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ctDNA clearance tracks with PFS in NSCLC subtype
The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).
“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.
Dr. Hartmaier presented these findings at the AACR virtual meeting II.
Prior results of TATTON
Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.
Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.
The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.
Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.
“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.
According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.
“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
ctDNA analysis
Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.
Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.
Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.
Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.
In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).
Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.
Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.
“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.
The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.
SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.
The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).
“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.
Dr. Hartmaier presented these findings at the AACR virtual meeting II.
Prior results of TATTON
Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.
Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.
The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.
Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.
“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.
According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.
“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
ctDNA analysis
Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.
Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.
Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.
Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.
In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).
Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.
Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.
“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.
The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.
SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.
The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).
“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.
Dr. Hartmaier presented these findings at the AACR virtual meeting II.
Prior results of TATTON
Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.
Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.
The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.
Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.
“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.
According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.
“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
ctDNA analysis
Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.
Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.
Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.
Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.
In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).
Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.
Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.
“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.
The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.
SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.
FROM AACR 2020
Hep C sofosbuvir/daclatasvir combo promising for COVID-19
research from an open-label Iranian study shows.
And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.
But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.
“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.
Three Trials, 176 Patients
Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.
All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.
The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.
All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.
More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.
However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).
The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.
A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.
The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.
However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.
Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.
These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”
But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.
Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.
“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.
“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
This article first appeared on Medscape.com.
research from an open-label Iranian study shows.
And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.
But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.
“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.
Three Trials, 176 Patients
Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.
All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.
The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.
All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.
More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.
However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).
The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.
A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.
The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.
However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.
Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.
These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”
But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.
Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.
“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.
“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
This article first appeared on Medscape.com.
research from an open-label Iranian study shows.
And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.
But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.
“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.
Three Trials, 176 Patients
Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.
All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.
The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.
All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.
More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.
However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).
The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.
A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.
The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.
However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.
Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.
These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”
But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.
Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.
“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.
“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
This article first appeared on Medscape.com.
AI markers can predict progression, survival in prostate cancer
An AI-based Gleason score – derived from 7,267 digitized biopsy slides, pathology reports, and clinical data from patient electronic medical records – was calculated for each of 599 prostate cancer patients.
The AI scores were compared with pathologists’ Gleason scores, which were obtained from pathology reports for each of the patients.
The two scores were “highly correlated,” according to investigators. The area under the curve (AUC) for the 7-year mortality rate was 0.667 for the AI-based scores and 0.659 for the pathologists’ scores.
The investigators also found that markers extracted using AI-based algorithms could predict disease progression in patients with low- and higher-grade disease.
Daphna Laifenfeld, PhD, chief scientific officer of Ibex Medical Analytics in Tel Aviv, reported these results in a poster at the AACR virtual meeting II. Ibex Medical Analytics is the company that developed the AI-based algorithms and Gleason score (the Ibex score).
In addition to comparing the Ibex Gleason scores with pathologists’ scores, Dr. Laifenfeld and colleagues sought to “develop AI markers – computational features extracted from slides using AI-based algorithms – that can predict disease progression in low-, and separately, higher-grade patients.”
Information extracted using the algorithms included Gleason scores; perineural invasion; and other characteristics such as inflammation, high-grade prostatic intraepithelial neoplasia, and atrophy.
“We used data ... to address each aim, analyzing hundreds of patients in each comparison, and employed logistic regression to develop the predictive models,” Dr. Laifenfeld said.
Of the 357 patients evaluated, 180 had low-grade disease, defined by a prebiopsy prostate-specific antigen (PSA) level less than 10 ng/mL (Gleason group 1), and 177 patients had higher-grade disease (Gleason group 2 or higher).
Gleason group 1 patients were considered to have progressed if they developed higher-grade cancer, underwent prostatectomy, or if their cancer had metastasized. Gleason group 2 and above patients were considered to have progressed if their cancer metastasized or if they had a postprostatectomy PSA level greater than 4 ng/ml.
In Gleason group 1 patients, combining multiple features from the pathology report with prebiopsy PSA levels was shown to predict disease progression better than prebiopsy PSA levels alone (AUC, 0.687).
“Importantly, AI markers that combine features automatically extracted by Ibex with prebiopsy PSA levels are even better associated with progression (AUC, 0.748),” Dr. Laifenfeld said.
Similarly, in the Gleason group 2 and above patients, the AI markers that combine Ibex-extracted features with prebiopsy PSA levels were also highly associated with progression (AUC, 0.862 vs. AUC, 0.77 for the non–Ibex-based approach) and can be used for patient stratification, Dr. Laifenfeld said.
“For each patient, we can predict whether or not their disease will progress,” she said. “[T]his type of stratification can then be used to support clinical disease management decisions, and [it can be used] in the course of drug development for patient stratification and trial enrichment strategies.”
Dr. Laifenfeld and some coinvestigators are employed by Ibex Medical Analytics.
SOURCE: Laifenfeld D et al. AACR 2020, Abstract 867.
An AI-based Gleason score – derived from 7,267 digitized biopsy slides, pathology reports, and clinical data from patient electronic medical records – was calculated for each of 599 prostate cancer patients.
The AI scores were compared with pathologists’ Gleason scores, which were obtained from pathology reports for each of the patients.
The two scores were “highly correlated,” according to investigators. The area under the curve (AUC) for the 7-year mortality rate was 0.667 for the AI-based scores and 0.659 for the pathologists’ scores.
The investigators also found that markers extracted using AI-based algorithms could predict disease progression in patients with low- and higher-grade disease.
Daphna Laifenfeld, PhD, chief scientific officer of Ibex Medical Analytics in Tel Aviv, reported these results in a poster at the AACR virtual meeting II. Ibex Medical Analytics is the company that developed the AI-based algorithms and Gleason score (the Ibex score).
In addition to comparing the Ibex Gleason scores with pathologists’ scores, Dr. Laifenfeld and colleagues sought to “develop AI markers – computational features extracted from slides using AI-based algorithms – that can predict disease progression in low-, and separately, higher-grade patients.”
Information extracted using the algorithms included Gleason scores; perineural invasion; and other characteristics such as inflammation, high-grade prostatic intraepithelial neoplasia, and atrophy.
“We used data ... to address each aim, analyzing hundreds of patients in each comparison, and employed logistic regression to develop the predictive models,” Dr. Laifenfeld said.
Of the 357 patients evaluated, 180 had low-grade disease, defined by a prebiopsy prostate-specific antigen (PSA) level less than 10 ng/mL (Gleason group 1), and 177 patients had higher-grade disease (Gleason group 2 or higher).
Gleason group 1 patients were considered to have progressed if they developed higher-grade cancer, underwent prostatectomy, or if their cancer had metastasized. Gleason group 2 and above patients were considered to have progressed if their cancer metastasized or if they had a postprostatectomy PSA level greater than 4 ng/ml.
In Gleason group 1 patients, combining multiple features from the pathology report with prebiopsy PSA levels was shown to predict disease progression better than prebiopsy PSA levels alone (AUC, 0.687).
“Importantly, AI markers that combine features automatically extracted by Ibex with prebiopsy PSA levels are even better associated with progression (AUC, 0.748),” Dr. Laifenfeld said.
Similarly, in the Gleason group 2 and above patients, the AI markers that combine Ibex-extracted features with prebiopsy PSA levels were also highly associated with progression (AUC, 0.862 vs. AUC, 0.77 for the non–Ibex-based approach) and can be used for patient stratification, Dr. Laifenfeld said.
“For each patient, we can predict whether or not their disease will progress,” she said. “[T]his type of stratification can then be used to support clinical disease management decisions, and [it can be used] in the course of drug development for patient stratification and trial enrichment strategies.”
Dr. Laifenfeld and some coinvestigators are employed by Ibex Medical Analytics.
SOURCE: Laifenfeld D et al. AACR 2020, Abstract 867.
An AI-based Gleason score – derived from 7,267 digitized biopsy slides, pathology reports, and clinical data from patient electronic medical records – was calculated for each of 599 prostate cancer patients.
The AI scores were compared with pathologists’ Gleason scores, which were obtained from pathology reports for each of the patients.
The two scores were “highly correlated,” according to investigators. The area under the curve (AUC) for the 7-year mortality rate was 0.667 for the AI-based scores and 0.659 for the pathologists’ scores.
The investigators also found that markers extracted using AI-based algorithms could predict disease progression in patients with low- and higher-grade disease.
Daphna Laifenfeld, PhD, chief scientific officer of Ibex Medical Analytics in Tel Aviv, reported these results in a poster at the AACR virtual meeting II. Ibex Medical Analytics is the company that developed the AI-based algorithms and Gleason score (the Ibex score).
In addition to comparing the Ibex Gleason scores with pathologists’ scores, Dr. Laifenfeld and colleagues sought to “develop AI markers – computational features extracted from slides using AI-based algorithms – that can predict disease progression in low-, and separately, higher-grade patients.”
Information extracted using the algorithms included Gleason scores; perineural invasion; and other characteristics such as inflammation, high-grade prostatic intraepithelial neoplasia, and atrophy.
“We used data ... to address each aim, analyzing hundreds of patients in each comparison, and employed logistic regression to develop the predictive models,” Dr. Laifenfeld said.
Of the 357 patients evaluated, 180 had low-grade disease, defined by a prebiopsy prostate-specific antigen (PSA) level less than 10 ng/mL (Gleason group 1), and 177 patients had higher-grade disease (Gleason group 2 or higher).
Gleason group 1 patients were considered to have progressed if they developed higher-grade cancer, underwent prostatectomy, or if their cancer had metastasized. Gleason group 2 and above patients were considered to have progressed if their cancer metastasized or if they had a postprostatectomy PSA level greater than 4 ng/ml.
In Gleason group 1 patients, combining multiple features from the pathology report with prebiopsy PSA levels was shown to predict disease progression better than prebiopsy PSA levels alone (AUC, 0.687).
“Importantly, AI markers that combine features automatically extracted by Ibex with prebiopsy PSA levels are even better associated with progression (AUC, 0.748),” Dr. Laifenfeld said.
Similarly, in the Gleason group 2 and above patients, the AI markers that combine Ibex-extracted features with prebiopsy PSA levels were also highly associated with progression (AUC, 0.862 vs. AUC, 0.77 for the non–Ibex-based approach) and can be used for patient stratification, Dr. Laifenfeld said.
“For each patient, we can predict whether or not their disease will progress,” she said. “[T]his type of stratification can then be used to support clinical disease management decisions, and [it can be used] in the course of drug development for patient stratification and trial enrichment strategies.”
Dr. Laifenfeld and some coinvestigators are employed by Ibex Medical Analytics.
SOURCE: Laifenfeld D et al. AACR 2020, Abstract 867.
FROM AACR 2020
Influenza vaccine efficacy called undiminished in MS
, Jackie Nguyen reported at the virtual annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). She presented a systematic review and meta-analysis of nine published cohort studies including 417 MS patients and more than 500 healthy controls, all of whom received inactivated seasonal influenza vaccine.
The impetus for this project was a recognition that the great majority of the research on the impact of influenza vaccine in patients with MS has focused on safety and MS relapse rates. In contrast, the nine studies included in the meta-analysis contained data on influenza vaccine efficacy as reflected in the ability to mount an adequate immune response. This was defined in standard fashion either by seroconversion, which required at least a fourfold increase in antibody titers following vaccination, or seroprotection, with a postvaccination antihemagglutination immunoglobulin G titer of at least 40. The analysis included patients with MS irrespective of disease duration or severity or treatment regimen, noted Ms. Nguyen, a third-year medical student at Nova Southeastern University College of Allopathic Medicine in Davie, Fla.
The researchers found that there was no significant difference between patients with MS and healthy controls in the rates of an adequate immune response for influenza H1N1, H3N2, or influenza B virus. “The vaccine should thus continue to be recommended for MS patients, as the data shows it to be efficacious,” she said.
Her conclusion is consistent with guidance provided in the American Academy of Neurology’s 2019 practice guideline update on immunization in MS, highlighted elsewhere at CMSC 2020 in a presentation by Marijean Buhse, PhD, of Stony Brook University in New York.
The guideline, updated for the first time in 17 years, states that all MS patients should be advised to receive influenza vaccine annually: “With known risks of exacerbation and other morbidity with influenza infection and no identified risks of exacerbation with influenza vaccines, benefits of influenza vaccination outweigh the risks in most scenarios. The exception involves the relatively few MS patients having a specific contraindication to the influenza vaccine, such as a previous severe reaction, noted Dr. Buhse, who wasn’t involved in developing the evidence-based guidelines.
The available evidence indicates that some but not all disease-modifying therapies for MS reduce the effectiveness of vaccination against influenza.
According to the guideline, “it is possible” that persons with MS being treated with glatiramer acetate have a reduced likelihood of seroprotection from influenza vaccine, a conclusion the guidelines committee drew with “low confidence in the evidence.” Further, the guideline states that “it is probable” MS patients on fingolimod have a lower likelihood of obtaining seroprotection from influenza vaccine than patients not on the drug, with moderate confidence in the evidence. Also, it is deemed probable that patients with MS who are taking mitoxantrone have a reduced likelihood of response to influenza vaccination, compared with healthy controls. But it is probable that patients with MS who are receiving interferon-beta have no diminution in the likelihood of seroprotection. According to the guideline, there is insufficient evidence to say whether patients with MS who are on natalizumab, teriflunomide, or methotrexate have a diminished response to influenza vaccination.
Dr. Buhse noted that rituximab is off-label therapy for MS, so there are no data available regarding the likelihood of seroprotection in response to influenza vaccination in that setting. However, rituximab profoundly decreases the immunogenicity of influenza and pneumococcal vaccines in rheumatoid arthritis patients. It is therefore recommended that inactivated influenza vaccine be given to patients with MS at least 2 weeks prior to starting rituximab or 6 months after the last dose in order to optimize the humoral results. Ms. Nguyen reported having no financial conflicts regarding her presentation. Dr. Buhse reported having received honoraria from Genzyme and Biogen.
, Jackie Nguyen reported at the virtual annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). She presented a systematic review and meta-analysis of nine published cohort studies including 417 MS patients and more than 500 healthy controls, all of whom received inactivated seasonal influenza vaccine.
The impetus for this project was a recognition that the great majority of the research on the impact of influenza vaccine in patients with MS has focused on safety and MS relapse rates. In contrast, the nine studies included in the meta-analysis contained data on influenza vaccine efficacy as reflected in the ability to mount an adequate immune response. This was defined in standard fashion either by seroconversion, which required at least a fourfold increase in antibody titers following vaccination, or seroprotection, with a postvaccination antihemagglutination immunoglobulin G titer of at least 40. The analysis included patients with MS irrespective of disease duration or severity or treatment regimen, noted Ms. Nguyen, a third-year medical student at Nova Southeastern University College of Allopathic Medicine in Davie, Fla.
The researchers found that there was no significant difference between patients with MS and healthy controls in the rates of an adequate immune response for influenza H1N1, H3N2, or influenza B virus. “The vaccine should thus continue to be recommended for MS patients, as the data shows it to be efficacious,” she said.
Her conclusion is consistent with guidance provided in the American Academy of Neurology’s 2019 practice guideline update on immunization in MS, highlighted elsewhere at CMSC 2020 in a presentation by Marijean Buhse, PhD, of Stony Brook University in New York.
The guideline, updated for the first time in 17 years, states that all MS patients should be advised to receive influenza vaccine annually: “With known risks of exacerbation and other morbidity with influenza infection and no identified risks of exacerbation with influenza vaccines, benefits of influenza vaccination outweigh the risks in most scenarios. The exception involves the relatively few MS patients having a specific contraindication to the influenza vaccine, such as a previous severe reaction, noted Dr. Buhse, who wasn’t involved in developing the evidence-based guidelines.
The available evidence indicates that some but not all disease-modifying therapies for MS reduce the effectiveness of vaccination against influenza.
According to the guideline, “it is possible” that persons with MS being treated with glatiramer acetate have a reduced likelihood of seroprotection from influenza vaccine, a conclusion the guidelines committee drew with “low confidence in the evidence.” Further, the guideline states that “it is probable” MS patients on fingolimod have a lower likelihood of obtaining seroprotection from influenza vaccine than patients not on the drug, with moderate confidence in the evidence. Also, it is deemed probable that patients with MS who are taking mitoxantrone have a reduced likelihood of response to influenza vaccination, compared with healthy controls. But it is probable that patients with MS who are receiving interferon-beta have no diminution in the likelihood of seroprotection. According to the guideline, there is insufficient evidence to say whether patients with MS who are on natalizumab, teriflunomide, or methotrexate have a diminished response to influenza vaccination.
Dr. Buhse noted that rituximab is off-label therapy for MS, so there are no data available regarding the likelihood of seroprotection in response to influenza vaccination in that setting. However, rituximab profoundly decreases the immunogenicity of influenza and pneumococcal vaccines in rheumatoid arthritis patients. It is therefore recommended that inactivated influenza vaccine be given to patients with MS at least 2 weeks prior to starting rituximab or 6 months after the last dose in order to optimize the humoral results. Ms. Nguyen reported having no financial conflicts regarding her presentation. Dr. Buhse reported having received honoraria from Genzyme and Biogen.
, Jackie Nguyen reported at the virtual annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). She presented a systematic review and meta-analysis of nine published cohort studies including 417 MS patients and more than 500 healthy controls, all of whom received inactivated seasonal influenza vaccine.
The impetus for this project was a recognition that the great majority of the research on the impact of influenza vaccine in patients with MS has focused on safety and MS relapse rates. In contrast, the nine studies included in the meta-analysis contained data on influenza vaccine efficacy as reflected in the ability to mount an adequate immune response. This was defined in standard fashion either by seroconversion, which required at least a fourfold increase in antibody titers following vaccination, or seroprotection, with a postvaccination antihemagglutination immunoglobulin G titer of at least 40. The analysis included patients with MS irrespective of disease duration or severity or treatment regimen, noted Ms. Nguyen, a third-year medical student at Nova Southeastern University College of Allopathic Medicine in Davie, Fla.
The researchers found that there was no significant difference between patients with MS and healthy controls in the rates of an adequate immune response for influenza H1N1, H3N2, or influenza B virus. “The vaccine should thus continue to be recommended for MS patients, as the data shows it to be efficacious,” she said.
Her conclusion is consistent with guidance provided in the American Academy of Neurology’s 2019 practice guideline update on immunization in MS, highlighted elsewhere at CMSC 2020 in a presentation by Marijean Buhse, PhD, of Stony Brook University in New York.
The guideline, updated for the first time in 17 years, states that all MS patients should be advised to receive influenza vaccine annually: “With known risks of exacerbation and other morbidity with influenza infection and no identified risks of exacerbation with influenza vaccines, benefits of influenza vaccination outweigh the risks in most scenarios. The exception involves the relatively few MS patients having a specific contraindication to the influenza vaccine, such as a previous severe reaction, noted Dr. Buhse, who wasn’t involved in developing the evidence-based guidelines.
The available evidence indicates that some but not all disease-modifying therapies for MS reduce the effectiveness of vaccination against influenza.
According to the guideline, “it is possible” that persons with MS being treated with glatiramer acetate have a reduced likelihood of seroprotection from influenza vaccine, a conclusion the guidelines committee drew with “low confidence in the evidence.” Further, the guideline states that “it is probable” MS patients on fingolimod have a lower likelihood of obtaining seroprotection from influenza vaccine than patients not on the drug, with moderate confidence in the evidence. Also, it is deemed probable that patients with MS who are taking mitoxantrone have a reduced likelihood of response to influenza vaccination, compared with healthy controls. But it is probable that patients with MS who are receiving interferon-beta have no diminution in the likelihood of seroprotection. According to the guideline, there is insufficient evidence to say whether patients with MS who are on natalizumab, teriflunomide, or methotrexate have a diminished response to influenza vaccination.
Dr. Buhse noted that rituximab is off-label therapy for MS, so there are no data available regarding the likelihood of seroprotection in response to influenza vaccination in that setting. However, rituximab profoundly decreases the immunogenicity of influenza and pneumococcal vaccines in rheumatoid arthritis patients. It is therefore recommended that inactivated influenza vaccine be given to patients with MS at least 2 weeks prior to starting rituximab or 6 months after the last dose in order to optimize the humoral results. Ms. Nguyen reported having no financial conflicts regarding her presentation. Dr. Buhse reported having received honoraria from Genzyme and Biogen.
REPORTING FROM CMSC 2020
Diagnosing molluscum contagiosum can be tricky
The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.
“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”
A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.
An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”
The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”
The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”
MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”
MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”
He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.
He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.
He reported having no financial disclosures.
The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.
“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”
A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.
An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”
The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”
The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”
MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”
MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”
He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.
He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.
He reported having no financial disclosures.
The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.
“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”
A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.
An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”
The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”
The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”
MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”
MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”
He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.
He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.
He reported having no financial disclosures.
FROM PEDIATRIC DERMATOLOGY 2020
How aging affects melanoma development and treatment response
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
FROM AACR 2020
Oral difelikefalin quells severe chronic kidney disease–associated itch
, in a first-of-its-kind randomized clinical trial, Gil Yosipovitch, MD, said at the virtual annual meeting of the American Academy of Dermatology.
“Difelikefalin at 1.0 mg was associated with clinically meaningful improvements in pruritus. The improvement in itch was significant by week 2. And nearly 40% of patients achieved a complete response, which was more than two-and-one-half times more than with placebo,” noted Dr. Yosipovitch, professor of dermatology and director of the Miami Itch Center at the University of Miami.
Pruritus associated with chronic kidney disease (CKD) is a common, underrecognized, and distressing condition that causes markedly impaired quality of life. It occurs in patients across all stages of CKD, not just in those on hemodialysis, as is widely but mistakenly believed. And at present there is no approved drug in any country for treatment of CKD-associated itch.
Difelikefalin, a novel selective agonist of peripheral kappa opioid receptors, is designed to have very limited CNS penetration. The drug, which is renally excreted, doesn’t bind to mu or delta opioid receptors. Its antipruritic effect arises from activation of kappa opioid receptors on peripheral sensory neurons and immune cells, the dermatologist explained.
Dr. Yosipovitch presented the results of a phase 2, randomized, double-blind, placebo-controlled, 12-week trial in which 240 patients with severe chronic pruritus and stage 3-5 CKD were assigned to once-daily oral difelikefalin at 0.25 mg, 0.5 mg, or 1.0 mg, or placebo. More than 80% of participants were not on dialysis. Indeed, this was the first-ever clinical trial targeting itch in patients across such a broad spectrum of CKD stages.
The primary study endpoint was change from baseline to week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale. The average baseline score was 7, considered severe pruritus on the 0-10 scale. Patients randomized to difelikefalin at 1.0 mg/day had a mean 4.4-point decrease, a significantly greater improvement than the 3.3-point reduction in placebo-treated controls.
“More than a 4-point decrease is considered a very meaningful itch reduction,” Dr. Yosipovitch noted.
The mean reductions in itch score in patients on 0.25 mg and 0.5 mg/day of difelikefalin were 4.0 and 3.8 points, respectively, which fell short of statistical significance versus placebo.
A key prespecified secondary endpoint was the proportion of subjects with at least a 3-point improvement in itch score over 12 weeks. This was achieved in 72% of patients on the top dose of difelikefalin, compared with 58% of controls, a significant difference. A 4-point or larger decrease in itch score occurred in 65% of patients on 1.0 mg/day of the kappa opioid recent agonist, versus 50% of controls, also a significant difference.
A complete response, defined as an itch score of 0 or 1 at least 80% of the time, was significantly more common in all three active treatment groups than in controls, with rates of 33%, 31.6%, and 38.6% at difelikefalin 0.25, 0.5, and 1.0 mg, compared with 4.4% among those on placebo.
Falls occurred in 1.5% of patients on difelikefalin. “The therapy does seem to increase the risk of dizziness, falls, fatigue, and GI complaints,” according to the investigator.
Still, most of these adverse events were mild or moderate in severity. Only about 1% of participants discontinued treatment for such reasons.
Earlier this year, a positive phase 3 trial of an intravenous formulation of difelikefalin for pruritus was reported in CKD patients on hemodialysis (N Engl J Med. 2020 Jan 16;382[3]:222-32).
In an interview, Dr. Yosipovitch said that this new phase 2 oral dose-finding study wasn’t powered to detect differences in treatment efficacy between the dialysis and nondialysis groups. However, the proportion of patients with at least a 3-point improvement in itch at week 12 was similar in the two groups.
“The oral formulation would of course be more convenient and would be preferred for patients not undergoing hemodialysis,” he said. “I would expect that the IV formulation would be the preferred route of administration for a patient undergoing hemodialysis. An IV formulation would be very convenient for such patients because it’s administered at the dialysis clinic at the end of the hemodialysis session.”
The oral difelikefalin phase 3 program is scheduled to start later in 2020.
CKD-associated itch poses a therapeutic challenge because it has so many contributory factors. These include CKD-induced peripheral neuropathy, functional and structural neuropathic changes in the brain, cutaneous mast cell activation, an imbalance between mu opioid receptor overexpression and kappa opioid receptor downregulation, secondary parathyroidism, and systemic accumulation of aluminum, beta 2 microglobulin, and other dialysis-related substances, the dermatologist observed.
Dr. Yosipovitch reported receiving research grants from a half-dozen pharmaceutical companies. He also serves as a consultant to numerous companies, including Cara Therapeutics, which sponsored the phase 2 trial.
, in a first-of-its-kind randomized clinical trial, Gil Yosipovitch, MD, said at the virtual annual meeting of the American Academy of Dermatology.
“Difelikefalin at 1.0 mg was associated with clinically meaningful improvements in pruritus. The improvement in itch was significant by week 2. And nearly 40% of patients achieved a complete response, which was more than two-and-one-half times more than with placebo,” noted Dr. Yosipovitch, professor of dermatology and director of the Miami Itch Center at the University of Miami.
Pruritus associated with chronic kidney disease (CKD) is a common, underrecognized, and distressing condition that causes markedly impaired quality of life. It occurs in patients across all stages of CKD, not just in those on hemodialysis, as is widely but mistakenly believed. And at present there is no approved drug in any country for treatment of CKD-associated itch.
Difelikefalin, a novel selective agonist of peripheral kappa opioid receptors, is designed to have very limited CNS penetration. The drug, which is renally excreted, doesn’t bind to mu or delta opioid receptors. Its antipruritic effect arises from activation of kappa opioid receptors on peripheral sensory neurons and immune cells, the dermatologist explained.
Dr. Yosipovitch presented the results of a phase 2, randomized, double-blind, placebo-controlled, 12-week trial in which 240 patients with severe chronic pruritus and stage 3-5 CKD were assigned to once-daily oral difelikefalin at 0.25 mg, 0.5 mg, or 1.0 mg, or placebo. More than 80% of participants were not on dialysis. Indeed, this was the first-ever clinical trial targeting itch in patients across such a broad spectrum of CKD stages.
The primary study endpoint was change from baseline to week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale. The average baseline score was 7, considered severe pruritus on the 0-10 scale. Patients randomized to difelikefalin at 1.0 mg/day had a mean 4.4-point decrease, a significantly greater improvement than the 3.3-point reduction in placebo-treated controls.
“More than a 4-point decrease is considered a very meaningful itch reduction,” Dr. Yosipovitch noted.
The mean reductions in itch score in patients on 0.25 mg and 0.5 mg/day of difelikefalin were 4.0 and 3.8 points, respectively, which fell short of statistical significance versus placebo.
A key prespecified secondary endpoint was the proportion of subjects with at least a 3-point improvement in itch score over 12 weeks. This was achieved in 72% of patients on the top dose of difelikefalin, compared with 58% of controls, a significant difference. A 4-point or larger decrease in itch score occurred in 65% of patients on 1.0 mg/day of the kappa opioid recent agonist, versus 50% of controls, also a significant difference.
A complete response, defined as an itch score of 0 or 1 at least 80% of the time, was significantly more common in all three active treatment groups than in controls, with rates of 33%, 31.6%, and 38.6% at difelikefalin 0.25, 0.5, and 1.0 mg, compared with 4.4% among those on placebo.
Falls occurred in 1.5% of patients on difelikefalin. “The therapy does seem to increase the risk of dizziness, falls, fatigue, and GI complaints,” according to the investigator.
Still, most of these adverse events were mild or moderate in severity. Only about 1% of participants discontinued treatment for such reasons.
Earlier this year, a positive phase 3 trial of an intravenous formulation of difelikefalin for pruritus was reported in CKD patients on hemodialysis (N Engl J Med. 2020 Jan 16;382[3]:222-32).
In an interview, Dr. Yosipovitch said that this new phase 2 oral dose-finding study wasn’t powered to detect differences in treatment efficacy between the dialysis and nondialysis groups. However, the proportion of patients with at least a 3-point improvement in itch at week 12 was similar in the two groups.
“The oral formulation would of course be more convenient and would be preferred for patients not undergoing hemodialysis,” he said. “I would expect that the IV formulation would be the preferred route of administration for a patient undergoing hemodialysis. An IV formulation would be very convenient for such patients because it’s administered at the dialysis clinic at the end of the hemodialysis session.”
The oral difelikefalin phase 3 program is scheduled to start later in 2020.
CKD-associated itch poses a therapeutic challenge because it has so many contributory factors. These include CKD-induced peripheral neuropathy, functional and structural neuropathic changes in the brain, cutaneous mast cell activation, an imbalance between mu opioid receptor overexpression and kappa opioid receptor downregulation, secondary parathyroidism, and systemic accumulation of aluminum, beta 2 microglobulin, and other dialysis-related substances, the dermatologist observed.
Dr. Yosipovitch reported receiving research grants from a half-dozen pharmaceutical companies. He also serves as a consultant to numerous companies, including Cara Therapeutics, which sponsored the phase 2 trial.
, in a first-of-its-kind randomized clinical trial, Gil Yosipovitch, MD, said at the virtual annual meeting of the American Academy of Dermatology.
“Difelikefalin at 1.0 mg was associated with clinically meaningful improvements in pruritus. The improvement in itch was significant by week 2. And nearly 40% of patients achieved a complete response, which was more than two-and-one-half times more than with placebo,” noted Dr. Yosipovitch, professor of dermatology and director of the Miami Itch Center at the University of Miami.
Pruritus associated with chronic kidney disease (CKD) is a common, underrecognized, and distressing condition that causes markedly impaired quality of life. It occurs in patients across all stages of CKD, not just in those on hemodialysis, as is widely but mistakenly believed. And at present there is no approved drug in any country for treatment of CKD-associated itch.
Difelikefalin, a novel selective agonist of peripheral kappa opioid receptors, is designed to have very limited CNS penetration. The drug, which is renally excreted, doesn’t bind to mu or delta opioid receptors. Its antipruritic effect arises from activation of kappa opioid receptors on peripheral sensory neurons and immune cells, the dermatologist explained.
Dr. Yosipovitch presented the results of a phase 2, randomized, double-blind, placebo-controlled, 12-week trial in which 240 patients with severe chronic pruritus and stage 3-5 CKD were assigned to once-daily oral difelikefalin at 0.25 mg, 0.5 mg, or 1.0 mg, or placebo. More than 80% of participants were not on dialysis. Indeed, this was the first-ever clinical trial targeting itch in patients across such a broad spectrum of CKD stages.
The primary study endpoint was change from baseline to week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale. The average baseline score was 7, considered severe pruritus on the 0-10 scale. Patients randomized to difelikefalin at 1.0 mg/day had a mean 4.4-point decrease, a significantly greater improvement than the 3.3-point reduction in placebo-treated controls.
“More than a 4-point decrease is considered a very meaningful itch reduction,” Dr. Yosipovitch noted.
The mean reductions in itch score in patients on 0.25 mg and 0.5 mg/day of difelikefalin were 4.0 and 3.8 points, respectively, which fell short of statistical significance versus placebo.
A key prespecified secondary endpoint was the proportion of subjects with at least a 3-point improvement in itch score over 12 weeks. This was achieved in 72% of patients on the top dose of difelikefalin, compared with 58% of controls, a significant difference. A 4-point or larger decrease in itch score occurred in 65% of patients on 1.0 mg/day of the kappa opioid recent agonist, versus 50% of controls, also a significant difference.
A complete response, defined as an itch score of 0 or 1 at least 80% of the time, was significantly more common in all three active treatment groups than in controls, with rates of 33%, 31.6%, and 38.6% at difelikefalin 0.25, 0.5, and 1.0 mg, compared with 4.4% among those on placebo.
Falls occurred in 1.5% of patients on difelikefalin. “The therapy does seem to increase the risk of dizziness, falls, fatigue, and GI complaints,” according to the investigator.
Still, most of these adverse events were mild or moderate in severity. Only about 1% of participants discontinued treatment for such reasons.
Earlier this year, a positive phase 3 trial of an intravenous formulation of difelikefalin for pruritus was reported in CKD patients on hemodialysis (N Engl J Med. 2020 Jan 16;382[3]:222-32).
In an interview, Dr. Yosipovitch said that this new phase 2 oral dose-finding study wasn’t powered to detect differences in treatment efficacy between the dialysis and nondialysis groups. However, the proportion of patients with at least a 3-point improvement in itch at week 12 was similar in the two groups.
“The oral formulation would of course be more convenient and would be preferred for patients not undergoing hemodialysis,” he said. “I would expect that the IV formulation would be the preferred route of administration for a patient undergoing hemodialysis. An IV formulation would be very convenient for such patients because it’s administered at the dialysis clinic at the end of the hemodialysis session.”
The oral difelikefalin phase 3 program is scheduled to start later in 2020.
CKD-associated itch poses a therapeutic challenge because it has so many contributory factors. These include CKD-induced peripheral neuropathy, functional and structural neuropathic changes in the brain, cutaneous mast cell activation, an imbalance between mu opioid receptor overexpression and kappa opioid receptor downregulation, secondary parathyroidism, and systemic accumulation of aluminum, beta 2 microglobulin, and other dialysis-related substances, the dermatologist observed.
Dr. Yosipovitch reported receiving research grants from a half-dozen pharmaceutical companies. He also serves as a consultant to numerous companies, including Cara Therapeutics, which sponsored the phase 2 trial.
FROM AAD 2020
Injection beats pill for long-lasting HIV prevention
Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.
The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).
At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”
Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
Early Study Termination
Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.
By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.
Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.
After the final injection, all participants continued on daily oral Truvada for 48 weeks.
The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.
Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, (hazard ratio, 0.34).
“This definitively establishes the superiority of cabotegravir,” said Landovitz.
He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.
“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
Five Surprising Seroconversions
Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.
But five of the transmissions occurred in participants who appeared to be perfectly adherent.
Landovitz offered a number of possible reasons for this surprising finding.
“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”
Breakthrough HIV transmissions have been rare in people taking oral PrEP.
Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.
“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
“Impressive” Findings
The findings were greeted with excitement, although questions remain.
They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.
However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.
“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”
Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.
“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”
But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.
“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”
We need to make sure this gets licensed for men and women and transgender individuals.
Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.
They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.
“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
ViiV seems to be making such a plan.
“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.
The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.
“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”
International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
This article first appeared on Medscape.com.
Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.
The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).
At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”
Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
Early Study Termination
Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.
By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.
Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.
After the final injection, all participants continued on daily oral Truvada for 48 weeks.
The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.
Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, (hazard ratio, 0.34).
“This definitively establishes the superiority of cabotegravir,” said Landovitz.
He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.
“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
Five Surprising Seroconversions
Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.
But five of the transmissions occurred in participants who appeared to be perfectly adherent.
Landovitz offered a number of possible reasons for this surprising finding.
“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”
Breakthrough HIV transmissions have been rare in people taking oral PrEP.
Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.
“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
“Impressive” Findings
The findings were greeted with excitement, although questions remain.
They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.
However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.
“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”
Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.
“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”
But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.
“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”
We need to make sure this gets licensed for men and women and transgender individuals.
Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.
They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.
“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
ViiV seems to be making such a plan.
“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.
The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.
“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”
International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
This article first appeared on Medscape.com.
Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.
The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).
At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”
Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
Early Study Termination
Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.
By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.
Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.
After the final injection, all participants continued on daily oral Truvada for 48 weeks.
The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.
Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, (hazard ratio, 0.34).
“This definitively establishes the superiority of cabotegravir,” said Landovitz.
He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.
“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
Five Surprising Seroconversions
Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.
But five of the transmissions occurred in participants who appeared to be perfectly adherent.
Landovitz offered a number of possible reasons for this surprising finding.
“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”
Breakthrough HIV transmissions have been rare in people taking oral PrEP.
Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.
“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
“Impressive” Findings
The findings were greeted with excitement, although questions remain.
They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.
However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.
“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”
Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.
“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”
But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.
“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”
We need to make sure this gets licensed for men and women and transgender individuals.
Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.
They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.
“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
ViiV seems to be making such a plan.
“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.
The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.
“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”
International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
This article first appeared on Medscape.com.
Family environment important in early psychosis outcomes
Family environment may influence subsequent functional outcomes in patients with first-episode psychosis, new research suggests.
A study of more than 300 patients with first-episode psychosis (FEP) showed that although family environment was not associated with functioning at initial presentation, an interaction developed over time that could have “important implications for early interventions for both patients and caregivers,” investigators reported.
study coinvestigator Norma Verdolini, MD, PhD, bipolar and depressive disorders unit, hospital Clinic Barcelona, University of Barcelona, said in an interview.
The findings were scheduled to be presented at the Congress of the Schizophrenia International Research Society 2020, but the meeting was canceled because of the coronavirus pandemic.
FAST measures
Previous research has shown that family environment influences the development of psychotic symptoms, with negative family environmental factors associated with poor prognoses.
Conversely, one study indicated that a positive family environment is linked to greater improvement in negative and disorganized symptoms in adolescents at imminent risk for psychosis onset.
However, the current investigators noted that the impact of family environment on longitudinal functioning in individuals presenting with FEP is unclear.
To investigate further, they conducted an analysis as part of the PEPs study, which included 335 patients with FEP and 253 healthy controls. Functioning was measured using the Functional Assessment Short Test (FAST), and family environmental styles were evaluated using the Family Environment Scale (FES), which assesses “emotional climate” of a family across 10 domains.
At baseline, the mean total FAST score was 27.8 in patients with FEP versus 3.5 in the healthy controls, indicating substantially worse functioning among the patients. Linear regression analysis indicated that at baseline there was no significant association between aspects of family environment on the FES and functional scores.
Patients were assessed again at 2 years, by which point 283 had been diagnosed with psychotic disorders and 52 with bipolar disorder. The mean total FAST scores were 20.98 among patients with psychotic disorders and 13.8 in those with bipolar disorder.
Family conflict
Results showed that, among those with bipolar disorder, worse functioning on FAST at 2 years was significantly associated with higher rates of open expression of conflict in the family (P = .004).
In patients with psychotic disorders, worse functioning was significantly associated with lower rates of participation in social activities (P = .006) and an achievement-oriented family environment (P = .039). Worse functioning in patients with psychotic disorders was also significantly associated with higher rates of religious practice and values (P = .003).
Dr. Verdolini noted the reason family environment does not appear to have an impact at initial FEP presentation may be that the “first kick” is given by an individual’s genetic liability for psychiatric disorders in combination with the family environment. In reality, the two are intertwined, especially when considering what it means to a family to have one member with a psychiatric disorder, which “will have an impact on the family environment.”
Dr. Verdolini added: “This is not actually the objective family environment,” but the perceived family environment.
“So maybe in the following 2 years the patient who experiences a first episode of psychosis may change their idea of the family environment itself,” she noted. She added that at her institution psychoeducation is offered to FEP patients’ families.
‘Interesting’ findings
Commenting on the study, Nicole Kozloff, MD, from the child, youth, and emerging adult program at the Centre for Addiction and Mental Health in Toronto, said one limitation of the study is that it’s not clear what care patients received – or who in the family completed the FES.
It is also important to note that “measures of association do not necessarily imply that one factor caused the other factor,” said Dr. Kozloff, who was not involved in the research. “For example, it may be that, among people with bipolar disorder, open expression of conflict in the family can lead to worse functioning, or that worse functioning can lead to more conflict in the family.”
Nevertheless, Dr. Kozloff described the finding of an emerging association between the family environment and functioning over time as “interesting.”
When young people with FEP enter treatment, “they have reached a crisis point and are functioning poorly,” she noted.
“It could be that there is less to differentiate among levels of functioning at treatment entry but, after 2 years, the individuals have separated into those who have been responsive to treatment and are functioning well, and those who continue to have functional challenges. And this is where we start to see a relationship with family environment emerge,” Dr. Kozloff said.
She also agreed with Dr. Verdolini’s take on the findings, and that family psychoeducation “can reduce relapse rates in schizophrenia and the emotional burden on the family.”
“We also know that having family involvement in care is one of the most robust predictors that young people with psychosis will remain engaged in mental health services,” she said.
Teaching families about psychosis and its treatment, about problem-solving and communication skills, and providing support to ensure that family members know how to get help in a crisis, “is a key part of comprehensive early psychosis intervention,” Dr. Kozloff said. “It is good for the patient and good for the family, and allows the clinicians to provide better care.”
Articulates clinical practice findings
Also commenting on the results, Brian O’Donoghue, MD, PhD, senior clinical research fellow at Orygen, the National Centre of Excellence in Youth Mental Health in Melbourne, described the research as important, adding that the study highlights the need for sufficient follow-up.
“It makes sense that the involvement of family over time has a strong impact upon outcome and functioning,” he said in an interview.
“These research findings articulate what we see in clinical practice, so it is good to see that it is captured,” added Dr. O’Donoghue, who was not associated with the study.
He noted that it is common for family involvement to influence outcome, especially if the family is positively involved. “It is invaluable toward their recovery. However, conversely, if there are ongoing family stressors, then this can be a trigger for relapse or lack of improvement.”
Overall, the results “really emphasize that the family needs to be involved in care.”
The Early Psychosis Prevention and Intervention Centre where Dr. O’Donoghue is a consultant psychiatrist offers a psychoeducational course “to inform families about psychosis, treatment, and how they can support their family members.”
“We also have family peer support workers and family therapists, which are essential to the service and for the young person’s recovery,” Dr. O’Donoghue said.
The investigators and Dr. O’Donoghue disclosed no relevant financial relationships. Dr. Kozloff reported receiving research funding from the CAMH Foundation, Brain & Behavior Research Foundation, Canadian Institutes of Health Research, and AFP Innovation Fund; honoraria from Humber River Hospital, the University of Calgary (Alta.), and the Canadian Consortium for Early Intervention in Psychosis; and salary support from Inner City Health Associates.
A version of this article originally appeared on Medscape.com.
Family environment may influence subsequent functional outcomes in patients with first-episode psychosis, new research suggests.
A study of more than 300 patients with first-episode psychosis (FEP) showed that although family environment was not associated with functioning at initial presentation, an interaction developed over time that could have “important implications for early interventions for both patients and caregivers,” investigators reported.
study coinvestigator Norma Verdolini, MD, PhD, bipolar and depressive disorders unit, hospital Clinic Barcelona, University of Barcelona, said in an interview.
The findings were scheduled to be presented at the Congress of the Schizophrenia International Research Society 2020, but the meeting was canceled because of the coronavirus pandemic.
FAST measures
Previous research has shown that family environment influences the development of psychotic symptoms, with negative family environmental factors associated with poor prognoses.
Conversely, one study indicated that a positive family environment is linked to greater improvement in negative and disorganized symptoms in adolescents at imminent risk for psychosis onset.
However, the current investigators noted that the impact of family environment on longitudinal functioning in individuals presenting with FEP is unclear.
To investigate further, they conducted an analysis as part of the PEPs study, which included 335 patients with FEP and 253 healthy controls. Functioning was measured using the Functional Assessment Short Test (FAST), and family environmental styles were evaluated using the Family Environment Scale (FES), which assesses “emotional climate” of a family across 10 domains.
At baseline, the mean total FAST score was 27.8 in patients with FEP versus 3.5 in the healthy controls, indicating substantially worse functioning among the patients. Linear regression analysis indicated that at baseline there was no significant association between aspects of family environment on the FES and functional scores.
Patients were assessed again at 2 years, by which point 283 had been diagnosed with psychotic disorders and 52 with bipolar disorder. The mean total FAST scores were 20.98 among patients with psychotic disorders and 13.8 in those with bipolar disorder.
Family conflict
Results showed that, among those with bipolar disorder, worse functioning on FAST at 2 years was significantly associated with higher rates of open expression of conflict in the family (P = .004).
In patients with psychotic disorders, worse functioning was significantly associated with lower rates of participation in social activities (P = .006) and an achievement-oriented family environment (P = .039). Worse functioning in patients with psychotic disorders was also significantly associated with higher rates of religious practice and values (P = .003).
Dr. Verdolini noted the reason family environment does not appear to have an impact at initial FEP presentation may be that the “first kick” is given by an individual’s genetic liability for psychiatric disorders in combination with the family environment. In reality, the two are intertwined, especially when considering what it means to a family to have one member with a psychiatric disorder, which “will have an impact on the family environment.”
Dr. Verdolini added: “This is not actually the objective family environment,” but the perceived family environment.
“So maybe in the following 2 years the patient who experiences a first episode of psychosis may change their idea of the family environment itself,” she noted. She added that at her institution psychoeducation is offered to FEP patients’ families.
‘Interesting’ findings
Commenting on the study, Nicole Kozloff, MD, from the child, youth, and emerging adult program at the Centre for Addiction and Mental Health in Toronto, said one limitation of the study is that it’s not clear what care patients received – or who in the family completed the FES.
It is also important to note that “measures of association do not necessarily imply that one factor caused the other factor,” said Dr. Kozloff, who was not involved in the research. “For example, it may be that, among people with bipolar disorder, open expression of conflict in the family can lead to worse functioning, or that worse functioning can lead to more conflict in the family.”
Nevertheless, Dr. Kozloff described the finding of an emerging association between the family environment and functioning over time as “interesting.”
When young people with FEP enter treatment, “they have reached a crisis point and are functioning poorly,” she noted.
“It could be that there is less to differentiate among levels of functioning at treatment entry but, after 2 years, the individuals have separated into those who have been responsive to treatment and are functioning well, and those who continue to have functional challenges. And this is where we start to see a relationship with family environment emerge,” Dr. Kozloff said.
She also agreed with Dr. Verdolini’s take on the findings, and that family psychoeducation “can reduce relapse rates in schizophrenia and the emotional burden on the family.”
“We also know that having family involvement in care is one of the most robust predictors that young people with psychosis will remain engaged in mental health services,” she said.
Teaching families about psychosis and its treatment, about problem-solving and communication skills, and providing support to ensure that family members know how to get help in a crisis, “is a key part of comprehensive early psychosis intervention,” Dr. Kozloff said. “It is good for the patient and good for the family, and allows the clinicians to provide better care.”
Articulates clinical practice findings
Also commenting on the results, Brian O’Donoghue, MD, PhD, senior clinical research fellow at Orygen, the National Centre of Excellence in Youth Mental Health in Melbourne, described the research as important, adding that the study highlights the need for sufficient follow-up.
“It makes sense that the involvement of family over time has a strong impact upon outcome and functioning,” he said in an interview.
“These research findings articulate what we see in clinical practice, so it is good to see that it is captured,” added Dr. O’Donoghue, who was not associated with the study.
He noted that it is common for family involvement to influence outcome, especially if the family is positively involved. “It is invaluable toward their recovery. However, conversely, if there are ongoing family stressors, then this can be a trigger for relapse or lack of improvement.”
Overall, the results “really emphasize that the family needs to be involved in care.”
The Early Psychosis Prevention and Intervention Centre where Dr. O’Donoghue is a consultant psychiatrist offers a psychoeducational course “to inform families about psychosis, treatment, and how they can support their family members.”
“We also have family peer support workers and family therapists, which are essential to the service and for the young person’s recovery,” Dr. O’Donoghue said.
The investigators and Dr. O’Donoghue disclosed no relevant financial relationships. Dr. Kozloff reported receiving research funding from the CAMH Foundation, Brain & Behavior Research Foundation, Canadian Institutes of Health Research, and AFP Innovation Fund; honoraria from Humber River Hospital, the University of Calgary (Alta.), and the Canadian Consortium for Early Intervention in Psychosis; and salary support from Inner City Health Associates.
A version of this article originally appeared on Medscape.com.
Family environment may influence subsequent functional outcomes in patients with first-episode psychosis, new research suggests.
A study of more than 300 patients with first-episode psychosis (FEP) showed that although family environment was not associated with functioning at initial presentation, an interaction developed over time that could have “important implications for early interventions for both patients and caregivers,” investigators reported.
study coinvestigator Norma Verdolini, MD, PhD, bipolar and depressive disorders unit, hospital Clinic Barcelona, University of Barcelona, said in an interview.
The findings were scheduled to be presented at the Congress of the Schizophrenia International Research Society 2020, but the meeting was canceled because of the coronavirus pandemic.
FAST measures
Previous research has shown that family environment influences the development of psychotic symptoms, with negative family environmental factors associated with poor prognoses.
Conversely, one study indicated that a positive family environment is linked to greater improvement in negative and disorganized symptoms in adolescents at imminent risk for psychosis onset.
However, the current investigators noted that the impact of family environment on longitudinal functioning in individuals presenting with FEP is unclear.
To investigate further, they conducted an analysis as part of the PEPs study, which included 335 patients with FEP and 253 healthy controls. Functioning was measured using the Functional Assessment Short Test (FAST), and family environmental styles were evaluated using the Family Environment Scale (FES), which assesses “emotional climate” of a family across 10 domains.
At baseline, the mean total FAST score was 27.8 in patients with FEP versus 3.5 in the healthy controls, indicating substantially worse functioning among the patients. Linear regression analysis indicated that at baseline there was no significant association between aspects of family environment on the FES and functional scores.
Patients were assessed again at 2 years, by which point 283 had been diagnosed with psychotic disorders and 52 with bipolar disorder. The mean total FAST scores were 20.98 among patients with psychotic disorders and 13.8 in those with bipolar disorder.
Family conflict
Results showed that, among those with bipolar disorder, worse functioning on FAST at 2 years was significantly associated with higher rates of open expression of conflict in the family (P = .004).
In patients with psychotic disorders, worse functioning was significantly associated with lower rates of participation in social activities (P = .006) and an achievement-oriented family environment (P = .039). Worse functioning in patients with psychotic disorders was also significantly associated with higher rates of religious practice and values (P = .003).
Dr. Verdolini noted the reason family environment does not appear to have an impact at initial FEP presentation may be that the “first kick” is given by an individual’s genetic liability for psychiatric disorders in combination with the family environment. In reality, the two are intertwined, especially when considering what it means to a family to have one member with a psychiatric disorder, which “will have an impact on the family environment.”
Dr. Verdolini added: “This is not actually the objective family environment,” but the perceived family environment.
“So maybe in the following 2 years the patient who experiences a first episode of psychosis may change their idea of the family environment itself,” she noted. She added that at her institution psychoeducation is offered to FEP patients’ families.
‘Interesting’ findings
Commenting on the study, Nicole Kozloff, MD, from the child, youth, and emerging adult program at the Centre for Addiction and Mental Health in Toronto, said one limitation of the study is that it’s not clear what care patients received – or who in the family completed the FES.
It is also important to note that “measures of association do not necessarily imply that one factor caused the other factor,” said Dr. Kozloff, who was not involved in the research. “For example, it may be that, among people with bipolar disorder, open expression of conflict in the family can lead to worse functioning, or that worse functioning can lead to more conflict in the family.”
Nevertheless, Dr. Kozloff described the finding of an emerging association between the family environment and functioning over time as “interesting.”
When young people with FEP enter treatment, “they have reached a crisis point and are functioning poorly,” she noted.
“It could be that there is less to differentiate among levels of functioning at treatment entry but, after 2 years, the individuals have separated into those who have been responsive to treatment and are functioning well, and those who continue to have functional challenges. And this is where we start to see a relationship with family environment emerge,” Dr. Kozloff said.
She also agreed with Dr. Verdolini’s take on the findings, and that family psychoeducation “can reduce relapse rates in schizophrenia and the emotional burden on the family.”
“We also know that having family involvement in care is one of the most robust predictors that young people with psychosis will remain engaged in mental health services,” she said.
Teaching families about psychosis and its treatment, about problem-solving and communication skills, and providing support to ensure that family members know how to get help in a crisis, “is a key part of comprehensive early psychosis intervention,” Dr. Kozloff said. “It is good for the patient and good for the family, and allows the clinicians to provide better care.”
Articulates clinical practice findings
Also commenting on the results, Brian O’Donoghue, MD, PhD, senior clinical research fellow at Orygen, the National Centre of Excellence in Youth Mental Health in Melbourne, described the research as important, adding that the study highlights the need for sufficient follow-up.
“It makes sense that the involvement of family over time has a strong impact upon outcome and functioning,” he said in an interview.
“These research findings articulate what we see in clinical practice, so it is good to see that it is captured,” added Dr. O’Donoghue, who was not associated with the study.
He noted that it is common for family involvement to influence outcome, especially if the family is positively involved. “It is invaluable toward their recovery. However, conversely, if there are ongoing family stressors, then this can be a trigger for relapse or lack of improvement.”
Overall, the results “really emphasize that the family needs to be involved in care.”
The Early Psychosis Prevention and Intervention Centre where Dr. O’Donoghue is a consultant psychiatrist offers a psychoeducational course “to inform families about psychosis, treatment, and how they can support their family members.”
“We also have family peer support workers and family therapists, which are essential to the service and for the young person’s recovery,” Dr. O’Donoghue said.
The investigators and Dr. O’Donoghue disclosed no relevant financial relationships. Dr. Kozloff reported receiving research funding from the CAMH Foundation, Brain & Behavior Research Foundation, Canadian Institutes of Health Research, and AFP Innovation Fund; honoraria from Humber River Hospital, the University of Calgary (Alta.), and the Canadian Consortium for Early Intervention in Psychosis; and salary support from Inner City Health Associates.
A version of this article originally appeared on Medscape.com.
FROM SIRS 2020
Drug-drug interactions to avoid in patients with GI cancer
warned a leading expert in the field.
Rachel P. Riechelmann, MD, AC Camargo Cancer Center, São Paulo, Brazil, was delivering a keynote speech during the ESMO 22nd World Congress on Gastrointestinal Cancer Virtual Experience on July 4.
One of the drug-drug interactions that can have a deleterious effect on patients with GI cancers is that occurring between proton pump inhibitors (PPIs), such as omeprazole, and chemotherapy regimens containing capecitabine, she said.
She cited clinical trial data showing that the use of PPIs can increase the risk for progression in colorectal cancer patients being treated with adjuvant CapeOx (capecitabine with oxaliplatin) or FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin). Further clinical trial data from the LOGIC trial show that PPIs have a significant effect on both progression-free and overall survival in HER2+ gastric cancer patients being treated with CapOx with or without lapatinib.
Commenting on the presentation on Twitter, Jose Fernando Moura, MD, PhD, Medical Oncology, Real Hospital Português, Recife, Brazil, agreed that it is better to avoid PPIs during chemotherapy for colorectal and gastrointestinal tumors.
Benedikt Westphalen, MD, PhD, coordinator, molecular oncology, University of Munich Comprehensive Cancer Center, Munich, Germany, replied that the data presented by Dr. Riechelmann are “clearly interesting.”
He added his own checklist of things to consider in regard to drug-drug interactions, including changes in drug levels, the effect on the microbiome, and gender differences.
Previous studies, including many from Dr. Riechelmann’s group, have indicated that potential drug-drug interactions occur in about two thirds of inpatients and in approximately one third of outpatients.
The frequency of clinically relevant drug interactions in oncology patients enrolled in clinical trials is “not that high,” however, at between 3% and 17%, depending on the mechanism of interaction, she commented.
“But it should be zero, because all clinical trials have a list of combinations that should not be prescribed and drugs that should be avoided,” she added.
There have been very few studies on the occurrence of drug-drug interactions in oncology patients in the real world, Dr. Riechelmann commented.
One study suggested that 4% of oncology deaths in hospitals were due to adverse drug reactions or interactions. Another study, conducted by Dr. Riechelmann’s team, suggested that 2% of nonelective hospitalizations among oncology patients were for drug-drug interactions.
She said that common potential drug interactions in oncology involve the use of aspirin, warfarin, beta blockers, and corticosteroids.
She also singled out olaparib (Lynparza, AstraZeneca) as an interesting case. Coadministration of drugs that act as CYP3A4 inhibitors or inducers can effect exposure to this drug; itraconazole significantly increases exposure, and rifampin significantly reduces exposure.
Avoiding interactions
In conclusion, Dr. Riechelmann made a series of recommendations for avoiding dangerous drug-drug interactions in cancer patients, the first of which is to avoid polypharmacy in the first place.
She also suggested that high-risk patients, such as those taking many drugs and who have comorbid illness, should be screened for potential drug interactions, and attention should be paid to “dangerous” combinations.
Combinations to avoid include those of two drugs that each prolong the QT interval. These include quinolones, azithromycin, and clarithromycin.
“I think every one of us has to develop our own list of dangerous combinations” that should be avoided if possible, she said. If their use is necessary, patients should be informed of the potential risk and should be monitored closely for adverse events.
No funding for the study has been reported. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
warned a leading expert in the field.
Rachel P. Riechelmann, MD, AC Camargo Cancer Center, São Paulo, Brazil, was delivering a keynote speech during the ESMO 22nd World Congress on Gastrointestinal Cancer Virtual Experience on July 4.
One of the drug-drug interactions that can have a deleterious effect on patients with GI cancers is that occurring between proton pump inhibitors (PPIs), such as omeprazole, and chemotherapy regimens containing capecitabine, she said.
She cited clinical trial data showing that the use of PPIs can increase the risk for progression in colorectal cancer patients being treated with adjuvant CapeOx (capecitabine with oxaliplatin) or FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin). Further clinical trial data from the LOGIC trial show that PPIs have a significant effect on both progression-free and overall survival in HER2+ gastric cancer patients being treated with CapOx with or without lapatinib.
Commenting on the presentation on Twitter, Jose Fernando Moura, MD, PhD, Medical Oncology, Real Hospital Português, Recife, Brazil, agreed that it is better to avoid PPIs during chemotherapy for colorectal and gastrointestinal tumors.
Benedikt Westphalen, MD, PhD, coordinator, molecular oncology, University of Munich Comprehensive Cancer Center, Munich, Germany, replied that the data presented by Dr. Riechelmann are “clearly interesting.”
He added his own checklist of things to consider in regard to drug-drug interactions, including changes in drug levels, the effect on the microbiome, and gender differences.
Previous studies, including many from Dr. Riechelmann’s group, have indicated that potential drug-drug interactions occur in about two thirds of inpatients and in approximately one third of outpatients.
The frequency of clinically relevant drug interactions in oncology patients enrolled in clinical trials is “not that high,” however, at between 3% and 17%, depending on the mechanism of interaction, she commented.
“But it should be zero, because all clinical trials have a list of combinations that should not be prescribed and drugs that should be avoided,” she added.
There have been very few studies on the occurrence of drug-drug interactions in oncology patients in the real world, Dr. Riechelmann commented.
One study suggested that 4% of oncology deaths in hospitals were due to adverse drug reactions or interactions. Another study, conducted by Dr. Riechelmann’s team, suggested that 2% of nonelective hospitalizations among oncology patients were for drug-drug interactions.
She said that common potential drug interactions in oncology involve the use of aspirin, warfarin, beta blockers, and corticosteroids.
She also singled out olaparib (Lynparza, AstraZeneca) as an interesting case. Coadministration of drugs that act as CYP3A4 inhibitors or inducers can effect exposure to this drug; itraconazole significantly increases exposure, and rifampin significantly reduces exposure.
Avoiding interactions
In conclusion, Dr. Riechelmann made a series of recommendations for avoiding dangerous drug-drug interactions in cancer patients, the first of which is to avoid polypharmacy in the first place.
She also suggested that high-risk patients, such as those taking many drugs and who have comorbid illness, should be screened for potential drug interactions, and attention should be paid to “dangerous” combinations.
Combinations to avoid include those of two drugs that each prolong the QT interval. These include quinolones, azithromycin, and clarithromycin.
“I think every one of us has to develop our own list of dangerous combinations” that should be avoided if possible, she said. If their use is necessary, patients should be informed of the potential risk and should be monitored closely for adverse events.
No funding for the study has been reported. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
warned a leading expert in the field.
Rachel P. Riechelmann, MD, AC Camargo Cancer Center, São Paulo, Brazil, was delivering a keynote speech during the ESMO 22nd World Congress on Gastrointestinal Cancer Virtual Experience on July 4.
One of the drug-drug interactions that can have a deleterious effect on patients with GI cancers is that occurring between proton pump inhibitors (PPIs), such as omeprazole, and chemotherapy regimens containing capecitabine, she said.
She cited clinical trial data showing that the use of PPIs can increase the risk for progression in colorectal cancer patients being treated with adjuvant CapeOx (capecitabine with oxaliplatin) or FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin). Further clinical trial data from the LOGIC trial show that PPIs have a significant effect on both progression-free and overall survival in HER2+ gastric cancer patients being treated with CapOx with or without lapatinib.
Commenting on the presentation on Twitter, Jose Fernando Moura, MD, PhD, Medical Oncology, Real Hospital Português, Recife, Brazil, agreed that it is better to avoid PPIs during chemotherapy for colorectal and gastrointestinal tumors.
Benedikt Westphalen, MD, PhD, coordinator, molecular oncology, University of Munich Comprehensive Cancer Center, Munich, Germany, replied that the data presented by Dr. Riechelmann are “clearly interesting.”
He added his own checklist of things to consider in regard to drug-drug interactions, including changes in drug levels, the effect on the microbiome, and gender differences.
Previous studies, including many from Dr. Riechelmann’s group, have indicated that potential drug-drug interactions occur in about two thirds of inpatients and in approximately one third of outpatients.
The frequency of clinically relevant drug interactions in oncology patients enrolled in clinical trials is “not that high,” however, at between 3% and 17%, depending on the mechanism of interaction, she commented.
“But it should be zero, because all clinical trials have a list of combinations that should not be prescribed and drugs that should be avoided,” she added.
There have been very few studies on the occurrence of drug-drug interactions in oncology patients in the real world, Dr. Riechelmann commented.
One study suggested that 4% of oncology deaths in hospitals were due to adverse drug reactions or interactions. Another study, conducted by Dr. Riechelmann’s team, suggested that 2% of nonelective hospitalizations among oncology patients were for drug-drug interactions.
She said that common potential drug interactions in oncology involve the use of aspirin, warfarin, beta blockers, and corticosteroids.
She also singled out olaparib (Lynparza, AstraZeneca) as an interesting case. Coadministration of drugs that act as CYP3A4 inhibitors or inducers can effect exposure to this drug; itraconazole significantly increases exposure, and rifampin significantly reduces exposure.
Avoiding interactions
In conclusion, Dr. Riechelmann made a series of recommendations for avoiding dangerous drug-drug interactions in cancer patients, the first of which is to avoid polypharmacy in the first place.
She also suggested that high-risk patients, such as those taking many drugs and who have comorbid illness, should be screened for potential drug interactions, and attention should be paid to “dangerous” combinations.
Combinations to avoid include those of two drugs that each prolong the QT interval. These include quinolones, azithromycin, and clarithromycin.
“I think every one of us has to develop our own list of dangerous combinations” that should be avoided if possible, she said. If their use is necessary, patients should be informed of the potential risk and should be monitored closely for adverse events.
No funding for the study has been reported. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.