Immuno-oncology

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

[email protected]

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.

Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).

Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.

John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
 

Obstacles to development

“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”

A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.

“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.

A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.

And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.

Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.

The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
 

UCART7

One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.

The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.

“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”

In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
 

UCART2 and NT-I7

Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.

The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.

NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).

Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.

Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.

The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.

Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).

Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.

John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
 

Obstacles to development

“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”

A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.

“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.

A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.

And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.

Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.

The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
 

UCART7

One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.

The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.

“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”

In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
 

UCART2 and NT-I7

Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.

The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.

NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).

Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.

Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.

The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.

Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).

Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.

John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
 

Obstacles to development

“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”

A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.

“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.

A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.

And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.

Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.

The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
 

UCART7

One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.

The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.

“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”

In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
 

UCART2 and NT-I7

Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.

The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.

NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).

Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.

Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.

The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.

[email protected]

ATLANTA – Intrapleurally administered, mesothelin-targeted chimeric antigen receptor (CAR) T cells combined with programmed death 1 (PD-1) inhibition showed CAR T-cell antitumor activity without toxicity in a phase 1 clinical trial of patients with malignant pleural disease.

The findings are encouraging, particularly given the aggressive nature of such tumors and the poor prognosis associated with mesothelin – a cell-surface antigen expressed on them, Prasad S. Adusumilli, MD, reported during a press briefing at the annual meeting of the American Association for Cancer Research.

In 21 patients, including 19 with malignant pleural mesothelioma and 1 each with metastatic lung cancer and metastatic breast cancer, a single dose of a second-generation, CD28-costimulated mesothelin CAR T-cell therapy (iCasM28z) was administered intrapleurally either with or without cyclophosphamide preconditioning.

Antitumor activity, as evidenced by the presence of CAR T cells in the blood for several months, was noted in 13 patients, and the presence of the cells was associated with a reduction in a mesothelin-related peptide in the blood, as well as with evidence of tumor regression on imaging studies, said Dr. Adusumilli, deputy chief of the thoracic service at Memorial Sloan Kettering Cancer Center, New York, and lead study author.


Intense clinical, laboratory, and radiological monitoring along with electrocardiography showed no evidence of toxicity.

“Most importantly, the neurotoxicity, serious cytokine release syndrome, and on-target off-target tumor toxicity that has been seen in other CAR T-cell trials, we did not notice in our trial,” he said.

Additionally, one patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion, followed by radiation therapy to the chest, said Dr. Adusumilli, who also is director of the mesothelioma program and head of solid tumor cell therapy at the at Memorial Sloan Kettering Cellular Therapeutic Center.

That patient is doing well at 20 months without further treatment, he noted.

Of a subset of 14 patients who received off-protocol anti-PD-1 checkpoint blockade once lack of toxicity was established for the CAR T-cell therapy, 2 achieved a complete metabolic response at 38 and 60 weeks following checkpoint blockade, 5 had a partial response, and 4 had stable disease.

The anti-PD-1 therapy was initiated in those patients based on prior preclinical data, showing that CAR T cells can become functionally exhausted in large tumors and that anti-PD-1 therapy can reactivate the exhausted cells and eradicate the tumors, he explained.

The findings are notable because malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease affects more than 150,000 patients a year in the United States alone, and effective therapies are lacking.

“[Our finding] strongly supports pursuing a CAR T-cell therapy combined with anti-PD-1 strategies is in solid tumors,” Dr. Adusumilli said, adding that such a trial is being planned for 2019, and another, with CAR T-cell intrinsic PD-1 dominant negative receptor (a decoy receptor) is planned for 2020.

Press briefing moderator Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said the findings represent “potentially the most compelling CAR T data that we’ve ever seen in solid tumors at this point,” and noted that a “vast number of patients” could potentially benefit from the approach.

Dr. Adusumilli agreed, suggesting that, with a system of regional factories and distribution centers and development of “some clever strategies,” it is possible the technology and treatment approach could be scaled up to the level necessary to help increasing numbers of patients.

Dr. Adusumilli reported receiving federal grant support from the National Cancer Institute and Department of Defense; peer-reviewed grant support from the Mesothelioma Applied Research Foundation, Experimental Therapeutics Center, Baker Street Foundation, Batishwa Fellowship, Dallepezze Foundation, Derfner Foundation, Emerson Collective Foundation, and MSK Technology Development Fund; and research grant support from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He also has a licensing/royalty agreement for Mesothelin CAR and PD-1 DNR (licensed to Atara Biotherapeutics).

[email protected]

SOURCE: Adusumilli PS et al. AACR 2019, Abstract CT036.

ATLANTA – Intrapleurally administered, mesothelin-targeted chimeric antigen receptor (CAR) T cells combined with programmed death 1 (PD-1) inhibition showed CAR T-cell antitumor activity without toxicity in a phase 1 clinical trial of patients with malignant pleural disease.

The findings are encouraging, particularly given the aggressive nature of such tumors and the poor prognosis associated with mesothelin – a cell-surface antigen expressed on them, Prasad S. Adusumilli, MD, reported during a press briefing at the annual meeting of the American Association for Cancer Research.

In 21 patients, including 19 with malignant pleural mesothelioma and 1 each with metastatic lung cancer and metastatic breast cancer, a single dose of a second-generation, CD28-costimulated mesothelin CAR T-cell therapy (iCasM28z) was administered intrapleurally either with or without cyclophosphamide preconditioning.

Antitumor activity, as evidenced by the presence of CAR T cells in the blood for several months, was noted in 13 patients, and the presence of the cells was associated with a reduction in a mesothelin-related peptide in the blood, as well as with evidence of tumor regression on imaging studies, said Dr. Adusumilli, deputy chief of the thoracic service at Memorial Sloan Kettering Cancer Center, New York, and lead study author.


Intense clinical, laboratory, and radiological monitoring along with electrocardiography showed no evidence of toxicity.

“Most importantly, the neurotoxicity, serious cytokine release syndrome, and on-target off-target tumor toxicity that has been seen in other CAR T-cell trials, we did not notice in our trial,” he said.

Additionally, one patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion, followed by radiation therapy to the chest, said Dr. Adusumilli, who also is director of the mesothelioma program and head of solid tumor cell therapy at the at Memorial Sloan Kettering Cellular Therapeutic Center.

That patient is doing well at 20 months without further treatment, he noted.

Of a subset of 14 patients who received off-protocol anti-PD-1 checkpoint blockade once lack of toxicity was established for the CAR T-cell therapy, 2 achieved a complete metabolic response at 38 and 60 weeks following checkpoint blockade, 5 had a partial response, and 4 had stable disease.

The anti-PD-1 therapy was initiated in those patients based on prior preclinical data, showing that CAR T cells can become functionally exhausted in large tumors and that anti-PD-1 therapy can reactivate the exhausted cells and eradicate the tumors, he explained.

The findings are notable because malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease affects more than 150,000 patients a year in the United States alone, and effective therapies are lacking.

“[Our finding] strongly supports pursuing a CAR T-cell therapy combined with anti-PD-1 strategies is in solid tumors,” Dr. Adusumilli said, adding that such a trial is being planned for 2019, and another, with CAR T-cell intrinsic PD-1 dominant negative receptor (a decoy receptor) is planned for 2020.

Press briefing moderator Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said the findings represent “potentially the most compelling CAR T data that we’ve ever seen in solid tumors at this point,” and noted that a “vast number of patients” could potentially benefit from the approach.

Dr. Adusumilli agreed, suggesting that, with a system of regional factories and distribution centers and development of “some clever strategies,” it is possible the technology and treatment approach could be scaled up to the level necessary to help increasing numbers of patients.

Dr. Adusumilli reported receiving federal grant support from the National Cancer Institute and Department of Defense; peer-reviewed grant support from the Mesothelioma Applied Research Foundation, Experimental Therapeutics Center, Baker Street Foundation, Batishwa Fellowship, Dallepezze Foundation, Derfner Foundation, Emerson Collective Foundation, and MSK Technology Development Fund; and research grant support from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He also has a licensing/royalty agreement for Mesothelin CAR and PD-1 DNR (licensed to Atara Biotherapeutics).

[email protected]

SOURCE: Adusumilli PS et al. AACR 2019, Abstract CT036.

ATLANTA – Intrapleurally administered, mesothelin-targeted chimeric antigen receptor (CAR) T cells combined with programmed death 1 (PD-1) inhibition showed CAR T-cell antitumor activity without toxicity in a phase 1 clinical trial of patients with malignant pleural disease.

The findings are encouraging, particularly given the aggressive nature of such tumors and the poor prognosis associated with mesothelin – a cell-surface antigen expressed on them, Prasad S. Adusumilli, MD, reported during a press briefing at the annual meeting of the American Association for Cancer Research.

In 21 patients, including 19 with malignant pleural mesothelioma and 1 each with metastatic lung cancer and metastatic breast cancer, a single dose of a second-generation, CD28-costimulated mesothelin CAR T-cell therapy (iCasM28z) was administered intrapleurally either with or without cyclophosphamide preconditioning.

Antitumor activity, as evidenced by the presence of CAR T cells in the blood for several months, was noted in 13 patients, and the presence of the cells was associated with a reduction in a mesothelin-related peptide in the blood, as well as with evidence of tumor regression on imaging studies, said Dr. Adusumilli, deputy chief of the thoracic service at Memorial Sloan Kettering Cancer Center, New York, and lead study author.


Intense clinical, laboratory, and radiological monitoring along with electrocardiography showed no evidence of toxicity.

“Most importantly, the neurotoxicity, serious cytokine release syndrome, and on-target off-target tumor toxicity that has been seen in other CAR T-cell trials, we did not notice in our trial,” he said.

Additionally, one patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion, followed by radiation therapy to the chest, said Dr. Adusumilli, who also is director of the mesothelioma program and head of solid tumor cell therapy at the at Memorial Sloan Kettering Cellular Therapeutic Center.

That patient is doing well at 20 months without further treatment, he noted.

Of a subset of 14 patients who received off-protocol anti-PD-1 checkpoint blockade once lack of toxicity was established for the CAR T-cell therapy, 2 achieved a complete metabolic response at 38 and 60 weeks following checkpoint blockade, 5 had a partial response, and 4 had stable disease.

The anti-PD-1 therapy was initiated in those patients based on prior preclinical data, showing that CAR T cells can become functionally exhausted in large tumors and that anti-PD-1 therapy can reactivate the exhausted cells and eradicate the tumors, he explained.

The findings are notable because malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease affects more than 150,000 patients a year in the United States alone, and effective therapies are lacking.

“[Our finding] strongly supports pursuing a CAR T-cell therapy combined with anti-PD-1 strategies is in solid tumors,” Dr. Adusumilli said, adding that such a trial is being planned for 2019, and another, with CAR T-cell intrinsic PD-1 dominant negative receptor (a decoy receptor) is planned for 2020.

Press briefing moderator Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said the findings represent “potentially the most compelling CAR T data that we’ve ever seen in solid tumors at this point,” and noted that a “vast number of patients” could potentially benefit from the approach.

Dr. Adusumilli agreed, suggesting that, with a system of regional factories and distribution centers and development of “some clever strategies,” it is possible the technology and treatment approach could be scaled up to the level necessary to help increasing numbers of patients.

Dr. Adusumilli reported receiving federal grant support from the National Cancer Institute and Department of Defense; peer-reviewed grant support from the Mesothelioma Applied Research Foundation, Experimental Therapeutics Center, Baker Street Foundation, Batishwa Fellowship, Dallepezze Foundation, Derfner Foundation, Emerson Collective Foundation, and MSK Technology Development Fund; and research grant support from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He also has a licensing/royalty agreement for Mesothelin CAR and PD-1 DNR (licensed to Atara Biotherapeutics).

[email protected]

SOURCE: Adusumilli PS et al. AACR 2019, Abstract CT036.

Combination treatment strategies that include immunotherapeutic agents are expected to become the future of breast cancer treatment, according to a review.

“There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing,” wrote Sylvia Adams, MD, MS, of New York University, along with her colleagues. The report is in JAMA Oncology.

“It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions, they said.

Dr. Adams and her colleagues searched major databases for clinical trials investigating the use of immunotherapy in both early-stage and metastatic breast cancer.

After the search, the team found that immune checkpoint blockade (ICB) agents were the most studied type of immunotherapy in breast cancer today.

In addition, Dr. Adams and her colleagues reported that when UCB agents were used as monotherapy in patients with breast cancer, objective responses have been seen, especially when given in the initial stages of treatment. “For responding patients, those responses are durable,” they added.

Recent findings have indicated that combining immune checkpoint blockade agents with chemotherapy may be useful in early breast cancer as neoadjuvant therapy.

“Combination trials were more common than single-agent studies, with the most commonly combined modalities being chemotherapy or targeted therapy,” the researchers wrote.

The review is limited by the rapid advancement of the current treatment landscape. As a result, additional data may now be available beyond the date of publication.

“Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Amgen, Celgene, Genentech, Eli Lilly, Ipsen, Novartis, Pfizer, and several others.

SOURCE: Adams S et al. JAMA Oncol. 2019 Apr 11. doi: 10.1001/jamaoncol.2018.7147.

Combination treatment strategies that include immunotherapeutic agents are expected to become the future of breast cancer treatment, according to a review.

“There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing,” wrote Sylvia Adams, MD, MS, of New York University, along with her colleagues. The report is in JAMA Oncology.

“It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions, they said.

Dr. Adams and her colleagues searched major databases for clinical trials investigating the use of immunotherapy in both early-stage and metastatic breast cancer.

After the search, the team found that immune checkpoint blockade (ICB) agents were the most studied type of immunotherapy in breast cancer today.

In addition, Dr. Adams and her colleagues reported that when UCB agents were used as monotherapy in patients with breast cancer, objective responses have been seen, especially when given in the initial stages of treatment. “For responding patients, those responses are durable,” they added.

Recent findings have indicated that combining immune checkpoint blockade agents with chemotherapy may be useful in early breast cancer as neoadjuvant therapy.

“Combination trials were more common than single-agent studies, with the most commonly combined modalities being chemotherapy or targeted therapy,” the researchers wrote.

The review is limited by the rapid advancement of the current treatment landscape. As a result, additional data may now be available beyond the date of publication.

“Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Amgen, Celgene, Genentech, Eli Lilly, Ipsen, Novartis, Pfizer, and several others.

SOURCE: Adams S et al. JAMA Oncol. 2019 Apr 11. doi: 10.1001/jamaoncol.2018.7147.

Combination treatment strategies that include immunotherapeutic agents are expected to become the future of breast cancer treatment, according to a review.

“There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing,” wrote Sylvia Adams, MD, MS, of New York University, along with her colleagues. The report is in JAMA Oncology.

“It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions, they said.

Dr. Adams and her colleagues searched major databases for clinical trials investigating the use of immunotherapy in both early-stage and metastatic breast cancer.

After the search, the team found that immune checkpoint blockade (ICB) agents were the most studied type of immunotherapy in breast cancer today.

In addition, Dr. Adams and her colleagues reported that when UCB agents were used as monotherapy in patients with breast cancer, objective responses have been seen, especially when given in the initial stages of treatment. “For responding patients, those responses are durable,” they added.

Recent findings have indicated that combining immune checkpoint blockade agents with chemotherapy may be useful in early breast cancer as neoadjuvant therapy.

“Combination trials were more common than single-agent studies, with the most commonly combined modalities being chemotherapy or targeted therapy,” the researchers wrote.

The review is limited by the rapid advancement of the current treatment landscape. As a result, additional data may now be available beyond the date of publication.

“Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Amgen, Celgene, Genentech, Eli Lilly, Ipsen, Novartis, Pfizer, and several others.

SOURCE: Adams S et al. JAMA Oncol. 2019 Apr 11. doi: 10.1001/jamaoncol.2018.7147.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, and for stage IV NSCLC.

Patients’ tumors must express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test (tumor proportion score ≥1%) and have no epidermal growth factor receptor or anaplastic lymphoma kinase mutations.

The checkpoint inhibitor was previously approved as a single agent for the first-line treatment of patients with metastatic disease with PD-L1 expression at a higher level (TPS ≥50%), the FDA said in a press statement.

Approval was based on statistically significant overall survival improvement with pembrolizumab, compared with investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel in KEYNOTE‑042. The trial enrolled 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%).

Overall survival was improved in all three subgroups for pembrolizumab, compared with chemotherapy: in the TPS ≥50% subgroup, the TPS ≥20% subgroup, and the overall population (TPS ≥1%). The median overall survival in the TPS ≥1% population was 16.7 for pembrolizumab and 12.1 months for the chemotherapy arms (hazard ratio, 0.81; 95% confidence interval, 0.71-0.93; P = .0036). For the TPS ≥50% subgroup, the estimated median overall survival was 20 months for pembrolizumab and 12.2 months for the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0006).

The most common adverse reactions reported for patients who received pembrolizumab included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss, the FDA said.

The recommended dose for NSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.






 

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, and for stage IV NSCLC.

Patients’ tumors must express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test (tumor proportion score ≥1%) and have no epidermal growth factor receptor or anaplastic lymphoma kinase mutations.

The checkpoint inhibitor was previously approved as a single agent for the first-line treatment of patients with metastatic disease with PD-L1 expression at a higher level (TPS ≥50%), the FDA said in a press statement.

Approval was based on statistically significant overall survival improvement with pembrolizumab, compared with investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel in KEYNOTE‑042. The trial enrolled 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%).

Overall survival was improved in all three subgroups for pembrolizumab, compared with chemotherapy: in the TPS ≥50% subgroup, the TPS ≥20% subgroup, and the overall population (TPS ≥1%). The median overall survival in the TPS ≥1% population was 16.7 for pembrolizumab and 12.1 months for the chemotherapy arms (hazard ratio, 0.81; 95% confidence interval, 0.71-0.93; P = .0036). For the TPS ≥50% subgroup, the estimated median overall survival was 20 months for pembrolizumab and 12.2 months for the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0006).

The most common adverse reactions reported for patients who received pembrolizumab included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss, the FDA said.

The recommended dose for NSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.






 

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, and for stage IV NSCLC.

Patients’ tumors must express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test (tumor proportion score ≥1%) and have no epidermal growth factor receptor or anaplastic lymphoma kinase mutations.

The checkpoint inhibitor was previously approved as a single agent for the first-line treatment of patients with metastatic disease with PD-L1 expression at a higher level (TPS ≥50%), the FDA said in a press statement.

Approval was based on statistically significant overall survival improvement with pembrolizumab, compared with investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel in KEYNOTE‑042. The trial enrolled 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%).

Overall survival was improved in all three subgroups for pembrolizumab, compared with chemotherapy: in the TPS ≥50% subgroup, the TPS ≥20% subgroup, and the overall population (TPS ≥1%). The median overall survival in the TPS ≥1% population was 16.7 for pembrolizumab and 12.1 months for the chemotherapy arms (hazard ratio, 0.81; 95% confidence interval, 0.71-0.93; P = .0036). For the TPS ≥50% subgroup, the estimated median overall survival was 20 months for pembrolizumab and 12.2 months for the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0006).

The most common adverse reactions reported for patients who received pembrolizumab included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss, the FDA said.

The recommended dose for NSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.






 

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.