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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Novel JAK1 inhibitor shows promise for myeloid malignancies
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
sworcester@frontlinemedcom.com
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
sworcester@frontlinemedcom.com
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
sworcester@frontlinemedcom.com
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: Overall response rates with INCB052793 plus azacitidine were 67% in AML and 56% in MDS or MDS/MPN.
Study details: A phase 1/2 study involving 58 initial patients.
Disclosures: This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
Source: Zeidan A et al. ASH 2017 Abstract 640.
Phase 1 study: Human IL-10 plus checkpoint blockade looks promising in RCC, NSCLC
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
sworcester@frontlinemedcom.com
SOURCE: Naing A et al. SITC Abstract 012.
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
sworcester@frontlinemedcom.com
SOURCE: Naing A et al. SITC Abstract 012.
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
sworcester@frontlinemedcom.com
SOURCE: Naing A et al. SITC Abstract 012.
REPORTING FROM SITC 2017
Key clinical point:
Major finding: 15 of 34 RCC patients had an objective response and two of those had a complete response.
Study details: Expansion cohorts including 64 patients from a phase 1 study.
Disclosures: Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
Source: A. Naing et al. SITC 2017 Abstract 012.
Non-PCOS IVF: Two trials show no benefit with frozen embryo transfer
Contrary to findings in women with polycystic ovary syndrome (PCOS), the transfer of frozen vs. fresh embryos does not lead to significantly higher live birth or ongoing pregnancy rates in women with non-PCOS infertility who undergo in vitro fertilization, according to findings from two randomized trials.
Frozen embryo transfer did, however, result in a lower risk of ovarian hyperstimulation syndrome in one of the trials. In that multicenter study, 2,157 women undergoing their first in vitro fertilization (IVF) cycle were randomized to undergo either fresh embryo transfer or embryo cryopreservation followed by frozen embryo transfer, with up to two cleavage-stage embryos transferred, Yuhua Shi, MD, of Shandong University, Jinan, China, and colleagues reported Jan. 11 in the New England Journal of Medicine. The live birth rate, defined as delivery of a viable neonate at 28 weeks of gestation or greater, was 50.2% and 48.7% in the fresh embryo and frozen embryo groups, respectively (relative risk, 0.97). The rate of ovarian hyperstimulation syndrome was 2.0% and 0.6% in the groups, respectively (RR, 0.32), the investigators reported.
Of note, the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy did not differ between the groups, but in a post hoc analysis, the rate of second-trimester pregnancy loss was lower with frozen embryo transfer (4.7% vs. 1.5%; RR, 0.33). However, the authors urged caution regarding the latter finding because of the post hoc setting and because the overall rates of pregnancy loss did not differ between the groups.
In the second study, 782 women without PCOS who were undergoing a first or second IVF cycle at a single center were randomized to receive either fresh or frozen embryo transfer with up to two embryos transferred.
After the first complete cycle, the ongoing pregnancy rate – the primary outcome in the study, defined as pregnancy with a detectable heart rate after 12 weeks of gestation – was 34.5% in the fresh embryo group and 36.3% in the frozen embryo group (RR in frozen embryo group, 1.05), Lan N. Vuong, MD, of My Duc Hospital, Ho Chi Minh City, Vietnam, and colleagues reported.
The live birth rates after the first transfer were 31.5% and 33.8%, respectively (risk ratio, 1.07). There also were no differences in rates of implantation or clinical pregnancy, or in rates of ectopic pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome in the primary cycle, or pregnancy complications.
The findings of both studies contrast with those from prior studies showing a higher live-birth rate among anovulatory women with PCOS who undergo frozen embryo transfer, compared with those who undergo fresh embryo transfer.
For example, Dr. Shi and associates found in a prior study of women with PCOS that the live birth rate was higher with frozen embryo transfer (42% vs. 49%), and they concluded that this was largely explained by a lower rate of pregnancy loss (N Engl J Med. 2016;375:523-33).
“However, patients with the polycystic ovary syndrome have a different reproductive, metabolic milieu than do other women with infertility; it is characterized by hyperandrogenism and insulin resistance, and these patients typically have a greater ovarian response to gonadotropin stimulation than do ovulatory women undergoing IVF,” they wrote in the current paper.
The findings of the current studies suggest the benefits of frozen vs. fresh embryo transfer, with respect to the primary outcome measures in the studies, do not apply in women with non-PCOS infertility.
Dr. Shi and colleagues speculated that “the difference is due to the unfavorable uterine environment after fresh embryo transfer in women with the polycystic ovary syndrome, as shown by a much lower rate of live birth overall in the previous trial than in the present trial.”
The “altered hormonal milieu” in women with PCOS, along with a need for ovarian stimulation cycle initiation with oral contraceptives or progestin may adversely affect endometrial receptivity after fresh embryo transfer, they explained.
Dr. Vuong and colleagues noted that their findings are not necessarily inconsistent with those reported in women with PCOS, because “the 95% confidence intervals around the risk ratios for live birth that were associated with frozen embryo transfer in our trial overlap with the 95% confidence intervals in that report,” adding that another contributing factor to the different results might be the timing of freezing, which differed in the studies.
They also said that a small difference in the time to conception, which was 1.4 months shorter in the fresh embryo group, could be “a relevant factor for some patients in terms of the overall treatment duration and both the direct and indirect costs of IVF.”
The study by Dr. Shi and associates was supported by grants from the National Key Research and Development Program of China, the Major Program of the National Natural Science Foundation of China, and the State Key Program of the National Natural Science Foundation of China. Dr. Shi reported having no conflicts of interest. One coauthor, Richard S. Legro, MD, reported receiving consulting fees from Ogeda, KinDex Pharmaceuticals, Fractyl Laboratories, Bayer, and AbbVie, and receiving grant support from Ferring Pharmaceuticals. The study by Dr. Vuong and associates was supported by My Duc Hospital. Author disclosures for that study are available with the full text of the article at NEJM.org.
sworcester@frontlinemedcom.com
SOURCES: Shi Y et al. N Engl J Med. 2018;378(2):126-36; Vuong N et al. N Engl J Med. 2018;378(2):137-47.
Contrary to findings in women with polycystic ovary syndrome (PCOS), the transfer of frozen vs. fresh embryos does not lead to significantly higher live birth or ongoing pregnancy rates in women with non-PCOS infertility who undergo in vitro fertilization, according to findings from two randomized trials.
Frozen embryo transfer did, however, result in a lower risk of ovarian hyperstimulation syndrome in one of the trials. In that multicenter study, 2,157 women undergoing their first in vitro fertilization (IVF) cycle were randomized to undergo either fresh embryo transfer or embryo cryopreservation followed by frozen embryo transfer, with up to two cleavage-stage embryos transferred, Yuhua Shi, MD, of Shandong University, Jinan, China, and colleagues reported Jan. 11 in the New England Journal of Medicine. The live birth rate, defined as delivery of a viable neonate at 28 weeks of gestation or greater, was 50.2% and 48.7% in the fresh embryo and frozen embryo groups, respectively (relative risk, 0.97). The rate of ovarian hyperstimulation syndrome was 2.0% and 0.6% in the groups, respectively (RR, 0.32), the investigators reported.
Of note, the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy did not differ between the groups, but in a post hoc analysis, the rate of second-trimester pregnancy loss was lower with frozen embryo transfer (4.7% vs. 1.5%; RR, 0.33). However, the authors urged caution regarding the latter finding because of the post hoc setting and because the overall rates of pregnancy loss did not differ between the groups.
In the second study, 782 women without PCOS who were undergoing a first or second IVF cycle at a single center were randomized to receive either fresh or frozen embryo transfer with up to two embryos transferred.
After the first complete cycle, the ongoing pregnancy rate – the primary outcome in the study, defined as pregnancy with a detectable heart rate after 12 weeks of gestation – was 34.5% in the fresh embryo group and 36.3% in the frozen embryo group (RR in frozen embryo group, 1.05), Lan N. Vuong, MD, of My Duc Hospital, Ho Chi Minh City, Vietnam, and colleagues reported.
The live birth rates after the first transfer were 31.5% and 33.8%, respectively (risk ratio, 1.07). There also were no differences in rates of implantation or clinical pregnancy, or in rates of ectopic pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome in the primary cycle, or pregnancy complications.
The findings of both studies contrast with those from prior studies showing a higher live-birth rate among anovulatory women with PCOS who undergo frozen embryo transfer, compared with those who undergo fresh embryo transfer.
For example, Dr. Shi and associates found in a prior study of women with PCOS that the live birth rate was higher with frozen embryo transfer (42% vs. 49%), and they concluded that this was largely explained by a lower rate of pregnancy loss (N Engl J Med. 2016;375:523-33).
“However, patients with the polycystic ovary syndrome have a different reproductive, metabolic milieu than do other women with infertility; it is characterized by hyperandrogenism and insulin resistance, and these patients typically have a greater ovarian response to gonadotropin stimulation than do ovulatory women undergoing IVF,” they wrote in the current paper.
The findings of the current studies suggest the benefits of frozen vs. fresh embryo transfer, with respect to the primary outcome measures in the studies, do not apply in women with non-PCOS infertility.
Dr. Shi and colleagues speculated that “the difference is due to the unfavorable uterine environment after fresh embryo transfer in women with the polycystic ovary syndrome, as shown by a much lower rate of live birth overall in the previous trial than in the present trial.”
The “altered hormonal milieu” in women with PCOS, along with a need for ovarian stimulation cycle initiation with oral contraceptives or progestin may adversely affect endometrial receptivity after fresh embryo transfer, they explained.
Dr. Vuong and colleagues noted that their findings are not necessarily inconsistent with those reported in women with PCOS, because “the 95% confidence intervals around the risk ratios for live birth that were associated with frozen embryo transfer in our trial overlap with the 95% confidence intervals in that report,” adding that another contributing factor to the different results might be the timing of freezing, which differed in the studies.
They also said that a small difference in the time to conception, which was 1.4 months shorter in the fresh embryo group, could be “a relevant factor for some patients in terms of the overall treatment duration and both the direct and indirect costs of IVF.”
The study by Dr. Shi and associates was supported by grants from the National Key Research and Development Program of China, the Major Program of the National Natural Science Foundation of China, and the State Key Program of the National Natural Science Foundation of China. Dr. Shi reported having no conflicts of interest. One coauthor, Richard S. Legro, MD, reported receiving consulting fees from Ogeda, KinDex Pharmaceuticals, Fractyl Laboratories, Bayer, and AbbVie, and receiving grant support from Ferring Pharmaceuticals. The study by Dr. Vuong and associates was supported by My Duc Hospital. Author disclosures for that study are available with the full text of the article at NEJM.org.
sworcester@frontlinemedcom.com
SOURCES: Shi Y et al. N Engl J Med. 2018;378(2):126-36; Vuong N et al. N Engl J Med. 2018;378(2):137-47.
Contrary to findings in women with polycystic ovary syndrome (PCOS), the transfer of frozen vs. fresh embryos does not lead to significantly higher live birth or ongoing pregnancy rates in women with non-PCOS infertility who undergo in vitro fertilization, according to findings from two randomized trials.
Frozen embryo transfer did, however, result in a lower risk of ovarian hyperstimulation syndrome in one of the trials. In that multicenter study, 2,157 women undergoing their first in vitro fertilization (IVF) cycle were randomized to undergo either fresh embryo transfer or embryo cryopreservation followed by frozen embryo transfer, with up to two cleavage-stage embryos transferred, Yuhua Shi, MD, of Shandong University, Jinan, China, and colleagues reported Jan. 11 in the New England Journal of Medicine. The live birth rate, defined as delivery of a viable neonate at 28 weeks of gestation or greater, was 50.2% and 48.7% in the fresh embryo and frozen embryo groups, respectively (relative risk, 0.97). The rate of ovarian hyperstimulation syndrome was 2.0% and 0.6% in the groups, respectively (RR, 0.32), the investigators reported.
Of note, the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy did not differ between the groups, but in a post hoc analysis, the rate of second-trimester pregnancy loss was lower with frozen embryo transfer (4.7% vs. 1.5%; RR, 0.33). However, the authors urged caution regarding the latter finding because of the post hoc setting and because the overall rates of pregnancy loss did not differ between the groups.
In the second study, 782 women without PCOS who were undergoing a first or second IVF cycle at a single center were randomized to receive either fresh or frozen embryo transfer with up to two embryos transferred.
After the first complete cycle, the ongoing pregnancy rate – the primary outcome in the study, defined as pregnancy with a detectable heart rate after 12 weeks of gestation – was 34.5% in the fresh embryo group and 36.3% in the frozen embryo group (RR in frozen embryo group, 1.05), Lan N. Vuong, MD, of My Duc Hospital, Ho Chi Minh City, Vietnam, and colleagues reported.
The live birth rates after the first transfer were 31.5% and 33.8%, respectively (risk ratio, 1.07). There also were no differences in rates of implantation or clinical pregnancy, or in rates of ectopic pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome in the primary cycle, or pregnancy complications.
The findings of both studies contrast with those from prior studies showing a higher live-birth rate among anovulatory women with PCOS who undergo frozen embryo transfer, compared with those who undergo fresh embryo transfer.
For example, Dr. Shi and associates found in a prior study of women with PCOS that the live birth rate was higher with frozen embryo transfer (42% vs. 49%), and they concluded that this was largely explained by a lower rate of pregnancy loss (N Engl J Med. 2016;375:523-33).
“However, patients with the polycystic ovary syndrome have a different reproductive, metabolic milieu than do other women with infertility; it is characterized by hyperandrogenism and insulin resistance, and these patients typically have a greater ovarian response to gonadotropin stimulation than do ovulatory women undergoing IVF,” they wrote in the current paper.
The findings of the current studies suggest the benefits of frozen vs. fresh embryo transfer, with respect to the primary outcome measures in the studies, do not apply in women with non-PCOS infertility.
Dr. Shi and colleagues speculated that “the difference is due to the unfavorable uterine environment after fresh embryo transfer in women with the polycystic ovary syndrome, as shown by a much lower rate of live birth overall in the previous trial than in the present trial.”
The “altered hormonal milieu” in women with PCOS, along with a need for ovarian stimulation cycle initiation with oral contraceptives or progestin may adversely affect endometrial receptivity after fresh embryo transfer, they explained.
Dr. Vuong and colleagues noted that their findings are not necessarily inconsistent with those reported in women with PCOS, because “the 95% confidence intervals around the risk ratios for live birth that were associated with frozen embryo transfer in our trial overlap with the 95% confidence intervals in that report,” adding that another contributing factor to the different results might be the timing of freezing, which differed in the studies.
They also said that a small difference in the time to conception, which was 1.4 months shorter in the fresh embryo group, could be “a relevant factor for some patients in terms of the overall treatment duration and both the direct and indirect costs of IVF.”
The study by Dr. Shi and associates was supported by grants from the National Key Research and Development Program of China, the Major Program of the National Natural Science Foundation of China, and the State Key Program of the National Natural Science Foundation of China. Dr. Shi reported having no conflicts of interest. One coauthor, Richard S. Legro, MD, reported receiving consulting fees from Ogeda, KinDex Pharmaceuticals, Fractyl Laboratories, Bayer, and AbbVie, and receiving grant support from Ferring Pharmaceuticals. The study by Dr. Vuong and associates was supported by My Duc Hospital. Author disclosures for that study are available with the full text of the article at NEJM.org.
sworcester@frontlinemedcom.com
SOURCES: Shi Y et al. N Engl J Med. 2018;378(2):126-36; Vuong N et al. N Engl J Med. 2018;378(2):137-47.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: The live birth rate was similar with fresh vs. frozen transfer (50.2% and 48.7% in one study; relative risk, 0.97).
Study details: Randomized trials including 2,157 and 782 women, respectively.
Disclosures: The study by Shi et al. was supported by grants from the National Key Research and Development Program of China, the Major Program of the National Natural Science Foundation of China, and the State Key Program of the National Natural Science Foundation of China. Dr. Shi reported having no conflicts of interest. One coauthor, Richard S. Legro, MD, reported receiving consulting fees from Ogeda, KinDex Pharmaceuticals, Fractyl Laboratories, Bayer, and AbbVie, and receiving grant support from Ferring Pharmaceuticals. The study by Vuong et al. was supported by My Duc Hospital. Author disclosures for that study are available with the full text of the article at NEJM.org.
Sources: Shi Y et al. N Engl J Med. 2018;378(2):126-36; Vuong N et al. N Engl J Med. 2018;378(2):137-47.
Modeling study: Screening, treatment effects on breast cancer mortality vary by subtype
, according to a simulation modeling study.
The estimated rate of reduction in overall breast cancer mortality in 2000 was 37% from an estimated baseline rate of 64 deaths per 100,000 women, with 44% and 56% of that associated with screening and treatment, respectively. In 2012 the estimated reduction was 49% from an estimated baseline rate of 63 per 100,000 women, with 37% and 63% associated with screening and treatment, respectively (estimated 12% difference in 2012 vs. 2000), Sylvia K. Plevritis, PhD, of Stanford (Calif.) University and her colleagues reported in JAMA.
Screening and treatment were estimated to contribute to the reductions at varying rates. For example, the relative contributions of screening vs. treatment were 36% vs. 64% for ER+/ERBB2– disease; 31% vs. 69% for ER+/ERBB2+ disease; 40% vs. 60% for ER–/ERBB2+ disease; and 48% vs. 52% for ER–/ERBB2– disease.
The model-based analysis provides clinically relevant insights about the contributions of screening and treatment to reductions in breast cancer mortality by molecular subtype, showing a greater relative contribution of treatment in 2012 overall and for all subtypes except ER–/ERBB2– disease, the authors said.
“Because ER+ cancers are the most prevalent and this group is expected to increase with time, additional advances for this subtype could have the largest effect on reducing the overall population burden of breast cancer,” they noted.
This study was supported by grants from the National Cancer Institute and the American Cancer Society. Dr. Plevritis reported consulting for GRAIL.
sworcester@frontlinemedcom.com
SOURCE: Plevritis S et al. JAMA. 2018 Jan 9;319(2):154-64. doi: 10.1001/jama.2017.19130.
.
, according to a simulation modeling study.
The estimated rate of reduction in overall breast cancer mortality in 2000 was 37% from an estimated baseline rate of 64 deaths per 100,000 women, with 44% and 56% of that associated with screening and treatment, respectively. In 2012 the estimated reduction was 49% from an estimated baseline rate of 63 per 100,000 women, with 37% and 63% associated with screening and treatment, respectively (estimated 12% difference in 2012 vs. 2000), Sylvia K. Plevritis, PhD, of Stanford (Calif.) University and her colleagues reported in JAMA.
Screening and treatment were estimated to contribute to the reductions at varying rates. For example, the relative contributions of screening vs. treatment were 36% vs. 64% for ER+/ERBB2– disease; 31% vs. 69% for ER+/ERBB2+ disease; 40% vs. 60% for ER–/ERBB2+ disease; and 48% vs. 52% for ER–/ERBB2– disease.
The model-based analysis provides clinically relevant insights about the contributions of screening and treatment to reductions in breast cancer mortality by molecular subtype, showing a greater relative contribution of treatment in 2012 overall and for all subtypes except ER–/ERBB2– disease, the authors said.
“Because ER+ cancers are the most prevalent and this group is expected to increase with time, additional advances for this subtype could have the largest effect on reducing the overall population burden of breast cancer,” they noted.
This study was supported by grants from the National Cancer Institute and the American Cancer Society. Dr. Plevritis reported consulting for GRAIL.
sworcester@frontlinemedcom.com
SOURCE: Plevritis S et al. JAMA. 2018 Jan 9;319(2):154-64. doi: 10.1001/jama.2017.19130.
.
, according to a simulation modeling study.
The estimated rate of reduction in overall breast cancer mortality in 2000 was 37% from an estimated baseline rate of 64 deaths per 100,000 women, with 44% and 56% of that associated with screening and treatment, respectively. In 2012 the estimated reduction was 49% from an estimated baseline rate of 63 per 100,000 women, with 37% and 63% associated with screening and treatment, respectively (estimated 12% difference in 2012 vs. 2000), Sylvia K. Plevritis, PhD, of Stanford (Calif.) University and her colleagues reported in JAMA.
Screening and treatment were estimated to contribute to the reductions at varying rates. For example, the relative contributions of screening vs. treatment were 36% vs. 64% for ER+/ERBB2– disease; 31% vs. 69% for ER+/ERBB2+ disease; 40% vs. 60% for ER–/ERBB2+ disease; and 48% vs. 52% for ER–/ERBB2– disease.
The model-based analysis provides clinically relevant insights about the contributions of screening and treatment to reductions in breast cancer mortality by molecular subtype, showing a greater relative contribution of treatment in 2012 overall and for all subtypes except ER–/ERBB2– disease, the authors said.
“Because ER+ cancers are the most prevalent and this group is expected to increase with time, additional advances for this subtype could have the largest effect on reducing the overall population burden of breast cancer,” they noted.
This study was supported by grants from the National Cancer Institute and the American Cancer Society. Dr. Plevritis reported consulting for GRAIL.
sworcester@frontlinemedcom.com
SOURCE: Plevritis S et al. JAMA. 2018 Jan 9;319(2):154-64. doi: 10.1001/jama.2017.19130.
.
FROM JAMA
Key clinical point: Effects of treatment and screening advances on breast cancer mortality vary by molecular subtype.
Major finding: The estimated rate of reduction on mortality was 12% greater in 2012.
Study details: A simulation study using six models and national breast cancer data.
Disclosures: This study was supported by grants from the National Cancer Institute and the American Cancer Society. Dr. Plevritis reported consulting for GRAIL.
Source: Plevritis S et al. JAMA. 2018 Jan 9;319(2):154-64.
FDA: Gadolinium retention prompts new GBCA class warning, safety measures
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
sworcester@frontlinemedcom.com
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
sworcester@frontlinemedcom.com
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
sworcester@frontlinemedcom.com
FDA: Gadolinium retention prompts new GBCA class warning, safety measures
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
CRB-410 update: Multiple myeloma response rates remain high with bb2121 CAR T-cell therapy
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The overall response rate was 94%.
Study details: An update from the phase 1 CRB-410 dose trial of 21 patients.
Disclosures: The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
Source: Berdeja J et al. ASH 2017 Abstract 740.
VIDEO - New lymphoma drug approvals: Clinical use, future directions
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
REPORTING FROM ASH 2017
VIDEO: Joint FDA-ASH session highlights new AML drugs
ATLANTA – The past year brought a flurry of new drug approvals for the treatment of acute myeloid leukemia (AML), including CPX-351, midostaurin, gemtuzumab ozogamicin, and enasidenib.
During a special interest session at the annual meeting of the American Society of Hematology, Food and Drug Administration representatives discussed the available data and approval process for these drugs, and clinicians discussed their use in the real-world setting.
In this video interview, – a liposome-encapsulated combination of daunorubicin and cytarabine approved in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, and midostaurin (Rydapt), which was approved in April for the treatment of newly diagnosed AML patients who are FLT3 mutation-positive. She also discussed future directions for these agents.
“So what clinicians are faced with is, all of a sudden, a number of new agents, and no particularly vetted or data-based algorithm by which to assign patients from one to the other,” said Dr. Michaelis, of the Medical College of Wisconsin, Milwaukee, adding that none of the drugs have been compared against one another.
In her own practice, when it comes to CPX-351, she said she first discusses the pros and cons with patients.
“This drug is used for older individuals ... with very adverse risk disease, and so the first question is do you fit the trial entry criteria, do you want to go through induction, do you understand what that’s going to mean, and am I going to take you to transplant after we go through this.”
As for midostaurin, she said she tries to use it on anyone who fits the trial criteria and is FLT-3 positive.
“The trick with that is that we don’t know the FLT-3 status at the time we have to start induction, so it’s hard to determine the exact right doses of your induction regimen knowing that you’re not going to get the test back until day 6, 7, 8, and you’re supposed to start delivering the drug on day 8, so we still have a ways as a care community to catch up with being able to give these drugs in a manner that was the same as what was delivered in the trials that led to approval.”
She also discussed the potential for combining treatments.
“I think there’s really room for studies on combinations of inhibitors plus the CPX, the safety of using a variety of induction regimens alongside midostaurin, and safety of combining things, like with midostaurin for example, with some of our antifungals ... and to make sure that that’s safe. So yeah, we’ve got a lot more to do,” she said.
Dr. Michaelis serves on an advisory board for Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – The past year brought a flurry of new drug approvals for the treatment of acute myeloid leukemia (AML), including CPX-351, midostaurin, gemtuzumab ozogamicin, and enasidenib.
During a special interest session at the annual meeting of the American Society of Hematology, Food and Drug Administration representatives discussed the available data and approval process for these drugs, and clinicians discussed their use in the real-world setting.
In this video interview, – a liposome-encapsulated combination of daunorubicin and cytarabine approved in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, and midostaurin (Rydapt), which was approved in April for the treatment of newly diagnosed AML patients who are FLT3 mutation-positive. She also discussed future directions for these agents.
“So what clinicians are faced with is, all of a sudden, a number of new agents, and no particularly vetted or data-based algorithm by which to assign patients from one to the other,” said Dr. Michaelis, of the Medical College of Wisconsin, Milwaukee, adding that none of the drugs have been compared against one another.
In her own practice, when it comes to CPX-351, she said she first discusses the pros and cons with patients.
“This drug is used for older individuals ... with very adverse risk disease, and so the first question is do you fit the trial entry criteria, do you want to go through induction, do you understand what that’s going to mean, and am I going to take you to transplant after we go through this.”
As for midostaurin, she said she tries to use it on anyone who fits the trial criteria and is FLT-3 positive.
“The trick with that is that we don’t know the FLT-3 status at the time we have to start induction, so it’s hard to determine the exact right doses of your induction regimen knowing that you’re not going to get the test back until day 6, 7, 8, and you’re supposed to start delivering the drug on day 8, so we still have a ways as a care community to catch up with being able to give these drugs in a manner that was the same as what was delivered in the trials that led to approval.”
She also discussed the potential for combining treatments.
“I think there’s really room for studies on combinations of inhibitors plus the CPX, the safety of using a variety of induction regimens alongside midostaurin, and safety of combining things, like with midostaurin for example, with some of our antifungals ... and to make sure that that’s safe. So yeah, we’ve got a lot more to do,” she said.
Dr. Michaelis serves on an advisory board for Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – The past year brought a flurry of new drug approvals for the treatment of acute myeloid leukemia (AML), including CPX-351, midostaurin, gemtuzumab ozogamicin, and enasidenib.
During a special interest session at the annual meeting of the American Society of Hematology, Food and Drug Administration representatives discussed the available data and approval process for these drugs, and clinicians discussed their use in the real-world setting.
In this video interview, – a liposome-encapsulated combination of daunorubicin and cytarabine approved in August for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, and midostaurin (Rydapt), which was approved in April for the treatment of newly diagnosed AML patients who are FLT3 mutation-positive. She also discussed future directions for these agents.
“So what clinicians are faced with is, all of a sudden, a number of new agents, and no particularly vetted or data-based algorithm by which to assign patients from one to the other,” said Dr. Michaelis, of the Medical College of Wisconsin, Milwaukee, adding that none of the drugs have been compared against one another.
In her own practice, when it comes to CPX-351, she said she first discusses the pros and cons with patients.
“This drug is used for older individuals ... with very adverse risk disease, and so the first question is do you fit the trial entry criteria, do you want to go through induction, do you understand what that’s going to mean, and am I going to take you to transplant after we go through this.”
As for midostaurin, she said she tries to use it on anyone who fits the trial criteria and is FLT-3 positive.
“The trick with that is that we don’t know the FLT-3 status at the time we have to start induction, so it’s hard to determine the exact right doses of your induction regimen knowing that you’re not going to get the test back until day 6, 7, 8, and you’re supposed to start delivering the drug on day 8, so we still have a ways as a care community to catch up with being able to give these drugs in a manner that was the same as what was delivered in the trials that led to approval.”
She also discussed the potential for combining treatments.
“I think there’s really room for studies on combinations of inhibitors plus the CPX, the safety of using a variety of induction regimens alongside midostaurin, and safety of combining things, like with midostaurin for example, with some of our antifungals ... and to make sure that that’s safe. So yeah, we’ve got a lot more to do,” she said.
Dr. Michaelis serves on an advisory board for Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM ASH 2017
CLARITY: Ibrutinib/venetoclax combo results look promising for relapsed/refractory CLL
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
sworcester@frontlinemedcom.com
SOURCE: Hillmen P et al., ASH abstract 428.
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
sworcester@frontlinemedcom.com
SOURCE: Hillmen P et al., ASH abstract 428.
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
sworcester@frontlinemedcom.com
SOURCE: Hillmen P et al., ASH abstract 428.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: 37% and 32% of patients achieved peripheral blood and marrow MRD negativity, respectively.
Study details: Initial results from 38 patients in the CLARITY feasibility trial.
Disclosures: Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham.
Source: Hillmen P et al. ASH Abstract 428.
