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MKIs can overcome resistance in CML
PHILADELPHIA—Two multikinase inhibitors (MKIs) can treat chronic myeloid leukemia (CML) that is resistant to other inhibitors, according to preclinical research.
A series of in vitro experiments showed that the MKIs, sorafenib and axitinib, can overcome treatment resistance mediated by hyperactivation of the Src kinase Lyn, overexpression of the docking protein Gab2, and the presence of the Bcr-Abl T315I mutation.
Sebastian Halbach, of the University of Freiburg in Germany, and his colleagues presented these findings in a poster at the AACR Annual Meeting 2015 (abstract 2708).
Mechanisms of resistance
Halbach noted that CML is driven by the hyperactive fusion kinase Bcr-Abl, which builds up its own signaling network with various proteins, such as Gab2 and Lyn.
Resistance to tyrosine kinase inhibitors (TKIs) and MKIs can be caused by mutations in the Bcr-Abl oncogene, such as T315I, or by aberrant activity of components of the Bcr-Abl signaling network.
“We have previously shown in our lab that overexpression of the docking protein Gab2 . . . confers resistance against imatinib and dasatinib,” Halbach said. “And another mechanism of resistance is hyperactivation of the Src kinase Lyn.”
For the current study, Halbach and his colleagues investigated the role of Lyn by introducing imatinib, dasatinib, or DMSO to K562 cells (blast-phase CML), Lyn-transformed K562 cells, and Lyn-Y508F-transformed K562 cells.
They also compared imatinib and DMSO in Ba/F3 cells (a murine pro-B cell line), Lyn-transformed Ba/F3 cells, and Lyn-Y508F-transformed Ba/F3 cells.
The results of these experiments showed that hyperactive Lyn confers resistance to imatinib but not dasatinib.
“That’s not that surprising because dasatinib is a multikinase inhibitor which targets Src kinases,” Halbach noted. “Therefore, the hyperactivity of Lyn is directly targeted.”
Identifying new drugs
Having established that TKI and MKI resistance in CML can be mediated by Lyn and Gab2, as well as T315I, Halbach and his colleagues wanted to find drugs that would overcome this problem. They screened a panel of inhibitors and identified sorafenib and axitinib.
The researchers first evaluated the effects of sorafenib and axitinib against the T315I mutation. They tested the 2 MKIs—as well as imatinib, dasatinib, nilotinib, ponatinib, and DMSO—in the KBM5 cell line (blast-phase CML) and the KBM5-T315I cell line (imatinib-resistant CML).
Sorafenib and axitinib killed KBM5-T315I cells more effectively than any of the other inhibitors. The 2 MKIs also decreased the metabolic activity of T315I-positive cells more effectively than imatinib, dasatinib, or nilotinib, but not ponatinib, which produced similar results.
Next, Halbach and his colleagues tested sorafenib, axitinib, and the aforementioned inhibitors in K562 cells overexpressing Gab2. Overexpression of Gab2 conferred resistance to imatinib, dasatinib, nilotinib, and ponatinib, but not sorafenib and axitinib.
Both sorafenib and axitinib decreased the metabolic activity of Gab2-overexpressing cells more effectively than any of the other inhibitors.
Lastly, the researchers tested all of the inhibitors in Lyn-transformed K562 cells, Lyn-Y508F-transformed K562 cells, and K562 cells. They found that sorafenib and axitinib both overcame Lyn-Y508F-mediated resistance.
Sorafenib and axitinib killed K562 cells and Lyn-transformed K562 cells more effectively than any of the other inhibitors. The 2 MKIs also killed Lyn-Y508F-transformed K562 cells more effectively than imatinib and nilotinib, but not ponatinib or dasatinib.
Sorafenib decreased the metabolic activity of Lyn-Y508F-transformed K562 cells more effectively than all of the other inhibitors. But axitinib only proved more effective than imatinib in this regard.
Halbach said he hopes sorafenib and axitinib can one day serve as alternatives to ponatinib for CML patients, especially those with T315I mutations or high Gab2 levels.
For now, his team’s next step is to further analyze the influence of axitinib and sorafenib on the Bcr-Abl—Gab2 signaling complex. 
PHILADELPHIA—Two multikinase inhibitors (MKIs) can treat chronic myeloid leukemia (CML) that is resistant to other inhibitors, according to preclinical research.
A series of in vitro experiments showed that the MKIs, sorafenib and axitinib, can overcome treatment resistance mediated by hyperactivation of the Src kinase Lyn, overexpression of the docking protein Gab2, and the presence of the Bcr-Abl T315I mutation.
Sebastian Halbach, of the University of Freiburg in Germany, and his colleagues presented these findings in a poster at the AACR Annual Meeting 2015 (abstract 2708).
Mechanisms of resistance
Halbach noted that CML is driven by the hyperactive fusion kinase Bcr-Abl, which builds up its own signaling network with various proteins, such as Gab2 and Lyn.
Resistance to tyrosine kinase inhibitors (TKIs) and MKIs can be caused by mutations in the Bcr-Abl oncogene, such as T315I, or by aberrant activity of components of the Bcr-Abl signaling network.
“We have previously shown in our lab that overexpression of the docking protein Gab2 . . . confers resistance against imatinib and dasatinib,” Halbach said. “And another mechanism of resistance is hyperactivation of the Src kinase Lyn.”
For the current study, Halbach and his colleagues investigated the role of Lyn by introducing imatinib, dasatinib, or DMSO to K562 cells (blast-phase CML), Lyn-transformed K562 cells, and Lyn-Y508F-transformed K562 cells.
They also compared imatinib and DMSO in Ba/F3 cells (a murine pro-B cell line), Lyn-transformed Ba/F3 cells, and Lyn-Y508F-transformed Ba/F3 cells.
The results of these experiments showed that hyperactive Lyn confers resistance to imatinib but not dasatinib.
“That’s not that surprising because dasatinib is a multikinase inhibitor which targets Src kinases,” Halbach noted. “Therefore, the hyperactivity of Lyn is directly targeted.”
Identifying new drugs
Having established that TKI and MKI resistance in CML can be mediated by Lyn and Gab2, as well as T315I, Halbach and his colleagues wanted to find drugs that would overcome this problem. They screened a panel of inhibitors and identified sorafenib and axitinib.
The researchers first evaluated the effects of sorafenib and axitinib against the T315I mutation. They tested the 2 MKIs—as well as imatinib, dasatinib, nilotinib, ponatinib, and DMSO—in the KBM5 cell line (blast-phase CML) and the KBM5-T315I cell line (imatinib-resistant CML).
Sorafenib and axitinib killed KBM5-T315I cells more effectively than any of the other inhibitors. The 2 MKIs also decreased the metabolic activity of T315I-positive cells more effectively than imatinib, dasatinib, or nilotinib, but not ponatinib, which produced similar results.
Next, Halbach and his colleagues tested sorafenib, axitinib, and the aforementioned inhibitors in K562 cells overexpressing Gab2. Overexpression of Gab2 conferred resistance to imatinib, dasatinib, nilotinib, and ponatinib, but not sorafenib and axitinib.
Both sorafenib and axitinib decreased the metabolic activity of Gab2-overexpressing cells more effectively than any of the other inhibitors.
Lastly, the researchers tested all of the inhibitors in Lyn-transformed K562 cells, Lyn-Y508F-transformed K562 cells, and K562 cells. They found that sorafenib and axitinib both overcame Lyn-Y508F-mediated resistance.
Sorafenib and axitinib killed K562 cells and Lyn-transformed K562 cells more effectively than any of the other inhibitors. The 2 MKIs also killed Lyn-Y508F-transformed K562 cells more effectively than imatinib and nilotinib, but not ponatinib or dasatinib.
Sorafenib decreased the metabolic activity of Lyn-Y508F-transformed K562 cells more effectively than all of the other inhibitors. But axitinib only proved more effective than imatinib in this regard.
Halbach said he hopes sorafenib and axitinib can one day serve as alternatives to ponatinib for CML patients, especially those with T315I mutations or high Gab2 levels.
For now, his team’s next step is to further analyze the influence of axitinib and sorafenib on the Bcr-Abl—Gab2 signaling complex.
PHILADELPHIA—Two multikinase inhibitors (MKIs) can treat chronic myeloid leukemia (CML) that is resistant to other inhibitors, according to preclinical research.
A series of in vitro experiments showed that the MKIs, sorafenib and axitinib, can overcome treatment resistance mediated by hyperactivation of the Src kinase Lyn, overexpression of the docking protein Gab2, and the presence of the Bcr-Abl T315I mutation.
Sebastian Halbach, of the University of Freiburg in Germany, and his colleagues presented these findings in a poster at the AACR Annual Meeting 2015 (abstract 2708).
Mechanisms of resistance
Halbach noted that CML is driven by the hyperactive fusion kinase Bcr-Abl, which builds up its own signaling network with various proteins, such as Gab2 and Lyn.
Resistance to tyrosine kinase inhibitors (TKIs) and MKIs can be caused by mutations in the Bcr-Abl oncogene, such as T315I, or by aberrant activity of components of the Bcr-Abl signaling network.
“We have previously shown in our lab that overexpression of the docking protein Gab2 . . . confers resistance against imatinib and dasatinib,” Halbach said. “And another mechanism of resistance is hyperactivation of the Src kinase Lyn.”
For the current study, Halbach and his colleagues investigated the role of Lyn by introducing imatinib, dasatinib, or DMSO to K562 cells (blast-phase CML), Lyn-transformed K562 cells, and Lyn-Y508F-transformed K562 cells.
They also compared imatinib and DMSO in Ba/F3 cells (a murine pro-B cell line), Lyn-transformed Ba/F3 cells, and Lyn-Y508F-transformed Ba/F3 cells.
The results of these experiments showed that hyperactive Lyn confers resistance to imatinib but not dasatinib.
“That’s not that surprising because dasatinib is a multikinase inhibitor which targets Src kinases,” Halbach noted. “Therefore, the hyperactivity of Lyn is directly targeted.”
Identifying new drugs
Having established that TKI and MKI resistance in CML can be mediated by Lyn and Gab2, as well as T315I, Halbach and his colleagues wanted to find drugs that would overcome this problem. They screened a panel of inhibitors and identified sorafenib and axitinib.
The researchers first evaluated the effects of sorafenib and axitinib against the T315I mutation. They tested the 2 MKIs—as well as imatinib, dasatinib, nilotinib, ponatinib, and DMSO—in the KBM5 cell line (blast-phase CML) and the KBM5-T315I cell line (imatinib-resistant CML).
Sorafenib and axitinib killed KBM5-T315I cells more effectively than any of the other inhibitors. The 2 MKIs also decreased the metabolic activity of T315I-positive cells more effectively than imatinib, dasatinib, or nilotinib, but not ponatinib, which produced similar results.
Next, Halbach and his colleagues tested sorafenib, axitinib, and the aforementioned inhibitors in K562 cells overexpressing Gab2. Overexpression of Gab2 conferred resistance to imatinib, dasatinib, nilotinib, and ponatinib, but not sorafenib and axitinib.
Both sorafenib and axitinib decreased the metabolic activity of Gab2-overexpressing cells more effectively than any of the other inhibitors.
Lastly, the researchers tested all of the inhibitors in Lyn-transformed K562 cells, Lyn-Y508F-transformed K562 cells, and K562 cells. They found that sorafenib and axitinib both overcame Lyn-Y508F-mediated resistance.
Sorafenib and axitinib killed K562 cells and Lyn-transformed K562 cells more effectively than any of the other inhibitors. The 2 MKIs also killed Lyn-Y508F-transformed K562 cells more effectively than imatinib and nilotinib, but not ponatinib or dasatinib.
Sorafenib decreased the metabolic activity of Lyn-Y508F-transformed K562 cells more effectively than all of the other inhibitors. But axitinib only proved more effective than imatinib in this regard.
Halbach said he hopes sorafenib and axitinib can one day serve as alternatives to ponatinib for CML patients, especially those with T315I mutations or high Gab2 levels.
For now, his team’s next step is to further analyze the influence of axitinib and sorafenib on the Bcr-Abl—Gab2 signaling complex.
Molecule increases TRAIL expression to fight NHL
Convention Center, site of the
AACR Annual Meeting 2015
PHILADELPHIA—When current treatment approaches failed to save a young patient with non-Hodgkin lymphoma (NHL), a researcher from The Children’s Hospital of Philadelphia was driven to investigate new therapeutic options.
The investigation led the researcher, Mala Talekar, MBBS, to ONC201 (formerly TIC10), a small molecule that induces apoptosis by increasing surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
Preclinical experiments showed that ONC201 is active against NHL as a single agent, and it synergizes with chemotherapeutic drugs that are already used to treat NHL.
Dr Talekar and her colleagues described these experiments in a poster presented at the AACR Annual Meeting 2015 (abstract 5387). Some of the investigators involved in this research are employed by Oncoceutics, Inc., the company developing ONC201.
A researcher’s inspiration
“When I was doing my fellowship training, I had a teenage boy who had a rare form of non-Hodgkin’s lymphoma,” Dr Talekar explained. “He did not survive, despite receiving multiple treatments that are available for pediatric non-Hodgkin’s lymphoma.”
The boy’s death inspired Dr Talekar to seek new and better approaches to treat NHL. A search of the medical literature unearthed several articles detailing a TRAIL-based approach to treating lymphoma. So she decided to further investigate the effects of TRAIL in NHL.
“I first tried TRAIL in one lymphoma cell line,” she said. “And even though it did kill the cancer cells, it did not really give a satisfactory response.”
So Dr Talekar turned to the TRAIL agonist antibodies lexatumumab and mapatumumab, introducing each of them to human lymphoma cells. Although the antibodies caused more cell death than TRAIL itself, the response was still not satisfactory, she said.
“Fortunately for me, while I was working in the lab, one of the postdocs, Joshua Allen, discovered a new molecule called TRAIL-inducing compound 10, or TIC10,” Dr Talekar said. “So I tried TIC10—it is now called ONC201—and it gave a beautiful dose-response curve, causing complete cell death of the lymphoma cells.”
Dr Talekar was “very inspired” by this result and decided to test ONC201 in 8 different NHL cell lines—4 Burkitt lymphoma (Daudi, Raji, Ramos, and BJAB), 1 anaplastic large-cell lymphoma (Karpas299), and 3 mantle cell lymphoma (UPN2, Granta, and NCEB) cell lines.
“I found a beautiful dose-response curve,” Dr Talekar said, “suggesting that this molecule works in micromolar concentrations across all of the lymphoma cell lines.”
Elucidating the mechanism
Dr Talekar then set out to determine exactly how ONC201 causes cell death in NHL. Flow cytometry revealed that, as the dose of ONC201 increases, cell death increases, as does sub-G1 DNA content. This suggests the drug is causing cell death by apoptosis.
Next, Dr Talekar introduced ONC201 to NHL cell lines along with a pan-caspase inhibitor. She found the inhibitor blocked ONC201-induced apoptosis, which suggests ONC201 works via the caspase-mediated apoptotic pathway.
“The initial mechanism of action proposed for ONC201 was dual inactivation of two kinases, Akt and ERK,” Dr Talekar noted. “The dual inactivation causes dephosphorylation of Foxo3a. This causes its translocation to the nucleus and downstream upregulation of TRAIL, and, therefore, increased surface TRAIL expression. And we know increases in surface TRAIL cause cell death by apoptosis.”
With this in mind, Dr Talekar looked for increases in surface TRIAL after she incubated lymphoma cells with ONC201. She observed a dose-dependent increase in surface TRAIL and a linear correlation between the increase in TRAIL and apoptosis.
Then, she introduced ONC201 and a TRAIL-sequestering antibody, RIK-2, to lymphoma cells. RIK-2 inhibited apoptosis, which suggests ONC201 works as an anti-apoptotic agent via the TRAIL pathway.
Further testing
As a final step, Dr Talekar tested ONC201 in combination with chemotherapy drugs that are already used to treat pediatric NHL. She observed at least an additive effect, and sometimes a synergistic effect, between the drugs. The best responses occurred when she combined ONC201 with cytarabine, bortezomib, or doxorubicin.
Now, Dr Talekar is working on testing ONC201 in combination with cytarabine in a xenograft model of Burkitt lymphoma.
She noted that other in vivo research has suggested ONC201 has a “very benign safety profile.” In another poster presented at AACR 2015 (abstract 4479), researchers reported results indicating that ONC201 is safe.
“They have tested it in mice and dogs and found that, at 10-fold the therapeutic dose, you don’t see much toxicity at all,” Dr Talekar said.
ONC201 is also being tested in a phase 1 study of adults with advanced solid tumors. Phase 1 studies of the drug in relapsed or refractory NHL and relapsed or refractory acute leukemias and high-risk myelodysplastic syndromes are not yet recruiting patients.
Convention Center, site of the
AACR Annual Meeting 2015
PHILADELPHIA—When current treatment approaches failed to save a young patient with non-Hodgkin lymphoma (NHL), a researcher from The Children’s Hospital of Philadelphia was driven to investigate new therapeutic options.
The investigation led the researcher, Mala Talekar, MBBS, to ONC201 (formerly TIC10), a small molecule that induces apoptosis by increasing surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
Preclinical experiments showed that ONC201 is active against NHL as a single agent, and it synergizes with chemotherapeutic drugs that are already used to treat NHL.
Dr Talekar and her colleagues described these experiments in a poster presented at the AACR Annual Meeting 2015 (abstract 5387). Some of the investigators involved in this research are employed by Oncoceutics, Inc., the company developing ONC201.
A researcher’s inspiration
“When I was doing my fellowship training, I had a teenage boy who had a rare form of non-Hodgkin’s lymphoma,” Dr Talekar explained. “He did not survive, despite receiving multiple treatments that are available for pediatric non-Hodgkin’s lymphoma.”
The boy’s death inspired Dr Talekar to seek new and better approaches to treat NHL. A search of the medical literature unearthed several articles detailing a TRAIL-based approach to treating lymphoma. So she decided to further investigate the effects of TRAIL in NHL.
“I first tried TRAIL in one lymphoma cell line,” she said. “And even though it did kill the cancer cells, it did not really give a satisfactory response.”
So Dr Talekar turned to the TRAIL agonist antibodies lexatumumab and mapatumumab, introducing each of them to human lymphoma cells. Although the antibodies caused more cell death than TRAIL itself, the response was still not satisfactory, she said.
“Fortunately for me, while I was working in the lab, one of the postdocs, Joshua Allen, discovered a new molecule called TRAIL-inducing compound 10, or TIC10,” Dr Talekar said. “So I tried TIC10—it is now called ONC201—and it gave a beautiful dose-response curve, causing complete cell death of the lymphoma cells.”
Dr Talekar was “very inspired” by this result and decided to test ONC201 in 8 different NHL cell lines—4 Burkitt lymphoma (Daudi, Raji, Ramos, and BJAB), 1 anaplastic large-cell lymphoma (Karpas299), and 3 mantle cell lymphoma (UPN2, Granta, and NCEB) cell lines.
“I found a beautiful dose-response curve,” Dr Talekar said, “suggesting that this molecule works in micromolar concentrations across all of the lymphoma cell lines.”
Elucidating the mechanism
Dr Talekar then set out to determine exactly how ONC201 causes cell death in NHL. Flow cytometry revealed that, as the dose of ONC201 increases, cell death increases, as does sub-G1 DNA content. This suggests the drug is causing cell death by apoptosis.
Next, Dr Talekar introduced ONC201 to NHL cell lines along with a pan-caspase inhibitor. She found the inhibitor blocked ONC201-induced apoptosis, which suggests ONC201 works via the caspase-mediated apoptotic pathway.
“The initial mechanism of action proposed for ONC201 was dual inactivation of two kinases, Akt and ERK,” Dr Talekar noted. “The dual inactivation causes dephosphorylation of Foxo3a. This causes its translocation to the nucleus and downstream upregulation of TRAIL, and, therefore, increased surface TRAIL expression. And we know increases in surface TRAIL cause cell death by apoptosis.”
With this in mind, Dr Talekar looked for increases in surface TRIAL after she incubated lymphoma cells with ONC201. She observed a dose-dependent increase in surface TRAIL and a linear correlation between the increase in TRAIL and apoptosis.
Then, she introduced ONC201 and a TRAIL-sequestering antibody, RIK-2, to lymphoma cells. RIK-2 inhibited apoptosis, which suggests ONC201 works as an anti-apoptotic agent via the TRAIL pathway.
Further testing
As a final step, Dr Talekar tested ONC201 in combination with chemotherapy drugs that are already used to treat pediatric NHL. She observed at least an additive effect, and sometimes a synergistic effect, between the drugs. The best responses occurred when she combined ONC201 with cytarabine, bortezomib, or doxorubicin.
Now, Dr Talekar is working on testing ONC201 in combination with cytarabine in a xenograft model of Burkitt lymphoma.
She noted that other in vivo research has suggested ONC201 has a “very benign safety profile.” In another poster presented at AACR 2015 (abstract 4479), researchers reported results indicating that ONC201 is safe.
“They have tested it in mice and dogs and found that, at 10-fold the therapeutic dose, you don’t see much toxicity at all,” Dr Talekar said.
ONC201 is also being tested in a phase 1 study of adults with advanced solid tumors. Phase 1 studies of the drug in relapsed or refractory NHL and relapsed or refractory acute leukemias and high-risk myelodysplastic syndromes are not yet recruiting patients.
Convention Center, site of the
AACR Annual Meeting 2015
PHILADELPHIA—When current treatment approaches failed to save a young patient with non-Hodgkin lymphoma (NHL), a researcher from The Children’s Hospital of Philadelphia was driven to investigate new therapeutic options.
The investigation led the researcher, Mala Talekar, MBBS, to ONC201 (formerly TIC10), a small molecule that induces apoptosis by increasing surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
Preclinical experiments showed that ONC201 is active against NHL as a single agent, and it synergizes with chemotherapeutic drugs that are already used to treat NHL.
Dr Talekar and her colleagues described these experiments in a poster presented at the AACR Annual Meeting 2015 (abstract 5387). Some of the investigators involved in this research are employed by Oncoceutics, Inc., the company developing ONC201.
A researcher’s inspiration
“When I was doing my fellowship training, I had a teenage boy who had a rare form of non-Hodgkin’s lymphoma,” Dr Talekar explained. “He did not survive, despite receiving multiple treatments that are available for pediatric non-Hodgkin’s lymphoma.”
The boy’s death inspired Dr Talekar to seek new and better approaches to treat NHL. A search of the medical literature unearthed several articles detailing a TRAIL-based approach to treating lymphoma. So she decided to further investigate the effects of TRAIL in NHL.
“I first tried TRAIL in one lymphoma cell line,” she said. “And even though it did kill the cancer cells, it did not really give a satisfactory response.”
So Dr Talekar turned to the TRAIL agonist antibodies lexatumumab and mapatumumab, introducing each of them to human lymphoma cells. Although the antibodies caused more cell death than TRAIL itself, the response was still not satisfactory, she said.
“Fortunately for me, while I was working in the lab, one of the postdocs, Joshua Allen, discovered a new molecule called TRAIL-inducing compound 10, or TIC10,” Dr Talekar said. “So I tried TIC10—it is now called ONC201—and it gave a beautiful dose-response curve, causing complete cell death of the lymphoma cells.”
Dr Talekar was “very inspired” by this result and decided to test ONC201 in 8 different NHL cell lines—4 Burkitt lymphoma (Daudi, Raji, Ramos, and BJAB), 1 anaplastic large-cell lymphoma (Karpas299), and 3 mantle cell lymphoma (UPN2, Granta, and NCEB) cell lines.
“I found a beautiful dose-response curve,” Dr Talekar said, “suggesting that this molecule works in micromolar concentrations across all of the lymphoma cell lines.”
Elucidating the mechanism
Dr Talekar then set out to determine exactly how ONC201 causes cell death in NHL. Flow cytometry revealed that, as the dose of ONC201 increases, cell death increases, as does sub-G1 DNA content. This suggests the drug is causing cell death by apoptosis.
Next, Dr Talekar introduced ONC201 to NHL cell lines along with a pan-caspase inhibitor. She found the inhibitor blocked ONC201-induced apoptosis, which suggests ONC201 works via the caspase-mediated apoptotic pathway.
“The initial mechanism of action proposed for ONC201 was dual inactivation of two kinases, Akt and ERK,” Dr Talekar noted. “The dual inactivation causes dephosphorylation of Foxo3a. This causes its translocation to the nucleus and downstream upregulation of TRAIL, and, therefore, increased surface TRAIL expression. And we know increases in surface TRAIL cause cell death by apoptosis.”
With this in mind, Dr Talekar looked for increases in surface TRIAL after she incubated lymphoma cells with ONC201. She observed a dose-dependent increase in surface TRAIL and a linear correlation between the increase in TRAIL and apoptosis.
Then, she introduced ONC201 and a TRAIL-sequestering antibody, RIK-2, to lymphoma cells. RIK-2 inhibited apoptosis, which suggests ONC201 works as an anti-apoptotic agent via the TRAIL pathway.
Further testing
As a final step, Dr Talekar tested ONC201 in combination with chemotherapy drugs that are already used to treat pediatric NHL. She observed at least an additive effect, and sometimes a synergistic effect, between the drugs. The best responses occurred when she combined ONC201 with cytarabine, bortezomib, or doxorubicin.
Now, Dr Talekar is working on testing ONC201 in combination with cytarabine in a xenograft model of Burkitt lymphoma.
She noted that other in vivo research has suggested ONC201 has a “very benign safety profile.” In another poster presented at AACR 2015 (abstract 4479), researchers reported results indicating that ONC201 is safe.
“They have tested it in mice and dogs and found that, at 10-fold the therapeutic dose, you don’t see much toxicity at all,” Dr Talekar said.
ONC201 is also being tested in a phase 1 study of adults with advanced solid tumors. Phase 1 studies of the drug in relapsed or refractory NHL and relapsed or refractory acute leukemias and high-risk myelodysplastic syndromes are not yet recruiting patients.
CDK inhibitor proves active against AML, ALL
PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).
CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.
Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.
Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.
The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).
They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC50/70/90 values were correlated with BclXL and inversely correlated with Bak.
Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.
The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.
In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).
In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.
The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.
CYC065 was “strongly synergistic” with Bcl2/BclXL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).
The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.
Drug that fell short in prostate cancer could treat MM
PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.
The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.
Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.
Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.
Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.
So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.
Activity in MM
Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.
Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.
The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.
Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.
The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).
Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.
Investigating the mechanism
To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.
“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.
“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”
The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.
The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis. 
*Information in the abstract differs from that presented at the meeting.
PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.
The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.
Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.
Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.
Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.
So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.
Activity in MM
Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.
Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.
The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.
Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.
The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).
Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.
Investigating the mechanism
To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.
“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.
“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”
The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.
The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.
*Information in the abstract differs from that presented at the meeting.
PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.
The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.
Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.
Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.
Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.
So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.
Activity in MM
Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.
Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.
The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.
Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.
The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).
Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.
Investigating the mechanism
To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.
“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.
“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”
The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.
The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.
*Information in the abstract differs from that presented at the meeting.
‘Watch and wait’ may be inadvisable for CLL
PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.
Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.
But less than a quarter of the patients died of comorbidities, and none of them died of old age.
Most patients died of CLL progression or conditions possibly related to CLL.
Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).
The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.
The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.
“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”
Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).
“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”
But Dr Strati and his colleagues found that was not the case for most of the patients they studied.
The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.
“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.
Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.
Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.
In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.
PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.
Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.
But less than a quarter of the patients died of comorbidities, and none of them died of old age.
Most patients died of CLL progression or conditions possibly related to CLL.
Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).
The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.
The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.
“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”
Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).
“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”
But Dr Strati and his colleagues found that was not the case for most of the patients they studied.
The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.
“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.
Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.
Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.
In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.
PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.
Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.
But less than a quarter of the patients died of comorbidities, and none of them died of old age.
Most patients died of CLL progression or conditions possibly related to CLL.
Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).
The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.
The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.
“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”
Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).
“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”
But Dr Strati and his colleagues found that was not the case for most of the patients they studied.
The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.
“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.
Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.
Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.
In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.
AACR: KEYNOTE-001 takes step toward PD-L1 blocker biomarker
Results from KEYNOTE-001 show that not only is the anti-PD-L1 antibody pembrolizumab clinically active in advanced non–small cell lung cancer, but that PD-L1 expression is a marker of response, as well.
The objective response rate was 45.2% for patients with programmed cell death ligand 1 (PD-L1) expression in at least half of their tumor cells, including 44% in previously treated patients and 50% in treatment-naive patients.
For patients with 1% to 49% and < 1% tumor PD-L1 expression, objective response rates were 16.5% and 10.7%, respectively, Dr. Edward Garon of the University of California, Los Angeles, reported at the annual meeting of the American Association for Cancer Research.
About a quarter of those screened had PD-L1 expression in at least half of their tumor cells.
Median progression-free survival (PFS) in this subgroup was 6.3 months vs. 3.3 months in patients with 1%-49% tumor PD-L1 and 2.3 months in those with < 1% PD-L1.
After a median follow-up of 10.9 months, median overall survival was not reached in patients with at least 50% tumor PD-L1 expression and was 8.8 months in both groups with lesser degrees of tumor PD-L1 expression, according to results simultaneously reported in the New England Journal of Medicine (2015 April 19 [doi:10.1056/NEJMoa1501824]).
“I think that with [these] data, we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells, pembrolizumab is associated with superior clinical outcomes, clearly, than what would be anticipated with cytotoxic chemotherapy,” Dr. Garon said during a press briefing.
Outcomes in patients with lesser tumor PD-L1 expression may also be better than what is seen with comparators, but complete data on that will require data from randomized studies, he added.
Press briefing moderator Dr. Suzanne Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, pointed out that more than three-fourths of patients in the study had progressed on prior systemic therapies.
“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive I think in this particular treatment setting.”
Results from KEYNOTE-001 were drawn from 495 patients with advanced or metastatic non–small cell lung cancer, including 182 patients assigned to a training group in which the PD-L1 cutoff value was selected and 313 patients with measurable disease assigned to an independent biomarker validation group. PD-L1 status was assessed in tumor samples by a prototype immunohistochemistry assay using the 22C3 antibody clone (Merck). Patients were randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.
In the training group, 171 patients were previously treated and 11 were treatment naive, with 129 remaining after exclusions for cutoff selection. In the validation group, 223 patients were previously treated and 90 were treatment naive, with 204 biomarker evaluable patients remaining after exclusions.
The objective response rate among the entire 495 patients was 19.4%, including 18% in previously treated patients and 24.8% in treatment-naive patients, Dr. Garon said.
Median PFS was 3.7 months, 3.0 months, and 6.0 months and median overall survival 12 months, 9.3 months, and 16.2 months, respectively.
There were no clear differences in efficacy and safety between dosing regimens, he said.
Treatment-related adverse events occurred in 351 patients (71%), the most common being fatigue, pruritus, and decreased appetite. Grade 3 or higher events were reported in 47 patients (9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.
Based on the current data, Dr. Topalian asked how the proposed PD-L1 biomarker would be used in clinical practice. She noted that the situation is more clearcut with the kinase inhibitor class of drugs in which the biology tells us whether the drug is unlikely to work based on whether the patient has a particular mutation, like the BRAFV600E mutation in melanoma.
“This kind of biomarker is a lot more blurry and you saw that even patients with lower levels of expression of this marker still have notable response rates,” Dr. Topalian said.
Dr. Garon responded that there are two important aspects to a biomarker.
“One is that when you select patients who are positive, you do a very good job of enriching for patients with good clinical outcome, and this data set I believe very well addresses that piece,” he said. “The other piece, which is a shortfall and in some respects a fortunate shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like with this biomarker of demonstrating the group of people who is not likely to benefit.”
On Twitter @pwendl
Results from KEYNOTE-001 show that not only is the anti-PD-L1 antibody pembrolizumab clinically active in advanced non–small cell lung cancer, but that PD-L1 expression is a marker of response, as well.
The objective response rate was 45.2% for patients with programmed cell death ligand 1 (PD-L1) expression in at least half of their tumor cells, including 44% in previously treated patients and 50% in treatment-naive patients.
For patients with 1% to 49% and < 1% tumor PD-L1 expression, objective response rates were 16.5% and 10.7%, respectively, Dr. Edward Garon of the University of California, Los Angeles, reported at the annual meeting of the American Association for Cancer Research.
About a quarter of those screened had PD-L1 expression in at least half of their tumor cells.
Median progression-free survival (PFS) in this subgroup was 6.3 months vs. 3.3 months in patients with 1%-49% tumor PD-L1 and 2.3 months in those with < 1% PD-L1.
After a median follow-up of 10.9 months, median overall survival was not reached in patients with at least 50% tumor PD-L1 expression and was 8.8 months in both groups with lesser degrees of tumor PD-L1 expression, according to results simultaneously reported in the New England Journal of Medicine (2015 April 19 [doi:10.1056/NEJMoa1501824]).
“I think that with [these] data, we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells, pembrolizumab is associated with superior clinical outcomes, clearly, than what would be anticipated with cytotoxic chemotherapy,” Dr. Garon said during a press briefing.
Outcomes in patients with lesser tumor PD-L1 expression may also be better than what is seen with comparators, but complete data on that will require data from randomized studies, he added.
Press briefing moderator Dr. Suzanne Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, pointed out that more than three-fourths of patients in the study had progressed on prior systemic therapies.
“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive I think in this particular treatment setting.”
Results from KEYNOTE-001 were drawn from 495 patients with advanced or metastatic non–small cell lung cancer, including 182 patients assigned to a training group in which the PD-L1 cutoff value was selected and 313 patients with measurable disease assigned to an independent biomarker validation group. PD-L1 status was assessed in tumor samples by a prototype immunohistochemistry assay using the 22C3 antibody clone (Merck). Patients were randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.
In the training group, 171 patients were previously treated and 11 were treatment naive, with 129 remaining after exclusions for cutoff selection. In the validation group, 223 patients were previously treated and 90 were treatment naive, with 204 biomarker evaluable patients remaining after exclusions.
The objective response rate among the entire 495 patients was 19.4%, including 18% in previously treated patients and 24.8% in treatment-naive patients, Dr. Garon said.
Median PFS was 3.7 months, 3.0 months, and 6.0 months and median overall survival 12 months, 9.3 months, and 16.2 months, respectively.
There were no clear differences in efficacy and safety between dosing regimens, he said.
Treatment-related adverse events occurred in 351 patients (71%), the most common being fatigue, pruritus, and decreased appetite. Grade 3 or higher events were reported in 47 patients (9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.
Based on the current data, Dr. Topalian asked how the proposed PD-L1 biomarker would be used in clinical practice. She noted that the situation is more clearcut with the kinase inhibitor class of drugs in which the biology tells us whether the drug is unlikely to work based on whether the patient has a particular mutation, like the BRAFV600E mutation in melanoma.
“This kind of biomarker is a lot more blurry and you saw that even patients with lower levels of expression of this marker still have notable response rates,” Dr. Topalian said.
Dr. Garon responded that there are two important aspects to a biomarker.
“One is that when you select patients who are positive, you do a very good job of enriching for patients with good clinical outcome, and this data set I believe very well addresses that piece,” he said. “The other piece, which is a shortfall and in some respects a fortunate shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like with this biomarker of demonstrating the group of people who is not likely to benefit.”
On Twitter @pwendl
Results from KEYNOTE-001 show that not only is the anti-PD-L1 antibody pembrolizumab clinically active in advanced non–small cell lung cancer, but that PD-L1 expression is a marker of response, as well.
The objective response rate was 45.2% for patients with programmed cell death ligand 1 (PD-L1) expression in at least half of their tumor cells, including 44% in previously treated patients and 50% in treatment-naive patients.
For patients with 1% to 49% and < 1% tumor PD-L1 expression, objective response rates were 16.5% and 10.7%, respectively, Dr. Edward Garon of the University of California, Los Angeles, reported at the annual meeting of the American Association for Cancer Research.
About a quarter of those screened had PD-L1 expression in at least half of their tumor cells.
Median progression-free survival (PFS) in this subgroup was 6.3 months vs. 3.3 months in patients with 1%-49% tumor PD-L1 and 2.3 months in those with < 1% PD-L1.
After a median follow-up of 10.9 months, median overall survival was not reached in patients with at least 50% tumor PD-L1 expression and was 8.8 months in both groups with lesser degrees of tumor PD-L1 expression, according to results simultaneously reported in the New England Journal of Medicine (2015 April 19 [doi:10.1056/NEJMoa1501824]).
“I think that with [these] data, we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells, pembrolizumab is associated with superior clinical outcomes, clearly, than what would be anticipated with cytotoxic chemotherapy,” Dr. Garon said during a press briefing.
Outcomes in patients with lesser tumor PD-L1 expression may also be better than what is seen with comparators, but complete data on that will require data from randomized studies, he added.
Press briefing moderator Dr. Suzanne Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, pointed out that more than three-fourths of patients in the study had progressed on prior systemic therapies.
“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive I think in this particular treatment setting.”
Results from KEYNOTE-001 were drawn from 495 patients with advanced or metastatic non–small cell lung cancer, including 182 patients assigned to a training group in which the PD-L1 cutoff value was selected and 313 patients with measurable disease assigned to an independent biomarker validation group. PD-L1 status was assessed in tumor samples by a prototype immunohistochemistry assay using the 22C3 antibody clone (Merck). Patients were randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.
In the training group, 171 patients were previously treated and 11 were treatment naive, with 129 remaining after exclusions for cutoff selection. In the validation group, 223 patients were previously treated and 90 were treatment naive, with 204 biomarker evaluable patients remaining after exclusions.
The objective response rate among the entire 495 patients was 19.4%, including 18% in previously treated patients and 24.8% in treatment-naive patients, Dr. Garon said.
Median PFS was 3.7 months, 3.0 months, and 6.0 months and median overall survival 12 months, 9.3 months, and 16.2 months, respectively.
There were no clear differences in efficacy and safety between dosing regimens, he said.
Treatment-related adverse events occurred in 351 patients (71%), the most common being fatigue, pruritus, and decreased appetite. Grade 3 or higher events were reported in 47 patients (9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.
Based on the current data, Dr. Topalian asked how the proposed PD-L1 biomarker would be used in clinical practice. She noted that the situation is more clearcut with the kinase inhibitor class of drugs in which the biology tells us whether the drug is unlikely to work based on whether the patient has a particular mutation, like the BRAFV600E mutation in melanoma.
“This kind of biomarker is a lot more blurry and you saw that even patients with lower levels of expression of this marker still have notable response rates,” Dr. Topalian said.
Dr. Garon responded that there are two important aspects to a biomarker.
“One is that when you select patients who are positive, you do a very good job of enriching for patients with good clinical outcome, and this data set I believe very well addresses that piece,” he said. “The other piece, which is a shortfall and in some respects a fortunate shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like with this biomarker of demonstrating the group of people who is not likely to benefit.”
On Twitter @pwendl
FROM THE AACR ANNUAL MEETING
Key clinical point: Pembrolizumab provided durable responses in NSCLC, with clinical outcomes correlating with a proposed biomarker.
Major finding: Objective response rates were 42.5% in patients with ≥ 50% PD-L1 tumor expression vs. 16.5% and 10.7% for patients with 1%-49% and < 1% PD-L1 tumor expression.
Data source: Phase I study in 495 patients with advanced or metastatic non–small cell lung cancer.
Disclosures: The study was funded by Merck. Dr. Caron’s institution received funds to conduct the trial, but he declared no other conflicts of interest. Dr. Topalian reported serving on a program committee or speaking for Bristol-Myers Squibb, Five Prime Therapeutics, GlaxoSmithKline, Jounce Therapeutics, and MedImmune.
AACR: Metformin survival benefit shaky in pancreatic cancer
A detailed survival analysis questions the rationale behind use of the diabetes drug metformin to improve pancreatic cancer survival.
Several epidemiologic studies have shown that metformin use reduces cancer mortality, leading the diabetes drug to be included in the treatment arm of 20 open clinical trials in recalcitrant cancers, Dr. Roongruedee Chaiteerakij reported at the annual meeting of the American Association for Cancer Research.
The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,” which may have introduced unintended biases.
To address these potential biases, Dr. Chaiteerakij and her colleagues at the Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and diabetes between 2000 and 2011 in the database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. More than half (59%) were male; the average age was 67 years.
A total of 380 patients were excluded for surgically induced diabetes, unknown diabetes duration, and PDAC diagnosis more than 90 days prior to the first Mayo visit. This left 980 patients in the final cohort.
An initial analysis using the ever vs. never classification suggested that metformin use was associated with marginally improved survival in patients with PDAC (median 9.9 months ever use vs. 8.9 months never use; unadjusted hazard ratio, 0.9; P = .08), Dr. Chaiteerakij said.
The association was most significant in locally advanced PDAC patients (10.2 months ever use vs. 8.1 months never use; unadjusted HR 0.7; P = .006).
The investigators then performed a subanalysis of locally advanced PDAC patients, this time stratified by timing of metformin initiation: never used (reference group), started more than 1 year before PDAC diagnosis, started within 1 year before PDAC diagnosis, started less than 30 days post PDAC diagnosis, and started more than 30 days post PDAC diagnosis.
Median survival was 8.1, 10.1, and 9.9 months in the first three groups, increasing to 11.4 months and 13.7 months in the two groups that started metformin after PDAC diagnosis, Dr. Chaiteerakij reported.
Hazard ratios for the four metformin groups were 0.7, 0.6, 0.9, and 0.5, after adjustment for age, sex, disease stage, body mass index, and diagnosis year.
The increased survival in patients who started metformin after PDAC diagnosis demonstrates the inherent survival bias in ever/never classification because these patients had lived long enough to receive the drug, she said.
The ever/never classification is commonly used because it can be difficult to extract detailed information on drug use, dose, or timing from retrospective medical records, she noted in a press briefing.
“Epidemiologic studies of medication exposure and cancer survival warrant very careful and detailed data collection and analysis to minimize biases,” Dr. Chaiteerakij concluded. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.”
That said, 11 pancreatic cancer trials are currently listed on www.clinicaltrials.gov, she told reporters.
A simple search of the site for “cancer and metformin” yields no fewer than 230 trials.
It isn’t possible to say at this time whether the Mayo results are applicable to other nonrecalcitrant cancers, Dr. Chaiteerakij said.
On Twitter @pwendl
A detailed survival analysis questions the rationale behind use of the diabetes drug metformin to improve pancreatic cancer survival.
Several epidemiologic studies have shown that metformin use reduces cancer mortality, leading the diabetes drug to be included in the treatment arm of 20 open clinical trials in recalcitrant cancers, Dr. Roongruedee Chaiteerakij reported at the annual meeting of the American Association for Cancer Research.
The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,” which may have introduced unintended biases.
To address these potential biases, Dr. Chaiteerakij and her colleagues at the Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and diabetes between 2000 and 2011 in the database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. More than half (59%) were male; the average age was 67 years.
A total of 380 patients were excluded for surgically induced diabetes, unknown diabetes duration, and PDAC diagnosis more than 90 days prior to the first Mayo visit. This left 980 patients in the final cohort.
An initial analysis using the ever vs. never classification suggested that metformin use was associated with marginally improved survival in patients with PDAC (median 9.9 months ever use vs. 8.9 months never use; unadjusted hazard ratio, 0.9; P = .08), Dr. Chaiteerakij said.
The association was most significant in locally advanced PDAC patients (10.2 months ever use vs. 8.1 months never use; unadjusted HR 0.7; P = .006).
The investigators then performed a subanalysis of locally advanced PDAC patients, this time stratified by timing of metformin initiation: never used (reference group), started more than 1 year before PDAC diagnosis, started within 1 year before PDAC diagnosis, started less than 30 days post PDAC diagnosis, and started more than 30 days post PDAC diagnosis.
Median survival was 8.1, 10.1, and 9.9 months in the first three groups, increasing to 11.4 months and 13.7 months in the two groups that started metformin after PDAC diagnosis, Dr. Chaiteerakij reported.
Hazard ratios for the four metformin groups were 0.7, 0.6, 0.9, and 0.5, after adjustment for age, sex, disease stage, body mass index, and diagnosis year.
The increased survival in patients who started metformin after PDAC diagnosis demonstrates the inherent survival bias in ever/never classification because these patients had lived long enough to receive the drug, she said.
The ever/never classification is commonly used because it can be difficult to extract detailed information on drug use, dose, or timing from retrospective medical records, she noted in a press briefing.
“Epidemiologic studies of medication exposure and cancer survival warrant very careful and detailed data collection and analysis to minimize biases,” Dr. Chaiteerakij concluded. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.”
That said, 11 pancreatic cancer trials are currently listed on www.clinicaltrials.gov, she told reporters.
A simple search of the site for “cancer and metformin” yields no fewer than 230 trials.
It isn’t possible to say at this time whether the Mayo results are applicable to other nonrecalcitrant cancers, Dr. Chaiteerakij said.
On Twitter @pwendl
A detailed survival analysis questions the rationale behind use of the diabetes drug metformin to improve pancreatic cancer survival.
Several epidemiologic studies have shown that metformin use reduces cancer mortality, leading the diabetes drug to be included in the treatment arm of 20 open clinical trials in recalcitrant cancers, Dr. Roongruedee Chaiteerakij reported at the annual meeting of the American Association for Cancer Research.
The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,” which may have introduced unintended biases.
To address these potential biases, Dr. Chaiteerakij and her colleagues at the Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and diabetes between 2000 and 2011 in the database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. More than half (59%) were male; the average age was 67 years.
A total of 380 patients were excluded for surgically induced diabetes, unknown diabetes duration, and PDAC diagnosis more than 90 days prior to the first Mayo visit. This left 980 patients in the final cohort.
An initial analysis using the ever vs. never classification suggested that metformin use was associated with marginally improved survival in patients with PDAC (median 9.9 months ever use vs. 8.9 months never use; unadjusted hazard ratio, 0.9; P = .08), Dr. Chaiteerakij said.
The association was most significant in locally advanced PDAC patients (10.2 months ever use vs. 8.1 months never use; unadjusted HR 0.7; P = .006).
The investigators then performed a subanalysis of locally advanced PDAC patients, this time stratified by timing of metformin initiation: never used (reference group), started more than 1 year before PDAC diagnosis, started within 1 year before PDAC diagnosis, started less than 30 days post PDAC diagnosis, and started more than 30 days post PDAC diagnosis.
Median survival was 8.1, 10.1, and 9.9 months in the first three groups, increasing to 11.4 months and 13.7 months in the two groups that started metformin after PDAC diagnosis, Dr. Chaiteerakij reported.
Hazard ratios for the four metformin groups were 0.7, 0.6, 0.9, and 0.5, after adjustment for age, sex, disease stage, body mass index, and diagnosis year.
The increased survival in patients who started metformin after PDAC diagnosis demonstrates the inherent survival bias in ever/never classification because these patients had lived long enough to receive the drug, she said.
The ever/never classification is commonly used because it can be difficult to extract detailed information on drug use, dose, or timing from retrospective medical records, she noted in a press briefing.
“Epidemiologic studies of medication exposure and cancer survival warrant very careful and detailed data collection and analysis to minimize biases,” Dr. Chaiteerakij concluded. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.”
That said, 11 pancreatic cancer trials are currently listed on www.clinicaltrials.gov, she told reporters.
A simple search of the site for “cancer and metformin” yields no fewer than 230 trials.
It isn’t possible to say at this time whether the Mayo results are applicable to other nonrecalcitrant cancers, Dr. Chaiteerakij said.
On Twitter @pwendl
FROM THE AACR ANNUAL MEETING
Key clinical point: Metformin use may not improve pancreatic cancer survival.
Major finding: Median survival was 8.1 months without metformin vs. 11.4 months if metformin started less than 30 days after cancer diagnosis and 13.7 months if started more than 30 days after diagnosis.
Data source: Retrospective cohort of 1,360 patients with pancreatic cancer and diabetes.
Disclosures: The study was funded by grants from the Mayo Clinic. Dr. Chaiteerakij reported having nothing to disclose.
PD-L1 blockade breaks through triple-negative breast cancer
Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.
MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).
This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.
“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”
There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.
TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.
TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.
MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.
The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.
The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.
At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.
Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.
“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”
Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.
MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.
Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.
Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.
A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.
On Twitter @pwendl
Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.
MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).
This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.
“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”
There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.
TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.
TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.
MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.
The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.
The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.
At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.
Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.
“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”
Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.
MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.
Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.
Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.
A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.
On Twitter @pwendl
Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.
MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).
This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.
“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”
There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.
TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.
TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.
MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.
The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.
The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.
At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.
Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.
“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”
Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.
MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.
Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.
Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.
A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.
On Twitter @pwendl
FROM THE AACR ANNUAL MEETING
Key clinical point: The investigative anti-PD-L1 immunotherapy MPDL3280A was clinically active and generally well tolerated in metastatic triple-negative breast cancer.
Major finding: The objective response rate was 19% and 24-week progression-free survival 27%.
Data source: Phase Ia trial in 54 women with metastatic triple-negative breast cancer.
Disclosures: Genentech/Roche sponsored the study. Dr. Emens reported consulting for Vaccinex, Celgene, Aveo, Bristol-Myers Squibb, and research/grant support from Genentech, Roche, EMD Serono, MaxCyte, Amplimmune, and Merck. Dr. Emens and her institution also receive payments and royalty on a breast cancer vaccine.
EBV-CTLs produce durable responses in EBV-LPD
among uninfected cells (blue)
Image courtesy of NIH/
Benjamin Chaigne-Delalande
PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients
with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.
Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.
Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.
The team presented these results as abstract CT107.*
“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.
“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”
In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.
Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.
Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.
Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.
For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).
Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.
Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.
All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.
He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.
“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”
Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.
Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.
*Information in the abstract differs from that presented at the meeting.
among uninfected cells (blue)
Image courtesy of NIH/
Benjamin Chaigne-Delalande
PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients
with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.
Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.
Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.
The team presented these results as abstract CT107.*
“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.
“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”
In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.
Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.
Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.
Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.
For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).
Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.
Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.
All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.
He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.
“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”
Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.
Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.
*Information in the abstract differs from that presented at the meeting.
among uninfected cells (blue)
Image courtesy of NIH/
Benjamin Chaigne-Delalande
PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients
with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.
Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.
Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.
The team presented these results as abstract CT107.*
“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.
“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”
In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.
Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.
Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.
Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.
For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).
Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.
Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.
All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.
He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.
“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”
Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.
Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.
*Information in the abstract differs from that presented at the meeting.
Pembrolizumab bests ipilimumab in advanced melanoma
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
FROM THE AACR ANNUAL MEETING
Key clinical point: Pembrolizumab was superior to ipilimumab, the standard of care, for first-line treatment of advanced melanoma.
Major finding: Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37% compared with ipilimumab.
Data source: Phase III, randomized, open-label trial in 834 patients with advanced melanoma with no more than one prior systemic therapy.
Disclosures: The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
