AVAHO

PHILADELPHIA – The latest published report links calcium intake from supplements to increased risk of cancer death, a nutrition specialist noted at the annual meeting of the American College of Physicians.

Andrew D. Bowser/MDedge News

The report, published (Ann Intern Med. 2019 Apr 9. doi: 10.7326/M18-2478) just 2 days before the start of the Internal Medicine meeting, found no mortality benefits associated with any reported dietary supplement use among nearly 31,000 adults in the National Health and Nutrition Examination Survey.

On the contrary, they found that excess calcium consumption was associated with increased risk for cancer-related deaths. Calcium supplements were specifically implicated in the excess of mortality, according to the investigators, with a rate ratio of 1.53 (95% confidence interval, 1.04-2.25) for intakes of 1,000 mg/day versus no intake.

“It’s better to get all of your vitamins from your food, over supplements,” said Marijane Hynes, MD, director of weight management at George Washington University, Washington, in a meet-the-professor session at the conference.

The amount of calcium patients are getting from food can be estimated with one rule of thumb: Multiply the number of dairy servings per day by 300 mg, Dr. Hynes said, who added that a serving is 8 ounces of milk or 1 ounce of hard cheese. Dark green vegetables, breads, cereals, and some nuts can provide 100-200 mg of calcium per day.

Calcium carbonate can be taken with food to enhance calcium absorption, according to Dr. Hynes, while calcium citrate can be taken without food, and is preferred for patients taking acid reflux medications.

Because calcium absorption is reduced at higher doses, patients who need more than 600 mg/day should be taking divided doses, she said.

Bone health goes beyond the dairy aisle, Dr. Hynes added. High vitamin K intake was linked to reduced hip fracture risk among the Framingham Heart Study participants. To get the recommended amount of vitamin K in the diet, patients can consume one or more servings of broccoli, kale, collard greens, or dark green lettuce.

Dr. Hynes reported she that had no relationships with entities producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients.

PHILADELPHIA – The latest published report links calcium intake from supplements to increased risk of cancer death, a nutrition specialist noted at the annual meeting of the American College of Physicians.

Andrew D. Bowser/MDedge News

The report, published (Ann Intern Med. 2019 Apr 9. doi: 10.7326/M18-2478) just 2 days before the start of the Internal Medicine meeting, found no mortality benefits associated with any reported dietary supplement use among nearly 31,000 adults in the National Health and Nutrition Examination Survey.

On the contrary, they found that excess calcium consumption was associated with increased risk for cancer-related deaths. Calcium supplements were specifically implicated in the excess of mortality, according to the investigators, with a rate ratio of 1.53 (95% confidence interval, 1.04-2.25) for intakes of 1,000 mg/day versus no intake.

“It’s better to get all of your vitamins from your food, over supplements,” said Marijane Hynes, MD, director of weight management at George Washington University, Washington, in a meet-the-professor session at the conference.

The amount of calcium patients are getting from food can be estimated with one rule of thumb: Multiply the number of dairy servings per day by 300 mg, Dr. Hynes said, who added that a serving is 8 ounces of milk or 1 ounce of hard cheese. Dark green vegetables, breads, cereals, and some nuts can provide 100-200 mg of calcium per day.

Calcium carbonate can be taken with food to enhance calcium absorption, according to Dr. Hynes, while calcium citrate can be taken without food, and is preferred for patients taking acid reflux medications.

Because calcium absorption is reduced at higher doses, patients who need more than 600 mg/day should be taking divided doses, she said.

Bone health goes beyond the dairy aisle, Dr. Hynes added. High vitamin K intake was linked to reduced hip fracture risk among the Framingham Heart Study participants. To get the recommended amount of vitamin K in the diet, patients can consume one or more servings of broccoli, kale, collard greens, or dark green lettuce.

Dr. Hynes reported she that had no relationships with entities producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients.

PHILADELPHIA – The latest published report links calcium intake from supplements to increased risk of cancer death, a nutrition specialist noted at the annual meeting of the American College of Physicians.

Andrew D. Bowser/MDedge News

The report, published (Ann Intern Med. 2019 Apr 9. doi: 10.7326/M18-2478) just 2 days before the start of the Internal Medicine meeting, found no mortality benefits associated with any reported dietary supplement use among nearly 31,000 adults in the National Health and Nutrition Examination Survey.

On the contrary, they found that excess calcium consumption was associated with increased risk for cancer-related deaths. Calcium supplements were specifically implicated in the excess of mortality, according to the investigators, with a rate ratio of 1.53 (95% confidence interval, 1.04-2.25) for intakes of 1,000 mg/day versus no intake.

“It’s better to get all of your vitamins from your food, over supplements,” said Marijane Hynes, MD, director of weight management at George Washington University, Washington, in a meet-the-professor session at the conference.

The amount of calcium patients are getting from food can be estimated with one rule of thumb: Multiply the number of dairy servings per day by 300 mg, Dr. Hynes said, who added that a serving is 8 ounces of milk or 1 ounce of hard cheese. Dark green vegetables, breads, cereals, and some nuts can provide 100-200 mg of calcium per day.

Calcium carbonate can be taken with food to enhance calcium absorption, according to Dr. Hynes, while calcium citrate can be taken without food, and is preferred for patients taking acid reflux medications.

Because calcium absorption is reduced at higher doses, patients who need more than 600 mg/day should be taking divided doses, she said.

Bone health goes beyond the dairy aisle, Dr. Hynes added. High vitamin K intake was linked to reduced hip fracture risk among the Framingham Heart Study participants. To get the recommended amount of vitamin K in the diet, patients can consume one or more servings of broccoli, kale, collard greens, or dark green lettuce.

Dr. Hynes reported she that had no relationships with entities producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients.

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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).

sworcester@mdedge.com

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).

sworcester@mdedge.com

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).

sworcester@mdedge.com

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

ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).

In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.

In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.

The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.

ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).

In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.

In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.

The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.

ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).

In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.

In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.

The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.

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.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

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.






 

The proportion of women speaking at medical conferences in the United States and Canada increased significantly between 2007 and 2017, while the proportion at surgical specialty conferences lagged noticeably behind, according to new research.

“Although female representation at academic meetings has been identified as an important gender equity issue, the proportion of conference speakers who are women has not yet been systematically measured across different medical subspecialties,” wrote Shannon M. Ruzycki, MD, and her colleagues from the University of Calgary (Alta.). The report is in JAMA Network Open.

Using the Web of Science Conference database, the investigators identified 181 conferences and 701 unique meetings (40 in 2007, 104 in 2013, 115 in 2014, 124 in 2015, 137 in 2016, and 181 in 2017). The list of names from each meeting program was analyzed by the Gender Balance Assessment Tool to identify the likely proportion of female speakers by assigning a probability of each name belonging to a gender, based on social media data.

In 2007, the proportion of female speakers was 24.6% , which increased to 34.1% by 2017, an average increase of 0.97% per year. The range of female speakers at each meeting ranged from 0% to 82.6%, with 82 (12%) of the 701 meetings having more than 50% female speakers. The proportion of female speakers was slightly less than the proportion of female doctors in the United States and Canada in 2007 (26.1%), but was slightly greater than the proportion of female doctors in 2015 (32.4%).

During the study period, the proportion of female speakers at surgical specialty conferences was significantly lower than that for medical specialty conferences (20.1% in 2007 and 28.4% in 2017 vs. 29.9% in 2007 and 38.8% in 2017). While the number of speakers at medical meetings in 2015 matched the proportion of doctors in the United States and Canada in that year, the proportion of speakers at surgical meetings was noticeably higher than the number of female surgeons.

“We hypothesize that the low proportion of female speakers at medical conferences reflects broader gender inequity within the medical profession, particularly in subspecialties where the majority of physicians are men. It has been shown that the presence of female role models in male-dominated career streams can increase engagement of young women,” the investigators wrote. “Exposure to female speakers at medical conferences may be a means of encouraging female medical students and residents to choose specialties that have historically been male dominated. Strategies to promote inclusivity of female speakers at academic conferences may therefore represent an important opportunity to influence gender equity within medicine,” they concluded.

The University of Calgary funded the study. The authors reported no conflicts of interest.

lfranki@mdedge.com

SOURCE: Ruzycki SM et al. JAMA Netw Open. 2019 Apr 12. doi: 10.1001/jamanetworkopen.2019.2103.

The proportion of women speaking at medical conferences in the United States and Canada increased significantly between 2007 and 2017, while the proportion at surgical specialty conferences lagged noticeably behind, according to new research.

“Although female representation at academic meetings has been identified as an important gender equity issue, the proportion of conference speakers who are women has not yet been systematically measured across different medical subspecialties,” wrote Shannon M. Ruzycki, MD, and her colleagues from the University of Calgary (Alta.). The report is in JAMA Network Open.

Using the Web of Science Conference database, the investigators identified 181 conferences and 701 unique meetings (40 in 2007, 104 in 2013, 115 in 2014, 124 in 2015, 137 in 2016, and 181 in 2017). The list of names from each meeting program was analyzed by the Gender Balance Assessment Tool to identify the likely proportion of female speakers by assigning a probability of each name belonging to a gender, based on social media data.

In 2007, the proportion of female speakers was 24.6% , which increased to 34.1% by 2017, an average increase of 0.97% per year. The range of female speakers at each meeting ranged from 0% to 82.6%, with 82 (12%) of the 701 meetings having more than 50% female speakers. The proportion of female speakers was slightly less than the proportion of female doctors in the United States and Canada in 2007 (26.1%), but was slightly greater than the proportion of female doctors in 2015 (32.4%).

During the study period, the proportion of female speakers at surgical specialty conferences was significantly lower than that for medical specialty conferences (20.1% in 2007 and 28.4% in 2017 vs. 29.9% in 2007 and 38.8% in 2017). While the number of speakers at medical meetings in 2015 matched the proportion of doctors in the United States and Canada in that year, the proportion of speakers at surgical meetings was noticeably higher than the number of female surgeons.

“We hypothesize that the low proportion of female speakers at medical conferences reflects broader gender inequity within the medical profession, particularly in subspecialties where the majority of physicians are men. It has been shown that the presence of female role models in male-dominated career streams can increase engagement of young women,” the investigators wrote. “Exposure to female speakers at medical conferences may be a means of encouraging female medical students and residents to choose specialties that have historically been male dominated. Strategies to promote inclusivity of female speakers at academic conferences may therefore represent an important opportunity to influence gender equity within medicine,” they concluded.

The University of Calgary funded the study. The authors reported no conflicts of interest.

lfranki@mdedge.com

SOURCE: Ruzycki SM et al. JAMA Netw Open. 2019 Apr 12. doi: 10.1001/jamanetworkopen.2019.2103.

The proportion of women speaking at medical conferences in the United States and Canada increased significantly between 2007 and 2017, while the proportion at surgical specialty conferences lagged noticeably behind, according to new research.

“Although female representation at academic meetings has been identified as an important gender equity issue, the proportion of conference speakers who are women has not yet been systematically measured across different medical subspecialties,” wrote Shannon M. Ruzycki, MD, and her colleagues from the University of Calgary (Alta.). The report is in JAMA Network Open.

Using the Web of Science Conference database, the investigators identified 181 conferences and 701 unique meetings (40 in 2007, 104 in 2013, 115 in 2014, 124 in 2015, 137 in 2016, and 181 in 2017). The list of names from each meeting program was analyzed by the Gender Balance Assessment Tool to identify the likely proportion of female speakers by assigning a probability of each name belonging to a gender, based on social media data.

In 2007, the proportion of female speakers was 24.6% , which increased to 34.1% by 2017, an average increase of 0.97% per year. The range of female speakers at each meeting ranged from 0% to 82.6%, with 82 (12%) of the 701 meetings having more than 50% female speakers. The proportion of female speakers was slightly less than the proportion of female doctors in the United States and Canada in 2007 (26.1%), but was slightly greater than the proportion of female doctors in 2015 (32.4%).

During the study period, the proportion of female speakers at surgical specialty conferences was significantly lower than that for medical specialty conferences (20.1% in 2007 and 28.4% in 2017 vs. 29.9% in 2007 and 38.8% in 2017). While the number of speakers at medical meetings in 2015 matched the proportion of doctors in the United States and Canada in that year, the proportion of speakers at surgical meetings was noticeably higher than the number of female surgeons.

“We hypothesize that the low proportion of female speakers at medical conferences reflects broader gender inequity within the medical profession, particularly in subspecialties where the majority of physicians are men. It has been shown that the presence of female role models in male-dominated career streams can increase engagement of young women,” the investigators wrote. “Exposure to female speakers at medical conferences may be a means of encouraging female medical students and residents to choose specialties that have historically been male dominated. Strategies to promote inclusivity of female speakers at academic conferences may therefore represent an important opportunity to influence gender equity within medicine,” they concluded.

The University of Calgary funded the study. The authors reported no conflicts of interest.

lfranki@mdedge.com

SOURCE: Ruzycki SM et al. JAMA Netw Open. 2019 Apr 12. doi: 10.1001/jamanetworkopen.2019.2103.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.