recent publication, the laboratory of Anil Mishra, PhD, showed that vasoactive intestinal peptide (VIP) serves as a potent chemoattractant for eosinophils and promotes accumulation of these innate immune cells adjacent to nerve cells in the muscular mucosa. Increased VIP expression was documented in EoE patients when compared to controls, and the authors identified the chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTH2) as a main binding receptor for VIP. Interestingly, CRTH2 was not only found to be expressed on eosinophils but also on tissue mast cells – another innate immune cell type that significantly contributes to the inflammatory tissue infiltrate in EoE patients. Based on the human findings, the authors tested whether VIP plays a major role in recruiting eosinophils and mast cells to the inflamed esophagus and whether CRTH2 blockade can modulate experimental EoE. Indeed, EoE pathology improved in animals that were treated with a CRTH2 antagonist.
In conclusion, these observations suggest that inhibiting the VIP-CRTH2 axis may serve as a therapeutic intervention pathway to ameliorate innate tissue inflammation in EoE patients.
Edda Fiebiger, PhD, is in the department of pediatrics in the division of gastroenterology, hepatology and nutrition at Boston Children’s Hospital, as well as in the department of medicine at Harvard Medical School, also in Boston. She had no disclosures.
Vasoactive intestinal peptide (VIP) appears to play an important role in the pathology of eosinophilic esophagitis (EoE) by recruiting mast cells and eosinophils that contribute to EoE’s hallmark symptoms of dysphagia and esophageal dysmotility, investigators reported in the February issue of Cellular and Molecular Gastroenterology and Hepatology.
Blocking one of three VIP receptors – chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2) – could reduce eosinophil infiltration and mast cell numbers in the esophagus, wrote Alok K. Verma, PhD, a postodoctoral fellow at Tulane University in New Orleans, and his colleagues.
“We suggest that inhibiting the VIP–CRTH2 axis may ameliorate the dysphagia, stricture, and motility dysfunction of chronic EoE,” they wrote in a research letter to Cellular and Molecular Gastroenterology and Hepatology.
Several cytokines and chemokines, notably interleukin-5 and eotaxin-3, have been fingered as suspects in eosinophil infiltration, but whether chemokines other than eotaxin play a role has not been well documented, the investigators noted.
They hypothesized that VIP may be a chemoattractant that draws eosinophils into perineural areas of the muscular mucosa of the esophagus.
To test this idea, they looked at VIP-expression in samples from patients both with and without EoE and found that VIP expression was low among controls (without EoE); they also found that eosinophils were seen to accumulate near VIP-expressing nerve cells in biopsy samples from patients with EoE.
When they performed in vitro studies of VIP binding and immunologic functions, they found that eosinophils primarily express the CRTH2 receptor rather than the vasoactive intestinal peptide receptor 1 (VPAC-1) or VPAC-2.
They also demonstrated that VIP’s effects on eosinophil motility was similar to that of eotaxin and that, when they pretreated eosinophils with a CRTH2 inhibitor, esoinophil motility was hampered.
The investigators next looked at biopsy specimens from patients with EoE and found that eosinophils that express CRTH2 accumulated in the epithelial mucosa.
To see whether (as they and other researchers had suspected) VIP and its interaction with the CRTH2 receptor might play a role in mast cell recruitment, they performed immunofluorescence analyses and confirmed the presence of the CRTH2 receptor on tryptase-positive mast cells in the esophageal mucosa of patients with EoE.
“These findings suggest that, similar to eosinophils, mast cells accumulate via interaction of the CRTH2 receptor with neutrally derived VIP,” they wrote.
Finally, to see whether a reduction in peak eosinophil levels in patients with EoE with a CRTH2 antagonist – as seen in prior studies – could also ameliorate the negative effects of mast cells on esophageal function, they looked at the effects of CRTH2 inhibition in a mouse model of human EoE.
They found that, in the mice treated with a CRTH2 blocker, each segment of the esophagus had significant reductions in both eosinophil infiltration and mast cell numbers (P less than .05 for each).
The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.
SOURCE: Verma AK et al. Cell Mol Gastroenterol Hepatol. 2018;5[1]:99-100.e7.
Vasoactive intestinal peptide (VIP) appears to play an important role in the pathology of eosinophilic esophagitis (EoE) by recruiting mast cells and eosinophils that contribute to EoE’s hallmark symptoms of dysphagia and esophageal dysmotility, investigators reported in the February issue of Cellular and Molecular Gastroenterology and Hepatology.
Blocking one of three VIP receptors – chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2) – could reduce eosinophil infiltration and mast cell numbers in the esophagus, wrote Alok K. Verma, PhD, a postodoctoral fellow at Tulane University in New Orleans, and his colleagues.
“We suggest that inhibiting the VIP–CRTH2 axis may ameliorate the dysphagia, stricture, and motility dysfunction of chronic EoE,” they wrote in a research letter to Cellular and Molecular Gastroenterology and Hepatology.
Several cytokines and chemokines, notably interleukin-5 and eotaxin-3, have been fingered as suspects in eosinophil infiltration, but whether chemokines other than eotaxin play a role has not been well documented, the investigators noted.
They hypothesized that VIP may be a chemoattractant that draws eosinophils into perineural areas of the muscular mucosa of the esophagus.
To test this idea, they looked at VIP-expression in samples from patients both with and without EoE and found that VIP expression was low among controls (without EoE); they also found that eosinophils were seen to accumulate near VIP-expressing nerve cells in biopsy samples from patients with EoE.
When they performed in vitro studies of VIP binding and immunologic functions, they found that eosinophils primarily express the CRTH2 receptor rather than the vasoactive intestinal peptide receptor 1 (VPAC-1) or VPAC-2.
They also demonstrated that VIP’s effects on eosinophil motility was similar to that of eotaxin and that, when they pretreated eosinophils with a CRTH2 inhibitor, esoinophil motility was hampered.
The investigators next looked at biopsy specimens from patients with EoE and found that eosinophils that express CRTH2 accumulated in the epithelial mucosa.
To see whether (as they and other researchers had suspected) VIP and its interaction with the CRTH2 receptor might play a role in mast cell recruitment, they performed immunofluorescence analyses and confirmed the presence of the CRTH2 receptor on tryptase-positive mast cells in the esophageal mucosa of patients with EoE.
“These findings suggest that, similar to eosinophils, mast cells accumulate via interaction of the CRTH2 receptor with neutrally derived VIP,” they wrote.
Finally, to see whether a reduction in peak eosinophil levels in patients with EoE with a CRTH2 antagonist – as seen in prior studies – could also ameliorate the negative effects of mast cells on esophageal function, they looked at the effects of CRTH2 inhibition in a mouse model of human EoE.
They found that, in the mice treated with a CRTH2 blocker, each segment of the esophagus had significant reductions in both eosinophil infiltration and mast cell numbers (P less than .05 for each).
The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.
SOURCE: Verma AK et al. Cell Mol Gastroenterol Hepatol. 2018;5[1]:99-100.e7.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: VIP appears to play an important role in the pathogenesis of eosinophilic esophagitis (EoE).
Major finding: Neurally derived VIP and its interaction with the CRTH2 receptor appear to recruit eosinophils and mast cells into the esophageal mucosa.
Data source: In vitro studies of human EoE biopsy samples and in vivo studies in mouse models of EoE.
Disclosures: The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.
Source: Verma AK et al. Cell Mol Gastroenterol Hepatol. 2018;5[1]:99-100.e7.
Desmoplastic melanoma yields to checkpoint inhibitors
Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.
Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas, MD, PhD, of the University of California, Los Angeles, and colleagues.
Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.
Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.
“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.
To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.
Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.
The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.
When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”
The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.
Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.
“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.
The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
SOURCE: Ribas A et al. Nature. 2018 Jan 10. doi: 10.1038/nature25187.
Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.
Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas, MD, PhD, of the University of California, Los Angeles, and colleagues.
Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.
Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.
“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.
To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.
Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.
The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.
When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”
The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.
Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.
“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.
The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
SOURCE: Ribas A et al. Nature. 2018 Jan 10. doi: 10.1038/nature25187.
Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.
Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas, MD, PhD, of the University of California, Los Angeles, and colleagues.
Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.
Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.
“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.
To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.
Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.
The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.
When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”
The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.
Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.
“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.
The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
SOURCE: Ribas A et al. Nature. 2018 Jan 10. doi: 10.1038/nature25187.
FROM NATURE
Key clinical point: Desmoplastic melanoma (DM) has a high mutational load that may make it susceptible to anti–PD-1 and PD-L1 therapy.
Major finding: The objective response rate was 70%, including 32% complete and 38% partial responses.
Data source: A retrospective review of data on 60 patients with desmoplastic melanoma treated with immune checkpoint inhibitors.
Disclosures: The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
Source: Ribas A et al. Nature. 2018 Jan 10. doi: 10.1038/nature25187.