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Minimal residual disease eyed for myeloma management
NEW YORK – Testing for minimal residual disease is clearly the state-of-the-art way to gauge the status of treated patients with multiple myeloma, agreed experts. The issue now is whether reliance on MRD to guide management remains investigational or ready for routine practice.
Paul G. Richardson, MD, gave MRD full endorsement as the wave of the future, but cautioned against routine use right now. “MRD is an exciting new tool [but] is not yet the standard of care for routine practice,” he said at the conference held by Imedex.
He cited results from a recent meta-analysis that included data from 14 studies of multiple myeloma patients that examined the correlation of MRD status with progression-free survival and 12 studies that addressed how MRD related to overall survival. The meta-analysis results showed that, among patients in complete remission, the average duration of progression-free survival was 56 months in patients who began follow-up without detectable MRD and 34 months in patients with detectable MRD (JAMA Oncology. 2017 Jan;3[1]:28-35). The average duration of overall survival was 112 months in patients with undetectable MRD and 82 months in those with detectable MRD.
But MRD assessment still has several limitations. Evaluations of its strength for prognosis have largely been based on flow cytometry measures of MRD, an approach recently eclipsed by next-generation sequencing and polymerase chain reaction–based assays. Lack of standardization across the multiple tests now available is another hindrance. In addition, undetectable MRD in a myeloma patient in no way means that the malignancy is gone and that treatment can stop. Patients with undetectable MRD may have better medium-term outcomes, compared with patients with detectable MRD, but even patients with undetectable multiple myeloma still succumb to disease progression several years later.
“Patients negative for MRD do better than patients with detectable MRD, but they still relapse and die. You must maintain treatment in patients negative for MRD,” Dr. Richardson said. The clinical experience “supports the idea that, going forward, MRD has real potential, but MRD is not yet standard of care for routine practice,” he said.
In late 2015, Memorial Sloan-Kettering Cancer Center began routinely using MRD to assess multiple myeloma patients, said C. Ola Landgren, MD, PhD, professor of medicine at Weill Cornell Medical College and chief of the Myeloma Service at Memorial Sloan-Kettering.
He and his associates focus on newly diagnosed multiple myeloma patients who have undergone induction therapy. Patients who come out of the regimen with an undetectable level of MRD at a sensitivity of one cell in a million have the option of receiving high-dose melphalan (Alkeran) followed by autologous stem cell transplantation or maintenance therapy with lenalidomide (Revlimid). Patients who finish induction with detectable MRD can either receive immediate treatment with high-dose melphalan followed by autologous stem cell transplantation or further combination treatment with lenalidomide, carfilzomib (Kyprolis), and dexamethasone, then followed by melphalan and stem cell transplantation (Bone Marrow Transplantation. 2016 July;51[7]:913-4).
“The data show that patients who become MRD negative have longer progression-free survival and overall survival, and we find that more and more patients achieve a MRD-negative state,” said Dr. Landgren. “In our practice, it’s about half of newly diagnosed patients. I think that achieving MRD negativity is more important than the specific treatment a patient receives” for predicting prognosis, he said.
Dr. Richardson has been a consultant to Celgene, Genmab, Janssen, Novartis, Oncopeptides, and Takeda and has received research funding from Celgene and Takeda. Dr. Landgren has been a consultant to Amgen and Takeda and a speaker on behalf of Plexus.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW YORK – Testing for minimal residual disease is clearly the state-of-the-art way to gauge the status of treated patients with multiple myeloma, agreed experts. The issue now is whether reliance on MRD to guide management remains investigational or ready for routine practice.
Paul G. Richardson, MD, gave MRD full endorsement as the wave of the future, but cautioned against routine use right now. “MRD is an exciting new tool [but] is not yet the standard of care for routine practice,” he said at the conference held by Imedex.
He cited results from a recent meta-analysis that included data from 14 studies of multiple myeloma patients that examined the correlation of MRD status with progression-free survival and 12 studies that addressed how MRD related to overall survival. The meta-analysis results showed that, among patients in complete remission, the average duration of progression-free survival was 56 months in patients who began follow-up without detectable MRD and 34 months in patients with detectable MRD (JAMA Oncology. 2017 Jan;3[1]:28-35). The average duration of overall survival was 112 months in patients with undetectable MRD and 82 months in those with detectable MRD.
But MRD assessment still has several limitations. Evaluations of its strength for prognosis have largely been based on flow cytometry measures of MRD, an approach recently eclipsed by next-generation sequencing and polymerase chain reaction–based assays. Lack of standardization across the multiple tests now available is another hindrance. In addition, undetectable MRD in a myeloma patient in no way means that the malignancy is gone and that treatment can stop. Patients with undetectable MRD may have better medium-term outcomes, compared with patients with detectable MRD, but even patients with undetectable multiple myeloma still succumb to disease progression several years later.
“Patients negative for MRD do better than patients with detectable MRD, but they still relapse and die. You must maintain treatment in patients negative for MRD,” Dr. Richardson said. The clinical experience “supports the idea that, going forward, MRD has real potential, but MRD is not yet standard of care for routine practice,” he said.
In late 2015, Memorial Sloan-Kettering Cancer Center began routinely using MRD to assess multiple myeloma patients, said C. Ola Landgren, MD, PhD, professor of medicine at Weill Cornell Medical College and chief of the Myeloma Service at Memorial Sloan-Kettering.
He and his associates focus on newly diagnosed multiple myeloma patients who have undergone induction therapy. Patients who come out of the regimen with an undetectable level of MRD at a sensitivity of one cell in a million have the option of receiving high-dose melphalan (Alkeran) followed by autologous stem cell transplantation or maintenance therapy with lenalidomide (Revlimid). Patients who finish induction with detectable MRD can either receive immediate treatment with high-dose melphalan followed by autologous stem cell transplantation or further combination treatment with lenalidomide, carfilzomib (Kyprolis), and dexamethasone, then followed by melphalan and stem cell transplantation (Bone Marrow Transplantation. 2016 July;51[7]:913-4).
“The data show that patients who become MRD negative have longer progression-free survival and overall survival, and we find that more and more patients achieve a MRD-negative state,” said Dr. Landgren. “In our practice, it’s about half of newly diagnosed patients. I think that achieving MRD negativity is more important than the specific treatment a patient receives” for predicting prognosis, he said.
Dr. Richardson has been a consultant to Celgene, Genmab, Janssen, Novartis, Oncopeptides, and Takeda and has received research funding from Celgene and Takeda. Dr. Landgren has been a consultant to Amgen and Takeda and a speaker on behalf of Plexus.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW YORK – Testing for minimal residual disease is clearly the state-of-the-art way to gauge the status of treated patients with multiple myeloma, agreed experts. The issue now is whether reliance on MRD to guide management remains investigational or ready for routine practice.
Paul G. Richardson, MD, gave MRD full endorsement as the wave of the future, but cautioned against routine use right now. “MRD is an exciting new tool [but] is not yet the standard of care for routine practice,” he said at the conference held by Imedex.
He cited results from a recent meta-analysis that included data from 14 studies of multiple myeloma patients that examined the correlation of MRD status with progression-free survival and 12 studies that addressed how MRD related to overall survival. The meta-analysis results showed that, among patients in complete remission, the average duration of progression-free survival was 56 months in patients who began follow-up without detectable MRD and 34 months in patients with detectable MRD (JAMA Oncology. 2017 Jan;3[1]:28-35). The average duration of overall survival was 112 months in patients with undetectable MRD and 82 months in those with detectable MRD.
But MRD assessment still has several limitations. Evaluations of its strength for prognosis have largely been based on flow cytometry measures of MRD, an approach recently eclipsed by next-generation sequencing and polymerase chain reaction–based assays. Lack of standardization across the multiple tests now available is another hindrance. In addition, undetectable MRD in a myeloma patient in no way means that the malignancy is gone and that treatment can stop. Patients with undetectable MRD may have better medium-term outcomes, compared with patients with detectable MRD, but even patients with undetectable multiple myeloma still succumb to disease progression several years later.
“Patients negative for MRD do better than patients with detectable MRD, but they still relapse and die. You must maintain treatment in patients negative for MRD,” Dr. Richardson said. The clinical experience “supports the idea that, going forward, MRD has real potential, but MRD is not yet standard of care for routine practice,” he said.
In late 2015, Memorial Sloan-Kettering Cancer Center began routinely using MRD to assess multiple myeloma patients, said C. Ola Landgren, MD, PhD, professor of medicine at Weill Cornell Medical College and chief of the Myeloma Service at Memorial Sloan-Kettering.
He and his associates focus on newly diagnosed multiple myeloma patients who have undergone induction therapy. Patients who come out of the regimen with an undetectable level of MRD at a sensitivity of one cell in a million have the option of receiving high-dose melphalan (Alkeran) followed by autologous stem cell transplantation or maintenance therapy with lenalidomide (Revlimid). Patients who finish induction with detectable MRD can either receive immediate treatment with high-dose melphalan followed by autologous stem cell transplantation or further combination treatment with lenalidomide, carfilzomib (Kyprolis), and dexamethasone, then followed by melphalan and stem cell transplantation (Bone Marrow Transplantation. 2016 July;51[7]:913-4).
“The data show that patients who become MRD negative have longer progression-free survival and overall survival, and we find that more and more patients achieve a MRD-negative state,” said Dr. Landgren. “In our practice, it’s about half of newly diagnosed patients. I think that achieving MRD negativity is more important than the specific treatment a patient receives” for predicting prognosis, he said.
Dr. Richardson has been a consultant to Celgene, Genmab, Janssen, Novartis, Oncopeptides, and Takeda and has received research funding from Celgene and Takeda. Dr. Landgren has been a consultant to Amgen and Takeda and a speaker on behalf of Plexus.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM A MEETING ON HEMATOLOGIC MALIGNANCIES
Expanded drug combinations produce best myeloma induction
NEW YORK – Optimal induction therapy for patients with multiple myeloma requires all the therapeutic tools currently available for combination therapy, which means using four agents followed by autologous stem cell transplantation, Paul G. Richardson, MD, said at a conference held by Imedex.
He suggested that a rational combination regimen for induction therapy of multiple myeloma would include a second- or third-generation immunomodulator such as lenalidomide (Revlimid) or pomalidomide (Pomalyst); a proteasome inhibitor such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro); plus standard dexamethasone to form a contemporary backbone regimen for inducing remission in patients with multiple myeloma.
“Therapeutic parsimony is not recommended. You need a combination” of all available drug classes, suggested Dr. Richardson, professor of medicine at Harvard Medical School and clinical program leader of the Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston.
“It isn’t rational to limit the treatment choices. We need to bring them all together,” he said. The “most rational” combination melds an immunomodulator, proteasome inhibitor, plus a monoclonal antibody that he called a “true game changer. Add the antibody on top of the three-drug platform” of an immunomodulator, proteasome inhibitor, and dexamethasone. Dr. Richardson conceded, however, that a concern with such combinations is how to manage the toxicity that would likely result.
He cited several recent examples of demonstrated superior efficacy in the form of more complete responses from combined regimens, followed by autologous stem cell transplantation.
For example, a recent report from a French-led group compared the efficacy of a combination of an immunomodulator, proteasome inhibitor, and dexamethasone against the same combination, followed by autologous stem cell transplantation (N Engl J Med. 2017 Apr 6;376[14]:1311-20). The combined regimen plus transplant resulted in a 59% complete response rate, “the best response rate we’ve ever seen” in multiple myeloma, Dr. Richardson noted, compared with a 48% complete response rate in patients who did not undergo a stem cell transplant.
Another speaker at the meeting, Ruben Niesvizky, MD, suggested a more cautious approach to using the monoclonal antibody daratumumab for induction. He cited the published experience in adding the antibody to pared-down backbone therapy in the setting of relapsed or relapsed and refractory disease, such as a proteasome inhibitor plus dexamethasone (N Engl J Med. 2016 Aug 25;375[8]:754-66) or an immunomodulator plus dexamethasone (N Engl J Med. 2016 Oct 6;375[14]:1319-31).
Adding a monoclonal antibody such as daratumumab to combination therapy is the “wave of the future,” said Dr. Niesvizky, professor of medicine and director of the Multiple Myeloma Center at New York Presbyterian Hospital/Weill Cornell Medical Center. It provides treatment that reduces disease-related complications and achieves effective and extended disease control with improved overall survival, while being well tolerated and facilitating stem cell collection.
Dr. Richardson has been a consultant to Celgene, Genmab, Janssen, Novartis, Oncopeptides AB, and Takeda and has received research funding from Celgene and Takeda. Dr. Niesvizky has been a consultant to Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda and has received research support from Amgen, Bristol-Myers Squibb, Celgene, and Takeda.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW YORK – Optimal induction therapy for patients with multiple myeloma requires all the therapeutic tools currently available for combination therapy, which means using four agents followed by autologous stem cell transplantation, Paul G. Richardson, MD, said at a conference held by Imedex.
He suggested that a rational combination regimen for induction therapy of multiple myeloma would include a second- or third-generation immunomodulator such as lenalidomide (Revlimid) or pomalidomide (Pomalyst); a proteasome inhibitor such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro); plus standard dexamethasone to form a contemporary backbone regimen for inducing remission in patients with multiple myeloma.
“Therapeutic parsimony is not recommended. You need a combination” of all available drug classes, suggested Dr. Richardson, professor of medicine at Harvard Medical School and clinical program leader of the Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston.
“It isn’t rational to limit the treatment choices. We need to bring them all together,” he said. The “most rational” combination melds an immunomodulator, proteasome inhibitor, plus a monoclonal antibody that he called a “true game changer. Add the antibody on top of the three-drug platform” of an immunomodulator, proteasome inhibitor, and dexamethasone. Dr. Richardson conceded, however, that a concern with such combinations is how to manage the toxicity that would likely result.
He cited several recent examples of demonstrated superior efficacy in the form of more complete responses from combined regimens, followed by autologous stem cell transplantation.
For example, a recent report from a French-led group compared the efficacy of a combination of an immunomodulator, proteasome inhibitor, and dexamethasone against the same combination, followed by autologous stem cell transplantation (N Engl J Med. 2017 Apr 6;376[14]:1311-20). The combined regimen plus transplant resulted in a 59% complete response rate, “the best response rate we’ve ever seen” in multiple myeloma, Dr. Richardson noted, compared with a 48% complete response rate in patients who did not undergo a stem cell transplant.
Another speaker at the meeting, Ruben Niesvizky, MD, suggested a more cautious approach to using the monoclonal antibody daratumumab for induction. He cited the published experience in adding the antibody to pared-down backbone therapy in the setting of relapsed or relapsed and refractory disease, such as a proteasome inhibitor plus dexamethasone (N Engl J Med. 2016 Aug 25;375[8]:754-66) or an immunomodulator plus dexamethasone (N Engl J Med. 2016 Oct 6;375[14]:1319-31).
Adding a monoclonal antibody such as daratumumab to combination therapy is the “wave of the future,” said Dr. Niesvizky, professor of medicine and director of the Multiple Myeloma Center at New York Presbyterian Hospital/Weill Cornell Medical Center. It provides treatment that reduces disease-related complications and achieves effective and extended disease control with improved overall survival, while being well tolerated and facilitating stem cell collection.
Dr. Richardson has been a consultant to Celgene, Genmab, Janssen, Novartis, Oncopeptides AB, and Takeda and has received research funding from Celgene and Takeda. Dr. Niesvizky has been a consultant to Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda and has received research support from Amgen, Bristol-Myers Squibb, Celgene, and Takeda.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW YORK – Optimal induction therapy for patients with multiple myeloma requires all the therapeutic tools currently available for combination therapy, which means using four agents followed by autologous stem cell transplantation, Paul G. Richardson, MD, said at a conference held by Imedex.
He suggested that a rational combination regimen for induction therapy of multiple myeloma would include a second- or third-generation immunomodulator such as lenalidomide (Revlimid) or pomalidomide (Pomalyst); a proteasome inhibitor such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro); plus standard dexamethasone to form a contemporary backbone regimen for inducing remission in patients with multiple myeloma.
“Therapeutic parsimony is not recommended. You need a combination” of all available drug classes, suggested Dr. Richardson, professor of medicine at Harvard Medical School and clinical program leader of the Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston.
“It isn’t rational to limit the treatment choices. We need to bring them all together,” he said. The “most rational” combination melds an immunomodulator, proteasome inhibitor, plus a monoclonal antibody that he called a “true game changer. Add the antibody on top of the three-drug platform” of an immunomodulator, proteasome inhibitor, and dexamethasone. Dr. Richardson conceded, however, that a concern with such combinations is how to manage the toxicity that would likely result.
He cited several recent examples of demonstrated superior efficacy in the form of more complete responses from combined regimens, followed by autologous stem cell transplantation.
For example, a recent report from a French-led group compared the efficacy of a combination of an immunomodulator, proteasome inhibitor, and dexamethasone against the same combination, followed by autologous stem cell transplantation (N Engl J Med. 2017 Apr 6;376[14]:1311-20). The combined regimen plus transplant resulted in a 59% complete response rate, “the best response rate we’ve ever seen” in multiple myeloma, Dr. Richardson noted, compared with a 48% complete response rate in patients who did not undergo a stem cell transplant.
Another speaker at the meeting, Ruben Niesvizky, MD, suggested a more cautious approach to using the monoclonal antibody daratumumab for induction. He cited the published experience in adding the antibody to pared-down backbone therapy in the setting of relapsed or relapsed and refractory disease, such as a proteasome inhibitor plus dexamethasone (N Engl J Med. 2016 Aug 25;375[8]:754-66) or an immunomodulator plus dexamethasone (N Engl J Med. 2016 Oct 6;375[14]:1319-31).
Adding a monoclonal antibody such as daratumumab to combination therapy is the “wave of the future,” said Dr. Niesvizky, professor of medicine and director of the Multiple Myeloma Center at New York Presbyterian Hospital/Weill Cornell Medical Center. It provides treatment that reduces disease-related complications and achieves effective and extended disease control with improved overall survival, while being well tolerated and facilitating stem cell collection.
Dr. Richardson has been a consultant to Celgene, Genmab, Janssen, Novartis, Oncopeptides AB, and Takeda and has received research funding from Celgene and Takeda. Dr. Niesvizky has been a consultant to Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda and has received research support from Amgen, Bristol-Myers Squibb, Celgene, and Takeda.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM A MEETING ON HEMATOLOGIC MALIGNANCIES
Leukemia, NHL more common in African-born blacks than US-born blacks
The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.
For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.
And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.
“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.
“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”
Dr Jemal and his colleagues described this study in the journal Cancer.
The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.
They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.
ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.
In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.
In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.
The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).
For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).
Leukemia was not included in this analysis because it was not among the top 5 cancers. 
The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.
For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.
And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.
“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.
“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”
Dr Jemal and his colleagues described this study in the journal Cancer.
The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.
They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.
ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.
In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.
In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.
The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).
For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).
Leukemia was not included in this analysis because it was not among the top 5 cancers.
The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.
For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.
And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.
“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.
“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”
Dr Jemal and his colleagues described this study in the journal Cancer.
The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.
They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.
ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.
In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.
In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.
The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).
For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).
Leukemia was not included in this analysis because it was not among the top 5 cancers.
Topical HDAC inhibitor shows activity in MF
Results of a phase 2 trial suggest a topical, skin-directed histone deacetylase (HDAC) inhibitor can elicit responses in patients with early stage mycosis fungoides (MF).
The drug, remetinostat, was designed to be active in the skin but rapidly broken down and inactivated in blood in order to limit the adverse effects associated with systemic exposure to HDAC inhibitors.
The trial included 60 MF patients who were randomized to receive 0.5% remetinostat gel twice daily, 1% remetinostat gel once daily, or 1% remetinostat gel twice daily for between 6 and 12 months.
Results from this trial were recently released by Medivir AB, the company developing remetinostat.
The primary endpoint of the study was the proportion of patients with either a complete or partial confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.
Based on an intent-to-treat analysis, patients receiving the 1% remetinostat gel twice daily arm had the highest proportion of confirmed responses. Eight of 20 patients (40%) responded, which included 1 complete response.
Five of 20 patients (25%) receiving 0.5% remetinostat gel twice daily responded, as did 4 of 20 (20%) patients receiving 1% remetinostat gel once daily. None of these responses were complete responses.
Remetinostat was well-tolerated across all the dose groups, according to Medivir. There were no signs of systemic adverse effects, including those associated with systemic HDAC inhibitors.
Based on these data, Medivir expects to initiate discussions with regulatory authorities with the aim of initiating a phase 3 study later this year, and to present full phase 2 trial data at scientific meetings in the second half of 2017.
“Remetinostat was designed to effectively inhibit HDACs within cutaneous lesions but to be rapidly broken down in the bloodstream, preventing the side effects associated with systemically administered HDAC inhibitors,” said Richard Bethell, Medivir’s chief scientific officer.
“Based on the efficacy and safety data from this phase 2 study, we believe that remetinostat is capable of meeting a very important unmet need in patients with this chronic and poorly treated orphan disease.”
Results of a phase 2 trial suggest a topical, skin-directed histone deacetylase (HDAC) inhibitor can elicit responses in patients with early stage mycosis fungoides (MF).
The drug, remetinostat, was designed to be active in the skin but rapidly broken down and inactivated in blood in order to limit the adverse effects associated with systemic exposure to HDAC inhibitors.
The trial included 60 MF patients who were randomized to receive 0.5% remetinostat gel twice daily, 1% remetinostat gel once daily, or 1% remetinostat gel twice daily for between 6 and 12 months.
Results from this trial were recently released by Medivir AB, the company developing remetinostat.
The primary endpoint of the study was the proportion of patients with either a complete or partial confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.
Based on an intent-to-treat analysis, patients receiving the 1% remetinostat gel twice daily arm had the highest proportion of confirmed responses. Eight of 20 patients (40%) responded, which included 1 complete response.
Five of 20 patients (25%) receiving 0.5% remetinostat gel twice daily responded, as did 4 of 20 (20%) patients receiving 1% remetinostat gel once daily. None of these responses were complete responses.
Remetinostat was well-tolerated across all the dose groups, according to Medivir. There were no signs of systemic adverse effects, including those associated with systemic HDAC inhibitors.
Based on these data, Medivir expects to initiate discussions with regulatory authorities with the aim of initiating a phase 3 study later this year, and to present full phase 2 trial data at scientific meetings in the second half of 2017.
“Remetinostat was designed to effectively inhibit HDACs within cutaneous lesions but to be rapidly broken down in the bloodstream, preventing the side effects associated with systemically administered HDAC inhibitors,” said Richard Bethell, Medivir’s chief scientific officer.
“Based on the efficacy and safety data from this phase 2 study, we believe that remetinostat is capable of meeting a very important unmet need in patients with this chronic and poorly treated orphan disease.”
Results of a phase 2 trial suggest a topical, skin-directed histone deacetylase (HDAC) inhibitor can elicit responses in patients with early stage mycosis fungoides (MF).
The drug, remetinostat, was designed to be active in the skin but rapidly broken down and inactivated in blood in order to limit the adverse effects associated with systemic exposure to HDAC inhibitors.
The trial included 60 MF patients who were randomized to receive 0.5% remetinostat gel twice daily, 1% remetinostat gel once daily, or 1% remetinostat gel twice daily for between 6 and 12 months.
Results from this trial were recently released by Medivir AB, the company developing remetinostat.
The primary endpoint of the study was the proportion of patients with either a complete or partial confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.
Based on an intent-to-treat analysis, patients receiving the 1% remetinostat gel twice daily arm had the highest proportion of confirmed responses. Eight of 20 patients (40%) responded, which included 1 complete response.
Five of 20 patients (25%) receiving 0.5% remetinostat gel twice daily responded, as did 4 of 20 (20%) patients receiving 1% remetinostat gel once daily. None of these responses were complete responses.
Remetinostat was well-tolerated across all the dose groups, according to Medivir. There were no signs of systemic adverse effects, including those associated with systemic HDAC inhibitors.
Based on these data, Medivir expects to initiate discussions with regulatory authorities with the aim of initiating a phase 3 study later this year, and to present full phase 2 trial data at scientific meetings in the second half of 2017.
“Remetinostat was designed to effectively inhibit HDACs within cutaneous lesions but to be rapidly broken down in the bloodstream, preventing the side effects associated with systemically administered HDAC inhibitors,” said Richard Bethell, Medivir’s chief scientific officer.
“Based on the efficacy and safety data from this phase 2 study, we believe that remetinostat is capable of meeting a very important unmet need in patients with this chronic and poorly treated orphan disease.”
Cancer risk, burden expected to shift in HIV population
WASHINGTON, DC—New research suggests HIV-positive adults in the US will see a shift in cancer risk and burden in the coming years.
The study indicates that, through 2030, people living with HIV will see a decrease in AIDS-defining cancers, such as non-Hodgkin lymphoma (NHL) and Kaposi sarcoma.
But this group will also see an increase in cancers not linked to AIDS, such as prostate and liver cancers.
Researchers made these projections in a presentation at the AACR Annual Meeting 2017 (abstract 5302).
“Declines in cancer incidence rates, particularly for AIDS-defining cancers, are likely driven by widespread treatment with modern antiretroviral therapies, which reduce immune suppression and decrease risk of some cancers,” said Jessica Y. Islam, a doctoral student at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.
She and her collaborators estimated future cancer risk and burden for HIV-positive people using age-specific cancer incidence data from the National Cancer Institute HIV/AIDS Cancer Match (HACM) Study, and projected HIV prevalence data from the Centers for Disease Control and Prevention.
Cancer incidence
From 2000 to 2012, there were 23,907 cancers reported in 463,300 HIV-infected adults in the HACM Study. Based on trends in this study, the researchers made projections for cancer incidence through 2030.
They projected that HIV-positive adults of all ages will see a significant decrease over time in the incidence of NHL, Kaposi sarcoma, cervical cancer, anal cancer among men who have sex with men (MSM), lung cancer, and Hodgkin lymphoma.
Patients age 65 and older will see a significant decrease in colon cancer incidence over time. However, there will be no significant change for patients younger than 65.
HIV-positive adults of all ages will see no significant change over time in the incidence of liver cancer, oral cavity cancer, anal cancer among non-MSMs, and breast cancer.
The incidence of prostate cancer will increase significantly among patients ages 35 to 44 and among patients ages 45 to 64.
Cancer burden
The researchers said the number of adults living with HIV in the US is projected to increase from 1.06 million in 2006 to 1.17 million in 2018, but it is expected to decline to 1.09 million in 2030.
The team noted that, in 2006, there were an estimated 8241 cancers in patients with HIV—3522 AIDS-defining cancers and 4719 malignancies not associated with AIDS.
In 2030, the total number of cancers in the HIV-positive population is projected to be 6692, with decreases in AIDS-defining cancers (n=716) and increases in other cancers (n=5976) from the 2006 data.
In 2010, the most common cancers among HIV-positive patients were estimated to be NHL (n=1488), Kaposi sarcoma (n=1133), and lung cancer (n=815).
But in 2030, the most common cancers are projected to be prostate (n=1587), lung (n=1027), and liver cancers (n=483).
“It is critical to understand both incidence rates and burden over time, as rates capture changes in cancer risk, and burden quantifies the actual number of cancer cases expected to occur,” said study investigator Meredith S. Shiels, PhD, of the National Cancer Institute in Bethesda, Maryland.
“For example, lung cancer rates are expected to decrease in the future, but the burden is expected to increase due to the growing number of older people living with HIV.”
WASHINGTON, DC—New research suggests HIV-positive adults in the US will see a shift in cancer risk and burden in the coming years.
The study indicates that, through 2030, people living with HIV will see a decrease in AIDS-defining cancers, such as non-Hodgkin lymphoma (NHL) and Kaposi sarcoma.
But this group will also see an increase in cancers not linked to AIDS, such as prostate and liver cancers.
Researchers made these projections in a presentation at the AACR Annual Meeting 2017 (abstract 5302).
“Declines in cancer incidence rates, particularly for AIDS-defining cancers, are likely driven by widespread treatment with modern antiretroviral therapies, which reduce immune suppression and decrease risk of some cancers,” said Jessica Y. Islam, a doctoral student at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.
She and her collaborators estimated future cancer risk and burden for HIV-positive people using age-specific cancer incidence data from the National Cancer Institute HIV/AIDS Cancer Match (HACM) Study, and projected HIV prevalence data from the Centers for Disease Control and Prevention.
Cancer incidence
From 2000 to 2012, there were 23,907 cancers reported in 463,300 HIV-infected adults in the HACM Study. Based on trends in this study, the researchers made projections for cancer incidence through 2030.
They projected that HIV-positive adults of all ages will see a significant decrease over time in the incidence of NHL, Kaposi sarcoma, cervical cancer, anal cancer among men who have sex with men (MSM), lung cancer, and Hodgkin lymphoma.
Patients age 65 and older will see a significant decrease in colon cancer incidence over time. However, there will be no significant change for patients younger than 65.
HIV-positive adults of all ages will see no significant change over time in the incidence of liver cancer, oral cavity cancer, anal cancer among non-MSMs, and breast cancer.
The incidence of prostate cancer will increase significantly among patients ages 35 to 44 and among patients ages 45 to 64.
Cancer burden
The researchers said the number of adults living with HIV in the US is projected to increase from 1.06 million in 2006 to 1.17 million in 2018, but it is expected to decline to 1.09 million in 2030.
The team noted that, in 2006, there were an estimated 8241 cancers in patients with HIV—3522 AIDS-defining cancers and 4719 malignancies not associated with AIDS.
In 2030, the total number of cancers in the HIV-positive population is projected to be 6692, with decreases in AIDS-defining cancers (n=716) and increases in other cancers (n=5976) from the 2006 data.
In 2010, the most common cancers among HIV-positive patients were estimated to be NHL (n=1488), Kaposi sarcoma (n=1133), and lung cancer (n=815).
But in 2030, the most common cancers are projected to be prostate (n=1587), lung (n=1027), and liver cancers (n=483).
“It is critical to understand both incidence rates and burden over time, as rates capture changes in cancer risk, and burden quantifies the actual number of cancer cases expected to occur,” said study investigator Meredith S. Shiels, PhD, of the National Cancer Institute in Bethesda, Maryland.
“For example, lung cancer rates are expected to decrease in the future, but the burden is expected to increase due to the growing number of older people living with HIV.”
WASHINGTON, DC—New research suggests HIV-positive adults in the US will see a shift in cancer risk and burden in the coming years.
The study indicates that, through 2030, people living with HIV will see a decrease in AIDS-defining cancers, such as non-Hodgkin lymphoma (NHL) and Kaposi sarcoma.
But this group will also see an increase in cancers not linked to AIDS, such as prostate and liver cancers.
Researchers made these projections in a presentation at the AACR Annual Meeting 2017 (abstract 5302).
“Declines in cancer incidence rates, particularly for AIDS-defining cancers, are likely driven by widespread treatment with modern antiretroviral therapies, which reduce immune suppression and decrease risk of some cancers,” said Jessica Y. Islam, a doctoral student at the University of North Carolina Gillings School of Global Public Health in Chapel Hill.
She and her collaborators estimated future cancer risk and burden for HIV-positive people using age-specific cancer incidence data from the National Cancer Institute HIV/AIDS Cancer Match (HACM) Study, and projected HIV prevalence data from the Centers for Disease Control and Prevention.
Cancer incidence
From 2000 to 2012, there were 23,907 cancers reported in 463,300 HIV-infected adults in the HACM Study. Based on trends in this study, the researchers made projections for cancer incidence through 2030.
They projected that HIV-positive adults of all ages will see a significant decrease over time in the incidence of NHL, Kaposi sarcoma, cervical cancer, anal cancer among men who have sex with men (MSM), lung cancer, and Hodgkin lymphoma.
Patients age 65 and older will see a significant decrease in colon cancer incidence over time. However, there will be no significant change for patients younger than 65.
HIV-positive adults of all ages will see no significant change over time in the incidence of liver cancer, oral cavity cancer, anal cancer among non-MSMs, and breast cancer.
The incidence of prostate cancer will increase significantly among patients ages 35 to 44 and among patients ages 45 to 64.
Cancer burden
The researchers said the number of adults living with HIV in the US is projected to increase from 1.06 million in 2006 to 1.17 million in 2018, but it is expected to decline to 1.09 million in 2030.
The team noted that, in 2006, there were an estimated 8241 cancers in patients with HIV—3522 AIDS-defining cancers and 4719 malignancies not associated with AIDS.
In 2030, the total number of cancers in the HIV-positive population is projected to be 6692, with decreases in AIDS-defining cancers (n=716) and increases in other cancers (n=5976) from the 2006 data.
In 2010, the most common cancers among HIV-positive patients were estimated to be NHL (n=1488), Kaposi sarcoma (n=1133), and lung cancer (n=815).
But in 2030, the most common cancers are projected to be prostate (n=1587), lung (n=1027), and liver cancers (n=483).
“It is critical to understand both incidence rates and burden over time, as rates capture changes in cancer risk, and burden quantifies the actual number of cancer cases expected to occur,” said study investigator Meredith S. Shiels, PhD, of the National Cancer Institute in Bethesda, Maryland.
“For example, lung cancer rates are expected to decrease in the future, but the burden is expected to increase due to the growing number of older people living with HIV.”
Drug may be new option for difficult-to-treat DLBCL, doc says
WASHINGTON, DC—Selinexor has demonstrated the potential to become a new oral treatment option for patients with difficult-to-treat diffuse large B-cell lymphoma (DLBCL), according to a presenter at the AACR Annual Meeting 2017.
Interim results from the phase 2b SADAL study showed that selinexor produced a 28.6% overall response rate (ORR), with an 11.1% complete response (CR) rate, in a heavily pretreated, older DLBCL population.
Responses were observed in GCB and non-GCB subtypes, and the median duration of response exceeded 7 months.
The most common adverse events (AEs) were fatigue, thrombocytopenia, nausea, anorexia, and vomiting.
Marie Maerevoet, MD, of the Institute Jules Bordet in Brussels, Belgium, presented data from the SADAL study as abstract CT132/13.*
The trial is sponsored by Karyopharm Therapeutics, the company developing selinexor.
Patients and treatment
The study enrolled 72 patients with relapsed or refractory DLBCL. At least 14 weeks had elapsed since their most recent systemic anti-DLBCL therapy.
The patients received selinexor—an oral selective inhibitor of nuclear export (SINE™) compound—at 60 mg or 100 mg twice weekly (days 1 and 3 each week) of each 28-day cycle.
60 mg arm
There were 37 patients in the 60 mg arm. Their median age was 71 (range, 38-87), and most (n=24) were male. Forty-nine percent of these patients (n=18) had GCB DLBCL.
Fourteen percent of patients had high-risk disease (according to the revised international prognostic index). Forty-three percent had high-intermediate-risk, 30% had low-intermediate-risk, and 14% had low-risk disease.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Twenty-seven percent had received a prior transplant.
100 mg arm
There were 35 patients in the 100 mg arm. Their median age was 68 (range, 32-82), and most (n=23) were male. Fifty-one percent of patients (n=18) had GCB DLBCL.
Eleven percent of patients had high-risk, 40% had high-intermediate-risk, 37% had low-intermediate-risk, and 6% had low-risk disease. For 6% of patients, their risk group was unknown.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Forty-six percent had received a prior transplant.
Safety
All 72 patients were evaluable for safety. The most common AEs across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%), and anemia (32%).
These events were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care.
The 60 mg dose was better tolerated than the 100 mg dose, with fewer dose interruptions and modifications required in the 60 mg arm.
Grade 3/4 AEs that were more common in the 100 mg arm than the 60 mg arm were fatigue (26% vs 11%), thrombocytopenia (46% vs 32%), and anorexia (11% vs 3%).
Efficacy
Sixty-three patients were analyzed for response. The ORR was 28.6% (18/63), with a CR rate of 11.1% (n=7) and a partial response (PR) rate of 17.5% (n=11).
The rate of stable disease (SD) was 14.3% (n=9), and the rate of progressive disease (PD) was 46% (n=29). Seven patients (11.1%) were not evaluable (NE).
The best responses as of March 1, 2017, according to subtype and selinexor dose, were as follows:
| Category | N | ORR | CR | PR | SD | PD | NE |
| 60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.4%) | 17 (53.1%) | 3 (9.4%) |
| 100 mg | 31 | 9 (29.0%) | 3 (9.7%) | 6 (19.4%) | 6 (19.4%) | 12 (38.7%) | 4 (12.9%) |
| GCB subtype | 32 | 8 (25.0%) | 3 (9.4%) | 5 (15.6%) | 6 (18.8%) | 13 (40.6%) | 5 (15.6%) |
| Non-GCB subtype | 31 | 10 (32.3%) | 4 (12.9%) | 6 (19.4%) | 3 (9.7%) | 16 (51.6%) | 2 (6.5%) |
The median duration of response was greater than 7 months. The median time to response was 2 months.
Among responders, the median time on treatment was 9 months, with a median follow-up of 13 months. As of the data cutoff date, 9 responders remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients. As of the cutoff date, the median survival for the responders had not been reached.
“With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult-to-treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents,” Dr Maerevoet said.
Trial update
As a result of the interim data from SADAL, and in consultation with the US Food and Drug Administration (FDA), Karyopharm is amending the study protocol.
SADAL will become a single-arm study focusing solely on single-agent selinexor dosed at 60 mg twice weekly.
The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory to or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period.
Karyopharm plans to enroll up to an additional 90 patients to the new 60 mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.
The FDA recently lifted a partial clinical hold placed on the SADAL trial and other trials of selinexor.
The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
*Data in the abstract differ from the presentation.
WASHINGTON, DC—Selinexor has demonstrated the potential to become a new oral treatment option for patients with difficult-to-treat diffuse large B-cell lymphoma (DLBCL), according to a presenter at the AACR Annual Meeting 2017.
Interim results from the phase 2b SADAL study showed that selinexor produced a 28.6% overall response rate (ORR), with an 11.1% complete response (CR) rate, in a heavily pretreated, older DLBCL population.
Responses were observed in GCB and non-GCB subtypes, and the median duration of response exceeded 7 months.
The most common adverse events (AEs) were fatigue, thrombocytopenia, nausea, anorexia, and vomiting.
Marie Maerevoet, MD, of the Institute Jules Bordet in Brussels, Belgium, presented data from the SADAL study as abstract CT132/13.*
The trial is sponsored by Karyopharm Therapeutics, the company developing selinexor.
Patients and treatment
The study enrolled 72 patients with relapsed or refractory DLBCL. At least 14 weeks had elapsed since their most recent systemic anti-DLBCL therapy.
The patients received selinexor—an oral selective inhibitor of nuclear export (SINE™) compound—at 60 mg or 100 mg twice weekly (days 1 and 3 each week) of each 28-day cycle.
60 mg arm
There were 37 patients in the 60 mg arm. Their median age was 71 (range, 38-87), and most (n=24) were male. Forty-nine percent of these patients (n=18) had GCB DLBCL.
Fourteen percent of patients had high-risk disease (according to the revised international prognostic index). Forty-three percent had high-intermediate-risk, 30% had low-intermediate-risk, and 14% had low-risk disease.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Twenty-seven percent had received a prior transplant.
100 mg arm
There were 35 patients in the 100 mg arm. Their median age was 68 (range, 32-82), and most (n=23) were male. Fifty-one percent of patients (n=18) had GCB DLBCL.
Eleven percent of patients had high-risk, 40% had high-intermediate-risk, 37% had low-intermediate-risk, and 6% had low-risk disease. For 6% of patients, their risk group was unknown.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Forty-six percent had received a prior transplant.
Safety
All 72 patients were evaluable for safety. The most common AEs across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%), and anemia (32%).
These events were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care.
The 60 mg dose was better tolerated than the 100 mg dose, with fewer dose interruptions and modifications required in the 60 mg arm.
Grade 3/4 AEs that were more common in the 100 mg arm than the 60 mg arm were fatigue (26% vs 11%), thrombocytopenia (46% vs 32%), and anorexia (11% vs 3%).
Efficacy
Sixty-three patients were analyzed for response. The ORR was 28.6% (18/63), with a CR rate of 11.1% (n=7) and a partial response (PR) rate of 17.5% (n=11).
The rate of stable disease (SD) was 14.3% (n=9), and the rate of progressive disease (PD) was 46% (n=29). Seven patients (11.1%) were not evaluable (NE).
The best responses as of March 1, 2017, according to subtype and selinexor dose, were as follows:
| Category | N | ORR | CR | PR | SD | PD | NE |
| 60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.4%) | 17 (53.1%) | 3 (9.4%) |
| 100 mg | 31 | 9 (29.0%) | 3 (9.7%) | 6 (19.4%) | 6 (19.4%) | 12 (38.7%) | 4 (12.9%) |
| GCB subtype | 32 | 8 (25.0%) | 3 (9.4%) | 5 (15.6%) | 6 (18.8%) | 13 (40.6%) | 5 (15.6%) |
| Non-GCB subtype | 31 | 10 (32.3%) | 4 (12.9%) | 6 (19.4%) | 3 (9.7%) | 16 (51.6%) | 2 (6.5%) |
The median duration of response was greater than 7 months. The median time to response was 2 months.
Among responders, the median time on treatment was 9 months, with a median follow-up of 13 months. As of the data cutoff date, 9 responders remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients. As of the cutoff date, the median survival for the responders had not been reached.
“With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult-to-treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents,” Dr Maerevoet said.
Trial update
As a result of the interim data from SADAL, and in consultation with the US Food and Drug Administration (FDA), Karyopharm is amending the study protocol.
SADAL will become a single-arm study focusing solely on single-agent selinexor dosed at 60 mg twice weekly.
The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory to or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period.
Karyopharm plans to enroll up to an additional 90 patients to the new 60 mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.
The FDA recently lifted a partial clinical hold placed on the SADAL trial and other trials of selinexor.
The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
*Data in the abstract differ from the presentation.
WASHINGTON, DC—Selinexor has demonstrated the potential to become a new oral treatment option for patients with difficult-to-treat diffuse large B-cell lymphoma (DLBCL), according to a presenter at the AACR Annual Meeting 2017.
Interim results from the phase 2b SADAL study showed that selinexor produced a 28.6% overall response rate (ORR), with an 11.1% complete response (CR) rate, in a heavily pretreated, older DLBCL population.
Responses were observed in GCB and non-GCB subtypes, and the median duration of response exceeded 7 months.
The most common adverse events (AEs) were fatigue, thrombocytopenia, nausea, anorexia, and vomiting.
Marie Maerevoet, MD, of the Institute Jules Bordet in Brussels, Belgium, presented data from the SADAL study as abstract CT132/13.*
The trial is sponsored by Karyopharm Therapeutics, the company developing selinexor.
Patients and treatment
The study enrolled 72 patients with relapsed or refractory DLBCL. At least 14 weeks had elapsed since their most recent systemic anti-DLBCL therapy.
The patients received selinexor—an oral selective inhibitor of nuclear export (SINE™) compound—at 60 mg or 100 mg twice weekly (days 1 and 3 each week) of each 28-day cycle.
60 mg arm
There were 37 patients in the 60 mg arm. Their median age was 71 (range, 38-87), and most (n=24) were male. Forty-nine percent of these patients (n=18) had GCB DLBCL.
Fourteen percent of patients had high-risk disease (according to the revised international prognostic index). Forty-three percent had high-intermediate-risk, 30% had low-intermediate-risk, and 14% had low-risk disease.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Twenty-seven percent had received a prior transplant.
100 mg arm
There were 35 patients in the 100 mg arm. Their median age was 68 (range, 32-82), and most (n=23) were male. Fifty-one percent of patients (n=18) had GCB DLBCL.
Eleven percent of patients had high-risk, 40% had high-intermediate-risk, 37% had low-intermediate-risk, and 6% had low-risk disease. For 6% of patients, their risk group was unknown.
The patients had received a median of 3 prior treatment regimens (range, 2-5). Forty-six percent had received a prior transplant.
Safety
All 72 patients were evaluable for safety. The most common AEs across both dosing groups were fatigue (65%), thrombocytopenia (54%), nausea (51%), anorexia (49%), vomiting (35%), and anemia (32%).
These events were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care.
The 60 mg dose was better tolerated than the 100 mg dose, with fewer dose interruptions and modifications required in the 60 mg arm.
Grade 3/4 AEs that were more common in the 100 mg arm than the 60 mg arm were fatigue (26% vs 11%), thrombocytopenia (46% vs 32%), and anorexia (11% vs 3%).
Efficacy
Sixty-three patients were analyzed for response. The ORR was 28.6% (18/63), with a CR rate of 11.1% (n=7) and a partial response (PR) rate of 17.5% (n=11).
The rate of stable disease (SD) was 14.3% (n=9), and the rate of progressive disease (PD) was 46% (n=29). Seven patients (11.1%) were not evaluable (NE).
The best responses as of March 1, 2017, according to subtype and selinexor dose, were as follows:
| Category | N | ORR | CR | PR | SD | PD | NE |
| 60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.4%) | 17 (53.1%) | 3 (9.4%) |
| 100 mg | 31 | 9 (29.0%) | 3 (9.7%) | 6 (19.4%) | 6 (19.4%) | 12 (38.7%) | 4 (12.9%) |
| GCB subtype | 32 | 8 (25.0%) | 3 (9.4%) | 5 (15.6%) | 6 (18.8%) | 13 (40.6%) | 5 (15.6%) |
| Non-GCB subtype | 31 | 10 (32.3%) | 4 (12.9%) | 6 (19.4%) | 3 (9.7%) | 16 (51.6%) | 2 (6.5%) |
The median duration of response was greater than 7 months. The median time to response was 2 months.
Among responders, the median time on treatment was 9 months, with a median follow-up of 13 months. As of the data cutoff date, 9 responders remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients. As of the cutoff date, the median survival for the responders had not been reached.
“With the impressive and durable responses observed to date, including in both the GCB and non-GCB subtypes of DLBCL, single-agent selinexor is demonstrating the potential to become a new oral option for this difficult-to-treat patient population who are not candidates for transplantation and whose disease is unlikely to respond to further chemotherapy or targeted agents,” Dr Maerevoet said.
Trial update
As a result of the interim data from SADAL, and in consultation with the US Food and Drug Administration (FDA), Karyopharm is amending the study protocol.
SADAL will become a single-arm study focusing solely on single-agent selinexor dosed at 60 mg twice weekly.
The study is also being amended to reduce the 14-week treatment-free period to 8 weeks in patients who achieved at least a PR on their most recent therapy. Patients who were refractory to or did not achieve at least a PR on their prior therapy will continue with the 14-week treatment-free period.
Karyopharm plans to enroll up to an additional 90 patients to the new 60 mg single-arm cohort and expects to report top-line results from the SADAL study in mid-2018.
The FDA recently lifted a partial clinical hold placed on the SADAL trial and other trials of selinexor.
The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.
*Data in the abstract differ from the presentation.
Transplantation plus VRD tops VRD alone in myeloma
Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long- term survival,” the researchers said. “Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
In the IFM 2009 trial, the planned treatments were realistic. The combination of immunomodulatory drugs and proteasome inhibitors is associated with high response rates similar to those achieved with transplantation, whereas previous trials had used less effective chemotherapy regimens as comparators.
[Transplantation] resulted in a deeper and longer initial treatment response than did nontransplantation. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative.
A question remains as to whether all patients with multiple myeloma should undergo immediate autologous stem-cell transplantation, since the use of delayed transplantation resulted in similar overall survival, with some patients not needing transplantation to date. The observed lack of a survival benefit for early transplantation was consistent with previous results that suggested salvage transplantation is an equalizer in this regard.
Charles A. Schiffer, MD, and Jeffrey A. Zonder, MD, are with Karmanos Cancer Institute, Wayne State University, Detroit, Mich. Dr. Zonder is a member of the editorial advisory board of Hematology News. Their comments were taken from an editorial (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMe1700453).
In the IFM 2009 trial, the planned treatments were realistic. The combination of immunomodulatory drugs and proteasome inhibitors is associated with high response rates similar to those achieved with transplantation, whereas previous trials had used less effective chemotherapy regimens as comparators.
[Transplantation] resulted in a deeper and longer initial treatment response than did nontransplantation. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative.
A question remains as to whether all patients with multiple myeloma should undergo immediate autologous stem-cell transplantation, since the use of delayed transplantation resulted in similar overall survival, with some patients not needing transplantation to date. The observed lack of a survival benefit for early transplantation was consistent with previous results that suggested salvage transplantation is an equalizer in this regard.
Charles A. Schiffer, MD, and Jeffrey A. Zonder, MD, are with Karmanos Cancer Institute, Wayne State University, Detroit, Mich. Dr. Zonder is a member of the editorial advisory board of Hematology News. Their comments were taken from an editorial (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMe1700453).
In the IFM 2009 trial, the planned treatments were realistic. The combination of immunomodulatory drugs and proteasome inhibitors is associated with high response rates similar to those achieved with transplantation, whereas previous trials had used less effective chemotherapy regimens as comparators.
[Transplantation] resulted in a deeper and longer initial treatment response than did nontransplantation. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative.
A question remains as to whether all patients with multiple myeloma should undergo immediate autologous stem-cell transplantation, since the use of delayed transplantation resulted in similar overall survival, with some patients not needing transplantation to date. The observed lack of a survival benefit for early transplantation was consistent with previous results that suggested salvage transplantation is an equalizer in this regard.
Charles A. Schiffer, MD, and Jeffrey A. Zonder, MD, are with Karmanos Cancer Institute, Wayne State University, Detroit, Mich. Dr. Zonder is a member of the editorial advisory board of Hematology News. Their comments were taken from an editorial (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMe1700453).
Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long- term survival,” the researchers said. “Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long- term survival,” the researchers said. “Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: High-dose chemotherapy and autologous stem cell transplantation plus bortezomib, lenalidomide, and dexamethasone (VRD) outperformed consolidation with VRD only in adults with newly diagnosed multiple myeloma.
Major finding: Median progression-free survival was 50 months with transplantation plus VRD and 36 months with VRD only (adjusted hazard ratio for disease progression or death, 0.65; P less than .001).
Data source: A randomized, multicenter, open-label, phase III trial of 700 patients with multiple myeloma.
Disclosures: Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
Inhibitor produces durable responses in rel/ref iNHL
WASHINGTON, DC—An investigational drug can produce durable responses and has a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL), according to researchers.
The drug is copanlisib, an intravenous pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor.
In the phase 2 CHRONOS-1 trial, copanlisib produced an objective response rate (ORR) of 59.2%, with a complete response (CR) rate of 12%, in patients with relapsed/refractory iNHL.
The median duration of response exceeded 98 weeks.
There were 3 deaths considered related to copanlisib, and the most common treatment-related adverse events (AEs) were transient hyperglycemia and hypertension.
These results were presented at the AACR Annual Meeting 2017 (abstract CT149). The study is supported by Bayer, the company developing copanlisib.
CHRONOS-1 included 141 patients with iNHL. Most (n=104) had follicular lymphoma (FL), 23 had marginal zone lymphoma (MZL), 8 had small lymphocytic lymphoma, and 6 had lymphoplasmacytoid/Waldenstrӧm’s macroglobulinemia.
All patients had relapsed after or were refractory to at least 2 prior lines of therapy, which included both rituximab and an alkylating agent.
For this study, the patients received 60 mg of intravenous copanlisib intermittently on days 1, 8, and 15 of a 28-day cycle.
At the time of analysis, the median duration of treatment was 22 weeks (range, 1-105), and 46 patients were still receiving copanlisib.
Efficacy
For the entire cohort, the ORR was 59.2%. Twelve percent of patients achieved a CR, 47.2% had a partial response (PR), 29.6% had stable disease, and 2.1% had progressive disease.
Among patients with FL, the ORR was 58.7%, the CR rate was 14.4%, and the PR rate was 44.2%.
Among patients with MZL, the ORR was 69.6%, with 8.7% of patients achieving a CR and 60.9% achieving a PR.
For the entire cohort, the estimated median duration of response was 687 days (range, 0-687). For patients with FL, it was 370 days (range, 0-687).
The estimated median progression-free survival was 340 days (range, 0-736), and the median overall survival had not been reached at the time of analysis.
Safety
The most common treatment-related AEs were transient hyperglycemia (all grades, 49%/grade 3+, 40%) and hypertension (all grades, 29%/grade 3+, 23%).
The researchers said other AEs of interest were neutropenia (all grades, 25%/grade 3+, 19%), diarrhea (all grades, 18%/grade 3+, 4%), lung infection (all grades, 14%/grade 3+, 11%), pneumonitis (all grades, 7%/grade 3+, 1.4%), and colitis (0.7%, all grade 3+).
Laboratory AEs of interest were alanine aminotransferase increase (all grades, 23%/grade 1, 19%) and aspartate aminotransferase increase (all grades, 28%/grade 1, 25%).
There were 2 non-fatal opportunistic infections.
There were 6 deaths, and 3 of them were considered related to copanlisib. These 3 deaths were due to lung infection, respiratory failure, and a thromboembolic event.
“[I]nhibition of the PI3K pathway has been shown to be an effective therapeutic strategy in treating indolent lymphomas . . .,” said study investigator Martin Dreyling, MD, of Klinikum der Universität München-Grosshadern in Munich, Germany.
“However, concerns exist about the safety of available oral PI3K inhibitors . . . . The results of CHRONOS-1 demonstrate that intermittent intravenous administration of copanlisib achieved durable efficacy with a manageable safety profile in this difficult-to-treat patient population.”
WASHINGTON, DC—An investigational drug can produce durable responses and has a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL), according to researchers.
The drug is copanlisib, an intravenous pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor.
In the phase 2 CHRONOS-1 trial, copanlisib produced an objective response rate (ORR) of 59.2%, with a complete response (CR) rate of 12%, in patients with relapsed/refractory iNHL.
The median duration of response exceeded 98 weeks.
There were 3 deaths considered related to copanlisib, and the most common treatment-related adverse events (AEs) were transient hyperglycemia and hypertension.
These results were presented at the AACR Annual Meeting 2017 (abstract CT149). The study is supported by Bayer, the company developing copanlisib.
CHRONOS-1 included 141 patients with iNHL. Most (n=104) had follicular lymphoma (FL), 23 had marginal zone lymphoma (MZL), 8 had small lymphocytic lymphoma, and 6 had lymphoplasmacytoid/Waldenstrӧm’s macroglobulinemia.
All patients had relapsed after or were refractory to at least 2 prior lines of therapy, which included both rituximab and an alkylating agent.
For this study, the patients received 60 mg of intravenous copanlisib intermittently on days 1, 8, and 15 of a 28-day cycle.
At the time of analysis, the median duration of treatment was 22 weeks (range, 1-105), and 46 patients were still receiving copanlisib.
Efficacy
For the entire cohort, the ORR was 59.2%. Twelve percent of patients achieved a CR, 47.2% had a partial response (PR), 29.6% had stable disease, and 2.1% had progressive disease.
Among patients with FL, the ORR was 58.7%, the CR rate was 14.4%, and the PR rate was 44.2%.
Among patients with MZL, the ORR was 69.6%, with 8.7% of patients achieving a CR and 60.9% achieving a PR.
For the entire cohort, the estimated median duration of response was 687 days (range, 0-687). For patients with FL, it was 370 days (range, 0-687).
The estimated median progression-free survival was 340 days (range, 0-736), and the median overall survival had not been reached at the time of analysis.
Safety
The most common treatment-related AEs were transient hyperglycemia (all grades, 49%/grade 3+, 40%) and hypertension (all grades, 29%/grade 3+, 23%).
The researchers said other AEs of interest were neutropenia (all grades, 25%/grade 3+, 19%), diarrhea (all grades, 18%/grade 3+, 4%), lung infection (all grades, 14%/grade 3+, 11%), pneumonitis (all grades, 7%/grade 3+, 1.4%), and colitis (0.7%, all grade 3+).
Laboratory AEs of interest were alanine aminotransferase increase (all grades, 23%/grade 1, 19%) and aspartate aminotransferase increase (all grades, 28%/grade 1, 25%).
There were 2 non-fatal opportunistic infections.
There were 6 deaths, and 3 of them were considered related to copanlisib. These 3 deaths were due to lung infection, respiratory failure, and a thromboembolic event.
“[I]nhibition of the PI3K pathway has been shown to be an effective therapeutic strategy in treating indolent lymphomas . . .,” said study investigator Martin Dreyling, MD, of Klinikum der Universität München-Grosshadern in Munich, Germany.
“However, concerns exist about the safety of available oral PI3K inhibitors . . . . The results of CHRONOS-1 demonstrate that intermittent intravenous administration of copanlisib achieved durable efficacy with a manageable safety profile in this difficult-to-treat patient population.”
WASHINGTON, DC—An investigational drug can produce durable responses and has a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL), according to researchers.
The drug is copanlisib, an intravenous pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor.
In the phase 2 CHRONOS-1 trial, copanlisib produced an objective response rate (ORR) of 59.2%, with a complete response (CR) rate of 12%, in patients with relapsed/refractory iNHL.
The median duration of response exceeded 98 weeks.
There were 3 deaths considered related to copanlisib, and the most common treatment-related adverse events (AEs) were transient hyperglycemia and hypertension.
These results were presented at the AACR Annual Meeting 2017 (abstract CT149). The study is supported by Bayer, the company developing copanlisib.
CHRONOS-1 included 141 patients with iNHL. Most (n=104) had follicular lymphoma (FL), 23 had marginal zone lymphoma (MZL), 8 had small lymphocytic lymphoma, and 6 had lymphoplasmacytoid/Waldenstrӧm’s macroglobulinemia.
All patients had relapsed after or were refractory to at least 2 prior lines of therapy, which included both rituximab and an alkylating agent.
For this study, the patients received 60 mg of intravenous copanlisib intermittently on days 1, 8, and 15 of a 28-day cycle.
At the time of analysis, the median duration of treatment was 22 weeks (range, 1-105), and 46 patients were still receiving copanlisib.
Efficacy
For the entire cohort, the ORR was 59.2%. Twelve percent of patients achieved a CR, 47.2% had a partial response (PR), 29.6% had stable disease, and 2.1% had progressive disease.
Among patients with FL, the ORR was 58.7%, the CR rate was 14.4%, and the PR rate was 44.2%.
Among patients with MZL, the ORR was 69.6%, with 8.7% of patients achieving a CR and 60.9% achieving a PR.
For the entire cohort, the estimated median duration of response was 687 days (range, 0-687). For patients with FL, it was 370 days (range, 0-687).
The estimated median progression-free survival was 340 days (range, 0-736), and the median overall survival had not been reached at the time of analysis.
Safety
The most common treatment-related AEs were transient hyperglycemia (all grades, 49%/grade 3+, 40%) and hypertension (all grades, 29%/grade 3+, 23%).
The researchers said other AEs of interest were neutropenia (all grades, 25%/grade 3+, 19%), diarrhea (all grades, 18%/grade 3+, 4%), lung infection (all grades, 14%/grade 3+, 11%), pneumonitis (all grades, 7%/grade 3+, 1.4%), and colitis (0.7%, all grade 3+).
Laboratory AEs of interest were alanine aminotransferase increase (all grades, 23%/grade 1, 19%) and aspartate aminotransferase increase (all grades, 28%/grade 1, 25%).
There were 2 non-fatal opportunistic infections.
There were 6 deaths, and 3 of them were considered related to copanlisib. These 3 deaths were due to lung infection, respiratory failure, and a thromboembolic event.
“[I]nhibition of the PI3K pathway has been shown to be an effective therapeutic strategy in treating indolent lymphomas . . .,” said study investigator Martin Dreyling, MD, of Klinikum der Universität München-Grosshadern in Munich, Germany.
“However, concerns exist about the safety of available oral PI3K inhibitors . . . . The results of CHRONOS-1 demonstrate that intermittent intravenous administration of copanlisib achieved durable efficacy with a manageable safety profile in this difficult-to-treat patient population.”
Half of patients retain response to CAR T-cell therapy
WASHINGTON, DC—Roughly half of patients who responded to chimeric antigen receptor (CAR) T-cell therapy in the ZUMA-1 trial have retained that response at a median follow-up exceeding 8 months.
The CAR T-cell therapy, axicabtagene ciloleucel (formerly KTE-C19), initially produced an objective response rate (ORR) of 82% in this trial of patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).
At a median follow-up of 8.7 months, 44% of all patients (53% of responders) are still in response, and 39% are in complete response (CR).
Thirteen percent of patients had grade 3 or higher cytokine release syndrome (CRS), and 28% had neurologic events.
There were 2 deaths related to axicabtagene ciloleucel.
Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, Florida, presented these updated results from ZUMA-1 at the AACR Annual Meeting 2017 (abstract CT019).
ZUMA-1 is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
Patients and treatment
The trial enrolled 111 patients, 101 of whom were successfully treated with axicabtagene ciloleucel. Seven patients could not be treated due to serious adverse events, 1 due to unavailable product, and 2 due to non-measurable disease.
Seventy-seven of the patients had diffuse large B-cell lymphoma (DLBCL), and 24 had transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL). Eighty-five percent of patients had stage III/IV disease.
Seventy-nine percent were refractory to chemotherapy and did not have a prior autologous stem cell transplant (auto-SCT). Twenty-one percent did undergo auto-SCT and relapsed within 12 months of the procedure.
Sixty-nine percent of patients had received 3 or more lines of prior therapy, and 54% were refractory to 2 consecutive lines of prior therapy.
For this study, the patients received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days.
Two days after the conditioning regimen was completed, patients received axicabtagene ciloleucel at a target dose of 2 × 106 CAR T cells/kg.
Efficacy
The following table shows overall response data, response data at 6 months, and ongoing responses at the primary analysis data cut-off.
| DLBCL (n=77) | TFL/PMBCL (n=24) | Combined (n=101) | ||||
| ORR (%) | CR (%) | ORR (%) | CR (%) | ORR (%) | CR (%) | |
| ORR | 82 | 49 | 83 | 71 | 82 | 54 |
| Month 6 | 36 | 31 | 54 | 50 | 41 | 36 |
| Ongoing | 36 | 31 | 67 | 63 | 44 | 39 |
The researchers said the ORR was generally consistent in key subgroups. The ORR was 83% in patients who were refractory to their second or greater line of therapy and 76% in patients who relapsed within 12 months of auto-SCT.
Overall, the median duration of response was 8.2 months. However, the median duration of response has not been reached for patients with a CR.
At a median follow-up of 8.7 months, the median overall survival has not been reached.
Safety
The most common grade 3 or higher adverse events included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).
The incidence of grade 3 or higher CRS was 13%, and the incidence of neurologic events was 28%. These represent decreases from the interim analysis of ZUMA-1, when the rate of grade 3+ CRS was 18%, and the rate of neurological events was 34%.
“We believe the rates of CRS and neurologic events decreased over the course of the study as clinicians gained experience in the management of adverse events,” said Jeff Wiezorek, MD, senior vice-president of clinical development at Kite Pharma.
There were 3 deaths throughout the course of the trial that were not a result of disease progression.
Two deaths were deemed related to axicabtagene ciloleucel. One was a case of hemophagocytic lymphohistiocytosis. The other was cardiac arrest in the setting of CRS.
The third death was the result of a pulmonary embolism and was considered unrelated to axicabtagene ciloleucel.
WASHINGTON, DC—Roughly half of patients who responded to chimeric antigen receptor (CAR) T-cell therapy in the ZUMA-1 trial have retained that response at a median follow-up exceeding 8 months.
The CAR T-cell therapy, axicabtagene ciloleucel (formerly KTE-C19), initially produced an objective response rate (ORR) of 82% in this trial of patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).
At a median follow-up of 8.7 months, 44% of all patients (53% of responders) are still in response, and 39% are in complete response (CR).
Thirteen percent of patients had grade 3 or higher cytokine release syndrome (CRS), and 28% had neurologic events.
There were 2 deaths related to axicabtagene ciloleucel.
Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, Florida, presented these updated results from ZUMA-1 at the AACR Annual Meeting 2017 (abstract CT019).
ZUMA-1 is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
Patients and treatment
The trial enrolled 111 patients, 101 of whom were successfully treated with axicabtagene ciloleucel. Seven patients could not be treated due to serious adverse events, 1 due to unavailable product, and 2 due to non-measurable disease.
Seventy-seven of the patients had diffuse large B-cell lymphoma (DLBCL), and 24 had transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL). Eighty-five percent of patients had stage III/IV disease.
Seventy-nine percent were refractory to chemotherapy and did not have a prior autologous stem cell transplant (auto-SCT). Twenty-one percent did undergo auto-SCT and relapsed within 12 months of the procedure.
Sixty-nine percent of patients had received 3 or more lines of prior therapy, and 54% were refractory to 2 consecutive lines of prior therapy.
For this study, the patients received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days.
Two days after the conditioning regimen was completed, patients received axicabtagene ciloleucel at a target dose of 2 × 106 CAR T cells/kg.
Efficacy
The following table shows overall response data, response data at 6 months, and ongoing responses at the primary analysis data cut-off.
| DLBCL (n=77) | TFL/PMBCL (n=24) | Combined (n=101) | ||||
| ORR (%) | CR (%) | ORR (%) | CR (%) | ORR (%) | CR (%) | |
| ORR | 82 | 49 | 83 | 71 | 82 | 54 |
| Month 6 | 36 | 31 | 54 | 50 | 41 | 36 |
| Ongoing | 36 | 31 | 67 | 63 | 44 | 39 |
The researchers said the ORR was generally consistent in key subgroups. The ORR was 83% in patients who were refractory to their second or greater line of therapy and 76% in patients who relapsed within 12 months of auto-SCT.
Overall, the median duration of response was 8.2 months. However, the median duration of response has not been reached for patients with a CR.
At a median follow-up of 8.7 months, the median overall survival has not been reached.
Safety
The most common grade 3 or higher adverse events included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).
The incidence of grade 3 or higher CRS was 13%, and the incidence of neurologic events was 28%. These represent decreases from the interim analysis of ZUMA-1, when the rate of grade 3+ CRS was 18%, and the rate of neurological events was 34%.
“We believe the rates of CRS and neurologic events decreased over the course of the study as clinicians gained experience in the management of adverse events,” said Jeff Wiezorek, MD, senior vice-president of clinical development at Kite Pharma.
There were 3 deaths throughout the course of the trial that were not a result of disease progression.
Two deaths were deemed related to axicabtagene ciloleucel. One was a case of hemophagocytic lymphohistiocytosis. The other was cardiac arrest in the setting of CRS.
The third death was the result of a pulmonary embolism and was considered unrelated to axicabtagene ciloleucel.
WASHINGTON, DC—Roughly half of patients who responded to chimeric antigen receptor (CAR) T-cell therapy in the ZUMA-1 trial have retained that response at a median follow-up exceeding 8 months.
The CAR T-cell therapy, axicabtagene ciloleucel (formerly KTE-C19), initially produced an objective response rate (ORR) of 82% in this trial of patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).
At a median follow-up of 8.7 months, 44% of all patients (53% of responders) are still in response, and 39% are in complete response (CR).
Thirteen percent of patients had grade 3 or higher cytokine release syndrome (CRS), and 28% had neurologic events.
There were 2 deaths related to axicabtagene ciloleucel.
Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, Florida, presented these updated results from ZUMA-1 at the AACR Annual Meeting 2017 (abstract CT019).
ZUMA-1 is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
Patients and treatment
The trial enrolled 111 patients, 101 of whom were successfully treated with axicabtagene ciloleucel. Seven patients could not be treated due to serious adverse events, 1 due to unavailable product, and 2 due to non-measurable disease.
Seventy-seven of the patients had diffuse large B-cell lymphoma (DLBCL), and 24 had transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL). Eighty-five percent of patients had stage III/IV disease.
Seventy-nine percent were refractory to chemotherapy and did not have a prior autologous stem cell transplant (auto-SCT). Twenty-one percent did undergo auto-SCT and relapsed within 12 months of the procedure.
Sixty-nine percent of patients had received 3 or more lines of prior therapy, and 54% were refractory to 2 consecutive lines of prior therapy.
For this study, the patients received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days.
Two days after the conditioning regimen was completed, patients received axicabtagene ciloleucel at a target dose of 2 × 106 CAR T cells/kg.
Efficacy
The following table shows overall response data, response data at 6 months, and ongoing responses at the primary analysis data cut-off.
| DLBCL (n=77) | TFL/PMBCL (n=24) | Combined (n=101) | ||||
| ORR (%) | CR (%) | ORR (%) | CR (%) | ORR (%) | CR (%) | |
| ORR | 82 | 49 | 83 | 71 | 82 | 54 |
| Month 6 | 36 | 31 | 54 | 50 | 41 | 36 |
| Ongoing | 36 | 31 | 67 | 63 | 44 | 39 |
The researchers said the ORR was generally consistent in key subgroups. The ORR was 83% in patients who were refractory to their second or greater line of therapy and 76% in patients who relapsed within 12 months of auto-SCT.
Overall, the median duration of response was 8.2 months. However, the median duration of response has not been reached for patients with a CR.
At a median follow-up of 8.7 months, the median overall survival has not been reached.
Safety
The most common grade 3 or higher adverse events included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).
The incidence of grade 3 or higher CRS was 13%, and the incidence of neurologic events was 28%. These represent decreases from the interim analysis of ZUMA-1, when the rate of grade 3+ CRS was 18%, and the rate of neurological events was 34%.
“We believe the rates of CRS and neurologic events decreased over the course of the study as clinicians gained experience in the management of adverse events,” said Jeff Wiezorek, MD, senior vice-president of clinical development at Kite Pharma.
There were 3 deaths throughout the course of the trial that were not a result of disease progression.
Two deaths were deemed related to axicabtagene ciloleucel. One was a case of hemophagocytic lymphohistiocytosis. The other was cardiac arrest in the setting of CRS.
The third death was the result of a pulmonary embolism and was considered unrelated to axicabtagene ciloleucel.
New BTK inhibitor may overcome resistance in CLL
WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).
Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.
“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.
“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”
“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”
Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).
SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.
For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.
The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.
SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.
The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.
The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.
Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.
WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).
Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.
“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.
“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”
“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”
Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).
SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.
For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.
The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.
SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.
The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.
The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.
Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.
WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).
Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.
“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.
“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”
“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”
Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).
SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.
For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.
The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.
SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.
The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.
The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.
Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.