User login
Fauci: Cautious optimism for COVID-19 vaccine by end of 2020
with distribution of first doses possible before the end of the year, according to Anthony S. Fauci, MD, director, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
“Given the rate of infection that’s going on in this country, and the distribution of the clinical trial sites involving tens of thousands of volunteers, we project that we will have an answer as to whether or not we have a safe and effective vaccine by November or December,” Dr. Fauci said today in his virtual keynote address during the annual meeting of the American College of Chest Physicians.
“It may come earlier -- this month, in October,” he added in his remarks. “That is unlikely – it is more likely that we’ll have an answer in November and December.”
If that timing does come to pass, Dr. Fauci said, it’s possible that distribution of doses could start at the end of the year, continuing throughout the beginning and middle of 2021.
Although there are no guarantees, Dr. Fauci said he is “cautiously optimistic” regarding the timeline.
He said that his optimism is based in part on animal studies and phase 1 data that demonstrate robust neutralizing antibody responses to a vaccine that are equivalent to, if not greater than, natural infection with the SARS-CoV-2 virus that causes COVID-19.
Rapid development gives reason for hope
Ryan C. Maves, MD, FCCP, a critical care and infectious disease specialist at Naval Medical Center San Diego, said there is reason to be hopeful that a vaccine will be available by the end of the calendar year. He cautioned, however, that this timing is based on the assumption that one of the vaccines will be proven safe and effective very soon.
“We’re lucky to have multiple phase 3 trials using multiple vaccine technologies in different platforms,” Dr. Maves said in a panel discussion following Dr. Fauci’s remarks. “I think the odds are very high that one of them will be effective.”
“I’m hoping that multiple vaccines will be effective,” Dr. Maves added. “Then we’ll be in a good position of determining which is the best of several good options, as a society and as a world.”
COVID-19 vaccine development over the past year has been remarkably fast, especially given the previous record set by the mumps vaccine, which took about four years to go from initial steps to rollout, Dr. Maves noted.
Dr. Fauci said the federal government has taken a “strategic approach” to the COVID-19 vaccine that includes direct involvement in the research and development of six different vaccine candidates, five of which are now in phase 3 trials.
As part of that strategic approach, the study protocols are harmonized to have a common data and safety monitoring board, common primary and secondary endpoints, and an independent statistical group to determine correlates of protection, Dr. Fauci said.
Prioritizing COVID-19 vaccine distribution
Who gets COVID-19 vaccine first will be a challenge for governmental organizations as well as bioethicists, who have proposed different strategies for fairly prioritizing different groups for access.
Reaching communities of color will be an important consideration for prioritization, according to Dr. Maves, given the disproportionate burden of disease on Black and Hispanic individuals, among other such populations.
COVID-19–related hospitalization rates have been substantially higher in communities of color, Dr. Fauci said in his keynote address. Age-adjusted hospitalization rates for Hispanic/Latinx and Black populations are 375 to 368 per 100,000, respectively, compared with just 82 per 100,000 for White non-Hispanics, according to data from the Centers for Disease Control and Prevention.
Outreach to those communities should include building trust in those populations that they will benefit from a safe and effective vaccine, and making sure that the vaccine is available to those communities as quickly as possible, Dr. Maves said.
Dr. Fauci and Dr. Maves provided no disclosures related to their presentations.
with distribution of first doses possible before the end of the year, according to Anthony S. Fauci, MD, director, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
“Given the rate of infection that’s going on in this country, and the distribution of the clinical trial sites involving tens of thousands of volunteers, we project that we will have an answer as to whether or not we have a safe and effective vaccine by November or December,” Dr. Fauci said today in his virtual keynote address during the annual meeting of the American College of Chest Physicians.
“It may come earlier -- this month, in October,” he added in his remarks. “That is unlikely – it is more likely that we’ll have an answer in November and December.”
If that timing does come to pass, Dr. Fauci said, it’s possible that distribution of doses could start at the end of the year, continuing throughout the beginning and middle of 2021.
Although there are no guarantees, Dr. Fauci said he is “cautiously optimistic” regarding the timeline.
He said that his optimism is based in part on animal studies and phase 1 data that demonstrate robust neutralizing antibody responses to a vaccine that are equivalent to, if not greater than, natural infection with the SARS-CoV-2 virus that causes COVID-19.
Rapid development gives reason for hope
Ryan C. Maves, MD, FCCP, a critical care and infectious disease specialist at Naval Medical Center San Diego, said there is reason to be hopeful that a vaccine will be available by the end of the calendar year. He cautioned, however, that this timing is based on the assumption that one of the vaccines will be proven safe and effective very soon.
“We’re lucky to have multiple phase 3 trials using multiple vaccine technologies in different platforms,” Dr. Maves said in a panel discussion following Dr. Fauci’s remarks. “I think the odds are very high that one of them will be effective.”
“I’m hoping that multiple vaccines will be effective,” Dr. Maves added. “Then we’ll be in a good position of determining which is the best of several good options, as a society and as a world.”
COVID-19 vaccine development over the past year has been remarkably fast, especially given the previous record set by the mumps vaccine, which took about four years to go from initial steps to rollout, Dr. Maves noted.
Dr. Fauci said the federal government has taken a “strategic approach” to the COVID-19 vaccine that includes direct involvement in the research and development of six different vaccine candidates, five of which are now in phase 3 trials.
As part of that strategic approach, the study protocols are harmonized to have a common data and safety monitoring board, common primary and secondary endpoints, and an independent statistical group to determine correlates of protection, Dr. Fauci said.
Prioritizing COVID-19 vaccine distribution
Who gets COVID-19 vaccine first will be a challenge for governmental organizations as well as bioethicists, who have proposed different strategies for fairly prioritizing different groups for access.
Reaching communities of color will be an important consideration for prioritization, according to Dr. Maves, given the disproportionate burden of disease on Black and Hispanic individuals, among other such populations.
COVID-19–related hospitalization rates have been substantially higher in communities of color, Dr. Fauci said in his keynote address. Age-adjusted hospitalization rates for Hispanic/Latinx and Black populations are 375 to 368 per 100,000, respectively, compared with just 82 per 100,000 for White non-Hispanics, according to data from the Centers for Disease Control and Prevention.
Outreach to those communities should include building trust in those populations that they will benefit from a safe and effective vaccine, and making sure that the vaccine is available to those communities as quickly as possible, Dr. Maves said.
Dr. Fauci and Dr. Maves provided no disclosures related to their presentations.
with distribution of first doses possible before the end of the year, according to Anthony S. Fauci, MD, director, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
“Given the rate of infection that’s going on in this country, and the distribution of the clinical trial sites involving tens of thousands of volunteers, we project that we will have an answer as to whether or not we have a safe and effective vaccine by November or December,” Dr. Fauci said today in his virtual keynote address during the annual meeting of the American College of Chest Physicians.
“It may come earlier -- this month, in October,” he added in his remarks. “That is unlikely – it is more likely that we’ll have an answer in November and December.”
If that timing does come to pass, Dr. Fauci said, it’s possible that distribution of doses could start at the end of the year, continuing throughout the beginning and middle of 2021.
Although there are no guarantees, Dr. Fauci said he is “cautiously optimistic” regarding the timeline.
He said that his optimism is based in part on animal studies and phase 1 data that demonstrate robust neutralizing antibody responses to a vaccine that are equivalent to, if not greater than, natural infection with the SARS-CoV-2 virus that causes COVID-19.
Rapid development gives reason for hope
Ryan C. Maves, MD, FCCP, a critical care and infectious disease specialist at Naval Medical Center San Diego, said there is reason to be hopeful that a vaccine will be available by the end of the calendar year. He cautioned, however, that this timing is based on the assumption that one of the vaccines will be proven safe and effective very soon.
“We’re lucky to have multiple phase 3 trials using multiple vaccine technologies in different platforms,” Dr. Maves said in a panel discussion following Dr. Fauci’s remarks. “I think the odds are very high that one of them will be effective.”
“I’m hoping that multiple vaccines will be effective,” Dr. Maves added. “Then we’ll be in a good position of determining which is the best of several good options, as a society and as a world.”
COVID-19 vaccine development over the past year has been remarkably fast, especially given the previous record set by the mumps vaccine, which took about four years to go from initial steps to rollout, Dr. Maves noted.
Dr. Fauci said the federal government has taken a “strategic approach” to the COVID-19 vaccine that includes direct involvement in the research and development of six different vaccine candidates, five of which are now in phase 3 trials.
As part of that strategic approach, the study protocols are harmonized to have a common data and safety monitoring board, common primary and secondary endpoints, and an independent statistical group to determine correlates of protection, Dr. Fauci said.
Prioritizing COVID-19 vaccine distribution
Who gets COVID-19 vaccine first will be a challenge for governmental organizations as well as bioethicists, who have proposed different strategies for fairly prioritizing different groups for access.
Reaching communities of color will be an important consideration for prioritization, according to Dr. Maves, given the disproportionate burden of disease on Black and Hispanic individuals, among other such populations.
COVID-19–related hospitalization rates have been substantially higher in communities of color, Dr. Fauci said in his keynote address. Age-adjusted hospitalization rates for Hispanic/Latinx and Black populations are 375 to 368 per 100,000, respectively, compared with just 82 per 100,000 for White non-Hispanics, according to data from the Centers for Disease Control and Prevention.
Outreach to those communities should include building trust in those populations that they will benefit from a safe and effective vaccine, and making sure that the vaccine is available to those communities as quickly as possible, Dr. Maves said.
Dr. Fauci and Dr. Maves provided no disclosures related to their presentations.
FROM CHEST 2020
COVID-19 outcomes no worse in patients on TNF inhibitors or methotrexate
Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.
Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.
Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.
Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.
“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.
The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.
In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”
That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.
In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.
“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.
To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.
They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.
Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).
Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.
Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.
“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.
Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.
SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.
Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.
Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.
Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.
Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.
“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.
The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.
In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”
That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.
In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.
“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.
To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.
They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.
Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).
Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.
Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.
“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.
Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.
SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.
Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.
Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.
Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.
Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.
“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.
The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.
In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”
That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.
In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.
“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.
To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.
They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.
Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).
Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.
Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.
“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.
Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.
SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
ctDNA clearance tracks with PFS in NSCLC subtype
The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).
“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.
Dr. Hartmaier presented these findings at the AACR virtual meeting II.
Prior results of TATTON
Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.
Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.
The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.
Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.
“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.
According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.
“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
ctDNA analysis
Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.
Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.
Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.
Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.
In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).
Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.
Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.
“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.
The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.
SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.
The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).
“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.
Dr. Hartmaier presented these findings at the AACR virtual meeting II.
Prior results of TATTON
Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.
Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.
The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.
Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.
“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.
According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.
“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
ctDNA analysis
Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.
Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.
Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.
Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.
In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).
Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.
Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.
“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.
The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.
SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.
The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).
“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.
Dr. Hartmaier presented these findings at the AACR virtual meeting II.
Prior results of TATTON
Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.
Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.
The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.
Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.
“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.
According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.
“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
ctDNA analysis
Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.
Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.
Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.
Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.
In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).
Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.
Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.
“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.
The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.
SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.
FROM AACR 2020
Cognitive deficits complex in youths with type 2 diabetes
Teens and young adults with diabetes have cognitive deficits that vary by diabetes type and could negatively impact their medical literacy and self-care, an investigator reported at the virtual annual scientific sessions of the American Diabetes Association.
Individuals with youth-onset type 1 or 2 diabetes all performed below average on tests that measure flexible thinking and problem solving, according to the investigator, who reported an analysis including 1,380 individuals enrolled in the SEARCH for Diabetes in Youth study.
That finding suggests that diabetes diagnosed before age 20 contributes to poor fluid cognitive function, which consists of skills that facilitate goal-directed behaviors, according to investigator Allison Shapiro, MPH, PhD, of the University of Colorado at Denver, Aurora.
However, individuals with type 2 diabetes (T2D) performed even worse than those with type 1 diabetes (T1D) on the fluid cognitive function tests, even after adjustment for demographic factors and other confounders, Dr. Shapiro said in her presentation.
Further analysis revealed that individuals with T2D performed significantly worse on measures of crystallized cognition, a domain that includes skills such as vocabulary and language. That suggests the poor fluid cognitive abilities in youths with diabetes may in fact be a result of poor crystallized cognitive development, according to the investigator.
“Among adolescents and young adults with youth-onset type 2 diabetes specifically, intervention should focus on developing both fluid cognitive skills and crystallized cognitive skills,” Dr. Shapiro said.
Deficits in fluid cognitive function (such as reasoning or processing speed) can negatively affect diabetes self-care, thereby potentially increasing the risk of diabetes-related complications, while deficits in crystallized cognitive function (such as vocabulary and understanding of language) could impact medical literacy further compounding the self-care issues.
The study is believed to be one of the first to compare cognitive function deficits in youths with type 1 or 2 diabetes. Although studies in adults clearly show a detrimental relationship between diabetes and cognitive function, according to Dr. Shapiro, the bulk of the research in youths has focused on T1D.
“While limited work has been done in youth-onset type 2 diabetes, cognitive deficits are consistently observed, compared to youth without diabetes,” she said.
Results of this study emphasize the importance of dietary changes and other lifestyle interventions in young patients with diabetes, according to David Della-Morte, MD, PhD, associate professor of neurology at the University of Miami.
“Even the youngest patients may develop cognitive dysfunction,” Dr. Della-Morte said in an interview. “That means that lifestyle is very important, especially in obese patients that are prone to develop type 2 diabetes.”
The analysis by Dr. Shapiro and coinvestigators included 1,095 youths and young adults with T1D and 285 with T2D who had undergone a cognition assessment as part of a study visit. They were aged an average of 22 years, and had an average diabetes duration of 11 years.
The overall fluid cognition score was significantly lower in those individuals with T2D, compared with those with T1D, investigators found. Compared with the national average score of 100, the T2D group scored 84.7, or a full standard deviation below that average, said Dr. Shapiro, while those with T1D scored 95.5 (P < .001).
Participants with T2D also scored significantly lower in individual measures of fluid cognition, including processing speed, inhibitory control and attention, working memory, and episodic memory, she reported. At first glance, that suggested youth-onset T2D has a specific effect on fluid cognition; however, the story remains incomplete without looking at crystallized cognition markers such as vocabulary and language.
Toward that end, a picture vocabulary test conducted as part of the cognitive assessment showed a significant difference between those with T2D, who on average scored 91.5, and those with T1D, who scored 103.6 (P < .001). Accounting for those picture vocabulary scores attenuated the differences between groups in fluid cognitive scores, suggesting that differences in crystallized cognitive function underly the observed differences in fluid cognitive function between groups, Dr. Shapiro said.
Skills such as vocabulary and language are thought to be stable and not influenced by neurologic changes brought on by disease processes such as youth-onset diabetes, but rather, influenced by factors such as childcare and education, according to Dr. Shapiro.
“Crystallized cognition therefore provides a window into an individual’s cognitive functioning, independent of their disease or premorbid to the onset of their disease,” she said.
Dr. Shapiro said she had no conflicts of interest to disclose.
SOURCE: Shapiro A et al. ADA 2020, Abstract 279-OR.
Teens and young adults with diabetes have cognitive deficits that vary by diabetes type and could negatively impact their medical literacy and self-care, an investigator reported at the virtual annual scientific sessions of the American Diabetes Association.
Individuals with youth-onset type 1 or 2 diabetes all performed below average on tests that measure flexible thinking and problem solving, according to the investigator, who reported an analysis including 1,380 individuals enrolled in the SEARCH for Diabetes in Youth study.
That finding suggests that diabetes diagnosed before age 20 contributes to poor fluid cognitive function, which consists of skills that facilitate goal-directed behaviors, according to investigator Allison Shapiro, MPH, PhD, of the University of Colorado at Denver, Aurora.
However, individuals with type 2 diabetes (T2D) performed even worse than those with type 1 diabetes (T1D) on the fluid cognitive function tests, even after adjustment for demographic factors and other confounders, Dr. Shapiro said in her presentation.
Further analysis revealed that individuals with T2D performed significantly worse on measures of crystallized cognition, a domain that includes skills such as vocabulary and language. That suggests the poor fluid cognitive abilities in youths with diabetes may in fact be a result of poor crystallized cognitive development, according to the investigator.
“Among adolescents and young adults with youth-onset type 2 diabetes specifically, intervention should focus on developing both fluid cognitive skills and crystallized cognitive skills,” Dr. Shapiro said.
Deficits in fluid cognitive function (such as reasoning or processing speed) can negatively affect diabetes self-care, thereby potentially increasing the risk of diabetes-related complications, while deficits in crystallized cognitive function (such as vocabulary and understanding of language) could impact medical literacy further compounding the self-care issues.
The study is believed to be one of the first to compare cognitive function deficits in youths with type 1 or 2 diabetes. Although studies in adults clearly show a detrimental relationship between diabetes and cognitive function, according to Dr. Shapiro, the bulk of the research in youths has focused on T1D.
“While limited work has been done in youth-onset type 2 diabetes, cognitive deficits are consistently observed, compared to youth without diabetes,” she said.
Results of this study emphasize the importance of dietary changes and other lifestyle interventions in young patients with diabetes, according to David Della-Morte, MD, PhD, associate professor of neurology at the University of Miami.
“Even the youngest patients may develop cognitive dysfunction,” Dr. Della-Morte said in an interview. “That means that lifestyle is very important, especially in obese patients that are prone to develop type 2 diabetes.”
The analysis by Dr. Shapiro and coinvestigators included 1,095 youths and young adults with T1D and 285 with T2D who had undergone a cognition assessment as part of a study visit. They were aged an average of 22 years, and had an average diabetes duration of 11 years.
The overall fluid cognition score was significantly lower in those individuals with T2D, compared with those with T1D, investigators found. Compared with the national average score of 100, the T2D group scored 84.7, or a full standard deviation below that average, said Dr. Shapiro, while those with T1D scored 95.5 (P < .001).
Participants with T2D also scored significantly lower in individual measures of fluid cognition, including processing speed, inhibitory control and attention, working memory, and episodic memory, she reported. At first glance, that suggested youth-onset T2D has a specific effect on fluid cognition; however, the story remains incomplete without looking at crystallized cognition markers such as vocabulary and language.
Toward that end, a picture vocabulary test conducted as part of the cognitive assessment showed a significant difference between those with T2D, who on average scored 91.5, and those with T1D, who scored 103.6 (P < .001). Accounting for those picture vocabulary scores attenuated the differences between groups in fluid cognitive scores, suggesting that differences in crystallized cognitive function underly the observed differences in fluid cognitive function between groups, Dr. Shapiro said.
Skills such as vocabulary and language are thought to be stable and not influenced by neurologic changes brought on by disease processes such as youth-onset diabetes, but rather, influenced by factors such as childcare and education, according to Dr. Shapiro.
“Crystallized cognition therefore provides a window into an individual’s cognitive functioning, independent of their disease or premorbid to the onset of their disease,” she said.
Dr. Shapiro said she had no conflicts of interest to disclose.
SOURCE: Shapiro A et al. ADA 2020, Abstract 279-OR.
Teens and young adults with diabetes have cognitive deficits that vary by diabetes type and could negatively impact their medical literacy and self-care, an investigator reported at the virtual annual scientific sessions of the American Diabetes Association.
Individuals with youth-onset type 1 or 2 diabetes all performed below average on tests that measure flexible thinking and problem solving, according to the investigator, who reported an analysis including 1,380 individuals enrolled in the SEARCH for Diabetes in Youth study.
That finding suggests that diabetes diagnosed before age 20 contributes to poor fluid cognitive function, which consists of skills that facilitate goal-directed behaviors, according to investigator Allison Shapiro, MPH, PhD, of the University of Colorado at Denver, Aurora.
However, individuals with type 2 diabetes (T2D) performed even worse than those with type 1 diabetes (T1D) on the fluid cognitive function tests, even after adjustment for demographic factors and other confounders, Dr. Shapiro said in her presentation.
Further analysis revealed that individuals with T2D performed significantly worse on measures of crystallized cognition, a domain that includes skills such as vocabulary and language. That suggests the poor fluid cognitive abilities in youths with diabetes may in fact be a result of poor crystallized cognitive development, according to the investigator.
“Among adolescents and young adults with youth-onset type 2 diabetes specifically, intervention should focus on developing both fluid cognitive skills and crystallized cognitive skills,” Dr. Shapiro said.
Deficits in fluid cognitive function (such as reasoning or processing speed) can negatively affect diabetes self-care, thereby potentially increasing the risk of diabetes-related complications, while deficits in crystallized cognitive function (such as vocabulary and understanding of language) could impact medical literacy further compounding the self-care issues.
The study is believed to be one of the first to compare cognitive function deficits in youths with type 1 or 2 diabetes. Although studies in adults clearly show a detrimental relationship between diabetes and cognitive function, according to Dr. Shapiro, the bulk of the research in youths has focused on T1D.
“While limited work has been done in youth-onset type 2 diabetes, cognitive deficits are consistently observed, compared to youth without diabetes,” she said.
Results of this study emphasize the importance of dietary changes and other lifestyle interventions in young patients with diabetes, according to David Della-Morte, MD, PhD, associate professor of neurology at the University of Miami.
“Even the youngest patients may develop cognitive dysfunction,” Dr. Della-Morte said in an interview. “That means that lifestyle is very important, especially in obese patients that are prone to develop type 2 diabetes.”
The analysis by Dr. Shapiro and coinvestigators included 1,095 youths and young adults with T1D and 285 with T2D who had undergone a cognition assessment as part of a study visit. They were aged an average of 22 years, and had an average diabetes duration of 11 years.
The overall fluid cognition score was significantly lower in those individuals with T2D, compared with those with T1D, investigators found. Compared with the national average score of 100, the T2D group scored 84.7, or a full standard deviation below that average, said Dr. Shapiro, while those with T1D scored 95.5 (P < .001).
Participants with T2D also scored significantly lower in individual measures of fluid cognition, including processing speed, inhibitory control and attention, working memory, and episodic memory, she reported. At first glance, that suggested youth-onset T2D has a specific effect on fluid cognition; however, the story remains incomplete without looking at crystallized cognition markers such as vocabulary and language.
Toward that end, a picture vocabulary test conducted as part of the cognitive assessment showed a significant difference between those with T2D, who on average scored 91.5, and those with T1D, who scored 103.6 (P < .001). Accounting for those picture vocabulary scores attenuated the differences between groups in fluid cognitive scores, suggesting that differences in crystallized cognitive function underly the observed differences in fluid cognitive function between groups, Dr. Shapiro said.
Skills such as vocabulary and language are thought to be stable and not influenced by neurologic changes brought on by disease processes such as youth-onset diabetes, but rather, influenced by factors such as childcare and education, according to Dr. Shapiro.
“Crystallized cognition therefore provides a window into an individual’s cognitive functioning, independent of their disease or premorbid to the onset of their disease,” she said.
Dr. Shapiro said she had no conflicts of interest to disclose.
SOURCE: Shapiro A et al. ADA 2020, Abstract 279-OR.
FROM ADA 2020
Tiragolumab plus atezolizumab active in PD-L1+ NSCLC
The combination of the anti-TIGIT antibody tiragolumab with the PD-L1 inhibitor atezolizumab was well tolerated and showed preliminary activity in the phase 1b portion of the study, according to investigator Johanna C. Bendell, MD, of Sarah Cannon Research Institute/Tennessee Oncology in Nashville, Tenn.
Objective responses occurred mainly in chemoimmunotherapy-naive, PD-L1-positive tumors. In an expansion cohort of 13 patients with PD-L1-positive non–small cell lung cancer (NSCLC), the confirmed overall response rate was 46%, with several responses demonstrating durability.
Dr. Bendell reported these results at the AACR virtual meeting II.
While several important research questions remain, the results in the lung cancer expansion cohort were encouraging, particularly in patients who were smokers and previous smokers, said invited discussant Michele Teng, PhD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia.
“Although it was [a] small cohort, the data suggest promising duration of response in some of the patients [n = 4] who have been under study for more than 700 days,” Dr. Teng said.
Based on the preliminary safety and activity seen in this study, the combination of tiragolumab and atezolizumab is being evaluated in a randomized, placebo-controlled phase 2 study, and a phase 3 study is recruiting.
Rationale, design, and safety
TIGIT is a novel inhibitory receptor expressed on multiple immune cells, especially CD8-positive T cells and natural killer cells, Dr. Bendell explained. She added that TIGIT is coexpressed with PD-1 on immune cells.
“Using anti-TIGIT antibodies to prevent TIGIT from binding, and cotargeting TIGIT and PD-L1, may restore antitumor response and enhance anti-PD-L1 effect,” Dr. Bendell said.
The phase 1 study Dr. Bendell presented, known as GO30103, was designed to evaluate tiragolumab as a single agent and in combination with atezolizumab in advanced solid tumors.
There were 24 patients in the phase 1a portion of GO30103, which was intended to determine the preliminary safety, tolerability, and recommended phase 2 dose of tiragolumab. There were 49 patients treated with tiragolumab plus atezolizumab in the phase 1b portion, which was intended to provide data on pharmacokinetics as well as preliminary antitumor activity of the combination.
No dose-limiting toxicities were seen in either cohort. The recommended phase 2 dose of tiragolumab was 600 mg every 3 weeks.
Tiragolumab was well tolerated in the phase 1a and 1b portions of the trial, according to Dr. Bendell.
“Immune-related adverse events were seen, but their incidence was not out of proportion to events seen with atezolizumab alone,” she said.
Treatment-related grade 3-4 adverse events occurred in one patient (4%) in the phase 1a portion of the trial and two patients (4%) in the phase 1b portion. There were no grade 5 adverse events related to treatment.
Efficacy and next steps
No objective responses were seen with tiragolumab monotherapy, although several patients did exhibit tumor reduction.
“We were not really expecting much single-agent activity of the anti-TIGIT drug,” Dr. Bendell said. “There’s some preclinical data that suggests that TIGIT may be more important as a single agent in earlier stages of cancer.”
In contrast, the combination of tiragolumab and atezolizumab resulted in several responses, including one in a patient with PD-L1-positive NSCLC who was previously treated with immunotherapy, according to Dr. Bendell.
The 13-patient expansion cohort of patients with PD-L1-positive NSCLC were treated at the recommended phase 2 dose of tiragolumab and atezolizumab. In these chemoimmunotherapy-naive patients, the overall response rate was 46%. Responses occurred in 6 of 13 patients and included 2 complete responses. Four patients had stable disease, so the disease control rate was 85% (11/13).
Based on that expansion cohort, a randomized, phase 2 study called CITYSCAPE was initiated. Results of CITYSCAPE were recently presented as part of the American Society of Clinical Oncology virtual scientific program.
In that study, tiragolumab plus atezolizumab improved the overall response rate and progression-free survival when compared with placebo plus atezolizumab. More substantial improvement was seen in the subgroup of patients with PD-L1 tumor proportion scores of 50% or greater.
The activity and safety of tiragolumab plus atezolizumab will be confirmed in the ongoing SKYSCRAPER-01 trial (NCT04294810), a phase 3 study of first-line treatment in patients with NSCLC and a PD-L1 tumor proportion score of 50% or greater, according to investigators.
The phase 1 study presented by Dr. Bendell was sponsored by Genentech. Dr. Bendell disclosed relationships with Genentech/Roche, Gilead, Five Prime, Lilly, and other companies.
SOURCE: Bendell JC et al. AACR 2020, Abstract CT302.
The combination of the anti-TIGIT antibody tiragolumab with the PD-L1 inhibitor atezolizumab was well tolerated and showed preliminary activity in the phase 1b portion of the study, according to investigator Johanna C. Bendell, MD, of Sarah Cannon Research Institute/Tennessee Oncology in Nashville, Tenn.
Objective responses occurred mainly in chemoimmunotherapy-naive, PD-L1-positive tumors. In an expansion cohort of 13 patients with PD-L1-positive non–small cell lung cancer (NSCLC), the confirmed overall response rate was 46%, with several responses demonstrating durability.
Dr. Bendell reported these results at the AACR virtual meeting II.
While several important research questions remain, the results in the lung cancer expansion cohort were encouraging, particularly in patients who were smokers and previous smokers, said invited discussant Michele Teng, PhD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia.
“Although it was [a] small cohort, the data suggest promising duration of response in some of the patients [n = 4] who have been under study for more than 700 days,” Dr. Teng said.
Based on the preliminary safety and activity seen in this study, the combination of tiragolumab and atezolizumab is being evaluated in a randomized, placebo-controlled phase 2 study, and a phase 3 study is recruiting.
Rationale, design, and safety
TIGIT is a novel inhibitory receptor expressed on multiple immune cells, especially CD8-positive T cells and natural killer cells, Dr. Bendell explained. She added that TIGIT is coexpressed with PD-1 on immune cells.
“Using anti-TIGIT antibodies to prevent TIGIT from binding, and cotargeting TIGIT and PD-L1, may restore antitumor response and enhance anti-PD-L1 effect,” Dr. Bendell said.
The phase 1 study Dr. Bendell presented, known as GO30103, was designed to evaluate tiragolumab as a single agent and in combination with atezolizumab in advanced solid tumors.
There were 24 patients in the phase 1a portion of GO30103, which was intended to determine the preliminary safety, tolerability, and recommended phase 2 dose of tiragolumab. There were 49 patients treated with tiragolumab plus atezolizumab in the phase 1b portion, which was intended to provide data on pharmacokinetics as well as preliminary antitumor activity of the combination.
No dose-limiting toxicities were seen in either cohort. The recommended phase 2 dose of tiragolumab was 600 mg every 3 weeks.
Tiragolumab was well tolerated in the phase 1a and 1b portions of the trial, according to Dr. Bendell.
“Immune-related adverse events were seen, but their incidence was not out of proportion to events seen with atezolizumab alone,” she said.
Treatment-related grade 3-4 adverse events occurred in one patient (4%) in the phase 1a portion of the trial and two patients (4%) in the phase 1b portion. There were no grade 5 adverse events related to treatment.
Efficacy and next steps
No objective responses were seen with tiragolumab monotherapy, although several patients did exhibit tumor reduction.
“We were not really expecting much single-agent activity of the anti-TIGIT drug,” Dr. Bendell said. “There’s some preclinical data that suggests that TIGIT may be more important as a single agent in earlier stages of cancer.”
In contrast, the combination of tiragolumab and atezolizumab resulted in several responses, including one in a patient with PD-L1-positive NSCLC who was previously treated with immunotherapy, according to Dr. Bendell.
The 13-patient expansion cohort of patients with PD-L1-positive NSCLC were treated at the recommended phase 2 dose of tiragolumab and atezolizumab. In these chemoimmunotherapy-naive patients, the overall response rate was 46%. Responses occurred in 6 of 13 patients and included 2 complete responses. Four patients had stable disease, so the disease control rate was 85% (11/13).
Based on that expansion cohort, a randomized, phase 2 study called CITYSCAPE was initiated. Results of CITYSCAPE were recently presented as part of the American Society of Clinical Oncology virtual scientific program.
In that study, tiragolumab plus atezolizumab improved the overall response rate and progression-free survival when compared with placebo plus atezolizumab. More substantial improvement was seen in the subgroup of patients with PD-L1 tumor proportion scores of 50% or greater.
The activity and safety of tiragolumab plus atezolizumab will be confirmed in the ongoing SKYSCRAPER-01 trial (NCT04294810), a phase 3 study of first-line treatment in patients with NSCLC and a PD-L1 tumor proportion score of 50% or greater, according to investigators.
The phase 1 study presented by Dr. Bendell was sponsored by Genentech. Dr. Bendell disclosed relationships with Genentech/Roche, Gilead, Five Prime, Lilly, and other companies.
SOURCE: Bendell JC et al. AACR 2020, Abstract CT302.
The combination of the anti-TIGIT antibody tiragolumab with the PD-L1 inhibitor atezolizumab was well tolerated and showed preliminary activity in the phase 1b portion of the study, according to investigator Johanna C. Bendell, MD, of Sarah Cannon Research Institute/Tennessee Oncology in Nashville, Tenn.
Objective responses occurred mainly in chemoimmunotherapy-naive, PD-L1-positive tumors. In an expansion cohort of 13 patients with PD-L1-positive non–small cell lung cancer (NSCLC), the confirmed overall response rate was 46%, with several responses demonstrating durability.
Dr. Bendell reported these results at the AACR virtual meeting II.
While several important research questions remain, the results in the lung cancer expansion cohort were encouraging, particularly in patients who were smokers and previous smokers, said invited discussant Michele Teng, PhD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia.
“Although it was [a] small cohort, the data suggest promising duration of response in some of the patients [n = 4] who have been under study for more than 700 days,” Dr. Teng said.
Based on the preliminary safety and activity seen in this study, the combination of tiragolumab and atezolizumab is being evaluated in a randomized, placebo-controlled phase 2 study, and a phase 3 study is recruiting.
Rationale, design, and safety
TIGIT is a novel inhibitory receptor expressed on multiple immune cells, especially CD8-positive T cells and natural killer cells, Dr. Bendell explained. She added that TIGIT is coexpressed with PD-1 on immune cells.
“Using anti-TIGIT antibodies to prevent TIGIT from binding, and cotargeting TIGIT and PD-L1, may restore antitumor response and enhance anti-PD-L1 effect,” Dr. Bendell said.
The phase 1 study Dr. Bendell presented, known as GO30103, was designed to evaluate tiragolumab as a single agent and in combination with atezolizumab in advanced solid tumors.
There were 24 patients in the phase 1a portion of GO30103, which was intended to determine the preliminary safety, tolerability, and recommended phase 2 dose of tiragolumab. There were 49 patients treated with tiragolumab plus atezolizumab in the phase 1b portion, which was intended to provide data on pharmacokinetics as well as preliminary antitumor activity of the combination.
No dose-limiting toxicities were seen in either cohort. The recommended phase 2 dose of tiragolumab was 600 mg every 3 weeks.
Tiragolumab was well tolerated in the phase 1a and 1b portions of the trial, according to Dr. Bendell.
“Immune-related adverse events were seen, but their incidence was not out of proportion to events seen with atezolizumab alone,” she said.
Treatment-related grade 3-4 adverse events occurred in one patient (4%) in the phase 1a portion of the trial and two patients (4%) in the phase 1b portion. There were no grade 5 adverse events related to treatment.
Efficacy and next steps
No objective responses were seen with tiragolumab monotherapy, although several patients did exhibit tumor reduction.
“We were not really expecting much single-agent activity of the anti-TIGIT drug,” Dr. Bendell said. “There’s some preclinical data that suggests that TIGIT may be more important as a single agent in earlier stages of cancer.”
In contrast, the combination of tiragolumab and atezolizumab resulted in several responses, including one in a patient with PD-L1-positive NSCLC who was previously treated with immunotherapy, according to Dr. Bendell.
The 13-patient expansion cohort of patients with PD-L1-positive NSCLC were treated at the recommended phase 2 dose of tiragolumab and atezolizumab. In these chemoimmunotherapy-naive patients, the overall response rate was 46%. Responses occurred in 6 of 13 patients and included 2 complete responses. Four patients had stable disease, so the disease control rate was 85% (11/13).
Based on that expansion cohort, a randomized, phase 2 study called CITYSCAPE was initiated. Results of CITYSCAPE were recently presented as part of the American Society of Clinical Oncology virtual scientific program.
In that study, tiragolumab plus atezolizumab improved the overall response rate and progression-free survival when compared with placebo plus atezolizumab. More substantial improvement was seen in the subgroup of patients with PD-L1 tumor proportion scores of 50% or greater.
The activity and safety of tiragolumab plus atezolizumab will be confirmed in the ongoing SKYSCRAPER-01 trial (NCT04294810), a phase 3 study of first-line treatment in patients with NSCLC and a PD-L1 tumor proportion score of 50% or greater, according to investigators.
The phase 1 study presented by Dr. Bendell was sponsored by Genentech. Dr. Bendell disclosed relationships with Genentech/Roche, Gilead, Five Prime, Lilly, and other companies.
SOURCE: Bendell JC et al. AACR 2020, Abstract CT302.
FROM AACR 2020
Lipid-lowering drugs appear to decrease risk of colorectal cancer death across subgroups
Use of lipid-lowering medication was linked to a 56% lower risk of colorectal cancer death among individuals with no cancer at baseline who were enrolled in the Atherosclerosis Risk in Communities (ARIC) study. The reduction in mortality risk was evident regardless of sex, race, age, or how long patients had been on lipid-lowering drugs.
Michael T. Marrone, PhD, of Johns Hopkins University, Baltimore, and colleagues detailed these findings in a poster presented at the AACR virtual meeting II.
“Definitely for those individuals at average risk for colorectal cancer, if their primary care doctor recommends a lipid-lowering medication for cardiovascular disease prevention, they should follow their doctor’s advice,” Dr. Marrone said in an interview.
“We really can’t say that they should take this specifically for colon cancer prevention, but they should just follow the recommendation for cardiovascular disease prevention,” he added.
While previous studies have linked lipid-lowering drugs, and statins in particular, to a modestly reduced risk of developing colorectal cancer, the impact on risk by factors such as sex, race, and duration of use have not been well characterized, according to Dr. Marrone.
Another motivation for this study was to determine, in participants free of cancer at baseline, the risk of actually dying from this cancer. “That endpoint has not been well studied in the literature at all,” Dr. Marrone said.
To address those gaps, Dr. Marrone and colleagues analyzed data on 14,428 patients from the ARIC study who were cancer free at study visits between 1990 and 1992. Follow-up continued through the end of 2015 or until death, whichever came first.
A total of 384 incident colorectal cancer cases and 144 deaths were seen over 290,249 person-years at risk. The patients’ mean age was 57 years, 54.9% were women, and 27.9% were black. At scheduled follow-up visits from 1996 to 1998, 22% of patients were taking lipid-lowering drugs, mostly statins.
Compared with patients who never used lipid-lowering medications, patients who had ever used a lipid-lowering drug had a lower risk of colorectal cancer incidence (hazard ratio, 0.72). The incidence of colorectal cancer was lower among all lipid-lowering drug users, including men (HR, 0.69), women (HR, 0.76), black patients (HR, 0.60), and white patients (HR, 0.77).
Similarly, colorectal cancer–related death was lower among patients who had ever used a lipid-lowering drug (HR, 0.44). That association was apparent in men (HR, 0.58), women (HR, 0.33), black patients (HR, 0.63), and white patients (HR, 0.40).
In addition, the mortality risk was lower among lipid-lowering drug users regardless of duration of use or age at first use. The HR was 0.50 for patients taking lipid-lowering drugs for less than 15 years and 0.44 for patients taking the drugs for 15 years or more. HRs by age were 0.69 for patients aged 50-59 years, 0.45 for patients aged 60-69 years, and 0.57 for patients aged 70 and older.
While results of this particular study do help “move the needle forward” in terms of characterizing the relationship between lipid-lowering drugs and colorectal cancer risk, further studies are needed to better characterize the effects of long-term statin use, said Jennifer M. Weiss, MD, of the University of Wisconsin–Madison.
Clinical studies of the impact of statins on colorectal neoplasias have produced inconsistent results, Dr. Weiss and coauthor Bryson W. Katona, MD, PhD, wrote in a review article on chemoprevention in colorectal cancer.
“I definitely think there have been some studies that showed a modestly reduced risk,” Dr. Weiss said in an interview. “Unfortunately, there are also are some studies that show an increased risk of adenomas, and then there’s some studies that show no significant change. So we just can’t unequivocally confirm that there’s a significant association between statin use and decreased risk of developing colorectal cancer or adenomas.”
This research was funded by grants from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Program of Cancer Registries; and the American Association for Cancer Research. Dr. Marrone disclosed no conflicts of interest. Dr. Weiss was an investigator for the CPP FAP-310 trial (NCT01483144) and received no salary support for her participation in the trial.
SOURCE: Marrone MT et al. AACR 2020, Abstract 2357.
Use of lipid-lowering medication was linked to a 56% lower risk of colorectal cancer death among individuals with no cancer at baseline who were enrolled in the Atherosclerosis Risk in Communities (ARIC) study. The reduction in mortality risk was evident regardless of sex, race, age, or how long patients had been on lipid-lowering drugs.
Michael T. Marrone, PhD, of Johns Hopkins University, Baltimore, and colleagues detailed these findings in a poster presented at the AACR virtual meeting II.
“Definitely for those individuals at average risk for colorectal cancer, if their primary care doctor recommends a lipid-lowering medication for cardiovascular disease prevention, they should follow their doctor’s advice,” Dr. Marrone said in an interview.
“We really can’t say that they should take this specifically for colon cancer prevention, but they should just follow the recommendation for cardiovascular disease prevention,” he added.
While previous studies have linked lipid-lowering drugs, and statins in particular, to a modestly reduced risk of developing colorectal cancer, the impact on risk by factors such as sex, race, and duration of use have not been well characterized, according to Dr. Marrone.
Another motivation for this study was to determine, in participants free of cancer at baseline, the risk of actually dying from this cancer. “That endpoint has not been well studied in the literature at all,” Dr. Marrone said.
To address those gaps, Dr. Marrone and colleagues analyzed data on 14,428 patients from the ARIC study who were cancer free at study visits between 1990 and 1992. Follow-up continued through the end of 2015 or until death, whichever came first.
A total of 384 incident colorectal cancer cases and 144 deaths were seen over 290,249 person-years at risk. The patients’ mean age was 57 years, 54.9% were women, and 27.9% were black. At scheduled follow-up visits from 1996 to 1998, 22% of patients were taking lipid-lowering drugs, mostly statins.
Compared with patients who never used lipid-lowering medications, patients who had ever used a lipid-lowering drug had a lower risk of colorectal cancer incidence (hazard ratio, 0.72). The incidence of colorectal cancer was lower among all lipid-lowering drug users, including men (HR, 0.69), women (HR, 0.76), black patients (HR, 0.60), and white patients (HR, 0.77).
Similarly, colorectal cancer–related death was lower among patients who had ever used a lipid-lowering drug (HR, 0.44). That association was apparent in men (HR, 0.58), women (HR, 0.33), black patients (HR, 0.63), and white patients (HR, 0.40).
In addition, the mortality risk was lower among lipid-lowering drug users regardless of duration of use or age at first use. The HR was 0.50 for patients taking lipid-lowering drugs for less than 15 years and 0.44 for patients taking the drugs for 15 years or more. HRs by age were 0.69 for patients aged 50-59 years, 0.45 for patients aged 60-69 years, and 0.57 for patients aged 70 and older.
While results of this particular study do help “move the needle forward” in terms of characterizing the relationship between lipid-lowering drugs and colorectal cancer risk, further studies are needed to better characterize the effects of long-term statin use, said Jennifer M. Weiss, MD, of the University of Wisconsin–Madison.
Clinical studies of the impact of statins on colorectal neoplasias have produced inconsistent results, Dr. Weiss and coauthor Bryson W. Katona, MD, PhD, wrote in a review article on chemoprevention in colorectal cancer.
“I definitely think there have been some studies that showed a modestly reduced risk,” Dr. Weiss said in an interview. “Unfortunately, there are also are some studies that show an increased risk of adenomas, and then there’s some studies that show no significant change. So we just can’t unequivocally confirm that there’s a significant association between statin use and decreased risk of developing colorectal cancer or adenomas.”
This research was funded by grants from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Program of Cancer Registries; and the American Association for Cancer Research. Dr. Marrone disclosed no conflicts of interest. Dr. Weiss was an investigator for the CPP FAP-310 trial (NCT01483144) and received no salary support for her participation in the trial.
SOURCE: Marrone MT et al. AACR 2020, Abstract 2357.
Use of lipid-lowering medication was linked to a 56% lower risk of colorectal cancer death among individuals with no cancer at baseline who were enrolled in the Atherosclerosis Risk in Communities (ARIC) study. The reduction in mortality risk was evident regardless of sex, race, age, or how long patients had been on lipid-lowering drugs.
Michael T. Marrone, PhD, of Johns Hopkins University, Baltimore, and colleagues detailed these findings in a poster presented at the AACR virtual meeting II.
“Definitely for those individuals at average risk for colorectal cancer, if their primary care doctor recommends a lipid-lowering medication for cardiovascular disease prevention, they should follow their doctor’s advice,” Dr. Marrone said in an interview.
“We really can’t say that they should take this specifically for colon cancer prevention, but they should just follow the recommendation for cardiovascular disease prevention,” he added.
While previous studies have linked lipid-lowering drugs, and statins in particular, to a modestly reduced risk of developing colorectal cancer, the impact on risk by factors such as sex, race, and duration of use have not been well characterized, according to Dr. Marrone.
Another motivation for this study was to determine, in participants free of cancer at baseline, the risk of actually dying from this cancer. “That endpoint has not been well studied in the literature at all,” Dr. Marrone said.
To address those gaps, Dr. Marrone and colleagues analyzed data on 14,428 patients from the ARIC study who were cancer free at study visits between 1990 and 1992. Follow-up continued through the end of 2015 or until death, whichever came first.
A total of 384 incident colorectal cancer cases and 144 deaths were seen over 290,249 person-years at risk. The patients’ mean age was 57 years, 54.9% were women, and 27.9% were black. At scheduled follow-up visits from 1996 to 1998, 22% of patients were taking lipid-lowering drugs, mostly statins.
Compared with patients who never used lipid-lowering medications, patients who had ever used a lipid-lowering drug had a lower risk of colorectal cancer incidence (hazard ratio, 0.72). The incidence of colorectal cancer was lower among all lipid-lowering drug users, including men (HR, 0.69), women (HR, 0.76), black patients (HR, 0.60), and white patients (HR, 0.77).
Similarly, colorectal cancer–related death was lower among patients who had ever used a lipid-lowering drug (HR, 0.44). That association was apparent in men (HR, 0.58), women (HR, 0.33), black patients (HR, 0.63), and white patients (HR, 0.40).
In addition, the mortality risk was lower among lipid-lowering drug users regardless of duration of use or age at first use. The HR was 0.50 for patients taking lipid-lowering drugs for less than 15 years and 0.44 for patients taking the drugs for 15 years or more. HRs by age were 0.69 for patients aged 50-59 years, 0.45 for patients aged 60-69 years, and 0.57 for patients aged 70 and older.
While results of this particular study do help “move the needle forward” in terms of characterizing the relationship between lipid-lowering drugs and colorectal cancer risk, further studies are needed to better characterize the effects of long-term statin use, said Jennifer M. Weiss, MD, of the University of Wisconsin–Madison.
Clinical studies of the impact of statins on colorectal neoplasias have produced inconsistent results, Dr. Weiss and coauthor Bryson W. Katona, MD, PhD, wrote in a review article on chemoprevention in colorectal cancer.
“I definitely think there have been some studies that showed a modestly reduced risk,” Dr. Weiss said in an interview. “Unfortunately, there are also are some studies that show an increased risk of adenomas, and then there’s some studies that show no significant change. So we just can’t unequivocally confirm that there’s a significant association between statin use and decreased risk of developing colorectal cancer or adenomas.”
This research was funded by grants from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Program of Cancer Registries; and the American Association for Cancer Research. Dr. Marrone disclosed no conflicts of interest. Dr. Weiss was an investigator for the CPP FAP-310 trial (NCT01483144) and received no salary support for her participation in the trial.
SOURCE: Marrone MT et al. AACR 2020, Abstract 2357.
FROM AACR 2020
Personalized cancer vaccine may enhance checkpoint inhibitor activity
Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.
Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.
Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.
“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”
Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.
Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.
“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.
RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
Study details
Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.
Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.
Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.
Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.
T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.
There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.
The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
Implications and next steps
This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.
That said, the implications for clinical practice remain unclear, according to Dr. Mardis.
“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”
The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez
Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).
The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.
SOURCE: Lopez J et al. AACR 2020, Abstract CT301.
Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.
Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.
Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.
“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”
Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.
Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.
“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.
RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
Study details
Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.
Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.
Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.
Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.
T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.
There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.
The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
Implications and next steps
This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.
That said, the implications for clinical practice remain unclear, according to Dr. Mardis.
“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”
The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez
Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).
The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.
SOURCE: Lopez J et al. AACR 2020, Abstract CT301.
Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.
Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.
Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.
“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”
Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.
Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.
“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.
RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
Study details
Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.
Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.
Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.
Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.
T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.
There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.
The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
Implications and next steps
This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.
That said, the implications for clinical practice remain unclear, according to Dr. Mardis.
“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”
The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez
Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).
The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.
SOURCE: Lopez J et al. AACR 2020, Abstract CT301.
FROM AACR 2020
Diabetes-related amputations on the rise in older adults
The recent resurgence in diabetes-related lower-extremity amputations in the United States is not limited to younger adults, according to the author of a recent study that documents similar increases among an older population of Medicare beneficiaries.
While the rate of amputations fell among these older adults from 2000 to 2009, it increased significantly from 2009 to 2017, albeit at a “less severe rate” than recently reported in younger populations, said study investigator Jessica Harding, PhD.
The rate of nontraumatic lower extremity amputation (NLEA) was ticking upward by more than 1% per year over the 2009-2017 period, according to Dr. Harding, assistant professor in the department of surgery at Emory University, Atlanta.
This latest report follows one from last year, published in Diabetes Care, that documented an annual percentage increase approaching 6% between 2009 and 2015, driven by larger increases among adults 18-64 years of age, as well as an increase among men.
It’s not clear why rates of NLEA would be on the rise among younger and older adults in the United States, Dr. Harding said, though factors she said could be implicated include changes in amputation practice, increased comorbidities, higher insulin costs, or shortcomings in early prevention programs.
“We need large-scale studies with granular data to tease out key risk factors that could help identify the drivers of these increases in amputations,” Dr. Harding said in a presentation at the virtual annual scientific sessions of the American Diabetes Association.
“In the interim, increased attention to preventive foot care across the age spectrum could benefit adults with diabetes,” she added.
Devastating complication in older adults
The latest findings from Dr. Harding and coauthors emphasize the importance of a “team approach” to early prevention in older adults with diabetes, said Derek LeRoith, MD, PhD, director of research in the division of endocrinology, diabetes, and bone diseases with Icahn School of Medicine at Mount Sinai, New York.
“If you take a 75-year-old or even an 80-year-old, their life expectancy can still be a good 10 years or more,” Dr. LeRoith said in an interview. “We shouldn’t give up on them – we should be treating them to prevent complications.”
Lower-extremity amputation is a “particularly devastating” complication that can compromise mobility, ability to exercise, and motivation, according to Dr. LeRoith, lead author of a recent Endocrine Society clinical practice guideline that urges referral of older adults with diabetes to a podiatrist, orthopedist, or vascular specialist for preventive care.
“Quite often, treating their glucose or high blood pressure will be much more difficult because of these changes,” he said.
Lower extremity amputation trends upward
Rates of NLEA declined for years, only to rebound by 50%, according to authors of a recent analysis of Nationwide Inpatient Sample (NIS) data reported last year. In their report, the age-standardized diabetes-related NLEA rate per 1,000 adults with diabetes went from 5.30 in 2000, down to 3.07 in 2009/2010, and back up to 4.62 by 2015 (Diabetes Care. 2019 Jan;42:50-4).
The resurgence was fueled mainly by an increased rate of amputations in younger and middle-aged adults and men, and through increases in minor amputations, notably the toe, according to the investigators. “These changes in trend are concerning because of the disabling and costly consequences of NLEAs as well as what they may mean for the direction of efforts to reduce diabetes-related complications,” authors of that report said at the time.
In the current study, Dr. Harding and colleagues included Medicare Parts A and B claims data for beneficiaries enrolled from 2000 to 2017. There were 4.6 million Medicare fee-for-service beneficiaries with diabetes in 2000, increasing to 6.9 million in 2017, she reported at the virtual ADA meeting.
Rates of NLEA followed a trajectory similar to what was seen in the earlier NIS report, falling from 8.5 per 1,000 persons in 2000 to 4.4 in 2009, for an annual percentage change of –7.9 (P < .001), Dr. Harding said. Then rates ticked upward again, to 4.8 in 2017, for an annual percentage change of 1.2 over that later period (P < .001).
While the trend was similar for most subgroups analyzed, the absolute rates were highest among men and black individuals in this older patient population, reported Dr. Harding and coauthors.
Dr. Harding said she and coauthors had no disclosures related to the research, which was performed as a collaboration between Emory University and the Centers for Disease Control and Prevention Division of Diabetes Translation.
SOURCE: Harding J. ADA 2020, Abstract 106-OR.
The recent resurgence in diabetes-related lower-extremity amputations in the United States is not limited to younger adults, according to the author of a recent study that documents similar increases among an older population of Medicare beneficiaries.
While the rate of amputations fell among these older adults from 2000 to 2009, it increased significantly from 2009 to 2017, albeit at a “less severe rate” than recently reported in younger populations, said study investigator Jessica Harding, PhD.
The rate of nontraumatic lower extremity amputation (NLEA) was ticking upward by more than 1% per year over the 2009-2017 period, according to Dr. Harding, assistant professor in the department of surgery at Emory University, Atlanta.
This latest report follows one from last year, published in Diabetes Care, that documented an annual percentage increase approaching 6% between 2009 and 2015, driven by larger increases among adults 18-64 years of age, as well as an increase among men.
It’s not clear why rates of NLEA would be on the rise among younger and older adults in the United States, Dr. Harding said, though factors she said could be implicated include changes in amputation practice, increased comorbidities, higher insulin costs, or shortcomings in early prevention programs.
“We need large-scale studies with granular data to tease out key risk factors that could help identify the drivers of these increases in amputations,” Dr. Harding said in a presentation at the virtual annual scientific sessions of the American Diabetes Association.
“In the interim, increased attention to preventive foot care across the age spectrum could benefit adults with diabetes,” she added.
Devastating complication in older adults
The latest findings from Dr. Harding and coauthors emphasize the importance of a “team approach” to early prevention in older adults with diabetes, said Derek LeRoith, MD, PhD, director of research in the division of endocrinology, diabetes, and bone diseases with Icahn School of Medicine at Mount Sinai, New York.
“If you take a 75-year-old or even an 80-year-old, their life expectancy can still be a good 10 years or more,” Dr. LeRoith said in an interview. “We shouldn’t give up on them – we should be treating them to prevent complications.”
Lower-extremity amputation is a “particularly devastating” complication that can compromise mobility, ability to exercise, and motivation, according to Dr. LeRoith, lead author of a recent Endocrine Society clinical practice guideline that urges referral of older adults with diabetes to a podiatrist, orthopedist, or vascular specialist for preventive care.
“Quite often, treating their glucose or high blood pressure will be much more difficult because of these changes,” he said.
Lower extremity amputation trends upward
Rates of NLEA declined for years, only to rebound by 50%, according to authors of a recent analysis of Nationwide Inpatient Sample (NIS) data reported last year. In their report, the age-standardized diabetes-related NLEA rate per 1,000 adults with diabetes went from 5.30 in 2000, down to 3.07 in 2009/2010, and back up to 4.62 by 2015 (Diabetes Care. 2019 Jan;42:50-4).
The resurgence was fueled mainly by an increased rate of amputations in younger and middle-aged adults and men, and through increases in minor amputations, notably the toe, according to the investigators. “These changes in trend are concerning because of the disabling and costly consequences of NLEAs as well as what they may mean for the direction of efforts to reduce diabetes-related complications,” authors of that report said at the time.
In the current study, Dr. Harding and colleagues included Medicare Parts A and B claims data for beneficiaries enrolled from 2000 to 2017. There were 4.6 million Medicare fee-for-service beneficiaries with diabetes in 2000, increasing to 6.9 million in 2017, she reported at the virtual ADA meeting.
Rates of NLEA followed a trajectory similar to what was seen in the earlier NIS report, falling from 8.5 per 1,000 persons in 2000 to 4.4 in 2009, for an annual percentage change of –7.9 (P < .001), Dr. Harding said. Then rates ticked upward again, to 4.8 in 2017, for an annual percentage change of 1.2 over that later period (P < .001).
While the trend was similar for most subgroups analyzed, the absolute rates were highest among men and black individuals in this older patient population, reported Dr. Harding and coauthors.
Dr. Harding said she and coauthors had no disclosures related to the research, which was performed as a collaboration between Emory University and the Centers for Disease Control and Prevention Division of Diabetes Translation.
SOURCE: Harding J. ADA 2020, Abstract 106-OR.
The recent resurgence in diabetes-related lower-extremity amputations in the United States is not limited to younger adults, according to the author of a recent study that documents similar increases among an older population of Medicare beneficiaries.
While the rate of amputations fell among these older adults from 2000 to 2009, it increased significantly from 2009 to 2017, albeit at a “less severe rate” than recently reported in younger populations, said study investigator Jessica Harding, PhD.
The rate of nontraumatic lower extremity amputation (NLEA) was ticking upward by more than 1% per year over the 2009-2017 period, according to Dr. Harding, assistant professor in the department of surgery at Emory University, Atlanta.
This latest report follows one from last year, published in Diabetes Care, that documented an annual percentage increase approaching 6% between 2009 and 2015, driven by larger increases among adults 18-64 years of age, as well as an increase among men.
It’s not clear why rates of NLEA would be on the rise among younger and older adults in the United States, Dr. Harding said, though factors she said could be implicated include changes in amputation practice, increased comorbidities, higher insulin costs, or shortcomings in early prevention programs.
“We need large-scale studies with granular data to tease out key risk factors that could help identify the drivers of these increases in amputations,” Dr. Harding said in a presentation at the virtual annual scientific sessions of the American Diabetes Association.
“In the interim, increased attention to preventive foot care across the age spectrum could benefit adults with diabetes,” she added.
Devastating complication in older adults
The latest findings from Dr. Harding and coauthors emphasize the importance of a “team approach” to early prevention in older adults with diabetes, said Derek LeRoith, MD, PhD, director of research in the division of endocrinology, diabetes, and bone diseases with Icahn School of Medicine at Mount Sinai, New York.
“If you take a 75-year-old or even an 80-year-old, their life expectancy can still be a good 10 years or more,” Dr. LeRoith said in an interview. “We shouldn’t give up on them – we should be treating them to prevent complications.”
Lower-extremity amputation is a “particularly devastating” complication that can compromise mobility, ability to exercise, and motivation, according to Dr. LeRoith, lead author of a recent Endocrine Society clinical practice guideline that urges referral of older adults with diabetes to a podiatrist, orthopedist, or vascular specialist for preventive care.
“Quite often, treating their glucose or high blood pressure will be much more difficult because of these changes,” he said.
Lower extremity amputation trends upward
Rates of NLEA declined for years, only to rebound by 50%, according to authors of a recent analysis of Nationwide Inpatient Sample (NIS) data reported last year. In their report, the age-standardized diabetes-related NLEA rate per 1,000 adults with diabetes went from 5.30 in 2000, down to 3.07 in 2009/2010, and back up to 4.62 by 2015 (Diabetes Care. 2019 Jan;42:50-4).
The resurgence was fueled mainly by an increased rate of amputations in younger and middle-aged adults and men, and through increases in minor amputations, notably the toe, according to the investigators. “These changes in trend are concerning because of the disabling and costly consequences of NLEAs as well as what they may mean for the direction of efforts to reduce diabetes-related complications,” authors of that report said at the time.
In the current study, Dr. Harding and colleagues included Medicare Parts A and B claims data for beneficiaries enrolled from 2000 to 2017. There were 4.6 million Medicare fee-for-service beneficiaries with diabetes in 2000, increasing to 6.9 million in 2017, she reported at the virtual ADA meeting.
Rates of NLEA followed a trajectory similar to what was seen in the earlier NIS report, falling from 8.5 per 1,000 persons in 2000 to 4.4 in 2009, for an annual percentage change of –7.9 (P < .001), Dr. Harding said. Then rates ticked upward again, to 4.8 in 2017, for an annual percentage change of 1.2 over that later period (P < .001).
While the trend was similar for most subgroups analyzed, the absolute rates were highest among men and black individuals in this older patient population, reported Dr. Harding and coauthors.
Dr. Harding said she and coauthors had no disclosures related to the research, which was performed as a collaboration between Emory University and the Centers for Disease Control and Prevention Division of Diabetes Translation.
SOURCE: Harding J. ADA 2020, Abstract 106-OR.
FROM ADA 2020
Normal-weight prediabetes patients also benefit from lifestyle intervention
Adults with prediabetes of normal weight may derive at least as much benefit from lifestyle health coaching programs as adults who are overweight or obese, results of a recent nonrandomized, real-world study show.
Fasting plasma glucose (FPG) normalized in about 63% of prediabetic adults with normal body mass index (BMI) participating in a personalized coaching program that emphasized exercise, nutrition, and weight management, according to researcher Mandy Salmon, MS.
By contrast, FPG normalized in about 52% of overweight and 44% of obese prediabetic individuals participating in the program, according to Ms. Salmon, a medical student at the University of Pennsylvania, Philadelphia.
The normal-weight individuals didn’t lose any weight after participating in the coaching program, but they did significantly increase exercise, as did their overweight and obese counterparts, Ms. Salmon said in a presentation of her findings at virtual annual scientific sessions of the American Diabetes Association.
That means not only that normal-weight individuals shouldn’t be excluded from coaching interventions for diabetes prevention, but also that the success of such programs shouldn’t be judged solely on the magnitude of weight loss, according to the researcher.
“It is interesting to note that, although the normal weight group lost the least amount of weight, they still benefited from the lifestyle health coaching program, but having a resultant greatest decrease in fasting plasma glucose and normalization to a range of someone without prediabetes,” Ms. Salmon said.
The fact that most of those patients experienced normalization of FPG despite no weight loss emphasizes the importance of physical activity as a lifestyle intervention, according to Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, who was not involved in the study.
“You hear these axioms that say things like, ‘you can never outexercise a bad diet,’ and that’s probably true. But all the studies will tell us that a fit, overweight diabetic has much lower risk of cardiovascular disease than an unfit overweight diabetic,” Dr. Schutta said in an interview.
Benefits in normal-weight individuals
One in three Americans has prediabetes, and of those individuals, one in five have a normal BMI, Ms. Salmon said in her virtual ADA presentation.
It’s thought that diabetes may develop in those normal-weight individuals through different pathological mechanisms than in overweight or obese individuals. In turn, that could mean that standard methods for staving off diabetes prevention may not be as effective for them, she said.
Those mechanisms are not well understood; even so, normal BMI is currently an exclusion criterion for many diabetes prevention programs, she added, including the Center for Disease Control and Prevention’s National Diabetes Prevention Program, which specifically requires that individuals have an elevated BMI to be eligible for referral.
To evaluate the potential benefits of coaching in normal-weight individuals, the investigators studied a cohort of 1,897 adults with prediabetes, defined as a baseline FPG of 100-125 mg/dL, who were participating in a lifestyle health coaching program. Of those participants, 188, or about 10% had a normal BMI of 18.5-24.9 mg/m2. Another 495 participants were overweight, with BMIs between 25 and 29.9, while 1,214 were obese, with a BMI of at least 30.
The intervention included an initial assessment to generate goals and a personalized action plan based on the individual’s risk factors, according to Ms. Salmon, along with an action plan that included one-on-one, behaviorally oriented, technology-enabled lifestyle health coaching focused on exercise and physical activity, weight management, and nutrition.
Key findings
With a mean follow-up of 145 days, weight loss in the obese group was greater than that of the overweight group, with mean BMI changes of –1.3 and –0.6, respectively, while there was no significant change in weight for the normal-weight individuals, according to Ms. Salmon.
By contrast, weekly aerobic activity increased significantly in all three groups, she added, with average increases of 95 minutes in the obese group, 98 minutes in the overweight group, and 77 minutes in the normal-weight group.
Likewise, significant decreases in FPG were seen in all 3 groups, with average changes of –6 mg/dL for the obese participants, –7 mg/dL for overweight participants, and –9 mg/dL for normal-weight participants, Ms. Salmon said.
The proportion of individuals whose FPG normalized was highest in the normal-weight group, at 62%, compared with 51.7% for overweight and 44% for obese individuals, she added.
Most previous studies of lifestyle interventions for prediabetes have excluded normal-weight individuals, according to Ms. Salmon, who said one strength of her study was that the subjects were already participating in the established lifestyle health coaching program and didn’t interact with the team of researchers.
“It was an effectiveness study in which we could see the real-world benefits of the program, rather than a theoretical efficacy study,” she said.
Ms. Salmon said she had no potential conflicts of interest to disclose. The coinvestigators of the study were members or employees of a privately held population health management company called INTERVENT International.
SOURCE: Salmon MK et al. ADA 2020, Abstract 273-OR.
Adults with prediabetes of normal weight may derive at least as much benefit from lifestyle health coaching programs as adults who are overweight or obese, results of a recent nonrandomized, real-world study show.
Fasting plasma glucose (FPG) normalized in about 63% of prediabetic adults with normal body mass index (BMI) participating in a personalized coaching program that emphasized exercise, nutrition, and weight management, according to researcher Mandy Salmon, MS.
By contrast, FPG normalized in about 52% of overweight and 44% of obese prediabetic individuals participating in the program, according to Ms. Salmon, a medical student at the University of Pennsylvania, Philadelphia.
The normal-weight individuals didn’t lose any weight after participating in the coaching program, but they did significantly increase exercise, as did their overweight and obese counterparts, Ms. Salmon said in a presentation of her findings at virtual annual scientific sessions of the American Diabetes Association.
That means not only that normal-weight individuals shouldn’t be excluded from coaching interventions for diabetes prevention, but also that the success of such programs shouldn’t be judged solely on the magnitude of weight loss, according to the researcher.
“It is interesting to note that, although the normal weight group lost the least amount of weight, they still benefited from the lifestyle health coaching program, but having a resultant greatest decrease in fasting plasma glucose and normalization to a range of someone without prediabetes,” Ms. Salmon said.
The fact that most of those patients experienced normalization of FPG despite no weight loss emphasizes the importance of physical activity as a lifestyle intervention, according to Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, who was not involved in the study.
“You hear these axioms that say things like, ‘you can never outexercise a bad diet,’ and that’s probably true. But all the studies will tell us that a fit, overweight diabetic has much lower risk of cardiovascular disease than an unfit overweight diabetic,” Dr. Schutta said in an interview.
Benefits in normal-weight individuals
One in three Americans has prediabetes, and of those individuals, one in five have a normal BMI, Ms. Salmon said in her virtual ADA presentation.
It’s thought that diabetes may develop in those normal-weight individuals through different pathological mechanisms than in overweight or obese individuals. In turn, that could mean that standard methods for staving off diabetes prevention may not be as effective for them, she said.
Those mechanisms are not well understood; even so, normal BMI is currently an exclusion criterion for many diabetes prevention programs, she added, including the Center for Disease Control and Prevention’s National Diabetes Prevention Program, which specifically requires that individuals have an elevated BMI to be eligible for referral.
To evaluate the potential benefits of coaching in normal-weight individuals, the investigators studied a cohort of 1,897 adults with prediabetes, defined as a baseline FPG of 100-125 mg/dL, who were participating in a lifestyle health coaching program. Of those participants, 188, or about 10% had a normal BMI of 18.5-24.9 mg/m2. Another 495 participants were overweight, with BMIs between 25 and 29.9, while 1,214 were obese, with a BMI of at least 30.
The intervention included an initial assessment to generate goals and a personalized action plan based on the individual’s risk factors, according to Ms. Salmon, along with an action plan that included one-on-one, behaviorally oriented, technology-enabled lifestyle health coaching focused on exercise and physical activity, weight management, and nutrition.
Key findings
With a mean follow-up of 145 days, weight loss in the obese group was greater than that of the overweight group, with mean BMI changes of –1.3 and –0.6, respectively, while there was no significant change in weight for the normal-weight individuals, according to Ms. Salmon.
By contrast, weekly aerobic activity increased significantly in all three groups, she added, with average increases of 95 minutes in the obese group, 98 minutes in the overweight group, and 77 minutes in the normal-weight group.
Likewise, significant decreases in FPG were seen in all 3 groups, with average changes of –6 mg/dL for the obese participants, –7 mg/dL for overweight participants, and –9 mg/dL for normal-weight participants, Ms. Salmon said.
The proportion of individuals whose FPG normalized was highest in the normal-weight group, at 62%, compared with 51.7% for overweight and 44% for obese individuals, she added.
Most previous studies of lifestyle interventions for prediabetes have excluded normal-weight individuals, according to Ms. Salmon, who said one strength of her study was that the subjects were already participating in the established lifestyle health coaching program and didn’t interact with the team of researchers.
“It was an effectiveness study in which we could see the real-world benefits of the program, rather than a theoretical efficacy study,” she said.
Ms. Salmon said she had no potential conflicts of interest to disclose. The coinvestigators of the study were members or employees of a privately held population health management company called INTERVENT International.
SOURCE: Salmon MK et al. ADA 2020, Abstract 273-OR.
Adults with prediabetes of normal weight may derive at least as much benefit from lifestyle health coaching programs as adults who are overweight or obese, results of a recent nonrandomized, real-world study show.
Fasting plasma glucose (FPG) normalized in about 63% of prediabetic adults with normal body mass index (BMI) participating in a personalized coaching program that emphasized exercise, nutrition, and weight management, according to researcher Mandy Salmon, MS.
By contrast, FPG normalized in about 52% of overweight and 44% of obese prediabetic individuals participating in the program, according to Ms. Salmon, a medical student at the University of Pennsylvania, Philadelphia.
The normal-weight individuals didn’t lose any weight after participating in the coaching program, but they did significantly increase exercise, as did their overweight and obese counterparts, Ms. Salmon said in a presentation of her findings at virtual annual scientific sessions of the American Diabetes Association.
That means not only that normal-weight individuals shouldn’t be excluded from coaching interventions for diabetes prevention, but also that the success of such programs shouldn’t be judged solely on the magnitude of weight loss, according to the researcher.
“It is interesting to note that, although the normal weight group lost the least amount of weight, they still benefited from the lifestyle health coaching program, but having a resultant greatest decrease in fasting plasma glucose and normalization to a range of someone without prediabetes,” Ms. Salmon said.
The fact that most of those patients experienced normalization of FPG despite no weight loss emphasizes the importance of physical activity as a lifestyle intervention, according to Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, who was not involved in the study.
“You hear these axioms that say things like, ‘you can never outexercise a bad diet,’ and that’s probably true. But all the studies will tell us that a fit, overweight diabetic has much lower risk of cardiovascular disease than an unfit overweight diabetic,” Dr. Schutta said in an interview.
Benefits in normal-weight individuals
One in three Americans has prediabetes, and of those individuals, one in five have a normal BMI, Ms. Salmon said in her virtual ADA presentation.
It’s thought that diabetes may develop in those normal-weight individuals through different pathological mechanisms than in overweight or obese individuals. In turn, that could mean that standard methods for staving off diabetes prevention may not be as effective for them, she said.
Those mechanisms are not well understood; even so, normal BMI is currently an exclusion criterion for many diabetes prevention programs, she added, including the Center for Disease Control and Prevention’s National Diabetes Prevention Program, which specifically requires that individuals have an elevated BMI to be eligible for referral.
To evaluate the potential benefits of coaching in normal-weight individuals, the investigators studied a cohort of 1,897 adults with prediabetes, defined as a baseline FPG of 100-125 mg/dL, who were participating in a lifestyle health coaching program. Of those participants, 188, or about 10% had a normal BMI of 18.5-24.9 mg/m2. Another 495 participants were overweight, with BMIs between 25 and 29.9, while 1,214 were obese, with a BMI of at least 30.
The intervention included an initial assessment to generate goals and a personalized action plan based on the individual’s risk factors, according to Ms. Salmon, along with an action plan that included one-on-one, behaviorally oriented, technology-enabled lifestyle health coaching focused on exercise and physical activity, weight management, and nutrition.
Key findings
With a mean follow-up of 145 days, weight loss in the obese group was greater than that of the overweight group, with mean BMI changes of –1.3 and –0.6, respectively, while there was no significant change in weight for the normal-weight individuals, according to Ms. Salmon.
By contrast, weekly aerobic activity increased significantly in all three groups, she added, with average increases of 95 minutes in the obese group, 98 minutes in the overweight group, and 77 minutes in the normal-weight group.
Likewise, significant decreases in FPG were seen in all 3 groups, with average changes of –6 mg/dL for the obese participants, –7 mg/dL for overweight participants, and –9 mg/dL for normal-weight participants, Ms. Salmon said.
The proportion of individuals whose FPG normalized was highest in the normal-weight group, at 62%, compared with 51.7% for overweight and 44% for obese individuals, she added.
Most previous studies of lifestyle interventions for prediabetes have excluded normal-weight individuals, according to Ms. Salmon, who said one strength of her study was that the subjects were already participating in the established lifestyle health coaching program and didn’t interact with the team of researchers.
“It was an effectiveness study in which we could see the real-world benefits of the program, rather than a theoretical efficacy study,” she said.
Ms. Salmon said she had no potential conflicts of interest to disclose. The coinvestigators of the study were members or employees of a privately held population health management company called INTERVENT International.
SOURCE: Salmon MK et al. ADA 2020, Abstract 273-OR.
FROM ADA 2020
Frequent hypoglycemic episodes raise cardiac event risk
Frequent hypoglycemic episodes were linked to a raised incidence of cardiovascular events in adults with type 2 diabetes in a recent retrospective study, suggesting certain hypoglycemia-associated diabetes drugs should be avoided, an investigator said.
Patients who had more than five hypoglycemic episodes per year had a 61% greater risk of cardiovascular (CV) events, compared with patients with less frequent episodes, according to results of the study.
Although there were fewer strokes among younger patients, the overall increase in cardiovascular event risk held up regardless of age group, according to investigator Aman Rajpal, MD, of Louis Stokes Veterans Affairs Medical Center and Case Western Reserve University, both in Cleveland.
On the basis of these and earlier studies tying hypoglycemia to CV risk, health care providers need to “pay close attention” to low blood sugar and personalize glycemic control targets for each patient based on risk of hypoglycemia, Dr. Rajpal said in a presentation of the study at the virtual annual scientific sessions of the American Diabetes Association.
“Also, this suggests that avoidance of drugs associated with increased risk of hypoglycemia – namely insulin, sulfonylureas, or others – is essential to avoid and minimize the risk of cardiovascular events in this patient population with type 2 diabetes,” said Dr. Rajpal. “Let us remember part of our Hippocratic oath: ‘Above all, do no harm.’ ”
Tailoring treatment to mitigate risk
Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, said that results of this study suggest a need to carefully select medical therapy for each individual patient with diabetes in order to mitigate CV risk.
“It’s really about tailoring their drugs to their personal situation,” Dr. Schutta said in an interview.
Although newer diabetes drug classes are associated with low to no risk of hypoglycemia, Dr. Schutta said that there is still a place for drugs such as sulfonylureas in certain situations.
Among sulfonylureas, glyburide comes with a much higher incidence of hypoglycemia, compared with glipizide and glimepiride, according to Dr. Schutta. “I think there’s a role for both drugs, but you have to be very careful, and you have to get the data from your patients.”
Hypoglycemia frequency and outcomes
Speculation that hypoglycemia could be linked to adverse CV outcomes was sparked years ago by trials such as ADVANCE. Severe hypoglycemia in that study was associated with a 168% increased risk of death from a CV cause (N Engl J Med. 2010 Oct 7;363:1410-8).
At the time, ADVANCE investigators said they were unable to find evidence that multiple severe hypoglycemia episodes conferred a greater risk of CV events versus a single hypoglycemia episode, though they added that few patients had recurrent events.
“In other words, the association between the number of hypoglycemia events, and adverse CV outcomes is still unclear,” said Dr. Rajpal in his virtual ADA presentation.
Potential elevated risks with more than five episodes
To evaluate the association between frequent hypoglycemic episodes (i.e., more than five per year, compared with one to five episodes) and CV events, Dr. Rajpal and colleagues evaluated outcomes data for 4.9 million adults with type 2 diabetes found in a large commercial database including information on patients in 27 U.S. health care networks.
Database records indicated that about 182,000 patients, or nearly 4%, had episodes of hyperglycemia, which Dr. Rajpal said was presumed to mean a plasma glucose level of less than 70 mg/dL.
Characteristics of the patients with more than five hypoglycemic episodes were similar to those with one to five episodes, although they were more likely to be 65 years or older, and were “slightly more likely” to be on insulin, which could possibly precipitate more hypoglycemic episodes in that group, Dr. Rajpal said.
Key findings
In the main analysis, Dr. Rajpal said, risk of CV events was significantly increased in those with more than five hypoglycemic episodes, compared with those with one to five episodes, with an odds ratio of 1.61 (95% confidence interval, 1.56-1.66). The incidence of cardiovascular events was 33.1% in those with more than five episodes and 23.5% in those with one to five episodes, according to the data presented.
Risks were also significantly increased specifically for cardiac arrhythmias, cerebrovascular accidents, and MI, Dr. Rajpal said, with ORs of 1.65 (95% CI, 1.9-1.71), 1.38 (95% CI, 1.22-1.56), and 1.43 (95% CI, 1.36-1.50), respectively.
Because individuals in the group with more than five hypoglycemic episodes were more likely to be elderly, Dr. Rajpal said that he and coinvestigators decided to perform an age-specific stratified analysis.
Although cerebral vascular incidence was low in younger patients, risk of CV events overall was nevertheless significantly elevated for those aged 65 years or older, 45-64 years, and 18-44 years, with ORs of 1.69 (95% CI, 1.61-1.7), 1.58 (95% CI, 1.48-1.69), and 1.62 (95% CI, 1.33-1.97).
“The results were still valid in stratified analysis based on different age groups,” Dr. Rajpal said.
Dr. Rajpal and coauthors reported that he had no conflicts of interest related to the research.
SOURCE: Rajpal A et al. ADA 2020, Abstract 161-OR.
Frequent hypoglycemic episodes were linked to a raised incidence of cardiovascular events in adults with type 2 diabetes in a recent retrospective study, suggesting certain hypoglycemia-associated diabetes drugs should be avoided, an investigator said.
Patients who had more than five hypoglycemic episodes per year had a 61% greater risk of cardiovascular (CV) events, compared with patients with less frequent episodes, according to results of the study.
Although there were fewer strokes among younger patients, the overall increase in cardiovascular event risk held up regardless of age group, according to investigator Aman Rajpal, MD, of Louis Stokes Veterans Affairs Medical Center and Case Western Reserve University, both in Cleveland.
On the basis of these and earlier studies tying hypoglycemia to CV risk, health care providers need to “pay close attention” to low blood sugar and personalize glycemic control targets for each patient based on risk of hypoglycemia, Dr. Rajpal said in a presentation of the study at the virtual annual scientific sessions of the American Diabetes Association.
“Also, this suggests that avoidance of drugs associated with increased risk of hypoglycemia – namely insulin, sulfonylureas, or others – is essential to avoid and minimize the risk of cardiovascular events in this patient population with type 2 diabetes,” said Dr. Rajpal. “Let us remember part of our Hippocratic oath: ‘Above all, do no harm.’ ”
Tailoring treatment to mitigate risk
Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, said that results of this study suggest a need to carefully select medical therapy for each individual patient with diabetes in order to mitigate CV risk.
“It’s really about tailoring their drugs to their personal situation,” Dr. Schutta said in an interview.
Although newer diabetes drug classes are associated with low to no risk of hypoglycemia, Dr. Schutta said that there is still a place for drugs such as sulfonylureas in certain situations.
Among sulfonylureas, glyburide comes with a much higher incidence of hypoglycemia, compared with glipizide and glimepiride, according to Dr. Schutta. “I think there’s a role for both drugs, but you have to be very careful, and you have to get the data from your patients.”
Hypoglycemia frequency and outcomes
Speculation that hypoglycemia could be linked to adverse CV outcomes was sparked years ago by trials such as ADVANCE. Severe hypoglycemia in that study was associated with a 168% increased risk of death from a CV cause (N Engl J Med. 2010 Oct 7;363:1410-8).
At the time, ADVANCE investigators said they were unable to find evidence that multiple severe hypoglycemia episodes conferred a greater risk of CV events versus a single hypoglycemia episode, though they added that few patients had recurrent events.
“In other words, the association between the number of hypoglycemia events, and adverse CV outcomes is still unclear,” said Dr. Rajpal in his virtual ADA presentation.
Potential elevated risks with more than five episodes
To evaluate the association between frequent hypoglycemic episodes (i.e., more than five per year, compared with one to five episodes) and CV events, Dr. Rajpal and colleagues evaluated outcomes data for 4.9 million adults with type 2 diabetes found in a large commercial database including information on patients in 27 U.S. health care networks.
Database records indicated that about 182,000 patients, or nearly 4%, had episodes of hyperglycemia, which Dr. Rajpal said was presumed to mean a plasma glucose level of less than 70 mg/dL.
Characteristics of the patients with more than five hypoglycemic episodes were similar to those with one to five episodes, although they were more likely to be 65 years or older, and were “slightly more likely” to be on insulin, which could possibly precipitate more hypoglycemic episodes in that group, Dr. Rajpal said.
Key findings
In the main analysis, Dr. Rajpal said, risk of CV events was significantly increased in those with more than five hypoglycemic episodes, compared with those with one to five episodes, with an odds ratio of 1.61 (95% confidence interval, 1.56-1.66). The incidence of cardiovascular events was 33.1% in those with more than five episodes and 23.5% in those with one to five episodes, according to the data presented.
Risks were also significantly increased specifically for cardiac arrhythmias, cerebrovascular accidents, and MI, Dr. Rajpal said, with ORs of 1.65 (95% CI, 1.9-1.71), 1.38 (95% CI, 1.22-1.56), and 1.43 (95% CI, 1.36-1.50), respectively.
Because individuals in the group with more than five hypoglycemic episodes were more likely to be elderly, Dr. Rajpal said that he and coinvestigators decided to perform an age-specific stratified analysis.
Although cerebral vascular incidence was low in younger patients, risk of CV events overall was nevertheless significantly elevated for those aged 65 years or older, 45-64 years, and 18-44 years, with ORs of 1.69 (95% CI, 1.61-1.7), 1.58 (95% CI, 1.48-1.69), and 1.62 (95% CI, 1.33-1.97).
“The results were still valid in stratified analysis based on different age groups,” Dr. Rajpal said.
Dr. Rajpal and coauthors reported that he had no conflicts of interest related to the research.
SOURCE: Rajpal A et al. ADA 2020, Abstract 161-OR.
Frequent hypoglycemic episodes were linked to a raised incidence of cardiovascular events in adults with type 2 diabetes in a recent retrospective study, suggesting certain hypoglycemia-associated diabetes drugs should be avoided, an investigator said.
Patients who had more than five hypoglycemic episodes per year had a 61% greater risk of cardiovascular (CV) events, compared with patients with less frequent episodes, according to results of the study.
Although there were fewer strokes among younger patients, the overall increase in cardiovascular event risk held up regardless of age group, according to investigator Aman Rajpal, MD, of Louis Stokes Veterans Affairs Medical Center and Case Western Reserve University, both in Cleveland.
On the basis of these and earlier studies tying hypoglycemia to CV risk, health care providers need to “pay close attention” to low blood sugar and personalize glycemic control targets for each patient based on risk of hypoglycemia, Dr. Rajpal said in a presentation of the study at the virtual annual scientific sessions of the American Diabetes Association.
“Also, this suggests that avoidance of drugs associated with increased risk of hypoglycemia – namely insulin, sulfonylureas, or others – is essential to avoid and minimize the risk of cardiovascular events in this patient population with type 2 diabetes,” said Dr. Rajpal. “Let us remember part of our Hippocratic oath: ‘Above all, do no harm.’ ”
Tailoring treatment to mitigate risk
Mark Schutta, MD, medical director of Penn Rodebaugh Diabetes Center in Philadelphia, said that results of this study suggest a need to carefully select medical therapy for each individual patient with diabetes in order to mitigate CV risk.
“It’s really about tailoring their drugs to their personal situation,” Dr. Schutta said in an interview.
Although newer diabetes drug classes are associated with low to no risk of hypoglycemia, Dr. Schutta said that there is still a place for drugs such as sulfonylureas in certain situations.
Among sulfonylureas, glyburide comes with a much higher incidence of hypoglycemia, compared with glipizide and glimepiride, according to Dr. Schutta. “I think there’s a role for both drugs, but you have to be very careful, and you have to get the data from your patients.”
Hypoglycemia frequency and outcomes
Speculation that hypoglycemia could be linked to adverse CV outcomes was sparked years ago by trials such as ADVANCE. Severe hypoglycemia in that study was associated with a 168% increased risk of death from a CV cause (N Engl J Med. 2010 Oct 7;363:1410-8).
At the time, ADVANCE investigators said they were unable to find evidence that multiple severe hypoglycemia episodes conferred a greater risk of CV events versus a single hypoglycemia episode, though they added that few patients had recurrent events.
“In other words, the association between the number of hypoglycemia events, and adverse CV outcomes is still unclear,” said Dr. Rajpal in his virtual ADA presentation.
Potential elevated risks with more than five episodes
To evaluate the association between frequent hypoglycemic episodes (i.e., more than five per year, compared with one to five episodes) and CV events, Dr. Rajpal and colleagues evaluated outcomes data for 4.9 million adults with type 2 diabetes found in a large commercial database including information on patients in 27 U.S. health care networks.
Database records indicated that about 182,000 patients, or nearly 4%, had episodes of hyperglycemia, which Dr. Rajpal said was presumed to mean a plasma glucose level of less than 70 mg/dL.
Characteristics of the patients with more than five hypoglycemic episodes were similar to those with one to five episodes, although they were more likely to be 65 years or older, and were “slightly more likely” to be on insulin, which could possibly precipitate more hypoglycemic episodes in that group, Dr. Rajpal said.
Key findings
In the main analysis, Dr. Rajpal said, risk of CV events was significantly increased in those with more than five hypoglycemic episodes, compared with those with one to five episodes, with an odds ratio of 1.61 (95% confidence interval, 1.56-1.66). The incidence of cardiovascular events was 33.1% in those with more than five episodes and 23.5% in those with one to five episodes, according to the data presented.
Risks were also significantly increased specifically for cardiac arrhythmias, cerebrovascular accidents, and MI, Dr. Rajpal said, with ORs of 1.65 (95% CI, 1.9-1.71), 1.38 (95% CI, 1.22-1.56), and 1.43 (95% CI, 1.36-1.50), respectively.
Because individuals in the group with more than five hypoglycemic episodes were more likely to be elderly, Dr. Rajpal said that he and coinvestigators decided to perform an age-specific stratified analysis.
Although cerebral vascular incidence was low in younger patients, risk of CV events overall was nevertheless significantly elevated for those aged 65 years or older, 45-64 years, and 18-44 years, with ORs of 1.69 (95% CI, 1.61-1.7), 1.58 (95% CI, 1.48-1.69), and 1.62 (95% CI, 1.33-1.97).
“The results were still valid in stratified analysis based on different age groups,” Dr. Rajpal said.
Dr. Rajpal and coauthors reported that he had no conflicts of interest related to the research.
SOURCE: Rajpal A et al. ADA 2020, Abstract 161-OR.
FROM ADA 2020