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C3 inhibitor shows potential in PNH and AIHA
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
REPORTING FROM BSH 2019
First-line afatinib responses encouraging across diverse population of EGFR TKI-naive patients
GENEVA – For EGFR TKI-naive patients with EGFR-positive non–small cell lung cancer (NSCLC), afatinib appears safe and effective in a “real-world” setting, based on results of a phase 3b study.
Across a diverse population of patients, including those with brain metastases, uncommon mutations, multiple lines of prior therapy, and/or an Eastern Cooperative Oncology Group (ECOG) performance status of 2, afatinib delivered “encouraging” responses, reported lead author Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan. During his presentation at the European Lung Cancer Conference, Dr. Passaro described the safety profile as “predictable and manageable.”
The findings follow on the heels of the LUX-Lung trials, which showed that afatinib could match the progression-free survival (PFS) achieved with gefitinib, at about 11 months, while beating chemotherapy, which was associated with a PFS of approximately 5-7 months.
“However,” the investigators noted in their abstract, “in real-world practice chemotherapy remains a first-line choice.”
The present study aimed to demonstrate the real-world potential of afatinib across treatment lines, Dr. Passaro said at the meeting, presented by the European Society for Medical Oncology.
The patient population was diverse, with multiple treatment lines represented. The majority of patients (78%) received afatinib as first-line treatment, while smaller groups received the treatment as second-line (17%), or third-line or greater (5%). About one-third of the patients (36%) had an ECOG score of 0, about half (57%) had a score of 1, and a small group (8%) had a score of 2. A minority of patients had brain metastases (17%) and/or uncommon mutations (13%). Patients received 40 mg of afatinib daily; dose reduction to 20 mg was allowed if necessary.
Analysis showed that patients received afatinib for a median of almost 1 year (359 days). Slightly more than half of the patients (54%) got reduced doses because of adverse events, most commonly, diarrhea (25%) and rash (11%). About one out of five patients (22%) discontinued treatment entirely.
Secondarily, the investigators analyzed efficacy, reporting that the objective response rate was 46% and the disease control rate was 86%. During his presentation, Dr. Passaro focused on median time to symptomatic progression (TTSP) and median progression-free survival (PFS), describing these outcomes in relation to patient subgroups. Across all patients, TTSP was 14.9 months and PFS was 13.4 months. Among subgroups, patients receiving afatinib as first-line therapy had the best median PFS, at 13.8 months, which was comparable with those who received the treatment second-line (13.2 months). In contrast, patients receiving afatinib as a third-line treatment or later had noticeably shorter PFS, at 6.6 months. Baseline ECOG performance status showed a similar trend; patients with scores of 0 had a median PFS of 15.4 months, compared with 12.9 months for those with a score of 1, and 6.2 months with a score of 2. Patients with brain metastases fared worse than did those without (PFS 10.1 months vs. 13.9 months), and patients with uncommon mutations had shorter PFS than that of those with common mutations (6.0 months vs. 14.1 months). TTSP durations paralleled the above PFS trends.Boehringer Ingelheim funded the study. The investigators reported financial relationships with Roche, MSD, Bristol-Myers Squibb, AstraZeneca, and others.
SOURCE: Passaro et al. ELCC 2019. Abstract 115O.
GENEVA – For EGFR TKI-naive patients with EGFR-positive non–small cell lung cancer (NSCLC), afatinib appears safe and effective in a “real-world” setting, based on results of a phase 3b study.
Across a diverse population of patients, including those with brain metastases, uncommon mutations, multiple lines of prior therapy, and/or an Eastern Cooperative Oncology Group (ECOG) performance status of 2, afatinib delivered “encouraging” responses, reported lead author Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan. During his presentation at the European Lung Cancer Conference, Dr. Passaro described the safety profile as “predictable and manageable.”
The findings follow on the heels of the LUX-Lung trials, which showed that afatinib could match the progression-free survival (PFS) achieved with gefitinib, at about 11 months, while beating chemotherapy, which was associated with a PFS of approximately 5-7 months.
“However,” the investigators noted in their abstract, “in real-world practice chemotherapy remains a first-line choice.”
The present study aimed to demonstrate the real-world potential of afatinib across treatment lines, Dr. Passaro said at the meeting, presented by the European Society for Medical Oncology.
The patient population was diverse, with multiple treatment lines represented. The majority of patients (78%) received afatinib as first-line treatment, while smaller groups received the treatment as second-line (17%), or third-line or greater (5%). About one-third of the patients (36%) had an ECOG score of 0, about half (57%) had a score of 1, and a small group (8%) had a score of 2. A minority of patients had brain metastases (17%) and/or uncommon mutations (13%). Patients received 40 mg of afatinib daily; dose reduction to 20 mg was allowed if necessary.
Analysis showed that patients received afatinib for a median of almost 1 year (359 days). Slightly more than half of the patients (54%) got reduced doses because of adverse events, most commonly, diarrhea (25%) and rash (11%). About one out of five patients (22%) discontinued treatment entirely.
Secondarily, the investigators analyzed efficacy, reporting that the objective response rate was 46% and the disease control rate was 86%. During his presentation, Dr. Passaro focused on median time to symptomatic progression (TTSP) and median progression-free survival (PFS), describing these outcomes in relation to patient subgroups. Across all patients, TTSP was 14.9 months and PFS was 13.4 months. Among subgroups, patients receiving afatinib as first-line therapy had the best median PFS, at 13.8 months, which was comparable with those who received the treatment second-line (13.2 months). In contrast, patients receiving afatinib as a third-line treatment or later had noticeably shorter PFS, at 6.6 months. Baseline ECOG performance status showed a similar trend; patients with scores of 0 had a median PFS of 15.4 months, compared with 12.9 months for those with a score of 1, and 6.2 months with a score of 2. Patients with brain metastases fared worse than did those without (PFS 10.1 months vs. 13.9 months), and patients with uncommon mutations had shorter PFS than that of those with common mutations (6.0 months vs. 14.1 months). TTSP durations paralleled the above PFS trends.Boehringer Ingelheim funded the study. The investigators reported financial relationships with Roche, MSD, Bristol-Myers Squibb, AstraZeneca, and others.
SOURCE: Passaro et al. ELCC 2019. Abstract 115O.
GENEVA – For EGFR TKI-naive patients with EGFR-positive non–small cell lung cancer (NSCLC), afatinib appears safe and effective in a “real-world” setting, based on results of a phase 3b study.
Across a diverse population of patients, including those with brain metastases, uncommon mutations, multiple lines of prior therapy, and/or an Eastern Cooperative Oncology Group (ECOG) performance status of 2, afatinib delivered “encouraging” responses, reported lead author Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan. During his presentation at the European Lung Cancer Conference, Dr. Passaro described the safety profile as “predictable and manageable.”
The findings follow on the heels of the LUX-Lung trials, which showed that afatinib could match the progression-free survival (PFS) achieved with gefitinib, at about 11 months, while beating chemotherapy, which was associated with a PFS of approximately 5-7 months.
“However,” the investigators noted in their abstract, “in real-world practice chemotherapy remains a first-line choice.”
The present study aimed to demonstrate the real-world potential of afatinib across treatment lines, Dr. Passaro said at the meeting, presented by the European Society for Medical Oncology.
The patient population was diverse, with multiple treatment lines represented. The majority of patients (78%) received afatinib as first-line treatment, while smaller groups received the treatment as second-line (17%), or third-line or greater (5%). About one-third of the patients (36%) had an ECOG score of 0, about half (57%) had a score of 1, and a small group (8%) had a score of 2. A minority of patients had brain metastases (17%) and/or uncommon mutations (13%). Patients received 40 mg of afatinib daily; dose reduction to 20 mg was allowed if necessary.
Analysis showed that patients received afatinib for a median of almost 1 year (359 days). Slightly more than half of the patients (54%) got reduced doses because of adverse events, most commonly, diarrhea (25%) and rash (11%). About one out of five patients (22%) discontinued treatment entirely.
Secondarily, the investigators analyzed efficacy, reporting that the objective response rate was 46% and the disease control rate was 86%. During his presentation, Dr. Passaro focused on median time to symptomatic progression (TTSP) and median progression-free survival (PFS), describing these outcomes in relation to patient subgroups. Across all patients, TTSP was 14.9 months and PFS was 13.4 months. Among subgroups, patients receiving afatinib as first-line therapy had the best median PFS, at 13.8 months, which was comparable with those who received the treatment second-line (13.2 months). In contrast, patients receiving afatinib as a third-line treatment or later had noticeably shorter PFS, at 6.6 months. Baseline ECOG performance status showed a similar trend; patients with scores of 0 had a median PFS of 15.4 months, compared with 12.9 months for those with a score of 1, and 6.2 months with a score of 2. Patients with brain metastases fared worse than did those without (PFS 10.1 months vs. 13.9 months), and patients with uncommon mutations had shorter PFS than that of those with common mutations (6.0 months vs. 14.1 months). TTSP durations paralleled the above PFS trends.Boehringer Ingelheim funded the study. The investigators reported financial relationships with Roche, MSD, Bristol-Myers Squibb, AstraZeneca, and others.
SOURCE: Passaro et al. ELCC 2019. Abstract 115O.
REPORTING FROM ELCC 2019
Liquid biopsy falls short for isolated brain lesions in lung cancer
GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.
Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.
Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.
“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”
Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.
Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.
“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.
The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
SOURCE: Aldea et al. ELCC 2019. Abstract 110O.
GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.
Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.
Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.
“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”
Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.
Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.
“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.
The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
SOURCE: Aldea et al. ELCC 2019. Abstract 110O.
GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.
Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.
Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.
“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”
Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.
Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.
“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.
The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
SOURCE: Aldea et al. ELCC 2019. Abstract 110O.
REPORTING FROM ELCC 2019
Key clinical point: Plasma circulating tumor DNA (ctDNA) analysis appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression.
Major finding: In patients with at least 1 known NSCLC molecular alteration, ctDNA analysis was positive in 38% of those with isolated CNS disease, compared with 98% of those with systemic disease progression (P less than .0001).
Study details: A retrospective analysis of 66 patients with NSCLC, drawn from a screened population of 959 patients.
Disclosures: The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
Source: Aldea et al. ELCC 2019. Abstract 110O.
Afatinib shows safety and efficacy among elderly
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.
REPORTING FROM ELCC 2019
MicroRNA-375 may be key to fibrolamellar carcinoma
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.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
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.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Larotrectinib responses support routine NTRK gene fusion testing for lung cancer
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.
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.
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.
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.
At ELCC 2019
Pooled KEYNOTE data support pembro for elderly patients with NSCLC
GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.
They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.
“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.
All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.
As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.
Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).
“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.
Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?
“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.
According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.
“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”
Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”
Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.
The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.
SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.
GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.
They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.
“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.
All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.
As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.
Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).
“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.
Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?
“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.
According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.
“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”
Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”
Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.
The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.
SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.
GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.
They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.
“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.
All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.
As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.
Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).
“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.
Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?
“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.
According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.
“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”
Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”
Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.
The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.
SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.
REPORTING FROM ELCC 2019
Tumor-treating fields boost chemo for mesothelioma
GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.
The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.
“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.
The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.
The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.
After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.
In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.
“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.
When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”
Dr. Ceresoli disclosed travel funding from Novocure.
SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.
GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.
The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.
“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.
The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.
The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.
After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.
In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.
“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.
When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”
Dr. Ceresoli disclosed travel funding from Novocure.
SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.
GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.
The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.
“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.
The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.
The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.
After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.
In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.
“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.
When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”
Dr. Ceresoli disclosed travel funding from Novocure.
SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.
At ELCC 2019
MRI predicts ALK status of NSCLC via brain lesions
GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.
In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.
“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”
Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.
Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”
In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”
Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.
“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.
“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”
The investigators reported no external study funding and reported no conflicts of interest.
SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.
GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.
In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.
“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”
Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.
Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”
In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”
Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.
“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.
“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”
The investigators reported no external study funding and reported no conflicts of interest.
SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.
GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.
In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.
“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”
Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.
Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”
In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”
Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.
“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.
“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”
The investigators reported no external study funding and reported no conflicts of interest.
SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.
REPORTING FROM ELCC 2019
European NAVIGATE data support safety of electromagnetic navigation bronchoscopy
GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.
In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.
“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.
Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.
Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.
The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.
“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”
Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.
“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.
“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.
However, Dr. Lau contested this figure.
“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”
Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.
“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”
When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.
“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.
Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.
Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.
Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.
SOURCE: Lau et al. ELCC 2019. Abstract 68O.
GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.
In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.
“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.
Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.
Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.
The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.
“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”
Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.
“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.
“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.
However, Dr. Lau contested this figure.
“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”
Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.
“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”
When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.
“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.
Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.
Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.
Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.
SOURCE: Lau et al. ELCC 2019. Abstract 68O.
GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.
In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.
“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.
Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.
Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.
The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.
“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”
Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.
“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.
“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.
However, Dr. Lau contested this figure.
“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”
Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.
“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”
When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.
“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.
Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.
Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.
Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.
SOURCE: Lau et al. ELCC 2019. Abstract 68O.
REPORTING FROM ELCC 2019