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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Frontline CLL treatment: Avoiding adverse events
NEW YORK – The Food and Drug Administration’s 2016 approval of the Bruton’s tyrosine kinase inhibitor ibrutinib (IB) as a frontline therapy for chronic lymphocytic leukemia (CLL) dramatically improved overall survival rates for patients with this condition. Follow-up data from 8 years after the RESONATE-2 trial indicated that patients with CLL (65 years or older) who remain on IB therapy can expect to live as long as someone in the general population.
Physicians now face two challenges in frontline CLL treatment: finding safe and effective drugs with fewer side effects, allowing patients to maintain therapy; and offering young or genomically high-risk patients treatments that reduce the risk of relapse.
said John N. Allan, associate professor at Weill Cornell Medicine, New York, in his presentation on frontline CLL treatments at the Great Debates and Updates Hematologic Malignancies Conference. “This is true even of older patients or those with comorbidities because this class of drug allows us to keep patients on treatment with excellent long-term outcomes.”
Results from the Alpine trial (NCT03734016), which included patients with and without high genomic risk, confirmed the superiority of the second generation Bruton’s tyrosine kinase inhibitor zanubrutinib (ZB) versus ibrutinib in terms of overall response rate 86.2% versus 75.5%, progression free survival 2-years after treatment 79.5% versus 67.3%, and adverse events (AEs) leading to discontinuation 15.4% versus 22.2% respectively.
The SEQUOIA trial (NCT03336333) demonstrated the effectiveness of ZB versus bendamustine + rituximab combination (BR) therapy in treatment-naive CLL / small lymphocytic leukemia patients with normal and high genomic risk. Overall 24-month progression free survival (PFS) was 85% in the ZB cohort vs. 69% in the BR cohort. This trend held true among high-risk subgroups like patients with an unmutated IgVH gene or 11q22.3 gene deletion.
Therapies known as “doublets” and “triplets” (which include a Bruton’s tyrosine kinase inhibitor in addition to other drugs) are not FDA approved for frontline CLL treatment. Yet studies suggest that young patients who are better able to tolerate AEs or high-risk patients with a greater risk of relapse (even on monotherapy maintenance), may derive benefits from multidrug frontline treatment.
“With doublets and triplets, doctors add treatment intensity up front so that patients can have a fixed duration of therapy versus continuous indefinite therapy,” said Vu Nguyen MD, a hematologist at Oakland (Calif.) Medical Center. “This is encouraging because if you can have a fixed duration of treatment, patients can come off treatment agents and hopefully have a prolonged remission and normal lifespan without chronic therapy and side effects.”
The CAPTIVATE study confirmed this approach with 3 cycles of IB followed by 12 cycles of IB + venetoclax leading to a 24-month PFS rate of 94% in patients with high risk or relapse. “Furthermore, 95% of study participants patients less than 70 years old completed 12 months of combination treatment without major problems,” said Dr. Allan. He concluded his remarks by noting that “we need longer term data on the use of combination therapy for frontline CLL treatment to confirm if and when it should be used.”
Dr. Allan disclosed relationships with Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Lilly, Pharmacyclics, and TG Therapeutics. Dr. Nguyen reported no disclosures.
NEW YORK – The Food and Drug Administration’s 2016 approval of the Bruton’s tyrosine kinase inhibitor ibrutinib (IB) as a frontline therapy for chronic lymphocytic leukemia (CLL) dramatically improved overall survival rates for patients with this condition. Follow-up data from 8 years after the RESONATE-2 trial indicated that patients with CLL (65 years or older) who remain on IB therapy can expect to live as long as someone in the general population.
Physicians now face two challenges in frontline CLL treatment: finding safe and effective drugs with fewer side effects, allowing patients to maintain therapy; and offering young or genomically high-risk patients treatments that reduce the risk of relapse.
said John N. Allan, associate professor at Weill Cornell Medicine, New York, in his presentation on frontline CLL treatments at the Great Debates and Updates Hematologic Malignancies Conference. “This is true even of older patients or those with comorbidities because this class of drug allows us to keep patients on treatment with excellent long-term outcomes.”
Results from the Alpine trial (NCT03734016), which included patients with and without high genomic risk, confirmed the superiority of the second generation Bruton’s tyrosine kinase inhibitor zanubrutinib (ZB) versus ibrutinib in terms of overall response rate 86.2% versus 75.5%, progression free survival 2-years after treatment 79.5% versus 67.3%, and adverse events (AEs) leading to discontinuation 15.4% versus 22.2% respectively.
The SEQUOIA trial (NCT03336333) demonstrated the effectiveness of ZB versus bendamustine + rituximab combination (BR) therapy in treatment-naive CLL / small lymphocytic leukemia patients with normal and high genomic risk. Overall 24-month progression free survival (PFS) was 85% in the ZB cohort vs. 69% in the BR cohort. This trend held true among high-risk subgroups like patients with an unmutated IgVH gene or 11q22.3 gene deletion.
Therapies known as “doublets” and “triplets” (which include a Bruton’s tyrosine kinase inhibitor in addition to other drugs) are not FDA approved for frontline CLL treatment. Yet studies suggest that young patients who are better able to tolerate AEs or high-risk patients with a greater risk of relapse (even on monotherapy maintenance), may derive benefits from multidrug frontline treatment.
“With doublets and triplets, doctors add treatment intensity up front so that patients can have a fixed duration of therapy versus continuous indefinite therapy,” said Vu Nguyen MD, a hematologist at Oakland (Calif.) Medical Center. “This is encouraging because if you can have a fixed duration of treatment, patients can come off treatment agents and hopefully have a prolonged remission and normal lifespan without chronic therapy and side effects.”
The CAPTIVATE study confirmed this approach with 3 cycles of IB followed by 12 cycles of IB + venetoclax leading to a 24-month PFS rate of 94% in patients with high risk or relapse. “Furthermore, 95% of study participants patients less than 70 years old completed 12 months of combination treatment without major problems,” said Dr. Allan. He concluded his remarks by noting that “we need longer term data on the use of combination therapy for frontline CLL treatment to confirm if and when it should be used.”
Dr. Allan disclosed relationships with Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Lilly, Pharmacyclics, and TG Therapeutics. Dr. Nguyen reported no disclosures.
NEW YORK – The Food and Drug Administration’s 2016 approval of the Bruton’s tyrosine kinase inhibitor ibrutinib (IB) as a frontline therapy for chronic lymphocytic leukemia (CLL) dramatically improved overall survival rates for patients with this condition. Follow-up data from 8 years after the RESONATE-2 trial indicated that patients with CLL (65 years or older) who remain on IB therapy can expect to live as long as someone in the general population.
Physicians now face two challenges in frontline CLL treatment: finding safe and effective drugs with fewer side effects, allowing patients to maintain therapy; and offering young or genomically high-risk patients treatments that reduce the risk of relapse.
said John N. Allan, associate professor at Weill Cornell Medicine, New York, in his presentation on frontline CLL treatments at the Great Debates and Updates Hematologic Malignancies Conference. “This is true even of older patients or those with comorbidities because this class of drug allows us to keep patients on treatment with excellent long-term outcomes.”
Results from the Alpine trial (NCT03734016), which included patients with and without high genomic risk, confirmed the superiority of the second generation Bruton’s tyrosine kinase inhibitor zanubrutinib (ZB) versus ibrutinib in terms of overall response rate 86.2% versus 75.5%, progression free survival 2-years after treatment 79.5% versus 67.3%, and adverse events (AEs) leading to discontinuation 15.4% versus 22.2% respectively.
The SEQUOIA trial (NCT03336333) demonstrated the effectiveness of ZB versus bendamustine + rituximab combination (BR) therapy in treatment-naive CLL / small lymphocytic leukemia patients with normal and high genomic risk. Overall 24-month progression free survival (PFS) was 85% in the ZB cohort vs. 69% in the BR cohort. This trend held true among high-risk subgroups like patients with an unmutated IgVH gene or 11q22.3 gene deletion.
Therapies known as “doublets” and “triplets” (which include a Bruton’s tyrosine kinase inhibitor in addition to other drugs) are not FDA approved for frontline CLL treatment. Yet studies suggest that young patients who are better able to tolerate AEs or high-risk patients with a greater risk of relapse (even on monotherapy maintenance), may derive benefits from multidrug frontline treatment.
“With doublets and triplets, doctors add treatment intensity up front so that patients can have a fixed duration of therapy versus continuous indefinite therapy,” said Vu Nguyen MD, a hematologist at Oakland (Calif.) Medical Center. “This is encouraging because if you can have a fixed duration of treatment, patients can come off treatment agents and hopefully have a prolonged remission and normal lifespan without chronic therapy and side effects.”
The CAPTIVATE study confirmed this approach with 3 cycles of IB followed by 12 cycles of IB + venetoclax leading to a 24-month PFS rate of 94% in patients with high risk or relapse. “Furthermore, 95% of study participants patients less than 70 years old completed 12 months of combination treatment without major problems,” said Dr. Allan. He concluded his remarks by noting that “we need longer term data on the use of combination therapy for frontline CLL treatment to confirm if and when it should be used.”
Dr. Allan disclosed relationships with Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Lilly, Pharmacyclics, and TG Therapeutics. Dr. Nguyen reported no disclosures.
AT 2023 GREAT DEBATES AND UPDATES HEMATOLOGIC MALIGNANCIES CONFERENCE
Ten-year analysis finds relatively low complication rate from fractional resurfacing lasers
PHOENIX – over a decade showed.
To investigate, Dr. Hashemi, a third-year dermatology resident at Harvard University and Massachusetts General Hospital, Boston, and Mathew M. Avram, MD, JD, director of laser, cosmetics, and dermatologic surgery at MGH, drew from the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database, which compiles medical device reports for suspected injuries from device use or malfunction and represents the largest repository of device adverse effects. Medical device reports are submitted by manufacturers, clinicians, patients, and others.
The researchers limited their query to MDRs related to ablative and nonablative fractional resurfacing lasers over the 10-year period from 2013 to 2022. The query was performed in January 2023 using a comprehensive list of product names and manufacturers.
The initial search yielded 240 MDRs, which were individually reviewed for duplicate records or insufficient data, and the final analysis included 165 MDRs. The 10 most reported adverse events were burns (30%), followed by dyspigmentation (14%), scarring (12%), other (11%), postoperative infection (8%), blisters (6%), pain (5%), hypertrophic scar (4%), post-treatment inflammation (4%), and textural changes (3%). Within the 10-year period analyzed, 56% of MDRs occurred between 2016 and 2019, with a disproportionately low percentage of MDRs occurring in 2022 (5%).
“Adverse events due to ablative and nonablative fractional resurfacing lasers are rare but potentially serious,” Dr. Hashemi concluded. “Care must be taken with counseling, patient selection, and treatment settings to optimize safety, informed consent, and patient satisfaction. Given the relatively low number of adverse events seen with fractional resurfacing lasers, factors driving their safety should be further explored.”
He added that he was surprised by the relatively low number of reported issues, referring to the total of 165 cases over 10 years. By comparison, he said, body contouring had 660 cases reported over a 7-year period in one recent study.
According to the MAUDE website, submitting MDRs to MAUDE is mandatory for manufacturers, importers, and device user facilities, and are voluntary for other groups, such as health care professionals, patients, and consumers.
Dr. Hashemi disclosed that he is a consultant for Castle Biosciences. He is also an entrepreneur in residence for Gore Range Capital.
PHOENIX – over a decade showed.
To investigate, Dr. Hashemi, a third-year dermatology resident at Harvard University and Massachusetts General Hospital, Boston, and Mathew M. Avram, MD, JD, director of laser, cosmetics, and dermatologic surgery at MGH, drew from the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database, which compiles medical device reports for suspected injuries from device use or malfunction and represents the largest repository of device adverse effects. Medical device reports are submitted by manufacturers, clinicians, patients, and others.
The researchers limited their query to MDRs related to ablative and nonablative fractional resurfacing lasers over the 10-year period from 2013 to 2022. The query was performed in January 2023 using a comprehensive list of product names and manufacturers.
The initial search yielded 240 MDRs, which were individually reviewed for duplicate records or insufficient data, and the final analysis included 165 MDRs. The 10 most reported adverse events were burns (30%), followed by dyspigmentation (14%), scarring (12%), other (11%), postoperative infection (8%), blisters (6%), pain (5%), hypertrophic scar (4%), post-treatment inflammation (4%), and textural changes (3%). Within the 10-year period analyzed, 56% of MDRs occurred between 2016 and 2019, with a disproportionately low percentage of MDRs occurring in 2022 (5%).
“Adverse events due to ablative and nonablative fractional resurfacing lasers are rare but potentially serious,” Dr. Hashemi concluded. “Care must be taken with counseling, patient selection, and treatment settings to optimize safety, informed consent, and patient satisfaction. Given the relatively low number of adverse events seen with fractional resurfacing lasers, factors driving their safety should be further explored.”
He added that he was surprised by the relatively low number of reported issues, referring to the total of 165 cases over 10 years. By comparison, he said, body contouring had 660 cases reported over a 7-year period in one recent study.
According to the MAUDE website, submitting MDRs to MAUDE is mandatory for manufacturers, importers, and device user facilities, and are voluntary for other groups, such as health care professionals, patients, and consumers.
Dr. Hashemi disclosed that he is a consultant for Castle Biosciences. He is also an entrepreneur in residence for Gore Range Capital.
PHOENIX – over a decade showed.
To investigate, Dr. Hashemi, a third-year dermatology resident at Harvard University and Massachusetts General Hospital, Boston, and Mathew M. Avram, MD, JD, director of laser, cosmetics, and dermatologic surgery at MGH, drew from the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database, which compiles medical device reports for suspected injuries from device use or malfunction and represents the largest repository of device adverse effects. Medical device reports are submitted by manufacturers, clinicians, patients, and others.
The researchers limited their query to MDRs related to ablative and nonablative fractional resurfacing lasers over the 10-year period from 2013 to 2022. The query was performed in January 2023 using a comprehensive list of product names and manufacturers.
The initial search yielded 240 MDRs, which were individually reviewed for duplicate records or insufficient data, and the final analysis included 165 MDRs. The 10 most reported adverse events were burns (30%), followed by dyspigmentation (14%), scarring (12%), other (11%), postoperative infection (8%), blisters (6%), pain (5%), hypertrophic scar (4%), post-treatment inflammation (4%), and textural changes (3%). Within the 10-year period analyzed, 56% of MDRs occurred between 2016 and 2019, with a disproportionately low percentage of MDRs occurring in 2022 (5%).
“Adverse events due to ablative and nonablative fractional resurfacing lasers are rare but potentially serious,” Dr. Hashemi concluded. “Care must be taken with counseling, patient selection, and treatment settings to optimize safety, informed consent, and patient satisfaction. Given the relatively low number of adverse events seen with fractional resurfacing lasers, factors driving their safety should be further explored.”
He added that he was surprised by the relatively low number of reported issues, referring to the total of 165 cases over 10 years. By comparison, he said, body contouring had 660 cases reported over a 7-year period in one recent study.
According to the MAUDE website, submitting MDRs to MAUDE is mandatory for manufacturers, importers, and device user facilities, and are voluntary for other groups, such as health care professionals, patients, and consumers.
Dr. Hashemi disclosed that he is a consultant for Castle Biosciences. He is also an entrepreneur in residence for Gore Range Capital.
AT ASLMS 2023
‘Exciting’ results for cancer vaccine plus pembro in melanoma
according to the latest data from the KEYNOTE-942 trial.
This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.
The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.
“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.
“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.
Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
A promising personalized vaccine
The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.
Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”
The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.
The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.
“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.
In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.
Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).
Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.
In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.
The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.
Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).
The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).
The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.
Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.
The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”
Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.
KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
A version of this article first appeared on Medscape.com.
according to the latest data from the KEYNOTE-942 trial.
This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.
The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.
“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.
“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.
Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
A promising personalized vaccine
The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.
Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”
The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.
The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.
“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.
In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.
Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).
Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.
In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.
The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.
Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).
The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).
The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.
Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.
The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”
Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.
KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
A version of this article first appeared on Medscape.com.
according to the latest data from the KEYNOTE-942 trial.
This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.
The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.
“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.
“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.
Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
A promising personalized vaccine
The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.
Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”
The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.
The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.
“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.
In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.
Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).
Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.
In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.
The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.
Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).
The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).
The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.
Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.
The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”
Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.
KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
Racial disparities in cardiotoxicity after chemotherapy
a research review indicates.
“It’s important that both patients and clinicians be aware of these disparities so that more meaningful conversations around long-term cardiac health and cancer treatment can take place,” lead investigator Wondewossen Gebeyehu, with the University of Toronto, said in an interview.
However, patients “should not avoid chemotherapy, as the most important thing is making sure they get the best cancer treatment possible, and studies already show Black patients may get less optimal cancer treatments,” Mr. Gebeyehu added in a statement.
Ana Barac, MD, PHD, chair of cardio-oncology at Inova Schar Cancer Institute and Inova Heart and Vascular Institute, Fairfax, Va., who wasn’t involved in the study, agreed.
“The most important message is to look at preexisting cardiovascular disease, oncology diagnosis, and be aware of existing disparities in a specific cancer and CVD,” Barac said in an interview.
“What should NOT happen is to overinterpret this report of cardiotoxicity as an indication to modify/avoid planned cancer treatment to decrease cardiotoxicity. This approach could worsen oncology outcomes and lead to undertreatment of cancer, therefore posing real danger,” said Dr. Barac.
The study was presented at the American College of Cardiology Advancing the Cardiovascular Care of the Oncology Patient 2023 conference.
Causes unclear
Chemotherapy is known to increase the risk of cardiovascular heart failure and other forms of CVD, but less is known about racial disparities in the incidence of chemotherapy-induced cardiotoxicity.
Mr. Gebeyehu and colleagues conducted a systematic review and meta-analysis of the available literature to assess racial disparities in CV adverse effects among cancer patients who were treated with chemotherapeutic agents. They screened 7,057 studies, fully reviewed 57, and included 24 studies, representing 683,749 participants, in their analysis.
Breast cancer was the most commonly reported malignancy. Other common malignancies were prostate, kidney, and hematologic malignancies such as leukemia and lymphoma.
Chemotherapeutic agents included anthracyclines (doxorubicin, daunorubicin), trastuzumab, and hormonal therapies.
Black race or African ancestry was associated with increased odds of chemotherapy-associated cardiotoxicity (odds ratio, 1.71; 95% confidence interval, 1.40-2.10), as well as congestive heart failure (OR, 1.92; 95% CI, 1.68-2.19).
Mr. Gebeyehu said in an interview that it’s hard to speculate on causation with an analysis of preexisting data such as this. “Our initial analysis that we’ve reported on so far are unadjusted values, meaning they don’t adjust for those potential underlying factors,” he noted.
“However, some of the studies individually controlled for socioeconomic factors and still found increased vulnerability to chemotherapy-associated cardiotoxicity in patients of Black race or African ancestry,” Mr. Gebeyehu said.
“It’s certainly possible that a mix of both biological and socioeconomic factors are interacting to lead to these disparities. One example could be the underrepresentation of Black patients in clinical trials to develop drugs. These could lead to chemotherapeutic agents being poorly optimized in this population relative to other racial/ethnic groups,” he added.
Dr. Barac said this study adds to the growing body of evidence about the importance of racial disparities in CVD and cancer outcomes.
“It is important to note that only the unadjusted odds ratio was reported and that much more detail is needed to understand what may be underlying the disparities. It is critically important to await the adjusted analysis, as well as details of the type of cancers and treatment used, before clinical implications can be discussed,” said Dr. Barac, who served as codirector of the conference.
“The risk of cardiotoxicity needs to be presented in the context of the oncology and CV disease burden, as both can influence the risk, and there could be a synergistic effect of disparities,” Dr. Barac added.
The study had no specific funding. Mr. Gebeyehu and Dr. Barac disclosed no relevant conflicts of interest.
A version of this article originally appeared on Medscape.com.
a research review indicates.
“It’s important that both patients and clinicians be aware of these disparities so that more meaningful conversations around long-term cardiac health and cancer treatment can take place,” lead investigator Wondewossen Gebeyehu, with the University of Toronto, said in an interview.
However, patients “should not avoid chemotherapy, as the most important thing is making sure they get the best cancer treatment possible, and studies already show Black patients may get less optimal cancer treatments,” Mr. Gebeyehu added in a statement.
Ana Barac, MD, PHD, chair of cardio-oncology at Inova Schar Cancer Institute and Inova Heart and Vascular Institute, Fairfax, Va., who wasn’t involved in the study, agreed.
“The most important message is to look at preexisting cardiovascular disease, oncology diagnosis, and be aware of existing disparities in a specific cancer and CVD,” Barac said in an interview.
“What should NOT happen is to overinterpret this report of cardiotoxicity as an indication to modify/avoid planned cancer treatment to decrease cardiotoxicity. This approach could worsen oncology outcomes and lead to undertreatment of cancer, therefore posing real danger,” said Dr. Barac.
The study was presented at the American College of Cardiology Advancing the Cardiovascular Care of the Oncology Patient 2023 conference.
Causes unclear
Chemotherapy is known to increase the risk of cardiovascular heart failure and other forms of CVD, but less is known about racial disparities in the incidence of chemotherapy-induced cardiotoxicity.
Mr. Gebeyehu and colleagues conducted a systematic review and meta-analysis of the available literature to assess racial disparities in CV adverse effects among cancer patients who were treated with chemotherapeutic agents. They screened 7,057 studies, fully reviewed 57, and included 24 studies, representing 683,749 participants, in their analysis.
Breast cancer was the most commonly reported malignancy. Other common malignancies were prostate, kidney, and hematologic malignancies such as leukemia and lymphoma.
Chemotherapeutic agents included anthracyclines (doxorubicin, daunorubicin), trastuzumab, and hormonal therapies.
Black race or African ancestry was associated with increased odds of chemotherapy-associated cardiotoxicity (odds ratio, 1.71; 95% confidence interval, 1.40-2.10), as well as congestive heart failure (OR, 1.92; 95% CI, 1.68-2.19).
Mr. Gebeyehu said in an interview that it’s hard to speculate on causation with an analysis of preexisting data such as this. “Our initial analysis that we’ve reported on so far are unadjusted values, meaning they don’t adjust for those potential underlying factors,” he noted.
“However, some of the studies individually controlled for socioeconomic factors and still found increased vulnerability to chemotherapy-associated cardiotoxicity in patients of Black race or African ancestry,” Mr. Gebeyehu said.
“It’s certainly possible that a mix of both biological and socioeconomic factors are interacting to lead to these disparities. One example could be the underrepresentation of Black patients in clinical trials to develop drugs. These could lead to chemotherapeutic agents being poorly optimized in this population relative to other racial/ethnic groups,” he added.
Dr. Barac said this study adds to the growing body of evidence about the importance of racial disparities in CVD and cancer outcomes.
“It is important to note that only the unadjusted odds ratio was reported and that much more detail is needed to understand what may be underlying the disparities. It is critically important to await the adjusted analysis, as well as details of the type of cancers and treatment used, before clinical implications can be discussed,” said Dr. Barac, who served as codirector of the conference.
“The risk of cardiotoxicity needs to be presented in the context of the oncology and CV disease burden, as both can influence the risk, and there could be a synergistic effect of disparities,” Dr. Barac added.
The study had no specific funding. Mr. Gebeyehu and Dr. Barac disclosed no relevant conflicts of interest.
A version of this article originally appeared on Medscape.com.
a research review indicates.
“It’s important that both patients and clinicians be aware of these disparities so that more meaningful conversations around long-term cardiac health and cancer treatment can take place,” lead investigator Wondewossen Gebeyehu, with the University of Toronto, said in an interview.
However, patients “should not avoid chemotherapy, as the most important thing is making sure they get the best cancer treatment possible, and studies already show Black patients may get less optimal cancer treatments,” Mr. Gebeyehu added in a statement.
Ana Barac, MD, PHD, chair of cardio-oncology at Inova Schar Cancer Institute and Inova Heart and Vascular Institute, Fairfax, Va., who wasn’t involved in the study, agreed.
“The most important message is to look at preexisting cardiovascular disease, oncology diagnosis, and be aware of existing disparities in a specific cancer and CVD,” Barac said in an interview.
“What should NOT happen is to overinterpret this report of cardiotoxicity as an indication to modify/avoid planned cancer treatment to decrease cardiotoxicity. This approach could worsen oncology outcomes and lead to undertreatment of cancer, therefore posing real danger,” said Dr. Barac.
The study was presented at the American College of Cardiology Advancing the Cardiovascular Care of the Oncology Patient 2023 conference.
Causes unclear
Chemotherapy is known to increase the risk of cardiovascular heart failure and other forms of CVD, but less is known about racial disparities in the incidence of chemotherapy-induced cardiotoxicity.
Mr. Gebeyehu and colleagues conducted a systematic review and meta-analysis of the available literature to assess racial disparities in CV adverse effects among cancer patients who were treated with chemotherapeutic agents. They screened 7,057 studies, fully reviewed 57, and included 24 studies, representing 683,749 participants, in their analysis.
Breast cancer was the most commonly reported malignancy. Other common malignancies were prostate, kidney, and hematologic malignancies such as leukemia and lymphoma.
Chemotherapeutic agents included anthracyclines (doxorubicin, daunorubicin), trastuzumab, and hormonal therapies.
Black race or African ancestry was associated with increased odds of chemotherapy-associated cardiotoxicity (odds ratio, 1.71; 95% confidence interval, 1.40-2.10), as well as congestive heart failure (OR, 1.92; 95% CI, 1.68-2.19).
Mr. Gebeyehu said in an interview that it’s hard to speculate on causation with an analysis of preexisting data such as this. “Our initial analysis that we’ve reported on so far are unadjusted values, meaning they don’t adjust for those potential underlying factors,” he noted.
“However, some of the studies individually controlled for socioeconomic factors and still found increased vulnerability to chemotherapy-associated cardiotoxicity in patients of Black race or African ancestry,” Mr. Gebeyehu said.
“It’s certainly possible that a mix of both biological and socioeconomic factors are interacting to lead to these disparities. One example could be the underrepresentation of Black patients in clinical trials to develop drugs. These could lead to chemotherapeutic agents being poorly optimized in this population relative to other racial/ethnic groups,” he added.
Dr. Barac said this study adds to the growing body of evidence about the importance of racial disparities in CVD and cancer outcomes.
“It is important to note that only the unadjusted odds ratio was reported and that much more detail is needed to understand what may be underlying the disparities. It is critically important to await the adjusted analysis, as well as details of the type of cancers and treatment used, before clinical implications can be discussed,” said Dr. Barac, who served as codirector of the conference.
“The risk of cardiotoxicity needs to be presented in the context of the oncology and CV disease burden, as both can influence the risk, and there could be a synergistic effect of disparities,” Dr. Barac added.
The study had no specific funding. Mr. Gebeyehu and Dr. Barac disclosed no relevant conflicts of interest.
A version of this article originally appeared on Medscape.com.
African ancestry genetically linked to worse CRC outcomes
, a disparity attributed to many factors, including socioeconomic, environmental, and genetic influences, as well as less access to care.
Results from a new genomic study provide greater clarity regarding the genetic piece of the puzzle: Persons of African background tend to have fewer targetable alterations, compared with patients of other races.
The findings were presented in a briefing and scientific poster session at the annual meeting of the American Association for Cancer Research.
Overall, the numbers to date show a clear trend: The incidence of and mortality from CRC are higher among Black patients than other populations. However, the extent to which genetic difference plays a role in these disparities remains unclear.
In the current study, researchers from Memorial Sloan Kettering (MSK) Cancer Center in New York explored how germline and somatic genomic alterations differ among patients of African ancestry, in comparison with those of European and other heritage, and how those differences might influence CRC outcomes.
Lead author Henry Walch, MS, a computational biologist at MSK, and colleagues compared genomic profiles among nearly 3,800 patients with CRC who were treated at MSK from 2014 to 2022. Patients in the study were classified by genetic ancestry as European (3,201 patients), African (236 patients), East Asian (253 patients), and South Asian (89 patients).
Tumor and normal tissues from the patients underwent next-generation DNA sequencing with a panel that covers 505 cancer-associated genes.
An analysis of overall survival by genetic ancestry confirmed findings from other studies: Overall survival was significantly worse among patients of African ancestry than among those of other groups (median 45.7 vs. 67.1 months).
The investigators used a precision oncology knowledge base (OncoKB) to assign levels of therapeutic actionability for each genomic alteration that was identified. The highest assigned value was for drugs that have been approved by the U.S. Food and Drug Administration and that target FDA-recognized biomarkers. The lowest value was assigned to biomarkers for which there was “compelling biological evidence” that the particular biomarker predicted response to a drug.
The team found that the percentage of patients who qualified for immunotherapy on the basis of microsatellite instability or high tumor mutational burden was significantly lower among patients of African heritage, compared with those of European heritage (13.5% vs. 20.4%; P = .008).
Compared with those of European ancestry, patients of African ancestry had significantly fewer actionable alterations (5.6% vs. 11.2%; P = .01). This difference was largely driven by the lack of targetable BRAF mutations (1.8% vs. 5.0%).
Mutations in APC, the most frequently altered gene in CRC, are typically associated with cancer outcomes, but the authors found that overall survival was similar for patients of African heritage regardless of whether they had altered or wild-type APC (median overall survival, 45.0 months for altered APC vs. 45.9 months for wild-type APC; P = .91). However, a significant association between APC status and overall survival was observed for patients of European ancestry (median, 64.6 months for altered APC vs. 45.6 months for wild-type APC; P < .0001).
Analyses that accounted for sex, age, primary tumor location, and stage at diagnosis also showed an association between APC status and overall survival for patients of European heritage (hazard ratio, 0.64), but not for patients of African heritage (HR, 0.74, P = .492).
Mr. Walch noted that a limitation of the study is that information regarding comprehensive treatment, environmental exposures, lifestyle, and socioeconomic factors was not available for the analysis but that these elements likely play an important role in patient outcomes.
“This is a complex problem involving many unseen factors, and the genomic landscape is a piece of a much larger puzzle,” said Mr. Walch. He noted that future studies will incorporate these factors into the models “with the ultimate goal of identifying opportunities to intervene and improve outcomes.”
Briefing moderator Lisa Newman, MD, MPH, of Weill Cornell Medicine and New York–Presbyterian, in New York, commented that Mr. Walch presented “some very compelling data that demonstrate the importance of including individuals from diverse backgrounds into [cancer] research.”
The study was funded in part by a Chris4Life Early Career Investigator Award Grant from the Colorectal Cancer Alliance for Francisco Sanchez-Vega, PhD, senior author of the study. Dr. Sanchez-Vega was also supported by an AACR-Minority and Minority-serving Institution Faculty Scholar in Cancer Research Award. Mr. Walch and Dr. Newman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a disparity attributed to many factors, including socioeconomic, environmental, and genetic influences, as well as less access to care.
Results from a new genomic study provide greater clarity regarding the genetic piece of the puzzle: Persons of African background tend to have fewer targetable alterations, compared with patients of other races.
The findings were presented in a briefing and scientific poster session at the annual meeting of the American Association for Cancer Research.
Overall, the numbers to date show a clear trend: The incidence of and mortality from CRC are higher among Black patients than other populations. However, the extent to which genetic difference plays a role in these disparities remains unclear.
In the current study, researchers from Memorial Sloan Kettering (MSK) Cancer Center in New York explored how germline and somatic genomic alterations differ among patients of African ancestry, in comparison with those of European and other heritage, and how those differences might influence CRC outcomes.
Lead author Henry Walch, MS, a computational biologist at MSK, and colleagues compared genomic profiles among nearly 3,800 patients with CRC who were treated at MSK from 2014 to 2022. Patients in the study were classified by genetic ancestry as European (3,201 patients), African (236 patients), East Asian (253 patients), and South Asian (89 patients).
Tumor and normal tissues from the patients underwent next-generation DNA sequencing with a panel that covers 505 cancer-associated genes.
An analysis of overall survival by genetic ancestry confirmed findings from other studies: Overall survival was significantly worse among patients of African ancestry than among those of other groups (median 45.7 vs. 67.1 months).
The investigators used a precision oncology knowledge base (OncoKB) to assign levels of therapeutic actionability for each genomic alteration that was identified. The highest assigned value was for drugs that have been approved by the U.S. Food and Drug Administration and that target FDA-recognized biomarkers. The lowest value was assigned to biomarkers for which there was “compelling biological evidence” that the particular biomarker predicted response to a drug.
The team found that the percentage of patients who qualified for immunotherapy on the basis of microsatellite instability or high tumor mutational burden was significantly lower among patients of African heritage, compared with those of European heritage (13.5% vs. 20.4%; P = .008).
Compared with those of European ancestry, patients of African ancestry had significantly fewer actionable alterations (5.6% vs. 11.2%; P = .01). This difference was largely driven by the lack of targetable BRAF mutations (1.8% vs. 5.0%).
Mutations in APC, the most frequently altered gene in CRC, are typically associated with cancer outcomes, but the authors found that overall survival was similar for patients of African heritage regardless of whether they had altered or wild-type APC (median overall survival, 45.0 months for altered APC vs. 45.9 months for wild-type APC; P = .91). However, a significant association between APC status and overall survival was observed for patients of European ancestry (median, 64.6 months for altered APC vs. 45.6 months for wild-type APC; P < .0001).
Analyses that accounted for sex, age, primary tumor location, and stage at diagnosis also showed an association between APC status and overall survival for patients of European heritage (hazard ratio, 0.64), but not for patients of African heritage (HR, 0.74, P = .492).
Mr. Walch noted that a limitation of the study is that information regarding comprehensive treatment, environmental exposures, lifestyle, and socioeconomic factors was not available for the analysis but that these elements likely play an important role in patient outcomes.
“This is a complex problem involving many unseen factors, and the genomic landscape is a piece of a much larger puzzle,” said Mr. Walch. He noted that future studies will incorporate these factors into the models “with the ultimate goal of identifying opportunities to intervene and improve outcomes.”
Briefing moderator Lisa Newman, MD, MPH, of Weill Cornell Medicine and New York–Presbyterian, in New York, commented that Mr. Walch presented “some very compelling data that demonstrate the importance of including individuals from diverse backgrounds into [cancer] research.”
The study was funded in part by a Chris4Life Early Career Investigator Award Grant from the Colorectal Cancer Alliance for Francisco Sanchez-Vega, PhD, senior author of the study. Dr. Sanchez-Vega was also supported by an AACR-Minority and Minority-serving Institution Faculty Scholar in Cancer Research Award. Mr. Walch and Dr. Newman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a disparity attributed to many factors, including socioeconomic, environmental, and genetic influences, as well as less access to care.
Results from a new genomic study provide greater clarity regarding the genetic piece of the puzzle: Persons of African background tend to have fewer targetable alterations, compared with patients of other races.
The findings were presented in a briefing and scientific poster session at the annual meeting of the American Association for Cancer Research.
Overall, the numbers to date show a clear trend: The incidence of and mortality from CRC are higher among Black patients than other populations. However, the extent to which genetic difference plays a role in these disparities remains unclear.
In the current study, researchers from Memorial Sloan Kettering (MSK) Cancer Center in New York explored how germline and somatic genomic alterations differ among patients of African ancestry, in comparison with those of European and other heritage, and how those differences might influence CRC outcomes.
Lead author Henry Walch, MS, a computational biologist at MSK, and colleagues compared genomic profiles among nearly 3,800 patients with CRC who were treated at MSK from 2014 to 2022. Patients in the study were classified by genetic ancestry as European (3,201 patients), African (236 patients), East Asian (253 patients), and South Asian (89 patients).
Tumor and normal tissues from the patients underwent next-generation DNA sequencing with a panel that covers 505 cancer-associated genes.
An analysis of overall survival by genetic ancestry confirmed findings from other studies: Overall survival was significantly worse among patients of African ancestry than among those of other groups (median 45.7 vs. 67.1 months).
The investigators used a precision oncology knowledge base (OncoKB) to assign levels of therapeutic actionability for each genomic alteration that was identified. The highest assigned value was for drugs that have been approved by the U.S. Food and Drug Administration and that target FDA-recognized biomarkers. The lowest value was assigned to biomarkers for which there was “compelling biological evidence” that the particular biomarker predicted response to a drug.
The team found that the percentage of patients who qualified for immunotherapy on the basis of microsatellite instability or high tumor mutational burden was significantly lower among patients of African heritage, compared with those of European heritage (13.5% vs. 20.4%; P = .008).
Compared with those of European ancestry, patients of African ancestry had significantly fewer actionable alterations (5.6% vs. 11.2%; P = .01). This difference was largely driven by the lack of targetable BRAF mutations (1.8% vs. 5.0%).
Mutations in APC, the most frequently altered gene in CRC, are typically associated with cancer outcomes, but the authors found that overall survival was similar for patients of African heritage regardless of whether they had altered or wild-type APC (median overall survival, 45.0 months for altered APC vs. 45.9 months for wild-type APC; P = .91). However, a significant association between APC status and overall survival was observed for patients of European ancestry (median, 64.6 months for altered APC vs. 45.6 months for wild-type APC; P < .0001).
Analyses that accounted for sex, age, primary tumor location, and stage at diagnosis also showed an association between APC status and overall survival for patients of European heritage (hazard ratio, 0.64), but not for patients of African heritage (HR, 0.74, P = .492).
Mr. Walch noted that a limitation of the study is that information regarding comprehensive treatment, environmental exposures, lifestyle, and socioeconomic factors was not available for the analysis but that these elements likely play an important role in patient outcomes.
“This is a complex problem involving many unseen factors, and the genomic landscape is a piece of a much larger puzzle,” said Mr. Walch. He noted that future studies will incorporate these factors into the models “with the ultimate goal of identifying opportunities to intervene and improve outcomes.”
Briefing moderator Lisa Newman, MD, MPH, of Weill Cornell Medicine and New York–Presbyterian, in New York, commented that Mr. Walch presented “some very compelling data that demonstrate the importance of including individuals from diverse backgrounds into [cancer] research.”
The study was funded in part by a Chris4Life Early Career Investigator Award Grant from the Colorectal Cancer Alliance for Francisco Sanchez-Vega, PhD, senior author of the study. Dr. Sanchez-Vega was also supported by an AACR-Minority and Minority-serving Institution Faculty Scholar in Cancer Research Award. Mr. Walch and Dr. Newman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
Durvalumab pre, post surgery in NSCLC: Practice changing?
FROM AACR 2023
(NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.
That may change, however, in light of new data from the phase 3 AEGEAN trial.
AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.
The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.
“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.
In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.
“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”
For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.
After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.
At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).
The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.
The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.
The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.
Are these data practice changing?
Dr. Herbst gave a “resounding ‘Yes.’ “
But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.
Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.
“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.
It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.
Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
(NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.
That may change, however, in light of new data from the phase 3 AEGEAN trial.
AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.
The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.
“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.
In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.
“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”
For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.
After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.
At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).
The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.
The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.
The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.
Are these data practice changing?
Dr. Herbst gave a “resounding ‘Yes.’ “
But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.
Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.
“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.
It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.
Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
(NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.
That may change, however, in light of new data from the phase 3 AEGEAN trial.
AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.
The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.
“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.
In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.
“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”
For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.
After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.
At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).
The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.
The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.
The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.
Are these data practice changing?
Dr. Herbst gave a “resounding ‘Yes.’ “
But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.
Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.
“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.
It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.
Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
A version of this article first appeared on Medscape.com.
Telehealth suicide prevention program safe, acceptable
WASHINGTON –
Skeptics had worried that participating in the program through telehealth would exacerbate safety and other issues veterans had about discussing suicide in a group setting, study investigator Sarah Sullivan, PhD student, Health Psychology & Clinical Science, City University of New York, told this news organization.
“But that for us was not really true. People opened up about their suicidal thoughts and triggers even on this telehealth format, and that’s really important for providers to know,” she said.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
Trial run
Suicide is a major public health issue, particularly for veterans. Recent data from the Veterans Administration show 17 veterans die by suicide every day.
The current study included 15 male and 2 female veterans (29.4% White, 70.6% Hispanic) from New York City and Philadelphia. Participants had an average age of 50 and all were either deemed by a clinician to be at extremely high risk for suicide or were hospitalized for this reason.
The individuals completed an online version of the Project Life Force (PLF) program, which uses dialectical behavioral therapy and psychoeducational approaches. The program includes the brief Safety Planning intervention (SPI), aimed at reducing short-term suicide risk.
Considered a best practice, the SPI includes a written list of personal suicide warning signs or triggers, internal coping strategies, social contacts who offer support and distraction from suicidal thoughts, contact information for professionals, a suicide crisis hotline, and nearby emergency services.
In addition to these steps, the PLF program focuses on sleep, exercise, and making the safety plan accessible.
The telehealth platform for the program was WebEx software. Participants were offered a “trial run” to orient them to the technology, said Ms. Sullivan.
Group sessions were held once weekly for 10 weeks, with optional “booster” sessions if needed. Each session included about five participants.
To ensure privacy, participants were provided with headphones and laptops. This was especially important for those sharing a living space, including spouses and children, said Ms. Sullivan.
High ratings
Participants completed the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Each of these yields scores from four items rated on a Likert scale of 1-5, for a total score ranging from 5 to 20, with higher scores indicating higher ratings.
Veterans rated PLF-T as highly acceptable (mean AIM, 17.50), appropriate (mean IAM, 17.25), and feasible (mean FIM, 18).
Study participants reported the program was convenient and noted that it decreased the burden of traveling to sessions, especially during the COVID-19 pandemic.
They also reported the program was less likely to compete with other demands such as childcare and other appointments, said Ms. Sullivan.
In addition, it helped those with comorbidities such as posttraumatic stress disorder, she added. She noted veterans with PTSD may be triggered on subways or buses when traveling to in-person treatment sessions.
“That can take away from addressing the suicidal triggers,” said Ms. Sullivan. “So, this program allows them to fully concentrate on the safety plan.”
Results showed that study participants “enjoyed the group and would recommend it to others,” said Ms. Sullivan. “I think that signifies the group was effective in its goal of mitigating loneliness, which was exacerbated during the COVID-19 pandemic, and creating a socially supportive environment, especially for the vets living alone.”
Veterans also reported that the program helped them understand the connection between depression or PTSD and suicidal thoughts, urges, and plans. In addition, they appreciated the group dynamics, where they felt connected to other veterans experiencing similar challenges.
Hopeful results
Commenting on the study, Paul E. Holtzheimer, MD, deputy director for research at the National Center for PTSD, praised the study for focusing on a very high-risk group.
“This gets you closer to the population you’re probably going to have an impact on in terms of preventing suicide,” said Dr. Holtzheimer, a professor of psychiatry and surgery at Dartmouth College’s Geisel School of Medicine, Hanover, N.H.
The fact that many of the participants had attempted suicide in the last year underlines that this was a very high-risk population, said Dr. Holtzheimer. “Not only are they thinking about suicide, but almost two-thirds had actually attempted or tried something.”
This kind of program “would be great for rural environments where people may be living like four hours away from the VA or a clinic,” said Dr. Holtzheimer, noting that many veterans are often quite isolated.
“One of the very positive outcomes of the COVID-19 pandemic was helping us strengthen our ability to do telehealth,” he said.
However, Dr. Holtzheimer noted the study was small and qualitative. “The next step ideally would be a controlled trial looking at not just ideation but at risky behavior or clear suicide attempts or preparation, like buying a gun or hoarding medication, to help determine efficacy.”
The researchers and Dr. Holtzheimer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON –
Skeptics had worried that participating in the program through telehealth would exacerbate safety and other issues veterans had about discussing suicide in a group setting, study investigator Sarah Sullivan, PhD student, Health Psychology & Clinical Science, City University of New York, told this news organization.
“But that for us was not really true. People opened up about their suicidal thoughts and triggers even on this telehealth format, and that’s really important for providers to know,” she said.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
Trial run
Suicide is a major public health issue, particularly for veterans. Recent data from the Veterans Administration show 17 veterans die by suicide every day.
The current study included 15 male and 2 female veterans (29.4% White, 70.6% Hispanic) from New York City and Philadelphia. Participants had an average age of 50 and all were either deemed by a clinician to be at extremely high risk for suicide or were hospitalized for this reason.
The individuals completed an online version of the Project Life Force (PLF) program, which uses dialectical behavioral therapy and psychoeducational approaches. The program includes the brief Safety Planning intervention (SPI), aimed at reducing short-term suicide risk.
Considered a best practice, the SPI includes a written list of personal suicide warning signs or triggers, internal coping strategies, social contacts who offer support and distraction from suicidal thoughts, contact information for professionals, a suicide crisis hotline, and nearby emergency services.
In addition to these steps, the PLF program focuses on sleep, exercise, and making the safety plan accessible.
The telehealth platform for the program was WebEx software. Participants were offered a “trial run” to orient them to the technology, said Ms. Sullivan.
Group sessions were held once weekly for 10 weeks, with optional “booster” sessions if needed. Each session included about five participants.
To ensure privacy, participants were provided with headphones and laptops. This was especially important for those sharing a living space, including spouses and children, said Ms. Sullivan.
High ratings
Participants completed the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Each of these yields scores from four items rated on a Likert scale of 1-5, for a total score ranging from 5 to 20, with higher scores indicating higher ratings.
Veterans rated PLF-T as highly acceptable (mean AIM, 17.50), appropriate (mean IAM, 17.25), and feasible (mean FIM, 18).
Study participants reported the program was convenient and noted that it decreased the burden of traveling to sessions, especially during the COVID-19 pandemic.
They also reported the program was less likely to compete with other demands such as childcare and other appointments, said Ms. Sullivan.
In addition, it helped those with comorbidities such as posttraumatic stress disorder, she added. She noted veterans with PTSD may be triggered on subways or buses when traveling to in-person treatment sessions.
“That can take away from addressing the suicidal triggers,” said Ms. Sullivan. “So, this program allows them to fully concentrate on the safety plan.”
Results showed that study participants “enjoyed the group and would recommend it to others,” said Ms. Sullivan. “I think that signifies the group was effective in its goal of mitigating loneliness, which was exacerbated during the COVID-19 pandemic, and creating a socially supportive environment, especially for the vets living alone.”
Veterans also reported that the program helped them understand the connection between depression or PTSD and suicidal thoughts, urges, and plans. In addition, they appreciated the group dynamics, where they felt connected to other veterans experiencing similar challenges.
Hopeful results
Commenting on the study, Paul E. Holtzheimer, MD, deputy director for research at the National Center for PTSD, praised the study for focusing on a very high-risk group.
“This gets you closer to the population you’re probably going to have an impact on in terms of preventing suicide,” said Dr. Holtzheimer, a professor of psychiatry and surgery at Dartmouth College’s Geisel School of Medicine, Hanover, N.H.
The fact that many of the participants had attempted suicide in the last year underlines that this was a very high-risk population, said Dr. Holtzheimer. “Not only are they thinking about suicide, but almost two-thirds had actually attempted or tried something.”
This kind of program “would be great for rural environments where people may be living like four hours away from the VA or a clinic,” said Dr. Holtzheimer, noting that many veterans are often quite isolated.
“One of the very positive outcomes of the COVID-19 pandemic was helping us strengthen our ability to do telehealth,” he said.
However, Dr. Holtzheimer noted the study was small and qualitative. “The next step ideally would be a controlled trial looking at not just ideation but at risky behavior or clear suicide attempts or preparation, like buying a gun or hoarding medication, to help determine efficacy.”
The researchers and Dr. Holtzheimer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON –
Skeptics had worried that participating in the program through telehealth would exacerbate safety and other issues veterans had about discussing suicide in a group setting, study investigator Sarah Sullivan, PhD student, Health Psychology & Clinical Science, City University of New York, told this news organization.
“But that for us was not really true. People opened up about their suicidal thoughts and triggers even on this telehealth format, and that’s really important for providers to know,” she said.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
Trial run
Suicide is a major public health issue, particularly for veterans. Recent data from the Veterans Administration show 17 veterans die by suicide every day.
The current study included 15 male and 2 female veterans (29.4% White, 70.6% Hispanic) from New York City and Philadelphia. Participants had an average age of 50 and all were either deemed by a clinician to be at extremely high risk for suicide or were hospitalized for this reason.
The individuals completed an online version of the Project Life Force (PLF) program, which uses dialectical behavioral therapy and psychoeducational approaches. The program includes the brief Safety Planning intervention (SPI), aimed at reducing short-term suicide risk.
Considered a best practice, the SPI includes a written list of personal suicide warning signs or triggers, internal coping strategies, social contacts who offer support and distraction from suicidal thoughts, contact information for professionals, a suicide crisis hotline, and nearby emergency services.
In addition to these steps, the PLF program focuses on sleep, exercise, and making the safety plan accessible.
The telehealth platform for the program was WebEx software. Participants were offered a “trial run” to orient them to the technology, said Ms. Sullivan.
Group sessions were held once weekly for 10 weeks, with optional “booster” sessions if needed. Each session included about five participants.
To ensure privacy, participants were provided with headphones and laptops. This was especially important for those sharing a living space, including spouses and children, said Ms. Sullivan.
High ratings
Participants completed the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Each of these yields scores from four items rated on a Likert scale of 1-5, for a total score ranging from 5 to 20, with higher scores indicating higher ratings.
Veterans rated PLF-T as highly acceptable (mean AIM, 17.50), appropriate (mean IAM, 17.25), and feasible (mean FIM, 18).
Study participants reported the program was convenient and noted that it decreased the burden of traveling to sessions, especially during the COVID-19 pandemic.
They also reported the program was less likely to compete with other demands such as childcare and other appointments, said Ms. Sullivan.
In addition, it helped those with comorbidities such as posttraumatic stress disorder, she added. She noted veterans with PTSD may be triggered on subways or buses when traveling to in-person treatment sessions.
“That can take away from addressing the suicidal triggers,” said Ms. Sullivan. “So, this program allows them to fully concentrate on the safety plan.”
Results showed that study participants “enjoyed the group and would recommend it to others,” said Ms. Sullivan. “I think that signifies the group was effective in its goal of mitigating loneliness, which was exacerbated during the COVID-19 pandemic, and creating a socially supportive environment, especially for the vets living alone.”
Veterans also reported that the program helped them understand the connection between depression or PTSD and suicidal thoughts, urges, and plans. In addition, they appreciated the group dynamics, where they felt connected to other veterans experiencing similar challenges.
Hopeful results
Commenting on the study, Paul E. Holtzheimer, MD, deputy director for research at the National Center for PTSD, praised the study for focusing on a very high-risk group.
“This gets you closer to the population you’re probably going to have an impact on in terms of preventing suicide,” said Dr. Holtzheimer, a professor of psychiatry and surgery at Dartmouth College’s Geisel School of Medicine, Hanover, N.H.
The fact that many of the participants had attempted suicide in the last year underlines that this was a very high-risk population, said Dr. Holtzheimer. “Not only are they thinking about suicide, but almost two-thirds had actually attempted or tried something.”
This kind of program “would be great for rural environments where people may be living like four hours away from the VA or a clinic,” said Dr. Holtzheimer, noting that many veterans are often quite isolated.
“One of the very positive outcomes of the COVID-19 pandemic was helping us strengthen our ability to do telehealth,” he said.
However, Dr. Holtzheimer noted the study was small and qualitative. “The next step ideally would be a controlled trial looking at not just ideation but at risky behavior or clear suicide attempts or preparation, like buying a gun or hoarding medication, to help determine efficacy.”
The researchers and Dr. Holtzheimer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ADAA 2023
Dried blood spot test validated for HIV, hep B, and hep C
A test that uses a single drop of dried blood to detect HIV, hepatitis B virus, and HCV has been validated and is now in use in some high-risk settings in Denmark, according to research presented at the annual European Congress of Clinical Microbiology & Infectious Diseases.
Molecular biologist Stephen Nilsson-Møller, MSc, and colleagues at the department of clinical microbiology, Copenhagen University Hospital, developed and validated the test, known as the Dried Blood Spot (DBS), for HIV, HBV, and HCV.
The “test that can detect low viral loads for all three viruses from a single drop of blood, and can be done using existing hospital equipment,” Mr. Nilsson-Møller said in an interview. “Importantly, it does not require venipuncture, but can be done from a drop of dried blood from the finger.”
He highlighted the utility of the new test in more challenging settings. “This method is particularly useful in high-risk settings such as homeless shelters, drug rehabilitation centers, and prisons, where needles might be misused, and it can be difficult to convince people to have the more invasive test.”
“Also, in some places – such as in low- and middle-income settings – there is a distinct risk of ruining blood samples before analysis due to limited refrigeration for transit and storage,” he added. “[Standard] blood samples need to be analyzed within 6 hours when kept at room temperature, while dried blood spots can last for 9 months at room temperature and can be mailed to a laboratory with the right equipment to analyze it.”
Tiny amounts of virus detected
Mr. Nilsson-Møller was tasked with developing a test for use by the university’s department of infectious diseases to screen people in high-risk settings in the capital region of Copenhagen. The work forms part of a PhD project by Jonas Demant at the University of Copenhagen, for which he is screening for HIV, HBV, and HCV in drug rehabilitation centers, prisons, and homeless shelters.
The study is the first to use the Hologic Panther system (a nucleic acid amplification test) combining all three viruses, Mr. Nilsson-Møller pointed out. “A tiny amount of virus can be detected because it is a very sensitive platform using transcription-mediated amplification.”
“If it detects low amounts of virus, it will create many copies very quickly, creating a signal that tells us that the sample is positive,” he explained.
The researchers collected whole blood from a finger prick, dried it out on a protein saver card (filter paper), and cut out a 1.2-cm diameter dry blood spot which was then prepared for analysis.
Twenty blood samples with known amounts of HIV, HBV, and HCV were analyzed via the DBS method (60 in total) and the viruses were detected in all of the samples.
To validate the method, the researchers used plasma with a known viral load, and a series of dilutions were performed to determine the lower limit for positive detection of all three viruses.
“Untreated patients typically have above 1 million IU/mL of viral loads in their plasma, and we found that we can detect much lower levels,” said Mr. Nilsson-Møller. “Ideally, 40 mcL of blood is good, but less should be sufficient if the test is on untreated patients.”
Early testing and treatment reduces morbidity and mortality
Elimination of HBV, HCV, and HIV by 2030 is a global health strategy set by the World Health Organization, but to meet this goal, new approaches for diagnostic testing are required. The DBS test for HIV, HBV, and HCV promises to make a significant contribution toward this goal.
“One in two people currently living with HIV is diagnosed late in the course of their infection, and an even larger proportion of the estimated 6 million Europeans living with chronic hepatitis B or C are not aware that they are infected,” said Anastasia Pharris, PhD, from the European Center for Disease Prevention and Control Principal Expert Infectious Diseases.
“Increasing testing coverage and uptake, especially for those most at risk, is an essential element of any strategy to eliminate HBV, HCV, and HIV in the European Union and European Economic Area,” she pointed out.
Dr. Pharris also highlighted that, while HIV, and often HBV infection, require lifelong treatment, HCV infection is now curable within a few weeks. “To maximize the benefits of individual treatment for all three infections, it is critical to test and diagnose people as soon as possible – in itself a challenge given that these infections can typically be asymptomatic for years.
“Early diagnosis of HBV, HCV, or HIV is vital as it allows people to access treatment, which significantly reduces associated long-term morbidity and mortality.
“In many cases, those most at risk of one of these infections are also more vulnerable to infection with one or both of the other viruses, making the argument for integrated testing even stronger,” she said in an interview.
Mr. Nilsson-Møller and Dr. Pharris reported no relevant financial relationships. Aptima kits for validation were provided by Hologic.
A version of this article first appeared on Medscape.com.
A test that uses a single drop of dried blood to detect HIV, hepatitis B virus, and HCV has been validated and is now in use in some high-risk settings in Denmark, according to research presented at the annual European Congress of Clinical Microbiology & Infectious Diseases.
Molecular biologist Stephen Nilsson-Møller, MSc, and colleagues at the department of clinical microbiology, Copenhagen University Hospital, developed and validated the test, known as the Dried Blood Spot (DBS), for HIV, HBV, and HCV.
The “test that can detect low viral loads for all three viruses from a single drop of blood, and can be done using existing hospital equipment,” Mr. Nilsson-Møller said in an interview. “Importantly, it does not require venipuncture, but can be done from a drop of dried blood from the finger.”
He highlighted the utility of the new test in more challenging settings. “This method is particularly useful in high-risk settings such as homeless shelters, drug rehabilitation centers, and prisons, where needles might be misused, and it can be difficult to convince people to have the more invasive test.”
“Also, in some places – such as in low- and middle-income settings – there is a distinct risk of ruining blood samples before analysis due to limited refrigeration for transit and storage,” he added. “[Standard] blood samples need to be analyzed within 6 hours when kept at room temperature, while dried blood spots can last for 9 months at room temperature and can be mailed to a laboratory with the right equipment to analyze it.”
Tiny amounts of virus detected
Mr. Nilsson-Møller was tasked with developing a test for use by the university’s department of infectious diseases to screen people in high-risk settings in the capital region of Copenhagen. The work forms part of a PhD project by Jonas Demant at the University of Copenhagen, for which he is screening for HIV, HBV, and HCV in drug rehabilitation centers, prisons, and homeless shelters.
The study is the first to use the Hologic Panther system (a nucleic acid amplification test) combining all three viruses, Mr. Nilsson-Møller pointed out. “A tiny amount of virus can be detected because it is a very sensitive platform using transcription-mediated amplification.”
“If it detects low amounts of virus, it will create many copies very quickly, creating a signal that tells us that the sample is positive,” he explained.
The researchers collected whole blood from a finger prick, dried it out on a protein saver card (filter paper), and cut out a 1.2-cm diameter dry blood spot which was then prepared for analysis.
Twenty blood samples with known amounts of HIV, HBV, and HCV were analyzed via the DBS method (60 in total) and the viruses were detected in all of the samples.
To validate the method, the researchers used plasma with a known viral load, and a series of dilutions were performed to determine the lower limit for positive detection of all three viruses.
“Untreated patients typically have above 1 million IU/mL of viral loads in their plasma, and we found that we can detect much lower levels,” said Mr. Nilsson-Møller. “Ideally, 40 mcL of blood is good, but less should be sufficient if the test is on untreated patients.”
Early testing and treatment reduces morbidity and mortality
Elimination of HBV, HCV, and HIV by 2030 is a global health strategy set by the World Health Organization, but to meet this goal, new approaches for diagnostic testing are required. The DBS test for HIV, HBV, and HCV promises to make a significant contribution toward this goal.
“One in two people currently living with HIV is diagnosed late in the course of their infection, and an even larger proportion of the estimated 6 million Europeans living with chronic hepatitis B or C are not aware that they are infected,” said Anastasia Pharris, PhD, from the European Center for Disease Prevention and Control Principal Expert Infectious Diseases.
“Increasing testing coverage and uptake, especially for those most at risk, is an essential element of any strategy to eliminate HBV, HCV, and HIV in the European Union and European Economic Area,” she pointed out.
Dr. Pharris also highlighted that, while HIV, and often HBV infection, require lifelong treatment, HCV infection is now curable within a few weeks. “To maximize the benefits of individual treatment for all three infections, it is critical to test and diagnose people as soon as possible – in itself a challenge given that these infections can typically be asymptomatic for years.
“Early diagnosis of HBV, HCV, or HIV is vital as it allows people to access treatment, which significantly reduces associated long-term morbidity and mortality.
“In many cases, those most at risk of one of these infections are also more vulnerable to infection with one or both of the other viruses, making the argument for integrated testing even stronger,” she said in an interview.
Mr. Nilsson-Møller and Dr. Pharris reported no relevant financial relationships. Aptima kits for validation were provided by Hologic.
A version of this article first appeared on Medscape.com.
A test that uses a single drop of dried blood to detect HIV, hepatitis B virus, and HCV has been validated and is now in use in some high-risk settings in Denmark, according to research presented at the annual European Congress of Clinical Microbiology & Infectious Diseases.
Molecular biologist Stephen Nilsson-Møller, MSc, and colleagues at the department of clinical microbiology, Copenhagen University Hospital, developed and validated the test, known as the Dried Blood Spot (DBS), for HIV, HBV, and HCV.
The “test that can detect low viral loads for all three viruses from a single drop of blood, and can be done using existing hospital equipment,” Mr. Nilsson-Møller said in an interview. “Importantly, it does not require venipuncture, but can be done from a drop of dried blood from the finger.”
He highlighted the utility of the new test in more challenging settings. “This method is particularly useful in high-risk settings such as homeless shelters, drug rehabilitation centers, and prisons, where needles might be misused, and it can be difficult to convince people to have the more invasive test.”
“Also, in some places – such as in low- and middle-income settings – there is a distinct risk of ruining blood samples before analysis due to limited refrigeration for transit and storage,” he added. “[Standard] blood samples need to be analyzed within 6 hours when kept at room temperature, while dried blood spots can last for 9 months at room temperature and can be mailed to a laboratory with the right equipment to analyze it.”
Tiny amounts of virus detected
Mr. Nilsson-Møller was tasked with developing a test for use by the university’s department of infectious diseases to screen people in high-risk settings in the capital region of Copenhagen. The work forms part of a PhD project by Jonas Demant at the University of Copenhagen, for which he is screening for HIV, HBV, and HCV in drug rehabilitation centers, prisons, and homeless shelters.
The study is the first to use the Hologic Panther system (a nucleic acid amplification test) combining all three viruses, Mr. Nilsson-Møller pointed out. “A tiny amount of virus can be detected because it is a very sensitive platform using transcription-mediated amplification.”
“If it detects low amounts of virus, it will create many copies very quickly, creating a signal that tells us that the sample is positive,” he explained.
The researchers collected whole blood from a finger prick, dried it out on a protein saver card (filter paper), and cut out a 1.2-cm diameter dry blood spot which was then prepared for analysis.
Twenty blood samples with known amounts of HIV, HBV, and HCV were analyzed via the DBS method (60 in total) and the viruses were detected in all of the samples.
To validate the method, the researchers used plasma with a known viral load, and a series of dilutions were performed to determine the lower limit for positive detection of all three viruses.
“Untreated patients typically have above 1 million IU/mL of viral loads in their plasma, and we found that we can detect much lower levels,” said Mr. Nilsson-Møller. “Ideally, 40 mcL of blood is good, but less should be sufficient if the test is on untreated patients.”
Early testing and treatment reduces morbidity and mortality
Elimination of HBV, HCV, and HIV by 2030 is a global health strategy set by the World Health Organization, but to meet this goal, new approaches for diagnostic testing are required. The DBS test for HIV, HBV, and HCV promises to make a significant contribution toward this goal.
“One in two people currently living with HIV is diagnosed late in the course of their infection, and an even larger proportion of the estimated 6 million Europeans living with chronic hepatitis B or C are not aware that they are infected,” said Anastasia Pharris, PhD, from the European Center for Disease Prevention and Control Principal Expert Infectious Diseases.
“Increasing testing coverage and uptake, especially for those most at risk, is an essential element of any strategy to eliminate HBV, HCV, and HIV in the European Union and European Economic Area,” she pointed out.
Dr. Pharris also highlighted that, while HIV, and often HBV infection, require lifelong treatment, HCV infection is now curable within a few weeks. “To maximize the benefits of individual treatment for all three infections, it is critical to test and diagnose people as soon as possible – in itself a challenge given that these infections can typically be asymptomatic for years.
“Early diagnosis of HBV, HCV, or HIV is vital as it allows people to access treatment, which significantly reduces associated long-term morbidity and mortality.
“In many cases, those most at risk of one of these infections are also more vulnerable to infection with one or both of the other viruses, making the argument for integrated testing even stronger,” she said in an interview.
Mr. Nilsson-Møller and Dr. Pharris reported no relevant financial relationships. Aptima kits for validation were provided by Hologic.
A version of this article first appeared on Medscape.com.
FROM ECCMID 2023
AI predicts endometrial cancer recurrence
Endometrial cancer is the most frequently occurring uterine cancer. Early-stage patients have about a 95% 5-year survival, but distant recurrence is associated with very poor survival, according to Sarah Fremond, MSc, an author of the research (Abstract 5695), which she presented at the annual meeting of the American Association for Cancer Research.
“Most patients with endometrial cancer have a good prognosis and would not require any adjuvant treatment, but there is a proportion that will develop distant recurrence. For those you want to recommend adjuvant chemotherapy, because currently in the adjuvant setting, that’s the only treatment that is known to lower the risk of distant recurrence. But that also causes morbidity. Therefore, our clinical question was how to accurately identify patients at low and high risk of distant recurrence to reduce under- and overtreatment,” said Ms. Fremond, a PhD candidate at Leiden (the Netherlands) University Medical Center.
Pathologists can attempt such predictions, but Ms. Fremond noted that there are challenges. “There is a lot of variability between pathologists, and we don’t even use the entire visual information present in the H&E [hematoxylin and eosin] tumor slide. When it comes to molecular testing, it is hampered by cost, turnaround time, and sometimes interpretation. It’s quite complex to combine those data to specifically target risk of distant recurrence for patients with endometrial cancer.”
In her presentation, Ms. Fremond described how she and her colleagues used digitized histopathological slides in their research. She and her coauthors developed the AI model as part of a collaboration that included the AIRMEC Consortium, Leiden University Medical Center, the TransPORTEC Consortium, and the University of Zürich.
The researchers used long-term follow-up data from 1,408 patients drawn from three clinical cohorts and participants in the PORTEC-1, PORTEC-2, and PORTEC-3 studies, which tested radiotherapy and adjuvant therapy outcomes in endometrial cancer. Patients who had received prior adjuvant chemotherapy were excluded. In the model development phase, the system analyzed a single representative histopathological slide image from each patient and compared it with the known time to distant recurrence to identify patterns.
Once the system had been trained, the researchers applied it to a novel group of 353 patients. It ranked 89 patients as having a low risk of recurrence, 175 at intermediate risk, and 89 at high risk of recurrence. The system performed well: 3.37% of low-risk patients experienced a distant recurrence, as did 15.43% of the intermediate-risk group and 36% of the high-risk group.
The researchers also employed an external validation group with 152 patients and three slides per patient, with a 2.8-year follow-up. The model performed with a C index of 0.805 (±0.0136) when a random slide was selected for each patient, and the median predicted risk score per patient was associated with differences in distant recurrence-free survival between the three risk groups with a C index of 0.816 (P < .0001).
Questions about research and their answers
Session moderator Kristin Swanson, PhD, asked if the AI could be used with the pathology slide’s visible features to learn more about the underlying biology and pathophysiology of tumors.
“Overlying the HECTOR on to the tissue seems like a logical opportunity to go and then explore the biology and what’s attributed as a high-risk region,” said Dr. Swanson, who is director of the Mathematical NeuroOncology Lab and codirector of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic Arizona, Phoenix.
Ms. Fremond agreed that the AI has the potential to be used that way.”
During the Q&A, an audience member asked how likely the model is to perform in populations that differ significantly from the populations used in her study.
Ms. Fremond responded that the populations used to develop and test the models were in or close to the Netherlands, and little information was available regarding patient ethnicity. “There is a possibility that perhaps we would have a different performance on a population that includes more minorities. That needs to be checked,” said Ms. Fremond.
The study is limited by its retrospective nature.
Ms. Fremond and Dr. Swanson have no relevant financial disclosures.
Endometrial cancer is the most frequently occurring uterine cancer. Early-stage patients have about a 95% 5-year survival, but distant recurrence is associated with very poor survival, according to Sarah Fremond, MSc, an author of the research (Abstract 5695), which she presented at the annual meeting of the American Association for Cancer Research.
“Most patients with endometrial cancer have a good prognosis and would not require any adjuvant treatment, but there is a proportion that will develop distant recurrence. For those you want to recommend adjuvant chemotherapy, because currently in the adjuvant setting, that’s the only treatment that is known to lower the risk of distant recurrence. But that also causes morbidity. Therefore, our clinical question was how to accurately identify patients at low and high risk of distant recurrence to reduce under- and overtreatment,” said Ms. Fremond, a PhD candidate at Leiden (the Netherlands) University Medical Center.
Pathologists can attempt such predictions, but Ms. Fremond noted that there are challenges. “There is a lot of variability between pathologists, and we don’t even use the entire visual information present in the H&E [hematoxylin and eosin] tumor slide. When it comes to molecular testing, it is hampered by cost, turnaround time, and sometimes interpretation. It’s quite complex to combine those data to specifically target risk of distant recurrence for patients with endometrial cancer.”
In her presentation, Ms. Fremond described how she and her colleagues used digitized histopathological slides in their research. She and her coauthors developed the AI model as part of a collaboration that included the AIRMEC Consortium, Leiden University Medical Center, the TransPORTEC Consortium, and the University of Zürich.
The researchers used long-term follow-up data from 1,408 patients drawn from three clinical cohorts and participants in the PORTEC-1, PORTEC-2, and PORTEC-3 studies, which tested radiotherapy and adjuvant therapy outcomes in endometrial cancer. Patients who had received prior adjuvant chemotherapy were excluded. In the model development phase, the system analyzed a single representative histopathological slide image from each patient and compared it with the known time to distant recurrence to identify patterns.
Once the system had been trained, the researchers applied it to a novel group of 353 patients. It ranked 89 patients as having a low risk of recurrence, 175 at intermediate risk, and 89 at high risk of recurrence. The system performed well: 3.37% of low-risk patients experienced a distant recurrence, as did 15.43% of the intermediate-risk group and 36% of the high-risk group.
The researchers also employed an external validation group with 152 patients and three slides per patient, with a 2.8-year follow-up. The model performed with a C index of 0.805 (±0.0136) when a random slide was selected for each patient, and the median predicted risk score per patient was associated with differences in distant recurrence-free survival between the three risk groups with a C index of 0.816 (P < .0001).
Questions about research and their answers
Session moderator Kristin Swanson, PhD, asked if the AI could be used with the pathology slide’s visible features to learn more about the underlying biology and pathophysiology of tumors.
“Overlying the HECTOR on to the tissue seems like a logical opportunity to go and then explore the biology and what’s attributed as a high-risk region,” said Dr. Swanson, who is director of the Mathematical NeuroOncology Lab and codirector of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic Arizona, Phoenix.
Ms. Fremond agreed that the AI has the potential to be used that way.”
During the Q&A, an audience member asked how likely the model is to perform in populations that differ significantly from the populations used in her study.
Ms. Fremond responded that the populations used to develop and test the models were in or close to the Netherlands, and little information was available regarding patient ethnicity. “There is a possibility that perhaps we would have a different performance on a population that includes more minorities. That needs to be checked,” said Ms. Fremond.
The study is limited by its retrospective nature.
Ms. Fremond and Dr. Swanson have no relevant financial disclosures.
Endometrial cancer is the most frequently occurring uterine cancer. Early-stage patients have about a 95% 5-year survival, but distant recurrence is associated with very poor survival, according to Sarah Fremond, MSc, an author of the research (Abstract 5695), which she presented at the annual meeting of the American Association for Cancer Research.
“Most patients with endometrial cancer have a good prognosis and would not require any adjuvant treatment, but there is a proportion that will develop distant recurrence. For those you want to recommend adjuvant chemotherapy, because currently in the adjuvant setting, that’s the only treatment that is known to lower the risk of distant recurrence. But that also causes morbidity. Therefore, our clinical question was how to accurately identify patients at low and high risk of distant recurrence to reduce under- and overtreatment,” said Ms. Fremond, a PhD candidate at Leiden (the Netherlands) University Medical Center.
Pathologists can attempt such predictions, but Ms. Fremond noted that there are challenges. “There is a lot of variability between pathologists, and we don’t even use the entire visual information present in the H&E [hematoxylin and eosin] tumor slide. When it comes to molecular testing, it is hampered by cost, turnaround time, and sometimes interpretation. It’s quite complex to combine those data to specifically target risk of distant recurrence for patients with endometrial cancer.”
In her presentation, Ms. Fremond described how she and her colleagues used digitized histopathological slides in their research. She and her coauthors developed the AI model as part of a collaboration that included the AIRMEC Consortium, Leiden University Medical Center, the TransPORTEC Consortium, and the University of Zürich.
The researchers used long-term follow-up data from 1,408 patients drawn from three clinical cohorts and participants in the PORTEC-1, PORTEC-2, and PORTEC-3 studies, which tested radiotherapy and adjuvant therapy outcomes in endometrial cancer. Patients who had received prior adjuvant chemotherapy were excluded. In the model development phase, the system analyzed a single representative histopathological slide image from each patient and compared it with the known time to distant recurrence to identify patterns.
Once the system had been trained, the researchers applied it to a novel group of 353 patients. It ranked 89 patients as having a low risk of recurrence, 175 at intermediate risk, and 89 at high risk of recurrence. The system performed well: 3.37% of low-risk patients experienced a distant recurrence, as did 15.43% of the intermediate-risk group and 36% of the high-risk group.
The researchers also employed an external validation group with 152 patients and three slides per patient, with a 2.8-year follow-up. The model performed with a C index of 0.805 (±0.0136) when a random slide was selected for each patient, and the median predicted risk score per patient was associated with differences in distant recurrence-free survival between the three risk groups with a C index of 0.816 (P < .0001).
Questions about research and their answers
Session moderator Kristin Swanson, PhD, asked if the AI could be used with the pathology slide’s visible features to learn more about the underlying biology and pathophysiology of tumors.
“Overlying the HECTOR on to the tissue seems like a logical opportunity to go and then explore the biology and what’s attributed as a high-risk region,” said Dr. Swanson, who is director of the Mathematical NeuroOncology Lab and codirector of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic Arizona, Phoenix.
Ms. Fremond agreed that the AI has the potential to be used that way.”
During the Q&A, an audience member asked how likely the model is to perform in populations that differ significantly from the populations used in her study.
Ms. Fremond responded that the populations used to develop and test the models were in or close to the Netherlands, and little information was available regarding patient ethnicity. “There is a possibility that perhaps we would have a different performance on a population that includes more minorities. That needs to be checked,” said Ms. Fremond.
The study is limited by its retrospective nature.
Ms. Fremond and Dr. Swanson have no relevant financial disclosures.
FROM AACR 2023
PARP/ATR inhibitor combo shows hints of promise in children with tumors
The small phase 1 trial also identified some molecular signatures in responders that may inform future clinical trials.
The results, presented at the annual meeting of the American Association of Cancer Research, came from a single arm of the European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) trial. This trial matches pediatric, adolescent, and young adult cancer patients with treatment regimens based on the molecular profile of their tumors.
In over 220 children to date, the trial has investigated 15 different treatment regimens, most of which are combination therapies.
In adults, PARP) inhibitors have been shown to be effective in tumors with deficiencies in homologous repair, which is a DNA repair mechanism, with notable successes in patients carrying the BRCA1 and BRCA2 mutations. But BRCA1 and BRCA2 mutations are rare in pediatric cancer, and there is a belief that there may be primary resistance to PARP inhibitors in pediatric tumors, according to Susanne Gatz, MD, PhD, who presented the research at the meeting.
Previous research identified alterations in pediatric tumors that are candidates for patient selection. “These tumors have alterations which could potentially cause this resistance effect [against PARP inhibitors] and [also cause] sensitivity to ataxia telangiectasia–mutated Rad3-related inhibitors. This is how this arm [of the ESMART trial] was born,” said Dr. Gatz.
The phase 1 portion of the study included 18 pediatric and young adult patients with relapsed or treatment-refractory tumors. There were eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. Each had mutations thought to lead to HR deficiency or replication stress. The study included three dose levels of twice-daily oral olaparib that was given continuously, and ceralasertib, which was given day 1-14 of each 28-day cycle.
Patients underwent a median of 3.5 cycles of treatment. There were dose-limiting adverse events of thrombocytopenia and neutropenia in five patients, two of which occurred at the dose that was recommended for phase 2.
There were some positive clinical signs, including one partial response in a pineoblastoma patient who received treatment for 11 cycles. A neuroblastoma patient had stable disease until cycle 9 of treatment, and then converted to a partial response and is currently in cycle 12. Two other patients remain in treatment at cycle 8 and one is in treatment at cycle 15. None of the patients who experienced clinical benefit had BRCA mutations.
An important goal of the study was to understand molecular signature that might predict response to the drug combination. Although no firm conclusions could be drawn, there were some interesting patterns. In particular, five of the six worst responders had TP53 mutations. “It is striking ... so we need to learn what TP53 in this setting means if it’s mutated, and if it could be a resistance factor,” said Dr. Gatz, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham, during her talk.
Although the study is too small and included too many tumor types to identify tumor-based patterns of response, it did provide some hints as to biomarkers that could inform future studies, according to Julia Glade Bender, MD, who served as a discussant following the presentation and is a pediatric oncologist at Memorial Sloan Kettering Cancer Center, New York.
“The pediatric frequency of the common DNA damage repair biomarkers that have been [identified in] the adult literature – that is to say, BRCA1 and 2 and [ataxia-telangiectasia mutation] – are exceedingly rare in pediatrics,” said Dr. Bender during the session while serving as a discussant. She highlighted the following findings: Loss of the 11q region on chromosome 11 is common among the patients and that region contains three genes involved in the DNA damage response, along with a gene involved in homologous recombination, telomere maintenance, and double strand break repair.
She added that 11q deletion is also found in up to 40% of neuroblastomas, and is associated with poor prognosis, and the patients have multiple segmental chromosomal abnormalities. “That begs the question [of] whether chromosomal instability is another biomarker for pediatric cancer,” said Dr. Bender.
“The research highlights the complexity of pediatric cancers, whose distinct biology could make them more vulnerable to ATR [kinase], [checkpoint kinase 1], and WEE1 pathway inhibition with a PARP inhibitor used to induce replication stress and be the sensitizer. The biomarker profiles are going to be complex, context-dependent, and likely to reflect a constellation of findings that would be signatures or algorithms, rather than single gene alterations. The post hoc iterative analysis of responders and nonresponders is going to be absolutely critical to understanding those biomarkers and the role of DNA damage response inhibitors in pediatrics. Given the rarity of these diagnoses, and then the molecular subclasses, I think collaboration across ages and geography is absolutely critical, and I really congratulate the ESMART consortium for doing just that in Europe,” said Dr. Bender.
The study is limited by its small sample size and the fact that it was not randomized.
The study received funding from French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group. Dr. Gatz has no relevant financial disclosures. Dr. Bender has done paid consulting for Jazz Pharmaceuticals and has done unpaid work for Bristol-Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, and Pfizer. She has received research support from Eli Lilly, Loxo-oncology, Eisai, Cellectar, Bayer, Amgen, and Jazz Pharmaceuticals.
From American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT019. Presented Tuesday, April 18.
The small phase 1 trial also identified some molecular signatures in responders that may inform future clinical trials.
The results, presented at the annual meeting of the American Association of Cancer Research, came from a single arm of the European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) trial. This trial matches pediatric, adolescent, and young adult cancer patients with treatment regimens based on the molecular profile of their tumors.
In over 220 children to date, the trial has investigated 15 different treatment regimens, most of which are combination therapies.
In adults, PARP) inhibitors have been shown to be effective in tumors with deficiencies in homologous repair, which is a DNA repair mechanism, with notable successes in patients carrying the BRCA1 and BRCA2 mutations. But BRCA1 and BRCA2 mutations are rare in pediatric cancer, and there is a belief that there may be primary resistance to PARP inhibitors in pediatric tumors, according to Susanne Gatz, MD, PhD, who presented the research at the meeting.
Previous research identified alterations in pediatric tumors that are candidates for patient selection. “These tumors have alterations which could potentially cause this resistance effect [against PARP inhibitors] and [also cause] sensitivity to ataxia telangiectasia–mutated Rad3-related inhibitors. This is how this arm [of the ESMART trial] was born,” said Dr. Gatz.
The phase 1 portion of the study included 18 pediatric and young adult patients with relapsed or treatment-refractory tumors. There were eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. Each had mutations thought to lead to HR deficiency or replication stress. The study included three dose levels of twice-daily oral olaparib that was given continuously, and ceralasertib, which was given day 1-14 of each 28-day cycle.
Patients underwent a median of 3.5 cycles of treatment. There were dose-limiting adverse events of thrombocytopenia and neutropenia in five patients, two of which occurred at the dose that was recommended for phase 2.
There were some positive clinical signs, including one partial response in a pineoblastoma patient who received treatment for 11 cycles. A neuroblastoma patient had stable disease until cycle 9 of treatment, and then converted to a partial response and is currently in cycle 12. Two other patients remain in treatment at cycle 8 and one is in treatment at cycle 15. None of the patients who experienced clinical benefit had BRCA mutations.
An important goal of the study was to understand molecular signature that might predict response to the drug combination. Although no firm conclusions could be drawn, there were some interesting patterns. In particular, five of the six worst responders had TP53 mutations. “It is striking ... so we need to learn what TP53 in this setting means if it’s mutated, and if it could be a resistance factor,” said Dr. Gatz, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham, during her talk.
Although the study is too small and included too many tumor types to identify tumor-based patterns of response, it did provide some hints as to biomarkers that could inform future studies, according to Julia Glade Bender, MD, who served as a discussant following the presentation and is a pediatric oncologist at Memorial Sloan Kettering Cancer Center, New York.
“The pediatric frequency of the common DNA damage repair biomarkers that have been [identified in] the adult literature – that is to say, BRCA1 and 2 and [ataxia-telangiectasia mutation] – are exceedingly rare in pediatrics,” said Dr. Bender during the session while serving as a discussant. She highlighted the following findings: Loss of the 11q region on chromosome 11 is common among the patients and that region contains three genes involved in the DNA damage response, along with a gene involved in homologous recombination, telomere maintenance, and double strand break repair.
She added that 11q deletion is also found in up to 40% of neuroblastomas, and is associated with poor prognosis, and the patients have multiple segmental chromosomal abnormalities. “That begs the question [of] whether chromosomal instability is another biomarker for pediatric cancer,” said Dr. Bender.
“The research highlights the complexity of pediatric cancers, whose distinct biology could make them more vulnerable to ATR [kinase], [checkpoint kinase 1], and WEE1 pathway inhibition with a PARP inhibitor used to induce replication stress and be the sensitizer. The biomarker profiles are going to be complex, context-dependent, and likely to reflect a constellation of findings that would be signatures or algorithms, rather than single gene alterations. The post hoc iterative analysis of responders and nonresponders is going to be absolutely critical to understanding those biomarkers and the role of DNA damage response inhibitors in pediatrics. Given the rarity of these diagnoses, and then the molecular subclasses, I think collaboration across ages and geography is absolutely critical, and I really congratulate the ESMART consortium for doing just that in Europe,” said Dr. Bender.
The study is limited by its small sample size and the fact that it was not randomized.
The study received funding from French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group. Dr. Gatz has no relevant financial disclosures. Dr. Bender has done paid consulting for Jazz Pharmaceuticals and has done unpaid work for Bristol-Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, and Pfizer. She has received research support from Eli Lilly, Loxo-oncology, Eisai, Cellectar, Bayer, Amgen, and Jazz Pharmaceuticals.
From American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT019. Presented Tuesday, April 18.
The small phase 1 trial also identified some molecular signatures in responders that may inform future clinical trials.
The results, presented at the annual meeting of the American Association of Cancer Research, came from a single arm of the European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) trial. This trial matches pediatric, adolescent, and young adult cancer patients with treatment regimens based on the molecular profile of their tumors.
In over 220 children to date, the trial has investigated 15 different treatment regimens, most of which are combination therapies.
In adults, PARP) inhibitors have been shown to be effective in tumors with deficiencies in homologous repair, which is a DNA repair mechanism, with notable successes in patients carrying the BRCA1 and BRCA2 mutations. But BRCA1 and BRCA2 mutations are rare in pediatric cancer, and there is a belief that there may be primary resistance to PARP inhibitors in pediatric tumors, according to Susanne Gatz, MD, PhD, who presented the research at the meeting.
Previous research identified alterations in pediatric tumors that are candidates for patient selection. “These tumors have alterations which could potentially cause this resistance effect [against PARP inhibitors] and [also cause] sensitivity to ataxia telangiectasia–mutated Rad3-related inhibitors. This is how this arm [of the ESMART trial] was born,” said Dr. Gatz.
The phase 1 portion of the study included 18 pediatric and young adult patients with relapsed or treatment-refractory tumors. There were eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. Each had mutations thought to lead to HR deficiency or replication stress. The study included three dose levels of twice-daily oral olaparib that was given continuously, and ceralasertib, which was given day 1-14 of each 28-day cycle.
Patients underwent a median of 3.5 cycles of treatment. There were dose-limiting adverse events of thrombocytopenia and neutropenia in five patients, two of which occurred at the dose that was recommended for phase 2.
There were some positive clinical signs, including one partial response in a pineoblastoma patient who received treatment for 11 cycles. A neuroblastoma patient had stable disease until cycle 9 of treatment, and then converted to a partial response and is currently in cycle 12. Two other patients remain in treatment at cycle 8 and one is in treatment at cycle 15. None of the patients who experienced clinical benefit had BRCA mutations.
An important goal of the study was to understand molecular signature that might predict response to the drug combination. Although no firm conclusions could be drawn, there were some interesting patterns. In particular, five of the six worst responders had TP53 mutations. “It is striking ... so we need to learn what TP53 in this setting means if it’s mutated, and if it could be a resistance factor,” said Dr. Gatz, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham, during her talk.
Although the study is too small and included too many tumor types to identify tumor-based patterns of response, it did provide some hints as to biomarkers that could inform future studies, according to Julia Glade Bender, MD, who served as a discussant following the presentation and is a pediatric oncologist at Memorial Sloan Kettering Cancer Center, New York.
“The pediatric frequency of the common DNA damage repair biomarkers that have been [identified in] the adult literature – that is to say, BRCA1 and 2 and [ataxia-telangiectasia mutation] – are exceedingly rare in pediatrics,” said Dr. Bender during the session while serving as a discussant. She highlighted the following findings: Loss of the 11q region on chromosome 11 is common among the patients and that region contains three genes involved in the DNA damage response, along with a gene involved in homologous recombination, telomere maintenance, and double strand break repair.
She added that 11q deletion is also found in up to 40% of neuroblastomas, and is associated with poor prognosis, and the patients have multiple segmental chromosomal abnormalities. “That begs the question [of] whether chromosomal instability is another biomarker for pediatric cancer,” said Dr. Bender.
“The research highlights the complexity of pediatric cancers, whose distinct biology could make them more vulnerable to ATR [kinase], [checkpoint kinase 1], and WEE1 pathway inhibition with a PARP inhibitor used to induce replication stress and be the sensitizer. The biomarker profiles are going to be complex, context-dependent, and likely to reflect a constellation of findings that would be signatures or algorithms, rather than single gene alterations. The post hoc iterative analysis of responders and nonresponders is going to be absolutely critical to understanding those biomarkers and the role of DNA damage response inhibitors in pediatrics. Given the rarity of these diagnoses, and then the molecular subclasses, I think collaboration across ages and geography is absolutely critical, and I really congratulate the ESMART consortium for doing just that in Europe,” said Dr. Bender.
The study is limited by its small sample size and the fact that it was not randomized.
The study received funding from French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group. Dr. Gatz has no relevant financial disclosures. Dr. Bender has done paid consulting for Jazz Pharmaceuticals and has done unpaid work for Bristol-Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, and Pfizer. She has received research support from Eli Lilly, Loxo-oncology, Eisai, Cellectar, Bayer, Amgen, and Jazz Pharmaceuticals.
From American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT019. Presented Tuesday, April 18.
FROM AACR 2023