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Unique T cell populations pinpointed in hepatocellular carcinoma tissue
Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.
The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.
“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.
A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”
However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.
The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.
Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.
Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.
Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.
The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.
Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.
Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.
Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.
“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.
The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.
SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.
Immunotherapy with checkpoint inhibitors has been suggested for the treatment of hepatocellular carcinoma (HCC) and finding relevant predictors of response to immunotherapy remains one of the most challenging tasks for solid gastrointestinal cancers such as HCC where efficiency of immune therapy suggests only a moderate response so far. Recently, two randomized phase 3 trials on checkpoint inhibitors in HCC, both first-line against sorafenib (Checkmate 459) as well as second-line against placebo (KEYNOTE-240), have failed to show an overall survival benefit despite clinical benefit in some patients and a manageable side effects profile. The study by Di Blasi et al. therefore provides important insights into the immune cell composition of tumor-infiltrating lymphocytes (TILs) in HCC. In this study it was possible to identify certain cell populations within TILs that resembled recently activated tumor-specific T cells that were in an exhausted state. It was possible to reinvigorate these exhausted cell clusters and to activate IFN-delta–producing T cells with the help of checkpoint inhibitor therapy in these patients. These data suggest that the enumeration of certain immune cell infiltrates may identify patients responding to checkpoint inhibitor therapy. Another important observation from this study was that not all immune-inflamed tumors identified by immunohistochemistry (or so-called “hot tumors”) responded to checkpoint inhibitor therapy and that more sophisticated analysis of the immune infiltrates with, e.g., flow cytometry or mass cytometry seems to be necessary to understand which patients respond. Different immune cell clusters have been suggested by other research groups and further research is needed to confirm this theory and to understand which of the proposed immune cell clusters and phenotypic profiles will prove most valuable in terms of prognosis for checkpoint inhibitor therapy in HCC.
Nico Buettner, MD, and Robert Thimme, MD, are professors in the department of medicine II, Medical Center University of Freiburg, Germany. They have no conflicts of interest.
Immunotherapy with checkpoint inhibitors has been suggested for the treatment of hepatocellular carcinoma (HCC) and finding relevant predictors of response to immunotherapy remains one of the most challenging tasks for solid gastrointestinal cancers such as HCC where efficiency of immune therapy suggests only a moderate response so far. Recently, two randomized phase 3 trials on checkpoint inhibitors in HCC, both first-line against sorafenib (Checkmate 459) as well as second-line against placebo (KEYNOTE-240), have failed to show an overall survival benefit despite clinical benefit in some patients and a manageable side effects profile. The study by Di Blasi et al. therefore provides important insights into the immune cell composition of tumor-infiltrating lymphocytes (TILs) in HCC. In this study it was possible to identify certain cell populations within TILs that resembled recently activated tumor-specific T cells that were in an exhausted state. It was possible to reinvigorate these exhausted cell clusters and to activate IFN-delta–producing T cells with the help of checkpoint inhibitor therapy in these patients. These data suggest that the enumeration of certain immune cell infiltrates may identify patients responding to checkpoint inhibitor therapy. Another important observation from this study was that not all immune-inflamed tumors identified by immunohistochemistry (or so-called “hot tumors”) responded to checkpoint inhibitor therapy and that more sophisticated analysis of the immune infiltrates with, e.g., flow cytometry or mass cytometry seems to be necessary to understand which patients respond. Different immune cell clusters have been suggested by other research groups and further research is needed to confirm this theory and to understand which of the proposed immune cell clusters and phenotypic profiles will prove most valuable in terms of prognosis for checkpoint inhibitor therapy in HCC.
Nico Buettner, MD, and Robert Thimme, MD, are professors in the department of medicine II, Medical Center University of Freiburg, Germany. They have no conflicts of interest.
Immunotherapy with checkpoint inhibitors has been suggested for the treatment of hepatocellular carcinoma (HCC) and finding relevant predictors of response to immunotherapy remains one of the most challenging tasks for solid gastrointestinal cancers such as HCC where efficiency of immune therapy suggests only a moderate response so far. Recently, two randomized phase 3 trials on checkpoint inhibitors in HCC, both first-line against sorafenib (Checkmate 459) as well as second-line against placebo (KEYNOTE-240), have failed to show an overall survival benefit despite clinical benefit in some patients and a manageable side effects profile. The study by Di Blasi et al. therefore provides important insights into the immune cell composition of tumor-infiltrating lymphocytes (TILs) in HCC. In this study it was possible to identify certain cell populations within TILs that resembled recently activated tumor-specific T cells that were in an exhausted state. It was possible to reinvigorate these exhausted cell clusters and to activate IFN-delta–producing T cells with the help of checkpoint inhibitor therapy in these patients. These data suggest that the enumeration of certain immune cell infiltrates may identify patients responding to checkpoint inhibitor therapy. Another important observation from this study was that not all immune-inflamed tumors identified by immunohistochemistry (or so-called “hot tumors”) responded to checkpoint inhibitor therapy and that more sophisticated analysis of the immune infiltrates with, e.g., flow cytometry or mass cytometry seems to be necessary to understand which patients respond. Different immune cell clusters have been suggested by other research groups and further research is needed to confirm this theory and to understand which of the proposed immune cell clusters and phenotypic profiles will prove most valuable in terms of prognosis for checkpoint inhibitor therapy in HCC.
Nico Buettner, MD, and Robert Thimme, MD, are professors in the department of medicine II, Medical Center University of Freiburg, Germany. They have no conflicts of interest.
Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.
The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.
“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.
A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”
However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.
The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.
Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.
Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.
Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.
The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.
Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.
Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.
Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.
“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.
The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.
SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.
Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.
The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.
“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.
A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”
However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.
The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.
Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.
Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.
Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.
The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.
Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.
Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.
Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.
“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.
The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.
SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Evidence builds for bariatric surgery’s role in cancer prevention
LAS VEGAS – The ability of bariatric surgery and substantial subsequent weight loss to cut the incidence of a variety of obesity-related cancers and other malignancies received further confirmation in results from two studies reported at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
In one study, 2,107 adults enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS-2) study showed a statistically significant halving of the cancer incidence during 7 years of follow-up in patients who underwent bariatric surgery and had a reduction of at least 20% in their presurgical body mass index (BMI), compared with patients in the study who underwent bariatric surgery but lost less weight, reported Andrea M. Stroud, MD, a bariatric surgeon at the Oregon Health & Science University, Portland.
In the second study, analysis of about 1.7 million hospitalized U.S. patients in the National Inpatient Sample showed that the incidence of an obesity-related cancer was 21% higher in more than 1.4 million obese individuals (BMI, 35 kg/m2 or greater) with no history of bariatric surgery, compared with nearly 247,000 people in the same database with a history of both obesity and bariatric surgery, said Juliana Henrique, MD, a bariatric surgeon at the Cleveland Clinic Florida in Weston.
The study reported by Dr. Henrique focused specifically on the 13 cancer types identified by the Centers for Disease Control and Prevention as having an incidence that links with overweight and obesity (Morb Mortal Wkly Rep. 2017;66[39]:1052-8), whereas the study presented by Dr. Stroud included all incident cancers during follow-up, but which were predominantly obesity related, with breast cancer – an obesity-related malignancy – having the highest incidence. Overall, 40% of all U.S. cancers in 2014 were obesity related, according to the CDC’s report.
“A number of studies have shown decreases in cancer rates after bariatric surgery, especially female cancers like breast and ovarian,” commented John Scott, MD, director of metabolic and bariatric surgery for Prism Health–Upstate in Greenville, S.C. “These two reports build on that.”
The evidence for weight loss after bariatric surgery as a means to cut the risk of a first or recurrent cancer has become strong enough for some patients to see cancer prophylaxis as a prime reason to undergo the procedure, said surgeons at the meeting.
Bariatric surgery and subsequent weight loss “is a substantial preventive factor for cancer, especially in patients who have obesity and diabetes,” commented Theresa LaMasters, MD, a bariatric surgeon in West Des Moines, Iowa. “It might not just be weight loss. It’s likely a multifactorial effect, including reduced inflammation after bariatric surgery, but weight loss is a component” of the effect, Dr. LaMasters said in an interview. It is now common for her to see patients seeking bariatric surgery because of a family or personal history of cancer. “Patients are trying to reduce their future risk” for cancer with bariatric surgery, she added.
The LABS-2 study enrolled 2,458 patients who were part of the first LABS cohort, LABS-1, but followed them longer term. The data Dr. Stroud reported came from 2,107 of the LABS-2 patients without a history of cancer, no cancer diagnosed in the first year after bariatric surgery, and longer-term follow-up of 7 years. About three-quarters of the patients underwent gastric bypass, with the rest undergoing laparoscopic gastric band placement. Nearly half of those included had diabetes. Their average BMI was 45-50 kg/m2.
Dr. Stroud and associates ran an analysis that divided the populations into tertiles based on percentage of baseline body mass lost at 12 months after surgery and cancer-free survival during the 7 years after the 12-month follow-up. The incidence of cancer was 51% lower in patients who lost 20%-34% of their BMI, compared with those who lost less than 20%, a statistically significant difference, and patients who lost 35% or more of their BMI had a 31% reduced cancer rate, compared with those who lost less than 20%, a difference that was not statistically significant, Dr. Stroud reported. The patients who lost less weight after surgery mostly underwent gastric banding, whereas those who lost more mostly underwent gastric bypass.
The analysis reported by Dr. Henrique used data collected in the U.S. National Inpatient Sample during 2010-2014, which totaled more than 7 million patients hospitalized for cancer, including 1,423,367 with a history of obesity and 246,668 with obesity who had undergone bariatric surgery. Those without bariatric surgery had a 21% higher rate of developing obesity-related cancers after adjustment for many baseline demographic and clinical features, Dr. Henrique said. The cancer protection after bariatric surgery was especially notable in the subset of patients in the sample with a genetic predisposition to developing cancer.
LABS-1 and LABS-2 were funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Stroud and Dr. Henrique had no disclosures.
SOURCES: Stroud AM et al. Obesity Week, Abstract A107; Henrique J et al. Obesity Week, Abstract A108.
LAS VEGAS – The ability of bariatric surgery and substantial subsequent weight loss to cut the incidence of a variety of obesity-related cancers and other malignancies received further confirmation in results from two studies reported at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
In one study, 2,107 adults enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS-2) study showed a statistically significant halving of the cancer incidence during 7 years of follow-up in patients who underwent bariatric surgery and had a reduction of at least 20% in their presurgical body mass index (BMI), compared with patients in the study who underwent bariatric surgery but lost less weight, reported Andrea M. Stroud, MD, a bariatric surgeon at the Oregon Health & Science University, Portland.
In the second study, analysis of about 1.7 million hospitalized U.S. patients in the National Inpatient Sample showed that the incidence of an obesity-related cancer was 21% higher in more than 1.4 million obese individuals (BMI, 35 kg/m2 or greater) with no history of bariatric surgery, compared with nearly 247,000 people in the same database with a history of both obesity and bariatric surgery, said Juliana Henrique, MD, a bariatric surgeon at the Cleveland Clinic Florida in Weston.
The study reported by Dr. Henrique focused specifically on the 13 cancer types identified by the Centers for Disease Control and Prevention as having an incidence that links with overweight and obesity (Morb Mortal Wkly Rep. 2017;66[39]:1052-8), whereas the study presented by Dr. Stroud included all incident cancers during follow-up, but which were predominantly obesity related, with breast cancer – an obesity-related malignancy – having the highest incidence. Overall, 40% of all U.S. cancers in 2014 were obesity related, according to the CDC’s report.
“A number of studies have shown decreases in cancer rates after bariatric surgery, especially female cancers like breast and ovarian,” commented John Scott, MD, director of metabolic and bariatric surgery for Prism Health–Upstate in Greenville, S.C. “These two reports build on that.”
The evidence for weight loss after bariatric surgery as a means to cut the risk of a first or recurrent cancer has become strong enough for some patients to see cancer prophylaxis as a prime reason to undergo the procedure, said surgeons at the meeting.
Bariatric surgery and subsequent weight loss “is a substantial preventive factor for cancer, especially in patients who have obesity and diabetes,” commented Theresa LaMasters, MD, a bariatric surgeon in West Des Moines, Iowa. “It might not just be weight loss. It’s likely a multifactorial effect, including reduced inflammation after bariatric surgery, but weight loss is a component” of the effect, Dr. LaMasters said in an interview. It is now common for her to see patients seeking bariatric surgery because of a family or personal history of cancer. “Patients are trying to reduce their future risk” for cancer with bariatric surgery, she added.
The LABS-2 study enrolled 2,458 patients who were part of the first LABS cohort, LABS-1, but followed them longer term. The data Dr. Stroud reported came from 2,107 of the LABS-2 patients without a history of cancer, no cancer diagnosed in the first year after bariatric surgery, and longer-term follow-up of 7 years. About three-quarters of the patients underwent gastric bypass, with the rest undergoing laparoscopic gastric band placement. Nearly half of those included had diabetes. Their average BMI was 45-50 kg/m2.
Dr. Stroud and associates ran an analysis that divided the populations into tertiles based on percentage of baseline body mass lost at 12 months after surgery and cancer-free survival during the 7 years after the 12-month follow-up. The incidence of cancer was 51% lower in patients who lost 20%-34% of their BMI, compared with those who lost less than 20%, a statistically significant difference, and patients who lost 35% or more of their BMI had a 31% reduced cancer rate, compared with those who lost less than 20%, a difference that was not statistically significant, Dr. Stroud reported. The patients who lost less weight after surgery mostly underwent gastric banding, whereas those who lost more mostly underwent gastric bypass.
The analysis reported by Dr. Henrique used data collected in the U.S. National Inpatient Sample during 2010-2014, which totaled more than 7 million patients hospitalized for cancer, including 1,423,367 with a history of obesity and 246,668 with obesity who had undergone bariatric surgery. Those without bariatric surgery had a 21% higher rate of developing obesity-related cancers after adjustment for many baseline demographic and clinical features, Dr. Henrique said. The cancer protection after bariatric surgery was especially notable in the subset of patients in the sample with a genetic predisposition to developing cancer.
LABS-1 and LABS-2 were funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Stroud and Dr. Henrique had no disclosures.
SOURCES: Stroud AM et al. Obesity Week, Abstract A107; Henrique J et al. Obesity Week, Abstract A108.
LAS VEGAS – The ability of bariatric surgery and substantial subsequent weight loss to cut the incidence of a variety of obesity-related cancers and other malignancies received further confirmation in results from two studies reported at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
In one study, 2,107 adults enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS-2) study showed a statistically significant halving of the cancer incidence during 7 years of follow-up in patients who underwent bariatric surgery and had a reduction of at least 20% in their presurgical body mass index (BMI), compared with patients in the study who underwent bariatric surgery but lost less weight, reported Andrea M. Stroud, MD, a bariatric surgeon at the Oregon Health & Science University, Portland.
In the second study, analysis of about 1.7 million hospitalized U.S. patients in the National Inpatient Sample showed that the incidence of an obesity-related cancer was 21% higher in more than 1.4 million obese individuals (BMI, 35 kg/m2 or greater) with no history of bariatric surgery, compared with nearly 247,000 people in the same database with a history of both obesity and bariatric surgery, said Juliana Henrique, MD, a bariatric surgeon at the Cleveland Clinic Florida in Weston.
The study reported by Dr. Henrique focused specifically on the 13 cancer types identified by the Centers for Disease Control and Prevention as having an incidence that links with overweight and obesity (Morb Mortal Wkly Rep. 2017;66[39]:1052-8), whereas the study presented by Dr. Stroud included all incident cancers during follow-up, but which were predominantly obesity related, with breast cancer – an obesity-related malignancy – having the highest incidence. Overall, 40% of all U.S. cancers in 2014 were obesity related, according to the CDC’s report.
“A number of studies have shown decreases in cancer rates after bariatric surgery, especially female cancers like breast and ovarian,” commented John Scott, MD, director of metabolic and bariatric surgery for Prism Health–Upstate in Greenville, S.C. “These two reports build on that.”
The evidence for weight loss after bariatric surgery as a means to cut the risk of a first or recurrent cancer has become strong enough for some patients to see cancer prophylaxis as a prime reason to undergo the procedure, said surgeons at the meeting.
Bariatric surgery and subsequent weight loss “is a substantial preventive factor for cancer, especially in patients who have obesity and diabetes,” commented Theresa LaMasters, MD, a bariatric surgeon in West Des Moines, Iowa. “It might not just be weight loss. It’s likely a multifactorial effect, including reduced inflammation after bariatric surgery, but weight loss is a component” of the effect, Dr. LaMasters said in an interview. It is now common for her to see patients seeking bariatric surgery because of a family or personal history of cancer. “Patients are trying to reduce their future risk” for cancer with bariatric surgery, she added.
The LABS-2 study enrolled 2,458 patients who were part of the first LABS cohort, LABS-1, but followed them longer term. The data Dr. Stroud reported came from 2,107 of the LABS-2 patients without a history of cancer, no cancer diagnosed in the first year after bariatric surgery, and longer-term follow-up of 7 years. About three-quarters of the patients underwent gastric bypass, with the rest undergoing laparoscopic gastric band placement. Nearly half of those included had diabetes. Their average BMI was 45-50 kg/m2.
Dr. Stroud and associates ran an analysis that divided the populations into tertiles based on percentage of baseline body mass lost at 12 months after surgery and cancer-free survival during the 7 years after the 12-month follow-up. The incidence of cancer was 51% lower in patients who lost 20%-34% of their BMI, compared with those who lost less than 20%, a statistically significant difference, and patients who lost 35% or more of their BMI had a 31% reduced cancer rate, compared with those who lost less than 20%, a difference that was not statistically significant, Dr. Stroud reported. The patients who lost less weight after surgery mostly underwent gastric banding, whereas those who lost more mostly underwent gastric bypass.
The analysis reported by Dr. Henrique used data collected in the U.S. National Inpatient Sample during 2010-2014, which totaled more than 7 million patients hospitalized for cancer, including 1,423,367 with a history of obesity and 246,668 with obesity who had undergone bariatric surgery. Those without bariatric surgery had a 21% higher rate of developing obesity-related cancers after adjustment for many baseline demographic and clinical features, Dr. Henrique said. The cancer protection after bariatric surgery was especially notable in the subset of patients in the sample with a genetic predisposition to developing cancer.
LABS-1 and LABS-2 were funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Stroud and Dr. Henrique had no disclosures.
SOURCES: Stroud AM et al. Obesity Week, Abstract A107; Henrique J et al. Obesity Week, Abstract A108.
REPORTING FROM OBESITY WEEK 2019
CAR T cells produce complete responses in T-cell malignancies
ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.
Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.
There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.
LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.
“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.
Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).
With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.
The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 107 or 5 x 107.
Response
Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.
One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.
The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.
One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.
Factors associated with response
Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.
“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”
Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.
“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”
Safety
“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”
Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.
Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.
One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.
One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.
“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”
Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 108), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.
Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.
SOURCE: Hill L et al. ASH 2019. Abstract 199.
ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.
Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.
There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.
LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.
“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.
Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).
With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.
The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 107 or 5 x 107.
Response
Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.
One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.
The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.
One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.
Factors associated with response
Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.
“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”
Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.
“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”
Safety
“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”
Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.
Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.
One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.
One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.
“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”
Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 108), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.
Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.
SOURCE: Hill L et al. ASH 2019. Abstract 199.
ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.
Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.
There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.
LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.
“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.
Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).
With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.
The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 107 or 5 x 107.
Response
Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.
One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.
The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.
One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.
Factors associated with response
Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.
“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”
Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.
“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”
Safety
“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”
Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.
Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.
One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.
One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.
“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”
Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 108), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.
Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.
SOURCE: Hill L et al. ASH 2019. Abstract 199.
REPORTING FROM ASH 2019
Survival data reported from largest CAR T trial in B-cell lymphoma
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
REPORTING FROM ASH 2019
New guideline provides recommendations for radiation therapy of basal cell, squamous cell cancers
who are not candidates for surgery, according to a new guideline from an American Society for Radiation Oncology task force.
“We hope that the dermatology community will find this guideline helpful, especially when it comes to defining clinical and pathological characteristics that may necessitate a discussion about the merits of postoperative radiation therapy,” said lead author Anna Likhacheva, MD, of the Sutter Medical Center in Sacramento, Calif., in an email. The guideline was published in Practical Radiation Oncology.
To address five key questions in regard to radiation therapy (RT) for the two most common skin cancers, the American Society for Radiation Oncology convened a task force of radiation, medical, and surgical oncologists; dermatopathologists; a radiation oncology resident; a medical physicist; and a dermatologist. They reviewed studies of adults with nonmetastatic, invasive basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) that were published between May 1998 and June 2018, with the caveat that “there are limited, well-conducted modern randomized trials” in this area. As such, the majority of the recommendations have low to moderate quality of evidence designations.
“The conspicuous lack of prospective and randomized data should serve as a reminder to open clinical trials and collect outcomes data in a prospective fashion,” added Dr. Likhacheva, noting that “improving the quality of data on this topic will ultimately serve our common goal of improving patient outcomes.”
Their first recommendation was to strongly consider definitive RT as an alternative to surgery for BCC and cSCC, especially in areas where a surgical procedure would potentially compromise function or cosmesis. However, they did discourage its use in patients with genetic conditions associated with increased radiosensitivity.
Their second recommendation was to strongly consider postoperative radiation therapy for clinically or radiologically apparent gross perineural spread. They also strongly recommended PORT for cSCC patients with close or positive margins, with T3 or T4 tumors, or with desmoplastic or infiltrative tumors.
Their third recommendation was to strongly consider therapeutic lymphadenectomy followed by adjuvant RT in patients with cSCC or BCC that has metastasized to the regional lymph nodes. They also recommended definitive RT in medically inoperable patients with the same metastasized cSCC or BCC. In addition, patients with BCC or cSCC undergoing adjuvant RT after therapeutic lymphadenectomy were recommended a dose of 6,000-6,600 cGy, while patients with cSCC undergoing elective RT without a lymphadenectomy were recommended a dose of 5,000-5,400 cGy.
Their fourth recommendation focused on techniques and dose-fractionation schedules for RT in the definitive or postoperative setting. For patients with BCC and cSCC receiving definitive RT, the biologically effective dose (BED10) range for conventional fractionation – defined as 180-200 cGy/fraction – should be 70-93.5 and the BED10 range for hypofractionation – defined as 210-500 cGy/fraction – should be 56-88. For patients with BCC and cSCC receiving postoperative RT, the BED10 range for conventional fractionation should be 59.5-79.2 and the BED10 range for hypofractionation should be 56-70.2.
Finally, their fifth recommendation was to not add concurrent carboplatin to adjuvant RT in patients with resected, locally advanced cSCC. They also conditionally recommended adding concurrent drug therapies to definitive RT in patients with unresected, locally advanced cSCC.
Several of the authors reported receiving honoraria and travel expenses from medical and pharmaceutical companies, along with serving on their advisory boards. The others reported no conflicts of interest.
SOURCE: Likhacheva A et al. Pract Radiat Oncol. 2019 Dec 9. doi: 10.1016/j.prro.2019.10.014.
who are not candidates for surgery, according to a new guideline from an American Society for Radiation Oncology task force.
“We hope that the dermatology community will find this guideline helpful, especially when it comes to defining clinical and pathological characteristics that may necessitate a discussion about the merits of postoperative radiation therapy,” said lead author Anna Likhacheva, MD, of the Sutter Medical Center in Sacramento, Calif., in an email. The guideline was published in Practical Radiation Oncology.
To address five key questions in regard to radiation therapy (RT) for the two most common skin cancers, the American Society for Radiation Oncology convened a task force of radiation, medical, and surgical oncologists; dermatopathologists; a radiation oncology resident; a medical physicist; and a dermatologist. They reviewed studies of adults with nonmetastatic, invasive basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) that were published between May 1998 and June 2018, with the caveat that “there are limited, well-conducted modern randomized trials” in this area. As such, the majority of the recommendations have low to moderate quality of evidence designations.
“The conspicuous lack of prospective and randomized data should serve as a reminder to open clinical trials and collect outcomes data in a prospective fashion,” added Dr. Likhacheva, noting that “improving the quality of data on this topic will ultimately serve our common goal of improving patient outcomes.”
Their first recommendation was to strongly consider definitive RT as an alternative to surgery for BCC and cSCC, especially in areas where a surgical procedure would potentially compromise function or cosmesis. However, they did discourage its use in patients with genetic conditions associated with increased radiosensitivity.
Their second recommendation was to strongly consider postoperative radiation therapy for clinically or radiologically apparent gross perineural spread. They also strongly recommended PORT for cSCC patients with close or positive margins, with T3 or T4 tumors, or with desmoplastic or infiltrative tumors.
Their third recommendation was to strongly consider therapeutic lymphadenectomy followed by adjuvant RT in patients with cSCC or BCC that has metastasized to the regional lymph nodes. They also recommended definitive RT in medically inoperable patients with the same metastasized cSCC or BCC. In addition, patients with BCC or cSCC undergoing adjuvant RT after therapeutic lymphadenectomy were recommended a dose of 6,000-6,600 cGy, while patients with cSCC undergoing elective RT without a lymphadenectomy were recommended a dose of 5,000-5,400 cGy.
Their fourth recommendation focused on techniques and dose-fractionation schedules for RT in the definitive or postoperative setting. For patients with BCC and cSCC receiving definitive RT, the biologically effective dose (BED10) range for conventional fractionation – defined as 180-200 cGy/fraction – should be 70-93.5 and the BED10 range for hypofractionation – defined as 210-500 cGy/fraction – should be 56-88. For patients with BCC and cSCC receiving postoperative RT, the BED10 range for conventional fractionation should be 59.5-79.2 and the BED10 range for hypofractionation should be 56-70.2.
Finally, their fifth recommendation was to not add concurrent carboplatin to adjuvant RT in patients with resected, locally advanced cSCC. They also conditionally recommended adding concurrent drug therapies to definitive RT in patients with unresected, locally advanced cSCC.
Several of the authors reported receiving honoraria and travel expenses from medical and pharmaceutical companies, along with serving on their advisory boards. The others reported no conflicts of interest.
SOURCE: Likhacheva A et al. Pract Radiat Oncol. 2019 Dec 9. doi: 10.1016/j.prro.2019.10.014.
who are not candidates for surgery, according to a new guideline from an American Society for Radiation Oncology task force.
“We hope that the dermatology community will find this guideline helpful, especially when it comes to defining clinical and pathological characteristics that may necessitate a discussion about the merits of postoperative radiation therapy,” said lead author Anna Likhacheva, MD, of the Sutter Medical Center in Sacramento, Calif., in an email. The guideline was published in Practical Radiation Oncology.
To address five key questions in regard to radiation therapy (RT) for the two most common skin cancers, the American Society for Radiation Oncology convened a task force of radiation, medical, and surgical oncologists; dermatopathologists; a radiation oncology resident; a medical physicist; and a dermatologist. They reviewed studies of adults with nonmetastatic, invasive basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) that were published between May 1998 and June 2018, with the caveat that “there are limited, well-conducted modern randomized trials” in this area. As such, the majority of the recommendations have low to moderate quality of evidence designations.
“The conspicuous lack of prospective and randomized data should serve as a reminder to open clinical trials and collect outcomes data in a prospective fashion,” added Dr. Likhacheva, noting that “improving the quality of data on this topic will ultimately serve our common goal of improving patient outcomes.”
Their first recommendation was to strongly consider definitive RT as an alternative to surgery for BCC and cSCC, especially in areas where a surgical procedure would potentially compromise function or cosmesis. However, they did discourage its use in patients with genetic conditions associated with increased radiosensitivity.
Their second recommendation was to strongly consider postoperative radiation therapy for clinically or radiologically apparent gross perineural spread. They also strongly recommended PORT for cSCC patients with close or positive margins, with T3 or T4 tumors, or with desmoplastic or infiltrative tumors.
Their third recommendation was to strongly consider therapeutic lymphadenectomy followed by adjuvant RT in patients with cSCC or BCC that has metastasized to the regional lymph nodes. They also recommended definitive RT in medically inoperable patients with the same metastasized cSCC or BCC. In addition, patients with BCC or cSCC undergoing adjuvant RT after therapeutic lymphadenectomy were recommended a dose of 6,000-6,600 cGy, while patients with cSCC undergoing elective RT without a lymphadenectomy were recommended a dose of 5,000-5,400 cGy.
Their fourth recommendation focused on techniques and dose-fractionation schedules for RT in the definitive or postoperative setting. For patients with BCC and cSCC receiving definitive RT, the biologically effective dose (BED10) range for conventional fractionation – defined as 180-200 cGy/fraction – should be 70-93.5 and the BED10 range for hypofractionation – defined as 210-500 cGy/fraction – should be 56-88. For patients with BCC and cSCC receiving postoperative RT, the BED10 range for conventional fractionation should be 59.5-79.2 and the BED10 range for hypofractionation should be 56-70.2.
Finally, their fifth recommendation was to not add concurrent carboplatin to adjuvant RT in patients with resected, locally advanced cSCC. They also conditionally recommended adding concurrent drug therapies to definitive RT in patients with unresected, locally advanced cSCC.
Several of the authors reported receiving honoraria and travel expenses from medical and pharmaceutical companies, along with serving on their advisory boards. The others reported no conflicts of interest.
SOURCE: Likhacheva A et al. Pract Radiat Oncol. 2019 Dec 9. doi: 10.1016/j.prro.2019.10.014.
FROM PRACTICAL RADIATION ONCOLOGY
Cancer researchers win grants from DOD, GO2 Foundation
The GO2 Foundation for Lung Cancer has granted the 2019 Young Innovators Team Awards to two groups of investigators studying non-small cell lung cancer (NSCLC). Each group received $250,000 to support their work.
Yanxiang (Jessie) Guo, PhD, of Rutgers Cancer Institute of New Jersey, and Shawn Davidson, PhD, of Princeton University in New Jersey, won the award for their research on tumor metabolism and immunotherapy in KRAS-mutant NSCLC.
Dr. Guo and Dr. Davidson aim to prove that cancer cell metabolism affects the tumor microenvironment and leads to an impaired antitumor immune response. The pair’s ultimate goal is to overcome resistance to immunotherapy in KRAS-mutant NSCLC.
Matthew Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, and Tuomas Tammela, MD, PhD, of Weill-Cornell Medical College in New York, won the award for their research on age-related differences in NSCLC.
Dr. Bott and Dr. Tammela aim to characterize differences in natural history and treatment response between younger and older patients with NSCLC. The main goal is to determine if different age groups require different approaches to treatment.
Two other researchers, both from Fox Chase Cancer Center in Philadelphia, received grants from the U.S. Department of Defense.
Jeffrey Peterson, PhD, was awarded a $1.4 million grant from the Department of Defense for his research on triple-negative breast cancer. Dr. Peterson will work with postdoctoral research fellows Alexander Beatty, PhD, and Tanu Singh, PhD, to determine if polyunsaturated fatty acids can be used to induce programmed cell death in triple-negative breast cancer.
Dr. Peterson theorizes that metastatic cells may be susceptible to preferential uptake of conjugated linoleic acid, which will trigger ferroptosis and destroy cancer cells without affecting normal cells. His ultimate goal is to set the stage for clinical trials of more effective, less toxic targeted therapies for triple-negative breast cancer.
Phillip Abbosh, MD, PhD, was awarded a $658,800 grant from the Department of Defense to investigate the role of the immune system and certain bacteria in mediating responses to therapy in bladder cancers.
Dr. Abbosh theorizes that a better understanding of the interaction between the immune system and bladder tumors could aid the development of new targeted therapies, and perhaps bacteria found in cancer patients’ bladders could be used to enhance treatment.
The GO2 Foundation for Lung Cancer has granted the 2019 Young Innovators Team Awards to two groups of investigators studying non-small cell lung cancer (NSCLC). Each group received $250,000 to support their work.
Yanxiang (Jessie) Guo, PhD, of Rutgers Cancer Institute of New Jersey, and Shawn Davidson, PhD, of Princeton University in New Jersey, won the award for their research on tumor metabolism and immunotherapy in KRAS-mutant NSCLC.
Dr. Guo and Dr. Davidson aim to prove that cancer cell metabolism affects the tumor microenvironment and leads to an impaired antitumor immune response. The pair’s ultimate goal is to overcome resistance to immunotherapy in KRAS-mutant NSCLC.
Matthew Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, and Tuomas Tammela, MD, PhD, of Weill-Cornell Medical College in New York, won the award for their research on age-related differences in NSCLC.
Dr. Bott and Dr. Tammela aim to characterize differences in natural history and treatment response between younger and older patients with NSCLC. The main goal is to determine if different age groups require different approaches to treatment.
Two other researchers, both from Fox Chase Cancer Center in Philadelphia, received grants from the U.S. Department of Defense.
Jeffrey Peterson, PhD, was awarded a $1.4 million grant from the Department of Defense for his research on triple-negative breast cancer. Dr. Peterson will work with postdoctoral research fellows Alexander Beatty, PhD, and Tanu Singh, PhD, to determine if polyunsaturated fatty acids can be used to induce programmed cell death in triple-negative breast cancer.
Dr. Peterson theorizes that metastatic cells may be susceptible to preferential uptake of conjugated linoleic acid, which will trigger ferroptosis and destroy cancer cells without affecting normal cells. His ultimate goal is to set the stage for clinical trials of more effective, less toxic targeted therapies for triple-negative breast cancer.
Phillip Abbosh, MD, PhD, was awarded a $658,800 grant from the Department of Defense to investigate the role of the immune system and certain bacteria in mediating responses to therapy in bladder cancers.
Dr. Abbosh theorizes that a better understanding of the interaction between the immune system and bladder tumors could aid the development of new targeted therapies, and perhaps bacteria found in cancer patients’ bladders could be used to enhance treatment.
The GO2 Foundation for Lung Cancer has granted the 2019 Young Innovators Team Awards to two groups of investigators studying non-small cell lung cancer (NSCLC). Each group received $250,000 to support their work.
Yanxiang (Jessie) Guo, PhD, of Rutgers Cancer Institute of New Jersey, and Shawn Davidson, PhD, of Princeton University in New Jersey, won the award for their research on tumor metabolism and immunotherapy in KRAS-mutant NSCLC.
Dr. Guo and Dr. Davidson aim to prove that cancer cell metabolism affects the tumor microenvironment and leads to an impaired antitumor immune response. The pair’s ultimate goal is to overcome resistance to immunotherapy in KRAS-mutant NSCLC.
Matthew Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, and Tuomas Tammela, MD, PhD, of Weill-Cornell Medical College in New York, won the award for their research on age-related differences in NSCLC.
Dr. Bott and Dr. Tammela aim to characterize differences in natural history and treatment response between younger and older patients with NSCLC. The main goal is to determine if different age groups require different approaches to treatment.
Two other researchers, both from Fox Chase Cancer Center in Philadelphia, received grants from the U.S. Department of Defense.
Jeffrey Peterson, PhD, was awarded a $1.4 million grant from the Department of Defense for his research on triple-negative breast cancer. Dr. Peterson will work with postdoctoral research fellows Alexander Beatty, PhD, and Tanu Singh, PhD, to determine if polyunsaturated fatty acids can be used to induce programmed cell death in triple-negative breast cancer.
Dr. Peterson theorizes that metastatic cells may be susceptible to preferential uptake of conjugated linoleic acid, which will trigger ferroptosis and destroy cancer cells without affecting normal cells. His ultimate goal is to set the stage for clinical trials of more effective, less toxic targeted therapies for triple-negative breast cancer.
Phillip Abbosh, MD, PhD, was awarded a $658,800 grant from the Department of Defense to investigate the role of the immune system and certain bacteria in mediating responses to therapy in bladder cancers.
Dr. Abbosh theorizes that a better understanding of the interaction between the immune system and bladder tumors could aid the development of new targeted therapies, and perhaps bacteria found in cancer patients’ bladders could be used to enhance treatment.
Some MCL patients can safely stop venetoclax-ibrutinib, study suggests
ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.
Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.
“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.
The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).
The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.
In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
Response and survival
For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.
Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.
Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.
Treatment status
Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.
Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.
One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
Safety update
Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.
Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.
SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.
ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.
Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.
“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.
The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).
The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.
In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
Response and survival
For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.
Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.
Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.
Treatment status
Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.
Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.
One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
Safety update
Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.
Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.
SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.
ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.
Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.
“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.
The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).
The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.
In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
Response and survival
For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.
Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.
Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.
Treatment status
Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.
Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.
One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
Safety update
Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.
Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.
SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.
REPORTING FROM ASH 2019
Pembrolizumab plus chemo boosts pCR rate in TNBC
SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.
Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.
“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.
The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.
Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).
After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.
At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.
When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:
- Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
- Stage IIB: 56.2% versus 48.4%, difference 7.8%.
- Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
- Stage IIIB: 48.6% versus 23.1%, difference 25.6%.
The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.
There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).
pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).
Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).
The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).
“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.
Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.
“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”
“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.
The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.
SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.
SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.
Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.
“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.
The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.
Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).
After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.
At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.
When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:
- Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
- Stage IIB: 56.2% versus 48.4%, difference 7.8%.
- Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
- Stage IIIB: 48.6% versus 23.1%, difference 25.6%.
The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.
There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).
pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).
Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).
The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).
“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.
Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.
“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”
“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.
The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.
SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.
SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.
Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.
“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.
The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.
Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).
After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.
At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.
When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:
- Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
- Stage IIB: 56.2% versus 48.4%, difference 7.8%.
- Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
- Stage IIIB: 48.6% versus 23.1%, difference 25.6%.
The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.
There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).
pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).
Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).
The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).
“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.
Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.
“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”
“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.
The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.
SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.
REPORTING FROM SABCS 2019
Ten-year results support partial breast irradiation
SAN ANTONIO – For patients with early, low-risk breast cancer, accelerated partial breast irradiation (APBI) may be considered a standard alternative to whole breast irradiation, according to investigators.
This conclusion was based on 10-year follow-up results from the APBI IMRT Florence phase III trial, which showed that APBI was associated with significantly fewer adverse events and better cosmetic results than whole breast irradiation without increasing risks of tumor recurrence or mortality, reported lead author Irco Meattini, MD, of the University of Florence, Italy, and colleagues.
“As we well know, recent developments in radiation oncology ... show a move toward a deescalation strategy for early breast cancer, including accelerated and nonaccelerated partial breast irradiation,” Dr. Meattini said during a presentation at the San Antonio Breast Cancer Symposium. “What we have learned from [previous] phase 3 trials [is that with adequate patient selection for] partial breast irradiation, safety profile and cosmetic outcome are strongly associated with technique – the approach, the dose, the number of fractions per day, and the total dose.”
The current phase 3 trial, which enrolled 520 patients with early breast cancer, aimed to determine long-term efficacy, safety, and cosmetic outcomes for partial versus whole breast irradiation. All patients enrolled were at least 40 years of age and had a maximum pathological tumor size of 25 mm. Patients were randomized in a 1:1 ratio to receive either whole breast irradiation (WBI) at a dose of 50 Gy in 25 fractions, followed by 10 Gy in five fractions delivered to the tumor bed; or APBI, which was delivered to the tumor bed at a dose of 30 Gy in five daily fractions.
The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were overall survival, breast cancer–specific survival, distant metastasis-free survival, locoregional recurrences, and contralateral breast cancer. Adverse events and cosmesis also were evaluated.
Five-year results, previously reported, revealed no significant difference in survival rates or IBTR between treatment techniques, and results of the present 10-year analysis maintained these findings. Between groups, no significant differences were observed in any of the primary or secondary endpoints, suggesting that major efficacy outcomes were unaffected by type of irradiation delivered.
While major efficacy endpoints were comparable between groups, safety profiles and cosmetic results differed significantly.
Adverse events of all levels of severity were significantly more common with WBI than APBI. Grade 2 or higher acute adverse events occurred in 37.7% of patients treated with WBI, compared with just 2.0% of patients treated with APBI (P = .0001). The rate of grade 2 or higher adverse events was also significantly higher in the WBI group than in the APBI group in the late setting, albeit with a narrower margin than in the acute setting (2.7% vs 0%; P = .015). Skin toxicity rates followed a similar pattern, favoring APBI both in the acute phase (66.5% vs. 21.1%; P = .0001) and the late phase (30.0% vs. 4.5%; P = .0001).
In further support of APBI, cosmetic results, as measured by the Harvard Breast Cosmesis Scale, were significantly better in the APBI group than in the WBI group. Both physicians and patients were significantly more likely to report good or excellent cosmetic results with APBI than WBI.
“APBI might be considered a standard alternative to WBI in low risk and very low risk early breast cancer patients,” Dr. Meattini concluded.
The investigators reported no disclosures.
SOURCE: Meattini et al. SABCS. 2019 Dec 12. Abstract GS4-06.
SAN ANTONIO – For patients with early, low-risk breast cancer, accelerated partial breast irradiation (APBI) may be considered a standard alternative to whole breast irradiation, according to investigators.
This conclusion was based on 10-year follow-up results from the APBI IMRT Florence phase III trial, which showed that APBI was associated with significantly fewer adverse events and better cosmetic results than whole breast irradiation without increasing risks of tumor recurrence or mortality, reported lead author Irco Meattini, MD, of the University of Florence, Italy, and colleagues.
“As we well know, recent developments in radiation oncology ... show a move toward a deescalation strategy for early breast cancer, including accelerated and nonaccelerated partial breast irradiation,” Dr. Meattini said during a presentation at the San Antonio Breast Cancer Symposium. “What we have learned from [previous] phase 3 trials [is that with adequate patient selection for] partial breast irradiation, safety profile and cosmetic outcome are strongly associated with technique – the approach, the dose, the number of fractions per day, and the total dose.”
The current phase 3 trial, which enrolled 520 patients with early breast cancer, aimed to determine long-term efficacy, safety, and cosmetic outcomes for partial versus whole breast irradiation. All patients enrolled were at least 40 years of age and had a maximum pathological tumor size of 25 mm. Patients were randomized in a 1:1 ratio to receive either whole breast irradiation (WBI) at a dose of 50 Gy in 25 fractions, followed by 10 Gy in five fractions delivered to the tumor bed; or APBI, which was delivered to the tumor bed at a dose of 30 Gy in five daily fractions.
The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were overall survival, breast cancer–specific survival, distant metastasis-free survival, locoregional recurrences, and contralateral breast cancer. Adverse events and cosmesis also were evaluated.
Five-year results, previously reported, revealed no significant difference in survival rates or IBTR between treatment techniques, and results of the present 10-year analysis maintained these findings. Between groups, no significant differences were observed in any of the primary or secondary endpoints, suggesting that major efficacy outcomes were unaffected by type of irradiation delivered.
While major efficacy endpoints were comparable between groups, safety profiles and cosmetic results differed significantly.
Adverse events of all levels of severity were significantly more common with WBI than APBI. Grade 2 or higher acute adverse events occurred in 37.7% of patients treated with WBI, compared with just 2.0% of patients treated with APBI (P = .0001). The rate of grade 2 or higher adverse events was also significantly higher in the WBI group than in the APBI group in the late setting, albeit with a narrower margin than in the acute setting (2.7% vs 0%; P = .015). Skin toxicity rates followed a similar pattern, favoring APBI both in the acute phase (66.5% vs. 21.1%; P = .0001) and the late phase (30.0% vs. 4.5%; P = .0001).
In further support of APBI, cosmetic results, as measured by the Harvard Breast Cosmesis Scale, were significantly better in the APBI group than in the WBI group. Both physicians and patients were significantly more likely to report good or excellent cosmetic results with APBI than WBI.
“APBI might be considered a standard alternative to WBI in low risk and very low risk early breast cancer patients,” Dr. Meattini concluded.
The investigators reported no disclosures.
SOURCE: Meattini et al. SABCS. 2019 Dec 12. Abstract GS4-06.
SAN ANTONIO – For patients with early, low-risk breast cancer, accelerated partial breast irradiation (APBI) may be considered a standard alternative to whole breast irradiation, according to investigators.
This conclusion was based on 10-year follow-up results from the APBI IMRT Florence phase III trial, which showed that APBI was associated with significantly fewer adverse events and better cosmetic results than whole breast irradiation without increasing risks of tumor recurrence or mortality, reported lead author Irco Meattini, MD, of the University of Florence, Italy, and colleagues.
“As we well know, recent developments in radiation oncology ... show a move toward a deescalation strategy for early breast cancer, including accelerated and nonaccelerated partial breast irradiation,” Dr. Meattini said during a presentation at the San Antonio Breast Cancer Symposium. “What we have learned from [previous] phase 3 trials [is that with adequate patient selection for] partial breast irradiation, safety profile and cosmetic outcome are strongly associated with technique – the approach, the dose, the number of fractions per day, and the total dose.”
The current phase 3 trial, which enrolled 520 patients with early breast cancer, aimed to determine long-term efficacy, safety, and cosmetic outcomes for partial versus whole breast irradiation. All patients enrolled were at least 40 years of age and had a maximum pathological tumor size of 25 mm. Patients were randomized in a 1:1 ratio to receive either whole breast irradiation (WBI) at a dose of 50 Gy in 25 fractions, followed by 10 Gy in five fractions delivered to the tumor bed; or APBI, which was delivered to the tumor bed at a dose of 30 Gy in five daily fractions.
The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were overall survival, breast cancer–specific survival, distant metastasis-free survival, locoregional recurrences, and contralateral breast cancer. Adverse events and cosmesis also were evaluated.
Five-year results, previously reported, revealed no significant difference in survival rates or IBTR between treatment techniques, and results of the present 10-year analysis maintained these findings. Between groups, no significant differences were observed in any of the primary or secondary endpoints, suggesting that major efficacy outcomes were unaffected by type of irradiation delivered.
While major efficacy endpoints were comparable between groups, safety profiles and cosmetic results differed significantly.
Adverse events of all levels of severity were significantly more common with WBI than APBI. Grade 2 or higher acute adverse events occurred in 37.7% of patients treated with WBI, compared with just 2.0% of patients treated with APBI (P = .0001). The rate of grade 2 or higher adverse events was also significantly higher in the WBI group than in the APBI group in the late setting, albeit with a narrower margin than in the acute setting (2.7% vs 0%; P = .015). Skin toxicity rates followed a similar pattern, favoring APBI both in the acute phase (66.5% vs. 21.1%; P = .0001) and the late phase (30.0% vs. 4.5%; P = .0001).
In further support of APBI, cosmetic results, as measured by the Harvard Breast Cosmesis Scale, were significantly better in the APBI group than in the WBI group. Both physicians and patients were significantly more likely to report good or excellent cosmetic results with APBI than WBI.
“APBI might be considered a standard alternative to WBI in low risk and very low risk early breast cancer patients,” Dr. Meattini concluded.
The investigators reported no disclosures.
SOURCE: Meattini et al. SABCS. 2019 Dec 12. Abstract GS4-06.
REPORTING FROM SABCS 2019
New evidence further supports starting CRC screening at age 45
SAN ANTONIO – The American Cancer Society’s 2018 qualified recommendation to lower the starting age for colorectal cancer screening from 50 to 45 years in average-risk individuals has picked up new support from a New Hampshire Colonoscopy Registry analysis.
Data from the population-based statewide colonoscopy registry demonstrated that the prevalence of both advanced adenomas and clinically significant serrated polyps was closely similar for average-risk New Hampshirites age 45-49 years and for those age 50-54, Lynn F. Butterly, MD, reported at the annual meeting of the American College of Gastroenterology.
“The clinical implication is that our data support the recommendation to begin average-risk colorectal cancer screening at age 45,” declared Dr. Butterly, a gastroenterologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
The American Cancer Society recommendation to lower the initial screening age was designed to address a disturbing national trend: the climbing incidence of colorectal cancer in young adults. Indeed, the incidence increased by 55% among 20- to 49-year-olds during 1995-2016, even while falling by 38% in individuals age 50 years and older. The 2018 recommendation was billed as “qualified” because it was based upon predictive modeling and National Cancer Institute Surveillance, Epidemiology, and End Results data which have been criticized as subject to potential bias. Several studies conducted in Korea and other Asian countries have reported a lower colorectal cancer risk in the younger adult population than in those age 50 or older, but questions have been raised about the applicability of such data to the U.S. population.
For Dr. Butterly and coinvestigators, the research imperative was clear: “We need to generate U.S. outcomes data for average-risk individuals age 45-49, versus those over age 50, for whom colorectal cancer screening is already strongly recommended.”
Toward that end, the investigators turned to the New Hampshire Colonoscopy Registry, which contains detailed data on 200,000 colonoscopies, with some 400 variables recorded per patient. To zero in on an average-risk population below age 50, they restricted the analysis to patients undergoing their first colonoscopy for evaluation of low-risk conditions including abdominal pain or constipation while excluding those with GI bleeding, iron-deficiency anemia, abnormal imaging, or a family history of colorectal cancer.
The final study population included 42,600 New Hampshire residents who underwent their first colonoscopy. The key outcomes were the prevalence of advanced adenomas, defined as adenomas more than 1 cm in size, or with high-grade dysplasia or villous elements, and the prevalence of clinically significant serrated polyps larger than 1 cm, or larger than 5 mm if proximally located, as well as traditional serrated adenomas and those with sessile features.
The prevalence of advanced adenomas in 1,870 average-risk patients aged 45-49 years was 3.7% and nearly identical at 3.6% in 22,160 individuals undergoing screening colonoscopy at age 50-54. The rate of clinically significant serrated polyps was 5.9% in the 45- to 49-year-olds, closely similar to the 6.1% rate in patients age 50-54.
Of note, the prevalence of advanced adenomas was just 1.1% in individuals younger than age 40 years, jumping to 3.0% among 40- to 44-year-olds, 5.1% in those age 55-59, and 6.9% at age 60 or more. Clinically significant serrated polyps followed a similar pattern, with rates of 3.0% before age 40, 5.1% in 40- to 44-year-olds, 6.6% in 55- to 59-year-olds, and 6.0% in those who were older.
In a multivariate logistic regression analysis adjusted for sex, body mass index, smoking, and other potential confounders, 45- to 49-year-olds were at a 243% increased risk of finding advanced adenomas on colonoscopy, compared with those less than 40 years old, while the 50- to 54-year-olds had a virtually identical 244% increased risk.
Dr. Butterly noted that there are now 15,000 cases of colorectal cancer occurring annually in individuals under age 50 in the United States, with 3,600 deaths.
“Prevention of colorectal cancer in young, productive individuals is an essential clinical imperative that must be addressed,” she concluded.
She reported having no financial conflicts regarding her study.
SAN ANTONIO – The American Cancer Society’s 2018 qualified recommendation to lower the starting age for colorectal cancer screening from 50 to 45 years in average-risk individuals has picked up new support from a New Hampshire Colonoscopy Registry analysis.
Data from the population-based statewide colonoscopy registry demonstrated that the prevalence of both advanced adenomas and clinically significant serrated polyps was closely similar for average-risk New Hampshirites age 45-49 years and for those age 50-54, Lynn F. Butterly, MD, reported at the annual meeting of the American College of Gastroenterology.
“The clinical implication is that our data support the recommendation to begin average-risk colorectal cancer screening at age 45,” declared Dr. Butterly, a gastroenterologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
The American Cancer Society recommendation to lower the initial screening age was designed to address a disturbing national trend: the climbing incidence of colorectal cancer in young adults. Indeed, the incidence increased by 55% among 20- to 49-year-olds during 1995-2016, even while falling by 38% in individuals age 50 years and older. The 2018 recommendation was billed as “qualified” because it was based upon predictive modeling and National Cancer Institute Surveillance, Epidemiology, and End Results data which have been criticized as subject to potential bias. Several studies conducted in Korea and other Asian countries have reported a lower colorectal cancer risk in the younger adult population than in those age 50 or older, but questions have been raised about the applicability of such data to the U.S. population.
For Dr. Butterly and coinvestigators, the research imperative was clear: “We need to generate U.S. outcomes data for average-risk individuals age 45-49, versus those over age 50, for whom colorectal cancer screening is already strongly recommended.”
Toward that end, the investigators turned to the New Hampshire Colonoscopy Registry, which contains detailed data on 200,000 colonoscopies, with some 400 variables recorded per patient. To zero in on an average-risk population below age 50, they restricted the analysis to patients undergoing their first colonoscopy for evaluation of low-risk conditions including abdominal pain or constipation while excluding those with GI bleeding, iron-deficiency anemia, abnormal imaging, or a family history of colorectal cancer.
The final study population included 42,600 New Hampshire residents who underwent their first colonoscopy. The key outcomes were the prevalence of advanced adenomas, defined as adenomas more than 1 cm in size, or with high-grade dysplasia or villous elements, and the prevalence of clinically significant serrated polyps larger than 1 cm, or larger than 5 mm if proximally located, as well as traditional serrated adenomas and those with sessile features.
The prevalence of advanced adenomas in 1,870 average-risk patients aged 45-49 years was 3.7% and nearly identical at 3.6% in 22,160 individuals undergoing screening colonoscopy at age 50-54. The rate of clinically significant serrated polyps was 5.9% in the 45- to 49-year-olds, closely similar to the 6.1% rate in patients age 50-54.
Of note, the prevalence of advanced adenomas was just 1.1% in individuals younger than age 40 years, jumping to 3.0% among 40- to 44-year-olds, 5.1% in those age 55-59, and 6.9% at age 60 or more. Clinically significant serrated polyps followed a similar pattern, with rates of 3.0% before age 40, 5.1% in 40- to 44-year-olds, 6.6% in 55- to 59-year-olds, and 6.0% in those who were older.
In a multivariate logistic regression analysis adjusted for sex, body mass index, smoking, and other potential confounders, 45- to 49-year-olds were at a 243% increased risk of finding advanced adenomas on colonoscopy, compared with those less than 40 years old, while the 50- to 54-year-olds had a virtually identical 244% increased risk.
Dr. Butterly noted that there are now 15,000 cases of colorectal cancer occurring annually in individuals under age 50 in the United States, with 3,600 deaths.
“Prevention of colorectal cancer in young, productive individuals is an essential clinical imperative that must be addressed,” she concluded.
She reported having no financial conflicts regarding her study.
SAN ANTONIO – The American Cancer Society’s 2018 qualified recommendation to lower the starting age for colorectal cancer screening from 50 to 45 years in average-risk individuals has picked up new support from a New Hampshire Colonoscopy Registry analysis.
Data from the population-based statewide colonoscopy registry demonstrated that the prevalence of both advanced adenomas and clinically significant serrated polyps was closely similar for average-risk New Hampshirites age 45-49 years and for those age 50-54, Lynn F. Butterly, MD, reported at the annual meeting of the American College of Gastroenterology.
“The clinical implication is that our data support the recommendation to begin average-risk colorectal cancer screening at age 45,” declared Dr. Butterly, a gastroenterologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
The American Cancer Society recommendation to lower the initial screening age was designed to address a disturbing national trend: the climbing incidence of colorectal cancer in young adults. Indeed, the incidence increased by 55% among 20- to 49-year-olds during 1995-2016, even while falling by 38% in individuals age 50 years and older. The 2018 recommendation was billed as “qualified” because it was based upon predictive modeling and National Cancer Institute Surveillance, Epidemiology, and End Results data which have been criticized as subject to potential bias. Several studies conducted in Korea and other Asian countries have reported a lower colorectal cancer risk in the younger adult population than in those age 50 or older, but questions have been raised about the applicability of such data to the U.S. population.
For Dr. Butterly and coinvestigators, the research imperative was clear: “We need to generate U.S. outcomes data for average-risk individuals age 45-49, versus those over age 50, for whom colorectal cancer screening is already strongly recommended.”
Toward that end, the investigators turned to the New Hampshire Colonoscopy Registry, which contains detailed data on 200,000 colonoscopies, with some 400 variables recorded per patient. To zero in on an average-risk population below age 50, they restricted the analysis to patients undergoing their first colonoscopy for evaluation of low-risk conditions including abdominal pain or constipation while excluding those with GI bleeding, iron-deficiency anemia, abnormal imaging, or a family history of colorectal cancer.
The final study population included 42,600 New Hampshire residents who underwent their first colonoscopy. The key outcomes were the prevalence of advanced adenomas, defined as adenomas more than 1 cm in size, or with high-grade dysplasia or villous elements, and the prevalence of clinically significant serrated polyps larger than 1 cm, or larger than 5 mm if proximally located, as well as traditional serrated adenomas and those with sessile features.
The prevalence of advanced adenomas in 1,870 average-risk patients aged 45-49 years was 3.7% and nearly identical at 3.6% in 22,160 individuals undergoing screening colonoscopy at age 50-54. The rate of clinically significant serrated polyps was 5.9% in the 45- to 49-year-olds, closely similar to the 6.1% rate in patients age 50-54.
Of note, the prevalence of advanced adenomas was just 1.1% in individuals younger than age 40 years, jumping to 3.0% among 40- to 44-year-olds, 5.1% in those age 55-59, and 6.9% at age 60 or more. Clinically significant serrated polyps followed a similar pattern, with rates of 3.0% before age 40, 5.1% in 40- to 44-year-olds, 6.6% in 55- to 59-year-olds, and 6.0% in those who were older.
In a multivariate logistic regression analysis adjusted for sex, body mass index, smoking, and other potential confounders, 45- to 49-year-olds were at a 243% increased risk of finding advanced adenomas on colonoscopy, compared with those less than 40 years old, while the 50- to 54-year-olds had a virtually identical 244% increased risk.
Dr. Butterly noted that there are now 15,000 cases of colorectal cancer occurring annually in individuals under age 50 in the United States, with 3,600 deaths.
“Prevention of colorectal cancer in young, productive individuals is an essential clinical imperative that must be addressed,” she concluded.
She reported having no financial conflicts regarding her study.
REPORTING FROM ACG 2019