GENEVA – Afatinib appears safe and effective for elderly patients with EGFR-positive non–small cell lung cancer (NSCLC), according to investigators.

A retrospective analysis of the phase 3 GIDEON trial showed similar objective responses, disease control rates, and progression-free survival rates among elderly patients, compared with younger patients, reported lead author Wolfgang M. Brückl, MD, of Universitätsklinik der Paracelsus Medizinischen Privatuniversität in Nürnberg, Germany, and his colleagues. These findings were presented in a poster at the European Lung Cancer Congress.

“Elderly patients are often underrepresented in clinical trials,” the investigators wrote, “which can lead to uncertainties regarding optimal treatment of such patients in routine clinical practice. The GIDEON noninterventional study enrolled a high proportion of patients aged 70 years or older, providing an opportunity to study the real-world use of afatinib in older individuals.”

The GIDEON study involved 160 patients with EGFR-positive NSCLC who were treated at 49 centers in Germany between 2014 and 2016. From this total, 151 patients were available for interim analysis, and 67 patients (44%) were at least 70-years old. Among this elderly group, about one out of five patients (22%) had brain metastases and Eastern Cooperative Oncology Group (ECOG) performance status scores were typically 1 (45%) or 0 (42%).

Compared with younger patients, elderly patients were more likely to receive a lower starting dose of afatinib (62% vs. 83%), which usually entailed a decrease from 40 mg to 30 mg. Thereafter, dose reduction rates were similar between age groups, with 58% of younger patients requiring lower doses and 55% of elderly patients requiring reduced doses. Adverse events were comparable across age groups, although a fraction more of the patients 70 years or older discontinued treatment because of serious adverse drug reactions (12% vs. 7%).

Efficacy results were also comparable between age groups. Overall response rates were slightly higher among elderly patients than younger patients, with a 70-year age threshold (78% vs. 70%); disease control rate was marginally higher among the elderly (93% vs. 89%); and elderly patients had a slightly better 12-month PFS rate (62.2% vs. 49.1%).

“Data from the GIDEON noninterventional study provide important information on the routine clinical use of afatinib in elderly patients,” the investigators concluded.

The study was funded by Boehringer Ingelheim. The investigators did not report conflicts of interest.

SOURCE: Brückl WM et al. ELCC 2019. Abstract 125P.

GENEVA – Afatinib appears safe and effective for elderly patients with EGFR-positive non–small cell lung cancer (NSCLC), according to investigators.

A retrospective analysis of the phase 3 GIDEON trial showed similar objective responses, disease control rates, and progression-free survival rates among elderly patients, compared with younger patients, reported lead author Wolfgang M. Brückl, MD, of Universitätsklinik der Paracelsus Medizinischen Privatuniversität in Nürnberg, Germany, and his colleagues. These findings were presented in a poster at the European Lung Cancer Congress.

“Elderly patients are often underrepresented in clinical trials,” the investigators wrote, “which can lead to uncertainties regarding optimal treatment of such patients in routine clinical practice. The GIDEON noninterventional study enrolled a high proportion of patients aged 70 years or older, providing an opportunity to study the real-world use of afatinib in older individuals.”

The GIDEON study involved 160 patients with EGFR-positive NSCLC who were treated at 49 centers in Germany between 2014 and 2016. From this total, 151 patients were available for interim analysis, and 67 patients (44%) were at least 70-years old. Among this elderly group, about one out of five patients (22%) had brain metastases and Eastern Cooperative Oncology Group (ECOG) performance status scores were typically 1 (45%) or 0 (42%).

Compared with younger patients, elderly patients were more likely to receive a lower starting dose of afatinib (62% vs. 83%), which usually entailed a decrease from 40 mg to 30 mg. Thereafter, dose reduction rates were similar between age groups, with 58% of younger patients requiring lower doses and 55% of elderly patients requiring reduced doses. Adverse events were comparable across age groups, although a fraction more of the patients 70 years or older discontinued treatment because of serious adverse drug reactions (12% vs. 7%).

Efficacy results were also comparable between age groups. Overall response rates were slightly higher among elderly patients than younger patients, with a 70-year age threshold (78% vs. 70%); disease control rate was marginally higher among the elderly (93% vs. 89%); and elderly patients had a slightly better 12-month PFS rate (62.2% vs. 49.1%).

“Data from the GIDEON noninterventional study provide important information on the routine clinical use of afatinib in elderly patients,” the investigators concluded.

The study was funded by Boehringer Ingelheim. The investigators did not report conflicts of interest.

SOURCE: Brückl WM et al. ELCC 2019. Abstract 125P.

GENEVA – Afatinib appears safe and effective for elderly patients with EGFR-positive non–small cell lung cancer (NSCLC), according to investigators.

A retrospective analysis of the phase 3 GIDEON trial showed similar objective responses, disease control rates, and progression-free survival rates among elderly patients, compared with younger patients, reported lead author Wolfgang M. Brückl, MD, of Universitätsklinik der Paracelsus Medizinischen Privatuniversität in Nürnberg, Germany, and his colleagues. These findings were presented in a poster at the European Lung Cancer Congress.

“Elderly patients are often underrepresented in clinical trials,” the investigators wrote, “which can lead to uncertainties regarding optimal treatment of such patients in routine clinical practice. The GIDEON noninterventional study enrolled a high proportion of patients aged 70 years or older, providing an opportunity to study the real-world use of afatinib in older individuals.”

The GIDEON study involved 160 patients with EGFR-positive NSCLC who were treated at 49 centers in Germany between 2014 and 2016. From this total, 151 patients were available for interim analysis, and 67 patients (44%) were at least 70-years old. Among this elderly group, about one out of five patients (22%) had brain metastases and Eastern Cooperative Oncology Group (ECOG) performance status scores were typically 1 (45%) or 0 (42%).

Compared with younger patients, elderly patients were more likely to receive a lower starting dose of afatinib (62% vs. 83%), which usually entailed a decrease from 40 mg to 30 mg. Thereafter, dose reduction rates were similar between age groups, with 58% of younger patients requiring lower doses and 55% of elderly patients requiring reduced doses. Adverse events were comparable across age groups, although a fraction more of the patients 70 years or older discontinued treatment because of serious adverse drug reactions (12% vs. 7%).

Efficacy results were also comparable between age groups. Overall response rates were slightly higher among elderly patients than younger patients, with a 70-year age threshold (78% vs. 70%); disease control rate was marginally higher among the elderly (93% vs. 89%); and elderly patients had a slightly better 12-month PFS rate (62.2% vs. 49.1%).

“Data from the GIDEON noninterventional study provide important information on the routine clinical use of afatinib in elderly patients,” the investigators concluded.

The study was funded by Boehringer Ingelheim. The investigators did not report conflicts of interest.

SOURCE: Brückl WM et al. ELCC 2019. Abstract 125P.

Former National Football League players with cognitive, mood, and behavioral symptoms may have higher tau levels in the brain than asymptomatic people without a history of traumatic brain injury, according to research published online ahead of print April 10 in the New England Journal of Medicine. The distribution of tau in the players’ brains appears to be similar to that in persons with chronic traumatic encephalopathy (CTE).

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, such as those withstood in contact sports. The basis for the neuropathological diagnosis of CTE is a distinct pattern of tau deposition with minimal deposition of amyloid-beta. Paired helical filament tau aggregates are first observed in the frontal, temporal, and parietal cortices. They later spread throughout the cerebral cortex, medial temporal lobe, diencephalon, and brainstem. CTE is diagnosed only through post mortem neuropathological examinations.

To examine whether tau and amyloid deposition can be detected in the brains of living people at risk for CTE, Robert A. Stern, PhD, and his colleagues studied living former NFL players and asymptomatic controls with flortaucipir PET (to detect tau) and ¹⁸F-florbetapir PET (to detect amyloid-beta). Dr. Stern is director of clinical research at the CTE Center at Boston University. Eligible former players were male, aged 40-69 years, had played football in the NFL for at least 2 years, had had at least 12 years of total tackle football experience, and reported cognitive, behavioral, and mood symptoms through telephone screening. Eligible controls were male, aged 40-69 years, and had no cognitive symptoms or history of traumatic brain injury.

All subjects underwent flortaucipir PET, florbetapir PET, and T₁-weighted volumetric MRI of the head. Dr. Stern and his colleagues used automated image-analysis algorithms to compare the regional tau standardized uptake value ratio (SUVR) between the two patient groups and to evaluate potential associations between that ratio and symptom severity or years of football play.

The investigators included 26 former players and 31 controls in their analysis. The group of former players had a higher percentage of black participants and a lower mean Mini-Mental State Examination score, compared with controls. The mean flortaucipir SUVR was higher among former players than among controls in the bilateral superior frontal (1.09 vs. 0.98), bilateral medial temporal (1.23 vs. 1.12), and left parietal (1.12 vs. 1.01) regions. Dr. Stern and his colleagues found no association between tau deposition in those regions and results on cognitive and neuropsychiatric tests. In a post hoc analysis, they calculated the correlation coefficients in the three brain regions between the SUVRs and years of play to be 0.58 in the bilateral superior frontal region, 0.45 in the bilateral medial temporal region, and 0.50 in the left parietal region. Mean cortical:cerebellar florbetapir SUVRs did not differ significantly between groups.

“These findings suggest that the cognitive difficulties reported by the former players were not related to Alzheimer’s disease amyloid-beta deposition,” said the authors. The study may have been insufficiently powered to detect associations between flortaucipir uptake and the clinical measures, they added. Also, paired helical filament tau pathology alone may not be associated with the former players’ neuropsychiatric symptoms and cognitive impairment. “Although this study showed between-group differences in flortaucipir PET measurements, our analyses do not pertain to detection of tau pathology in individual participants,” the authors concluded.

The study was supported by an investigator-initiated grant from Avid Radiopharmaceuticals. The National Institutes of Health, the state of Arizona, and the U.S. Department of Defense also supported the study.

[email protected]

SOURCE: Stern RA et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1900757 (Epub ahead of print).

Former National Football League players with cognitive, mood, and behavioral symptoms may have higher tau levels in the brain than asymptomatic people without a history of traumatic brain injury, according to research published online ahead of print April 10 in the New England Journal of Medicine. The distribution of tau in the players’ brains appears to be similar to that in persons with chronic traumatic encephalopathy (CTE).

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, such as those withstood in contact sports. The basis for the neuropathological diagnosis of CTE is a distinct pattern of tau deposition with minimal deposition of amyloid-beta. Paired helical filament tau aggregates are first observed in the frontal, temporal, and parietal cortices. They later spread throughout the cerebral cortex, medial temporal lobe, diencephalon, and brainstem. CTE is diagnosed only through post mortem neuropathological examinations.

To examine whether tau and amyloid deposition can be detected in the brains of living people at risk for CTE, Robert A. Stern, PhD, and his colleagues studied living former NFL players and asymptomatic controls with flortaucipir PET (to detect tau) and ¹⁸F-florbetapir PET (to detect amyloid-beta). Dr. Stern is director of clinical research at the CTE Center at Boston University. Eligible former players were male, aged 40-69 years, had played football in the NFL for at least 2 years, had had at least 12 years of total tackle football experience, and reported cognitive, behavioral, and mood symptoms through telephone screening. Eligible controls were male, aged 40-69 years, and had no cognitive symptoms or history of traumatic brain injury.

All subjects underwent flortaucipir PET, florbetapir PET, and T₁-weighted volumetric MRI of the head. Dr. Stern and his colleagues used automated image-analysis algorithms to compare the regional tau standardized uptake value ratio (SUVR) between the two patient groups and to evaluate potential associations between that ratio and symptom severity or years of football play.

The investigators included 26 former players and 31 controls in their analysis. The group of former players had a higher percentage of black participants and a lower mean Mini-Mental State Examination score, compared with controls. The mean flortaucipir SUVR was higher among former players than among controls in the bilateral superior frontal (1.09 vs. 0.98), bilateral medial temporal (1.23 vs. 1.12), and left parietal (1.12 vs. 1.01) regions. Dr. Stern and his colleagues found no association between tau deposition in those regions and results on cognitive and neuropsychiatric tests. In a post hoc analysis, they calculated the correlation coefficients in the three brain regions between the SUVRs and years of play to be 0.58 in the bilateral superior frontal region, 0.45 in the bilateral medial temporal region, and 0.50 in the left parietal region. Mean cortical:cerebellar florbetapir SUVRs did not differ significantly between groups.

“These findings suggest that the cognitive difficulties reported by the former players were not related to Alzheimer’s disease amyloid-beta deposition,” said the authors. The study may have been insufficiently powered to detect associations between flortaucipir uptake and the clinical measures, they added. Also, paired helical filament tau pathology alone may not be associated with the former players’ neuropsychiatric symptoms and cognitive impairment. “Although this study showed between-group differences in flortaucipir PET measurements, our analyses do not pertain to detection of tau pathology in individual participants,” the authors concluded.

The study was supported by an investigator-initiated grant from Avid Radiopharmaceuticals. The National Institutes of Health, the state of Arizona, and the U.S. Department of Defense also supported the study.

[email protected]

SOURCE: Stern RA et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1900757 (Epub ahead of print).

Former National Football League players with cognitive, mood, and behavioral symptoms may have higher tau levels in the brain than asymptomatic people without a history of traumatic brain injury, according to research published online ahead of print April 10 in the New England Journal of Medicine. The distribution of tau in the players’ brains appears to be similar to that in persons with chronic traumatic encephalopathy (CTE).

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, such as those withstood in contact sports. The basis for the neuropathological diagnosis of CTE is a distinct pattern of tau deposition with minimal deposition of amyloid-beta. Paired helical filament tau aggregates are first observed in the frontal, temporal, and parietal cortices. They later spread throughout the cerebral cortex, medial temporal lobe, diencephalon, and brainstem. CTE is diagnosed only through post mortem neuropathological examinations.

To examine whether tau and amyloid deposition can be detected in the brains of living people at risk for CTE, Robert A. Stern, PhD, and his colleagues studied living former NFL players and asymptomatic controls with flortaucipir PET (to detect tau) and ¹⁸F-florbetapir PET (to detect amyloid-beta). Dr. Stern is director of clinical research at the CTE Center at Boston University. Eligible former players were male, aged 40-69 years, had played football in the NFL for at least 2 years, had had at least 12 years of total tackle football experience, and reported cognitive, behavioral, and mood symptoms through telephone screening. Eligible controls were male, aged 40-69 years, and had no cognitive symptoms or history of traumatic brain injury.

All subjects underwent flortaucipir PET, florbetapir PET, and T₁-weighted volumetric MRI of the head. Dr. Stern and his colleagues used automated image-analysis algorithms to compare the regional tau standardized uptake value ratio (SUVR) between the two patient groups and to evaluate potential associations between that ratio and symptom severity or years of football play.

The investigators included 26 former players and 31 controls in their analysis. The group of former players had a higher percentage of black participants and a lower mean Mini-Mental State Examination score, compared with controls. The mean flortaucipir SUVR was higher among former players than among controls in the bilateral superior frontal (1.09 vs. 0.98), bilateral medial temporal (1.23 vs. 1.12), and left parietal (1.12 vs. 1.01) regions. Dr. Stern and his colleagues found no association between tau deposition in those regions and results on cognitive and neuropsychiatric tests. In a post hoc analysis, they calculated the correlation coefficients in the three brain regions between the SUVRs and years of play to be 0.58 in the bilateral superior frontal region, 0.45 in the bilateral medial temporal region, and 0.50 in the left parietal region. Mean cortical:cerebellar florbetapir SUVRs did not differ significantly between groups.

“These findings suggest that the cognitive difficulties reported by the former players were not related to Alzheimer’s disease amyloid-beta deposition,” said the authors. The study may have been insufficiently powered to detect associations between flortaucipir uptake and the clinical measures, they added. Also, paired helical filament tau pathology alone may not be associated with the former players’ neuropsychiatric symptoms and cognitive impairment. “Although this study showed between-group differences in flortaucipir PET measurements, our analyses do not pertain to detection of tau pathology in individual participants,” the authors concluded.

The study was supported by an investigator-initiated grant from Avid Radiopharmaceuticals. The National Institutes of Health, the state of Arizona, and the U.S. Department of Defense also supported the study.

[email protected]

SOURCE: Stern RA et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1900757 (Epub ahead of print).

Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.

Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.

“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.

FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.

“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.

Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.

First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.

The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.

Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).

“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.

Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.

Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.

“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.

“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.

Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.

“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.

FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.

“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.

Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.

First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.

The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.

Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).

“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.

Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.

Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.

“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.

“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.

Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.

“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.

FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.

“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.

Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.

First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.

The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.

Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).

“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.

Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.

Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.

“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.

“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

Combination treatment strategies that include immunotherapeutic agents are expected to become the future of breast cancer treatment, according to a review.

“There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing,” wrote Sylvia Adams, MD, MS, of New York University, along with her colleagues. The report is in JAMA Oncology.

“It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions, they said.

Dr. Adams and her colleagues searched major databases for clinical trials investigating the use of immunotherapy in both early-stage and metastatic breast cancer.

After the search, the team found that immune checkpoint blockade (ICB) agents were the most studied type of immunotherapy in breast cancer today.

In addition, Dr. Adams and her colleagues reported that when UCB agents were used as monotherapy in patients with breast cancer, objective responses have been seen, especially when given in the initial stages of treatment. “For responding patients, those responses are durable,” they added.

Recent findings have indicated that combining immune checkpoint blockade agents with chemotherapy may be useful in early breast cancer as neoadjuvant therapy.

“Combination trials were more common than single-agent studies, with the most commonly combined modalities being chemotherapy or targeted therapy,” the researchers wrote.

The review is limited by the rapid advancement of the current treatment landscape. As a result, additional data may now be available beyond the date of publication.

“Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Amgen, Celgene, Genentech, Eli Lilly, Ipsen, Novartis, Pfizer, and several others.

SOURCE: Adams S et al. JAMA Oncol. 2019 Apr 11. doi: 10.1001/jamaoncol.2018.7147.

Combination treatment strategies that include immunotherapeutic agents are expected to become the future of breast cancer treatment, according to a review.

“There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing,” wrote Sylvia Adams, MD, MS, of New York University, along with her colleagues. The report is in JAMA Oncology.

“It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions, they said.

Dr. Adams and her colleagues searched major databases for clinical trials investigating the use of immunotherapy in both early-stage and metastatic breast cancer.

After the search, the team found that immune checkpoint blockade (ICB) agents were the most studied type of immunotherapy in breast cancer today.

In addition, Dr. Adams and her colleagues reported that when UCB agents were used as monotherapy in patients with breast cancer, objective responses have been seen, especially when given in the initial stages of treatment. “For responding patients, those responses are durable,” they added.

Recent findings have indicated that combining immune checkpoint blockade agents with chemotherapy may be useful in early breast cancer as neoadjuvant therapy.

“Combination trials were more common than single-agent studies, with the most commonly combined modalities being chemotherapy or targeted therapy,” the researchers wrote.

The review is limited by the rapid advancement of the current treatment landscape. As a result, additional data may now be available beyond the date of publication.

“Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Amgen, Celgene, Genentech, Eli Lilly, Ipsen, Novartis, Pfizer, and several others.

SOURCE: Adams S et al. JAMA Oncol. 2019 Apr 11. doi: 10.1001/jamaoncol.2018.7147.

Combination treatment strategies that include immunotherapeutic agents are expected to become the future of breast cancer treatment, according to a review.

“There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing,” wrote Sylvia Adams, MD, MS, of New York University, along with her colleagues. The report is in JAMA Oncology.

“It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions, they said.

Dr. Adams and her colleagues searched major databases for clinical trials investigating the use of immunotherapy in both early-stage and metastatic breast cancer.

After the search, the team found that immune checkpoint blockade (ICB) agents were the most studied type of immunotherapy in breast cancer today.

In addition, Dr. Adams and her colleagues reported that when UCB agents were used as monotherapy in patients with breast cancer, objective responses have been seen, especially when given in the initial stages of treatment. “For responding patients, those responses are durable,” they added.

Recent findings have indicated that combining immune checkpoint blockade agents with chemotherapy may be useful in early breast cancer as neoadjuvant therapy.

“Combination trials were more common than single-agent studies, with the most commonly combined modalities being chemotherapy or targeted therapy,” the researchers wrote.

The review is limited by the rapid advancement of the current treatment landscape. As a result, additional data may now be available beyond the date of publication.

“Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Amgen, Celgene, Genentech, Eli Lilly, Ipsen, Novartis, Pfizer, and several others.

SOURCE: Adams S et al. JAMA Oncol. 2019 Apr 11. doi: 10.1001/jamaoncol.2018.7147.

The SVS recently established the Section on Outpatient & Office Vascular Care (SOOVC) for clinicians who work in outpatient and office vascular care centers. SOOVC membership is available to all SVS members in good standing, and hospital/practice administrators are welcome to join as Affiliate Members. Benefits for SOOVC members include, but are not limited to, specific programming at the Vascular Annual Meeting, discounts on SVS events, networking opportunities and access to SVSConnect. Please reach out to [email protected] or 312-334-2349 with questions. 

The SVS recently established the Section on Outpatient & Office Vascular Care (SOOVC) for clinicians who work in outpatient and office vascular care centers. SOOVC membership is available to all SVS members in good standing, and hospital/practice administrators are welcome to join as Affiliate Members. Benefits for SOOVC members include, but are not limited to, specific programming at the Vascular Annual Meeting, discounts on SVS events, networking opportunities and access to SVSConnect. Please reach out to [email protected] or 312-334-2349 with questions. 

The SVS recently established the Section on Outpatient & Office Vascular Care (SOOVC) for clinicians who work in outpatient and office vascular care centers. SOOVC membership is available to all SVS members in good standing, and hospital/practice administrators are welcome to join as Affiliate Members. Benefits for SOOVC members include, but are not limited to, specific programming at the Vascular Annual Meeting, discounts on SVS events, networking opportunities and access to SVSConnect. Please reach out to [email protected] or 312-334-2349 with questions. 

Begin planning your Vascular Annual Meeting experience today with the recently launched SVS Online Planner. This includes the entire VAM schedule, as well as the schedule for the Society for Vascular Nursing’s annual conference. The Vascular Quality Initiative’s meeting, VQI@VAM, will be available on the planner soon. With the Online Planner, you can easily search for information, such as presenters, specific topics, session types, intended audience and credit availability. It also makes creating a schedule simple and time-efficient. Access the online planner now.

Begin planning your Vascular Annual Meeting experience today with the recently launched SVS Online Planner. This includes the entire VAM schedule, as well as the schedule for the Society for Vascular Nursing’s annual conference. The Vascular Quality Initiative’s meeting, VQI@VAM, will be available on the planner soon. With the Online Planner, you can easily search for information, such as presenters, specific topics, session types, intended audience and credit availability. It also makes creating a schedule simple and time-efficient. Access the online planner now.

Begin planning your Vascular Annual Meeting experience today with the recently launched SVS Online Planner. This includes the entire VAM schedule, as well as the schedule for the Society for Vascular Nursing’s annual conference. The Vascular Quality Initiative’s meeting, VQI@VAM, will be available on the planner soon. With the Online Planner, you can easily search for information, such as presenters, specific topics, session types, intended audience and credit availability. It also makes creating a schedule simple and time-efficient. Access the online planner now.

The SVS is now seeking comments on draft Clinical Practice Guidelines on the Management of Visceral Aneurysms. Your comments are essential to strengthen the content of these guidelines, and to ensure relevance in clinical practice and potential for improvements in patient care. Feedback received during the comment period will be shared with the writing committee. Anyone, from SVS members to patients, is welcome to review these draft guidelines and provide comments before April 23.

The SVS is now seeking comments on draft Clinical Practice Guidelines on the Management of Visceral Aneurysms. Your comments are essential to strengthen the content of these guidelines, and to ensure relevance in clinical practice and potential for improvements in patient care. Feedback received during the comment period will be shared with the writing committee. Anyone, from SVS members to patients, is welcome to review these draft guidelines and provide comments before April 23.

The SVS is now seeking comments on draft Clinical Practice Guidelines on the Management of Visceral Aneurysms. Your comments are essential to strengthen the content of these guidelines, and to ensure relevance in clinical practice and potential for improvements in patient care. Feedback received during the comment period will be shared with the writing committee. Anyone, from SVS members to patients, is welcome to review these draft guidelines and provide comments before April 23.

VIENNA – The prevalence of liver steatosis among unselected English young adults was 21% in a study of just over 4,000 people. The prevalence of apparent liver fibrosis was 2.4%, and among the 21% with steatosis, nearly half – 10% of the studied cohort – had severe, S3 steatosis.

Mitchel L. Zoler/MDedge News

The prevalence of steatosis, a marker of nonalcoholic fatty liver disease (NAFLD), seemed to be linked with obesity. Among the 79% of the study group who had no steatosis the obesity prevalence was 6%, compared with a 26% prevalence among those with S1 steatosis, a 33% obesity rate among those with S2 steatosis, and a 57% obesity prevalence among those with S3 steatosis, Kushala Abeysekera, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.

He and his associates determined these prevalence rates in a population that excluded people who reported consuming what was deemed “excessive” alcohol use.

Another notable finding was that 1,874 of the same people had undergone ultrasound assessment for NAFLD when they were 18 years old, and that assessment found a prevalence of 2.5% (J Clin Endocrinol Metab. 2014 March;99[3]:e410-7), which meant that during the subsequent 6 years prevalence of NAFLD jumped nearly 900%.

Both the 2014 report and the current study used people who had been enrolled in the Avon Longitudinal Study of Parents and Children, a prospective population-based study that began by recruiting a cohort of more than 14,000 pregnant women during 1991-1992, and then followed the more than 13,000 children who resulted from those pregnancies. The study reported by Dr. Abeysekera focused on 4,021 of these children – now young adults – who responded to an invitation to participate in this follow-up, a number that then reduced to 3,600 with informative transient elastography results that quantified fibrosis, and 3,768 with valid Controlled Attenuated Parameter scores from elastography that reflected steatosis extent. Transient elastography is a noninvasive method of measuring liver stiffness using ultrasound and an elastic shear wave (Clin Mol Hepatol. 2012 June;18[2]:163-73).

“To the best of my knowledge, this is the only study that has assessed NAFLD in young adults using transient elastography,” said Dr. Abeysekera, an epidemiologist at the University of Bristol (England).

After subtracting from the study cohort people with excessive alcohol use, the study had transient elastography data from 3,277 24-year-olds that could calculate steatosis severity, and data from 3,128 that could quantify fibrosis.

The analysis also showed a statistically significant link between sex and the presence and severity of steatosis. Among women, 18% had steatosis, including 7% with S3 steatosis, defined as involving at least two-thirds of the liver. Among men, 26% had some degree of steatosis and 14% had the most severe form.

The presence of more severe liver fibrosis also showed a strong link to obesity. The eight people identified with F4 fibrosis (with cirrhosis) had a median body mass index of 32 kg/m2, compared with a median body mass index of 25 kg/m2 or less among those either without fibrosis or with a milder form of F1, F2, or F3 fibrosis.

Dr. Abeysekera reported no disclosures.

[email protected]

VIENNA – The prevalence of liver steatosis among unselected English young adults was 21% in a study of just over 4,000 people. The prevalence of apparent liver fibrosis was 2.4%, and among the 21% with steatosis, nearly half – 10% of the studied cohort – had severe, S3 steatosis.

Mitchel L. Zoler/MDedge News

The prevalence of steatosis, a marker of nonalcoholic fatty liver disease (NAFLD), seemed to be linked with obesity. Among the 79% of the study group who had no steatosis the obesity prevalence was 6%, compared with a 26% prevalence among those with S1 steatosis, a 33% obesity rate among those with S2 steatosis, and a 57% obesity prevalence among those with S3 steatosis, Kushala Abeysekera, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.

He and his associates determined these prevalence rates in a population that excluded people who reported consuming what was deemed “excessive” alcohol use.

Another notable finding was that 1,874 of the same people had undergone ultrasound assessment for NAFLD when they were 18 years old, and that assessment found a prevalence of 2.5% (J Clin Endocrinol Metab. 2014 March;99[3]:e410-7), which meant that during the subsequent 6 years prevalence of NAFLD jumped nearly 900%.

Both the 2014 report and the current study used people who had been enrolled in the Avon Longitudinal Study of Parents and Children, a prospective population-based study that began by recruiting a cohort of more than 14,000 pregnant women during 1991-1992, and then followed the more than 13,000 children who resulted from those pregnancies. The study reported by Dr. Abeysekera focused on 4,021 of these children – now young adults – who responded to an invitation to participate in this follow-up, a number that then reduced to 3,600 with informative transient elastography results that quantified fibrosis, and 3,768 with valid Controlled Attenuated Parameter scores from elastography that reflected steatosis extent. Transient elastography is a noninvasive method of measuring liver stiffness using ultrasound and an elastic shear wave (Clin Mol Hepatol. 2012 June;18[2]:163-73).

“To the best of my knowledge, this is the only study that has assessed NAFLD in young adults using transient elastography,” said Dr. Abeysekera, an epidemiologist at the University of Bristol (England).

After subtracting from the study cohort people with excessive alcohol use, the study had transient elastography data from 3,277 24-year-olds that could calculate steatosis severity, and data from 3,128 that could quantify fibrosis.

The analysis also showed a statistically significant link between sex and the presence and severity of steatosis. Among women, 18% had steatosis, including 7% with S3 steatosis, defined as involving at least two-thirds of the liver. Among men, 26% had some degree of steatosis and 14% had the most severe form.

The presence of more severe liver fibrosis also showed a strong link to obesity. The eight people identified with F4 fibrosis (with cirrhosis) had a median body mass index of 32 kg/m2, compared with a median body mass index of 25 kg/m2 or less among those either without fibrosis or with a milder form of F1, F2, or F3 fibrosis.

Dr. Abeysekera reported no disclosures.

[email protected]

VIENNA – The prevalence of liver steatosis among unselected English young adults was 21% in a study of just over 4,000 people. The prevalence of apparent liver fibrosis was 2.4%, and among the 21% with steatosis, nearly half – 10% of the studied cohort – had severe, S3 steatosis.

Mitchel L. Zoler/MDedge News

The prevalence of steatosis, a marker of nonalcoholic fatty liver disease (NAFLD), seemed to be linked with obesity. Among the 79% of the study group who had no steatosis the obesity prevalence was 6%, compared with a 26% prevalence among those with S1 steatosis, a 33% obesity rate among those with S2 steatosis, and a 57% obesity prevalence among those with S3 steatosis, Kushala Abeysekera, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.

He and his associates determined these prevalence rates in a population that excluded people who reported consuming what was deemed “excessive” alcohol use.

Another notable finding was that 1,874 of the same people had undergone ultrasound assessment for NAFLD when they were 18 years old, and that assessment found a prevalence of 2.5% (J Clin Endocrinol Metab. 2014 March;99[3]:e410-7), which meant that during the subsequent 6 years prevalence of NAFLD jumped nearly 900%.

Both the 2014 report and the current study used people who had been enrolled in the Avon Longitudinal Study of Parents and Children, a prospective population-based study that began by recruiting a cohort of more than 14,000 pregnant women during 1991-1992, and then followed the more than 13,000 children who resulted from those pregnancies. The study reported by Dr. Abeysekera focused on 4,021 of these children – now young adults – who responded to an invitation to participate in this follow-up, a number that then reduced to 3,600 with informative transient elastography results that quantified fibrosis, and 3,768 with valid Controlled Attenuated Parameter scores from elastography that reflected steatosis extent. Transient elastography is a noninvasive method of measuring liver stiffness using ultrasound and an elastic shear wave (Clin Mol Hepatol. 2012 June;18[2]:163-73).

“To the best of my knowledge, this is the only study that has assessed NAFLD in young adults using transient elastography,” said Dr. Abeysekera, an epidemiologist at the University of Bristol (England).

After subtracting from the study cohort people with excessive alcohol use, the study had transient elastography data from 3,277 24-year-olds that could calculate steatosis severity, and data from 3,128 that could quantify fibrosis.

The analysis also showed a statistically significant link between sex and the presence and severity of steatosis. Among women, 18% had steatosis, including 7% with S3 steatosis, defined as involving at least two-thirds of the liver. Among men, 26% had some degree of steatosis and 14% had the most severe form.

The presence of more severe liver fibrosis also showed a strong link to obesity. The eight people identified with F4 fibrosis (with cirrhosis) had a median body mass index of 32 kg/m2, compared with a median body mass index of 25 kg/m2 or less among those either without fibrosis or with a milder form of F1, F2, or F3 fibrosis.

Dr. Abeysekera reported no disclosures.

[email protected]

The Society for Vascular Surgery will provide complimentary meeting registration to a lucky attendee. To be eligible, all you must do is register for the meeting before 5 p.m. CDT Wednesday, April 24. The winner will be selected at random. This year’s meeting will be June 12 to 15 at the Gaylord National Resort & Convention Center in National Harbor, Md., just outside Washington D.C. Read more about the VAM contest, and more, in the latest SVS VAMail.

The Society for Vascular Surgery will provide complimentary meeting registration to a lucky attendee. To be eligible, all you must do is register for the meeting before 5 p.m. CDT Wednesday, April 24. The winner will be selected at random. This year’s meeting will be June 12 to 15 at the Gaylord National Resort & Convention Center in National Harbor, Md., just outside Washington D.C. Read more about the VAM contest, and more, in the latest SVS VAMail.

The Society for Vascular Surgery will provide complimentary meeting registration to a lucky attendee. To be eligible, all you must do is register for the meeting before 5 p.m. CDT Wednesday, April 24. The winner will be selected at random. This year’s meeting will be June 12 to 15 at the Gaylord National Resort & Convention Center in National Harbor, Md., just outside Washington D.C. Read more about the VAM contest, and more, in the latest SVS VAMail.

GENEVA – The TRK inhibitor larotrectinib is highly active in lung cancer patients with NTRK gene fusions, supporting routine screening for such fusions in cases of lung cancer, according to investigators.

Will Pass/MDedge News

Although NTRK fusions are relatively infrequent in lung cancer, lead author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that their low frequency should not preclude testing in the current diagnostic setting.

“The frequency of TRK fusions in lung cancers in a prospective series that we put together was at the order of 0.23%, recognizing that the paradigm now for molecular profiling in lung cancer screens for many different drivers together, and not just single-gene testing,” Dr. Drilon said at the European Lung Cancer Conference. Dr. Drilon noted that larotrectinib is now approved by the Food and Drug Administration for the treatment of adult and pediatric patients with TRK fusion-positive cancers.

The present analysis involved 11 patients with metastatic lung adenocarcinoma and NTRK gene fusions from two previous clinical trials (NCT02122913 and NCT02576431); of these patients, 8 had NTRK1 fusions and 3 had NTRK3 fusions. Patients were given larotrectinib 100 mg twice daily on a continuous 28-day schedule until disease progression, unacceptable toxicity, or withdrawal. Almost all patients (10 out of 11) had a prior systemic therapy, and 5 patients had three or more prior therapies. The best response to previous therapies included four stable disease and one partial response. Out of 11 patients, 4 were ineligible for response analysis because of a treatment period of less than 1 month, leaving 7 evaluable patients; of these, 2 patients had stable disease, 4 had a partial response, and 1 had a complete response, translating to an overall response rate of 71%. On average, patients responded in just 1.8 months, with responses ranging from 7.4 months to 17.6 months, with the caveat that median duration of response has yet to be met. Treatment was generally well tolerated, with most adverse events being grade 1 or 2. Dr. Drilon cited a historical dose reduction rate of 9% and a discontinuation rate of less than 1% (out of 122 patients across cancer types).

Although most patients were heavily pretreated, Dr. Drilon highlighted one patient, a 76-year-old woman with non–small cell lung cancer, who had an NTRK1 gene fusion and multiple metastases to the brain and contralateral lung. This patient received larotrectinib as first-line therapy after refusing standard platinum doublet chemotherapy. The woman had a partial response, including “a near complete intracranial response with 95% volumetric shrinkage,” Dr. Drilon said at the meeting, presented by the European Society for Medical Oncology. “She remains on therapy as of six and a half months per the last data cutoff and is still doing well without any substantial toxicities from this drug.”

“In conclusion, larotrectinib is active in advanced lung cancers that harbor a TRK fusion,” Dr. Drilon said. “Of course, these [findings] underscore the utility of molecular profiling for TRK fusions when we look for drivers in patients with non–small cell lung cancer.”

When asked by the invited discussant if NTRK fusions should be tested up-front in all cases of non–small cell lung cancer, Dr. Drilon said, “I think the answer is absolutely yes.” He highlighted the fact that this study and other existing research has shown an overall response rate of about 70%, “which certainly beats the outcomes that we see with other systemic therapies, including, arguably, chemoimmunotherapy for this population. So I think that the paradigm here should be similar to the paradigm for EGFR and ALK, where we have an active target therapeutic that we can use up front, which would likely really improve outcomes for patients.”

Loxo Oncology Inc. and Bayer AG funded the study. The investigators reported financial relationships with Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, and others.

SOURCE: Drilon et al. ELCC 2019. Abstract 111O.

GENEVA – The TRK inhibitor larotrectinib is highly active in lung cancer patients with NTRK gene fusions, supporting routine screening for such fusions in cases of lung cancer, according to investigators.

Will Pass/MDedge News

Although NTRK fusions are relatively infrequent in lung cancer, lead author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that their low frequency should not preclude testing in the current diagnostic setting.

“The frequency of TRK fusions in lung cancers in a prospective series that we put together was at the order of 0.23%, recognizing that the paradigm now for molecular profiling in lung cancer screens for many different drivers together, and not just single-gene testing,” Dr. Drilon said at the European Lung Cancer Conference. Dr. Drilon noted that larotrectinib is now approved by the Food and Drug Administration for the treatment of adult and pediatric patients with TRK fusion-positive cancers.

The present analysis involved 11 patients with metastatic lung adenocarcinoma and NTRK gene fusions from two previous clinical trials (NCT02122913 and NCT02576431); of these patients, 8 had NTRK1 fusions and 3 had NTRK3 fusions. Patients were given larotrectinib 100 mg twice daily on a continuous 28-day schedule until disease progression, unacceptable toxicity, or withdrawal. Almost all patients (10 out of 11) had a prior systemic therapy, and 5 patients had three or more prior therapies. The best response to previous therapies included four stable disease and one partial response. Out of 11 patients, 4 were ineligible for response analysis because of a treatment period of less than 1 month, leaving 7 evaluable patients; of these, 2 patients had stable disease, 4 had a partial response, and 1 had a complete response, translating to an overall response rate of 71%. On average, patients responded in just 1.8 months, with responses ranging from 7.4 months to 17.6 months, with the caveat that median duration of response has yet to be met. Treatment was generally well tolerated, with most adverse events being grade 1 or 2. Dr. Drilon cited a historical dose reduction rate of 9% and a discontinuation rate of less than 1% (out of 122 patients across cancer types).

Although most patients were heavily pretreated, Dr. Drilon highlighted one patient, a 76-year-old woman with non–small cell lung cancer, who had an NTRK1 gene fusion and multiple metastases to the brain and contralateral lung. This patient received larotrectinib as first-line therapy after refusing standard platinum doublet chemotherapy. The woman had a partial response, including “a near complete intracranial response with 95% volumetric shrinkage,” Dr. Drilon said at the meeting, presented by the European Society for Medical Oncology. “She remains on therapy as of six and a half months per the last data cutoff and is still doing well without any substantial toxicities from this drug.”

“In conclusion, larotrectinib is active in advanced lung cancers that harbor a TRK fusion,” Dr. Drilon said. “Of course, these [findings] underscore the utility of molecular profiling for TRK fusions when we look for drivers in patients with non–small cell lung cancer.”

When asked by the invited discussant if NTRK fusions should be tested up-front in all cases of non–small cell lung cancer, Dr. Drilon said, “I think the answer is absolutely yes.” He highlighted the fact that this study and other existing research has shown an overall response rate of about 70%, “which certainly beats the outcomes that we see with other systemic therapies, including, arguably, chemoimmunotherapy for this population. So I think that the paradigm here should be similar to the paradigm for EGFR and ALK, where we have an active target therapeutic that we can use up front, which would likely really improve outcomes for patients.”

Loxo Oncology Inc. and Bayer AG funded the study. The investigators reported financial relationships with Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, and others.

SOURCE: Drilon et al. ELCC 2019. Abstract 111O.

GENEVA – The TRK inhibitor larotrectinib is highly active in lung cancer patients with NTRK gene fusions, supporting routine screening for such fusions in cases of lung cancer, according to investigators.

Will Pass/MDedge News

Although NTRK fusions are relatively infrequent in lung cancer, lead author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that their low frequency should not preclude testing in the current diagnostic setting.

“The frequency of TRK fusions in lung cancers in a prospective series that we put together was at the order of 0.23%, recognizing that the paradigm now for molecular profiling in lung cancer screens for many different drivers together, and not just single-gene testing,” Dr. Drilon said at the European Lung Cancer Conference. Dr. Drilon noted that larotrectinib is now approved by the Food and Drug Administration for the treatment of adult and pediatric patients with TRK fusion-positive cancers.

The present analysis involved 11 patients with metastatic lung adenocarcinoma and NTRK gene fusions from two previous clinical trials (NCT02122913 and NCT02576431); of these patients, 8 had NTRK1 fusions and 3 had NTRK3 fusions. Patients were given larotrectinib 100 mg twice daily on a continuous 28-day schedule until disease progression, unacceptable toxicity, or withdrawal. Almost all patients (10 out of 11) had a prior systemic therapy, and 5 patients had three or more prior therapies. The best response to previous therapies included four stable disease and one partial response. Out of 11 patients, 4 were ineligible for response analysis because of a treatment period of less than 1 month, leaving 7 evaluable patients; of these, 2 patients had stable disease, 4 had a partial response, and 1 had a complete response, translating to an overall response rate of 71%. On average, patients responded in just 1.8 months, with responses ranging from 7.4 months to 17.6 months, with the caveat that median duration of response has yet to be met. Treatment was generally well tolerated, with most adverse events being grade 1 or 2. Dr. Drilon cited a historical dose reduction rate of 9% and a discontinuation rate of less than 1% (out of 122 patients across cancer types).

Although most patients were heavily pretreated, Dr. Drilon highlighted one patient, a 76-year-old woman with non–small cell lung cancer, who had an NTRK1 gene fusion and multiple metastases to the brain and contralateral lung. This patient received larotrectinib as first-line therapy after refusing standard platinum doublet chemotherapy. The woman had a partial response, including “a near complete intracranial response with 95% volumetric shrinkage,” Dr. Drilon said at the meeting, presented by the European Society for Medical Oncology. “She remains on therapy as of six and a half months per the last data cutoff and is still doing well without any substantial toxicities from this drug.”

“In conclusion, larotrectinib is active in advanced lung cancers that harbor a TRK fusion,” Dr. Drilon said. “Of course, these [findings] underscore the utility of molecular profiling for TRK fusions when we look for drivers in patients with non–small cell lung cancer.”

When asked by the invited discussant if NTRK fusions should be tested up-front in all cases of non–small cell lung cancer, Dr. Drilon said, “I think the answer is absolutely yes.” He highlighted the fact that this study and other existing research has shown an overall response rate of about 70%, “which certainly beats the outcomes that we see with other systemic therapies, including, arguably, chemoimmunotherapy for this population. So I think that the paradigm here should be similar to the paradigm for EGFR and ALK, where we have an active target therapeutic that we can use up front, which would likely really improve outcomes for patients.”

Loxo Oncology Inc. and Bayer AG funded the study. The investigators reported financial relationships with Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, and others.

SOURCE: Drilon et al. ELCC 2019. Abstract 111O.