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STAMPEDE: Radiation to prostate boosts survival of metastatic cancer
MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.
Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.
“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.
The study was published online in the Lancet Oncology to coincide with the presentation.
Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.
Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”
The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.
For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.
As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.
In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.
In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.
Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.
He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”
The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.
“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.
The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.
SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.
MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.
Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.
“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.
The study was published online in the Lancet Oncology to coincide with the presentation.
Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.
Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”
The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.
For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.
As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.
In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.
In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.
Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.
He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”
The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.
“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.
The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.
SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.
MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.
Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.
“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.
The study was published online in the Lancet Oncology to coincide with the presentation.
Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.
Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”
The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.
For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.
As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.
In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.
In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.
Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.
He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”
The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.
“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.
The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.
SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.
REPORTING FROM ESMO 2018
Key clinical point: Local radiation can improve survival of low-burden metastatic prostate cancer.
Major finding: In men with low-burden metastatic disease, the 3-year overall survival rate was 81% with radiation versus 73% without.
Study details: A prospective study of 2,061 men in a randomized, phase 3 trial exploring new therapeutic options for prostate cancer.
Disclosures: The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.
Source: Parker C et al. ESMO 2018, Abstract LBA5_PR.
Readmission to non-index hospital following acute stroke linked to worse outcomes
ATLANTA – Following an acute stroke, optimizing stroke secondary prevention measures, medical complications, and transitions of care is essential to reducing 30-day readmissions and improving patient outcomes, a large analysis of national data showed.
“Care that is fragmented with readmissions to other hospitals results not only in more expensive care and longer length of stay but also increased mortality for our acute stroke patients,” lead study author Laura K. Stein, MD, said in an interview in advance of the annual meeting of the American Neurological Association.
In 2017, a study of the Nationwide Readmissions Database demonstrated that 12.1% of patients with acute ischemic stroke were readmitted within 30 days (Stroke 2017;48:1386-8). It cited that 89.6% were unplanned and 12.9% were preventable. “However, this study did not examine whether patients were admitted to the discharging hospital or a different hospital,” said Dr. Stein, a neurologist at the Icahn School of Medicine at Mount Sinai, New York. “Furthermore, it did not include metrics such as cost, length of stay, and mortality with 30-day readmissions. Hospitals are increasingly held accountable and penalized for metrics such as length of stay and 30-day readmissions.”
In 2010, the Centers for Medicare & Medicaid Services introduced the Hospital Readmissions Reduction Program in an attempt to decrease readmissions following hospitalizations for acute myocardial infarction, heart failure, and pneumonia. “In 2012, CMS started reducing Medicare payments for hospitals with excess readmissions,” said Dr. Stein, who is a fellowship-trained stroke specialist. “While readmission to the same hospital has great implications for hospital systems, any readmission has great implications for patients.”
In what is believed to be the first study of its kind, Dr. Stein and her colleagues drew from the 2013 Nationwide Readmissions Database to examine in-hospital outcomes associated with 30-day readmission to a different hospital for acute ischemic stroke. They used ICD-9 codes to identify index stroke admissions and all-cause readmissions. Outcomes of interest were length of stay, total charges, and in-hospital mortality during the 30-day readmission. The main predictor was readmission to another hospital, compared with readmission to the same hospital as the index acute stroke admission. The researchers used linear regression for the outcomes of length of stay and charges, and logistic regression for in-hospital mortality. They adjusted for several variables during the index admission, including age, sex, vascular risk factors, hospital bed size, teaching hospital status, insurance status, discharge destination, National Center for Health Statistics urban-rural location classification, length of stay, and total charges.
Of 24,545 acute stroke patients readmitted within 30 days, 7,274 (30%) were readmitted to a different hospital. The top three reasons for readmission were acute cerebrovascular disease, septicemia, and renal failure. In fully adjusted models, readmission to a different hospital was associated with an increased length of stay of 0.97 days (P less than .0001) and a mean of $7,677.28 greater total charges, compared with readmission to the same hospital (P less than .0001). The fully adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).
“While it is conceivable that cost and length of stay could be higher with readmission to a different hospital because of a need for additional testing with a lack of familiarity with the patient, it is concerning that mortality is higher,” Dr. Stein said. “These findings emphasize the importance of optimizing secondary stroke prevention and medical complications following acute stroke before discharge. Additionally, they emphasize the importance of good transitions of care from the inpatient to outpatient setting (whether that’s to a rehabilitation facility, skilled nursing facility, or home) and accessibility of the discharging stroke team after discharge.”
She acknowledged certain limitations of the analysis, including its reliance of administrative data, which could include misclassification of diagnoses and comorbidities based on ICD-9 codes. “However, we have chosen ICD-9 codes for stroke that have been previously validated in the literature,” Dr. Stein said. “For instance, the validated codes for stroke as the primary discharge diagnosis have a sensitivity of 74%, specificity of 95%, and positive predictive value of 88%. Second, we do not know stroke subtype or severity of stroke. Third, we do not know what the transitions of care plan were when the patients left the hospital following index acute ischemic stroke admission and why these patients ended up being readmitted to a different hospital rather than the one that treated them for their acute stroke.”
The researchers reported having no financial disclosures.
SOURCE: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.
ATLANTA – Following an acute stroke, optimizing stroke secondary prevention measures, medical complications, and transitions of care is essential to reducing 30-day readmissions and improving patient outcomes, a large analysis of national data showed.
“Care that is fragmented with readmissions to other hospitals results not only in more expensive care and longer length of stay but also increased mortality for our acute stroke patients,” lead study author Laura K. Stein, MD, said in an interview in advance of the annual meeting of the American Neurological Association.
In 2017, a study of the Nationwide Readmissions Database demonstrated that 12.1% of patients with acute ischemic stroke were readmitted within 30 days (Stroke 2017;48:1386-8). It cited that 89.6% were unplanned and 12.9% were preventable. “However, this study did not examine whether patients were admitted to the discharging hospital or a different hospital,” said Dr. Stein, a neurologist at the Icahn School of Medicine at Mount Sinai, New York. “Furthermore, it did not include metrics such as cost, length of stay, and mortality with 30-day readmissions. Hospitals are increasingly held accountable and penalized for metrics such as length of stay and 30-day readmissions.”
In 2010, the Centers for Medicare & Medicaid Services introduced the Hospital Readmissions Reduction Program in an attempt to decrease readmissions following hospitalizations for acute myocardial infarction, heart failure, and pneumonia. “In 2012, CMS started reducing Medicare payments for hospitals with excess readmissions,” said Dr. Stein, who is a fellowship-trained stroke specialist. “While readmission to the same hospital has great implications for hospital systems, any readmission has great implications for patients.”
In what is believed to be the first study of its kind, Dr. Stein and her colleagues drew from the 2013 Nationwide Readmissions Database to examine in-hospital outcomes associated with 30-day readmission to a different hospital for acute ischemic stroke. They used ICD-9 codes to identify index stroke admissions and all-cause readmissions. Outcomes of interest were length of stay, total charges, and in-hospital mortality during the 30-day readmission. The main predictor was readmission to another hospital, compared with readmission to the same hospital as the index acute stroke admission. The researchers used linear regression for the outcomes of length of stay and charges, and logistic regression for in-hospital mortality. They adjusted for several variables during the index admission, including age, sex, vascular risk factors, hospital bed size, teaching hospital status, insurance status, discharge destination, National Center for Health Statistics urban-rural location classification, length of stay, and total charges.
Of 24,545 acute stroke patients readmitted within 30 days, 7,274 (30%) were readmitted to a different hospital. The top three reasons for readmission were acute cerebrovascular disease, septicemia, and renal failure. In fully adjusted models, readmission to a different hospital was associated with an increased length of stay of 0.97 days (P less than .0001) and a mean of $7,677.28 greater total charges, compared with readmission to the same hospital (P less than .0001). The fully adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).
“While it is conceivable that cost and length of stay could be higher with readmission to a different hospital because of a need for additional testing with a lack of familiarity with the patient, it is concerning that mortality is higher,” Dr. Stein said. “These findings emphasize the importance of optimizing secondary stroke prevention and medical complications following acute stroke before discharge. Additionally, they emphasize the importance of good transitions of care from the inpatient to outpatient setting (whether that’s to a rehabilitation facility, skilled nursing facility, or home) and accessibility of the discharging stroke team after discharge.”
She acknowledged certain limitations of the analysis, including its reliance of administrative data, which could include misclassification of diagnoses and comorbidities based on ICD-9 codes. “However, we have chosen ICD-9 codes for stroke that have been previously validated in the literature,” Dr. Stein said. “For instance, the validated codes for stroke as the primary discharge diagnosis have a sensitivity of 74%, specificity of 95%, and positive predictive value of 88%. Second, we do not know stroke subtype or severity of stroke. Third, we do not know what the transitions of care plan were when the patients left the hospital following index acute ischemic stroke admission and why these patients ended up being readmitted to a different hospital rather than the one that treated them for their acute stroke.”
The researchers reported having no financial disclosures.
SOURCE: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.
ATLANTA – Following an acute stroke, optimizing stroke secondary prevention measures, medical complications, and transitions of care is essential to reducing 30-day readmissions and improving patient outcomes, a large analysis of national data showed.
“Care that is fragmented with readmissions to other hospitals results not only in more expensive care and longer length of stay but also increased mortality for our acute stroke patients,” lead study author Laura K. Stein, MD, said in an interview in advance of the annual meeting of the American Neurological Association.
In 2017, a study of the Nationwide Readmissions Database demonstrated that 12.1% of patients with acute ischemic stroke were readmitted within 30 days (Stroke 2017;48:1386-8). It cited that 89.6% were unplanned and 12.9% were preventable. “However, this study did not examine whether patients were admitted to the discharging hospital or a different hospital,” said Dr. Stein, a neurologist at the Icahn School of Medicine at Mount Sinai, New York. “Furthermore, it did not include metrics such as cost, length of stay, and mortality with 30-day readmissions. Hospitals are increasingly held accountable and penalized for metrics such as length of stay and 30-day readmissions.”
In 2010, the Centers for Medicare & Medicaid Services introduced the Hospital Readmissions Reduction Program in an attempt to decrease readmissions following hospitalizations for acute myocardial infarction, heart failure, and pneumonia. “In 2012, CMS started reducing Medicare payments for hospitals with excess readmissions,” said Dr. Stein, who is a fellowship-trained stroke specialist. “While readmission to the same hospital has great implications for hospital systems, any readmission has great implications for patients.”
In what is believed to be the first study of its kind, Dr. Stein and her colleagues drew from the 2013 Nationwide Readmissions Database to examine in-hospital outcomes associated with 30-day readmission to a different hospital for acute ischemic stroke. They used ICD-9 codes to identify index stroke admissions and all-cause readmissions. Outcomes of interest were length of stay, total charges, and in-hospital mortality during the 30-day readmission. The main predictor was readmission to another hospital, compared with readmission to the same hospital as the index acute stroke admission. The researchers used linear regression for the outcomes of length of stay and charges, and logistic regression for in-hospital mortality. They adjusted for several variables during the index admission, including age, sex, vascular risk factors, hospital bed size, teaching hospital status, insurance status, discharge destination, National Center for Health Statistics urban-rural location classification, length of stay, and total charges.
Of 24,545 acute stroke patients readmitted within 30 days, 7,274 (30%) were readmitted to a different hospital. The top three reasons for readmission were acute cerebrovascular disease, septicemia, and renal failure. In fully adjusted models, readmission to a different hospital was associated with an increased length of stay of 0.97 days (P less than .0001) and a mean of $7,677.28 greater total charges, compared with readmission to the same hospital (P less than .0001). The fully adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).
“While it is conceivable that cost and length of stay could be higher with readmission to a different hospital because of a need for additional testing with a lack of familiarity with the patient, it is concerning that mortality is higher,” Dr. Stein said. “These findings emphasize the importance of optimizing secondary stroke prevention and medical complications following acute stroke before discharge. Additionally, they emphasize the importance of good transitions of care from the inpatient to outpatient setting (whether that’s to a rehabilitation facility, skilled nursing facility, or home) and accessibility of the discharging stroke team after discharge.”
She acknowledged certain limitations of the analysis, including its reliance of administrative data, which could include misclassification of diagnoses and comorbidities based on ICD-9 codes. “However, we have chosen ICD-9 codes for stroke that have been previously validated in the literature,” Dr. Stein said. “For instance, the validated codes for stroke as the primary discharge diagnosis have a sensitivity of 74%, specificity of 95%, and positive predictive value of 88%. Second, we do not know stroke subtype or severity of stroke. Third, we do not know what the transitions of care plan were when the patients left the hospital following index acute ischemic stroke admission and why these patients ended up being readmitted to a different hospital rather than the one that treated them for their acute stroke.”
The researchers reported having no financial disclosures.
SOURCE: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.
REPORTING FROM ANA 2018
Key clinical point:
Major finding: The adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).
Study details: A review of 24,545 acute stroke patients 2013 from the Nationwide Readmissions Database.
Disclosures: The researchers reported having no financial disclosures.
Source: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.
Checkpoint inhibitor/TKI combo improves PFS of RCC over sunitinib
MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.
The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.
“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.
Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.
“This is the first study of a TKI plus and anti-PD-L1 drug showing an improved progression-free survival in this patient population,” he added.
On Oct. 18, the day before the start of ESMO 2018, Merck announced in a press release positive results of a phase 3 trial comparing axitinib in combination with a different checkpoint inhibitor, pembrolizumab (Keytruda), compared with sunitinib monotherapy. The press release, typically sparse on details, said that the trial met both primary endpoints of overall survival (OS) and PFS in the first-line treatment of advanced or metastatic RCC.
In the JAVELIN Renal 101 trial, investigators enrolled and randomized 886 patients, 873 of whom went on to treatment: 434 assigned to avelumab plus axitinib, and 439 to sunitinib.
A total of 560 patients were determined to be PD-L1-positive according to the Ventana assay: 270 assigned to the combination, and 290 assigned to sunitinib.
Avelumab was delivered 10 mg/kg intravenously every 2 weeks, and oral axitinib was given 5 mg twice daily over a 6-week cycle. Oral sunitinib was give 50 mg daily for 4 weeks, followed by 2 weeks off, for every cycle.
Median PFS by independent review in the PD-L1-positive patients, one of two primary endpoints, was 13.8 months in the avelumab/axitinib arm, vs. 7.2 months in the sunitinib arm. This translated into a stratified hazard ratio (HR) of 0.61 (P less than .001) favoring the combination.
The respective median PFS in the overall population was 13.8 vs. 8.4 months, respectively (HR, 0.69; P = .0001).
Objective response rates also were higher with the combination in both the PD-L1-positive population (55% vs. 26%), and in the overall population (51% vs. 26%). At the time of data cutoff, the median duration of response had not been reached in either treatment arm in either population.
The stratified odds ratio for response with avelumab/axitinib was 3.098 (P less than .001).
At the time of the data cutoff for this interim analysis, overall survival data were not mature. OS in the PD-L1-positive population, the second primary endpoint, will be reported at a later date, Dr. Motzer said.
The incidence of treatment-related adverse events was similar in the groups, at 95% of patients in the avelumab arm and 96% in the sunitinib arm. Grade 3 or 4 events occurred in 51% and 48% of patients respectively. Grade 3/4 hypertension was the highest-frequency event, occurring in 24% of patients on avelumab/axitinib vs. 15% on sunitinib.
Immune-related adverse events occurred in 38% of patients in the avelumab group, including hypothyroidism, liver function test abnormalities, adrenal insufficiency, acute kidney injury, colitis, and hepatotoxicity. Most of the events occurred in 1% or 2% of patients, except hypothyroidism, which occurred in 21%.
High-dose corticosteroids were administered to 11% of patients who experienced an immune-related adverse event.
“One of the beauties of this combination is really its tolerability,” said Viktor Grünwald, MD, of the West German Cancer Center in Essen, the invited discussant at the symposium.
“When it comes to toxicities, they are pretty much in the same range, which is really surprising,” he said.
He noted, however, that it’s still an open question whether the combination of avelumab and axitinib is better than sequencing of other agents, given the current absence of evidence of an OS or quality-of-life benefit for the combination.
At present, the best evidence supports the use of ipilimumab (Yervoy) and nivolumab (Opdivo), which provides a clinically relevant OS benefit in patients with intermediate and high-risk disease, and this therapy should remain the standard of care, Dr. Grünwald said.
“I do believe that there is a niche, in favorable-risk patients, for this specific combination [avelumab/axitinib],” he said.
The trial was sponsored by Pfizer as part of an alliance between Pfizer and Merck KGaA. Dr. Motzer disclosed consulting or advisory roles with Pfizer, Merck, and others, and research funding from Pfizer and others. Dr. Haanen disclosed financial compensation for advisory work he did for Pfizer, Merck, Sharpe & Dohme, and others, and grant support from Bristol-Myers Squibb, MSD, and Novartis. Dr. Grünwald disclosed honoraria for speaking and advising from MSD, and funding from Pfizer, MSD, and others.
MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.
The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.
“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.
Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.
“This is the first study of a TKI plus and anti-PD-L1 drug showing an improved progression-free survival in this patient population,” he added.
On Oct. 18, the day before the start of ESMO 2018, Merck announced in a press release positive results of a phase 3 trial comparing axitinib in combination with a different checkpoint inhibitor, pembrolizumab (Keytruda), compared with sunitinib monotherapy. The press release, typically sparse on details, said that the trial met both primary endpoints of overall survival (OS) and PFS in the first-line treatment of advanced or metastatic RCC.
In the JAVELIN Renal 101 trial, investigators enrolled and randomized 886 patients, 873 of whom went on to treatment: 434 assigned to avelumab plus axitinib, and 439 to sunitinib.
A total of 560 patients were determined to be PD-L1-positive according to the Ventana assay: 270 assigned to the combination, and 290 assigned to sunitinib.
Avelumab was delivered 10 mg/kg intravenously every 2 weeks, and oral axitinib was given 5 mg twice daily over a 6-week cycle. Oral sunitinib was give 50 mg daily for 4 weeks, followed by 2 weeks off, for every cycle.
Median PFS by independent review in the PD-L1-positive patients, one of two primary endpoints, was 13.8 months in the avelumab/axitinib arm, vs. 7.2 months in the sunitinib arm. This translated into a stratified hazard ratio (HR) of 0.61 (P less than .001) favoring the combination.
The respective median PFS in the overall population was 13.8 vs. 8.4 months, respectively (HR, 0.69; P = .0001).
Objective response rates also were higher with the combination in both the PD-L1-positive population (55% vs. 26%), and in the overall population (51% vs. 26%). At the time of data cutoff, the median duration of response had not been reached in either treatment arm in either population.
The stratified odds ratio for response with avelumab/axitinib was 3.098 (P less than .001).
At the time of the data cutoff for this interim analysis, overall survival data were not mature. OS in the PD-L1-positive population, the second primary endpoint, will be reported at a later date, Dr. Motzer said.
The incidence of treatment-related adverse events was similar in the groups, at 95% of patients in the avelumab arm and 96% in the sunitinib arm. Grade 3 or 4 events occurred in 51% and 48% of patients respectively. Grade 3/4 hypertension was the highest-frequency event, occurring in 24% of patients on avelumab/axitinib vs. 15% on sunitinib.
Immune-related adverse events occurred in 38% of patients in the avelumab group, including hypothyroidism, liver function test abnormalities, adrenal insufficiency, acute kidney injury, colitis, and hepatotoxicity. Most of the events occurred in 1% or 2% of patients, except hypothyroidism, which occurred in 21%.
High-dose corticosteroids were administered to 11% of patients who experienced an immune-related adverse event.
“One of the beauties of this combination is really its tolerability,” said Viktor Grünwald, MD, of the West German Cancer Center in Essen, the invited discussant at the symposium.
“When it comes to toxicities, they are pretty much in the same range, which is really surprising,” he said.
He noted, however, that it’s still an open question whether the combination of avelumab and axitinib is better than sequencing of other agents, given the current absence of evidence of an OS or quality-of-life benefit for the combination.
At present, the best evidence supports the use of ipilimumab (Yervoy) and nivolumab (Opdivo), which provides a clinically relevant OS benefit in patients with intermediate and high-risk disease, and this therapy should remain the standard of care, Dr. Grünwald said.
“I do believe that there is a niche, in favorable-risk patients, for this specific combination [avelumab/axitinib],” he said.
The trial was sponsored by Pfizer as part of an alliance between Pfizer and Merck KGaA. Dr. Motzer disclosed consulting or advisory roles with Pfizer, Merck, and others, and research funding from Pfizer and others. Dr. Haanen disclosed financial compensation for advisory work he did for Pfizer, Merck, Sharpe & Dohme, and others, and grant support from Bristol-Myers Squibb, MSD, and Novartis. Dr. Grünwald disclosed honoraria for speaking and advising from MSD, and funding from Pfizer, MSD, and others.
MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.
The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.
“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.
Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.
“This is the first study of a TKI plus and anti-PD-L1 drug showing an improved progression-free survival in this patient population,” he added.
On Oct. 18, the day before the start of ESMO 2018, Merck announced in a press release positive results of a phase 3 trial comparing axitinib in combination with a different checkpoint inhibitor, pembrolizumab (Keytruda), compared with sunitinib monotherapy. The press release, typically sparse on details, said that the trial met both primary endpoints of overall survival (OS) and PFS in the first-line treatment of advanced or metastatic RCC.
In the JAVELIN Renal 101 trial, investigators enrolled and randomized 886 patients, 873 of whom went on to treatment: 434 assigned to avelumab plus axitinib, and 439 to sunitinib.
A total of 560 patients were determined to be PD-L1-positive according to the Ventana assay: 270 assigned to the combination, and 290 assigned to sunitinib.
Avelumab was delivered 10 mg/kg intravenously every 2 weeks, and oral axitinib was given 5 mg twice daily over a 6-week cycle. Oral sunitinib was give 50 mg daily for 4 weeks, followed by 2 weeks off, for every cycle.
Median PFS by independent review in the PD-L1-positive patients, one of two primary endpoints, was 13.8 months in the avelumab/axitinib arm, vs. 7.2 months in the sunitinib arm. This translated into a stratified hazard ratio (HR) of 0.61 (P less than .001) favoring the combination.
The respective median PFS in the overall population was 13.8 vs. 8.4 months, respectively (HR, 0.69; P = .0001).
Objective response rates also were higher with the combination in both the PD-L1-positive population (55% vs. 26%), and in the overall population (51% vs. 26%). At the time of data cutoff, the median duration of response had not been reached in either treatment arm in either population.
The stratified odds ratio for response with avelumab/axitinib was 3.098 (P less than .001).
At the time of the data cutoff for this interim analysis, overall survival data were not mature. OS in the PD-L1-positive population, the second primary endpoint, will be reported at a later date, Dr. Motzer said.
The incidence of treatment-related adverse events was similar in the groups, at 95% of patients in the avelumab arm and 96% in the sunitinib arm. Grade 3 or 4 events occurred in 51% and 48% of patients respectively. Grade 3/4 hypertension was the highest-frequency event, occurring in 24% of patients on avelumab/axitinib vs. 15% on sunitinib.
Immune-related adverse events occurred in 38% of patients in the avelumab group, including hypothyroidism, liver function test abnormalities, adrenal insufficiency, acute kidney injury, colitis, and hepatotoxicity. Most of the events occurred in 1% or 2% of patients, except hypothyroidism, which occurred in 21%.
High-dose corticosteroids were administered to 11% of patients who experienced an immune-related adverse event.
“One of the beauties of this combination is really its tolerability,” said Viktor Grünwald, MD, of the West German Cancer Center in Essen, the invited discussant at the symposium.
“When it comes to toxicities, they are pretty much in the same range, which is really surprising,” he said.
He noted, however, that it’s still an open question whether the combination of avelumab and axitinib is better than sequencing of other agents, given the current absence of evidence of an OS or quality-of-life benefit for the combination.
At present, the best evidence supports the use of ipilimumab (Yervoy) and nivolumab (Opdivo), which provides a clinically relevant OS benefit in patients with intermediate and high-risk disease, and this therapy should remain the standard of care, Dr. Grünwald said.
“I do believe that there is a niche, in favorable-risk patients, for this specific combination [avelumab/axitinib],” he said.
The trial was sponsored by Pfizer as part of an alliance between Pfizer and Merck KGaA. Dr. Motzer disclosed consulting or advisory roles with Pfizer, Merck, and others, and research funding from Pfizer and others. Dr. Haanen disclosed financial compensation for advisory work he did for Pfizer, Merck, Sharpe & Dohme, and others, and grant support from Bristol-Myers Squibb, MSD, and Novartis. Dr. Grünwald disclosed honoraria for speaking and advising from MSD, and funding from Pfizer, MSD, and others.
REPORTING FROM ESMO 2018
Key clinical point: Progression-free survival was superior with avelumab and axitinib vs. sunitinib regardless of PD-L1-status.
Major finding: Median PFS by independent review in PD-L1-positive patients was 13.8 months with avelumab/axitinib vs. 7.2 months with sunitinib.
Study details: Prospective randomized phase 3 trial of 560 patients with advanced RCC.
Disclosures: The trial was sponsored by Pfizer as part of an alliance between Pfizer and Merck KGaA. Dr. Motzer disclosed consulting or advisory roles with Pfizer, Merck, and others, and research funding from Pfizer and others. Dr. Haanen disclosed financial compensation for advisory work he did for Pfizer, Merck, Sharpe & Dohme, and others, and grant support from Bristol-Myers Squibb, MSD, and Novartis. Dr. Grünwald disclosed honoraria for speaking and advising from MSD, and funding from Pfizer, MSD, and others.
Source: Motzer RJ et al. ESMO 2018. Abstract LBA6_PR.
Neoadjuvant TKI for advanced NSCLC falls short
MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.
Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.
Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.
Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.
CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m2 (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.
The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).
The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.
Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.
In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”
While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.
Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.
“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).
Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.
“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”
CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.
MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.
Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.
Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.
Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.
CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m2 (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.
The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).
The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.
Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.
In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”
While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.
Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.
“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).
Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.
“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”
CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.
MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.
Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.
Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.
Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.
CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m2 (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.
The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).
The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.
Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.
In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”
While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.
Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.
“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).
Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.
“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”
CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.
REPORTING FROM ESMO 2018
Key clinical point: Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer may increase progression-free survival, compared with gemcitabine and cisplatin, but clinical benefits fall short of current standards.
Major finding: Median progression-free survival for erlotinib was 21.5 months, compared with 11.9 months for gemcitabine and cisplatin (P = .003).
Study details: CTONG 1103 is an ongoing, phase 2, open-label study involving 72 patients with stage IIIA (N2) epithelial growth factor receptor–mutant non–small cell lung cancer
Disclosures: The study was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported affiliations with Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.
Multiple interventions boost RA treat-to-target success
CHICAGO – A novel disease-management approach that paired routine monitoring of the clinical status of patients with RA and training for their rheumatologists on how to refine their treat-to-target practices led to a modest but meaningful boost in the achievement of treat-to-target goals in a single-center study with 2,549 patients.
After 1 year, patients assigned to the intervention program had a 12% improvement in their treat-to-target implementation score, compared with patients who received standard care, an increase that was “clinically meaningful,” Cianna L. Leatherwood, MD, said while presenting a poster at the annual meeting of the American College of Rheumatology.
This increased score represented improvements in its four components: measuring disease activity, using a disease activity score in treatment decision making, documenting evidence for creating a treatment goal, and making shared decisions, Dr. Leatherwood explained in a video interview. Some of Dr. Leatherwood’s collaborators in this study from Brigham and Women’s Hospital in Boston developed and first introduced the treat-to-target implementation score a few years ago (Arthritis Rheum. 2017 July;69[7]:1374-80).
The major interventions used in this program included having patients complete the Routine Assessment of Patient Index Data 3 index (Rheum Dis Clin North Am. 2009 Nov;35[4]:773-8) at every clinic encounter, focus-group discussions with panels of patients both prior to and during the year-long program, and monthly “learning collaborative sessions” for the nine rheumatologists in the intervention arm to discuss and develop treat-to-target practices, said Dr. Leatherwood, a rheumatologist at Kaiser Permanente in Oakland, Calif. The physicians in the intervention group also received frequent email reminders about adopting a treat-to-target approach. The control arm of the study included 11 rheumatologists who did not participate in these sessions or receive the reminders.
Dr. Leatherwood expressed confidence that other health systems could now adapt and use the treatment model she and her associates developed and tested after tailoring it to better match their local conditions.
The study received partial funding from Pfizer. Dr. Leatherwood had no disclosures to report.
SOURCE: Leatherwood CL et al. ACR Annual Meeting, Abstract 326.
CHICAGO – A novel disease-management approach that paired routine monitoring of the clinical status of patients with RA and training for their rheumatologists on how to refine their treat-to-target practices led to a modest but meaningful boost in the achievement of treat-to-target goals in a single-center study with 2,549 patients.
After 1 year, patients assigned to the intervention program had a 12% improvement in their treat-to-target implementation score, compared with patients who received standard care, an increase that was “clinically meaningful,” Cianna L. Leatherwood, MD, said while presenting a poster at the annual meeting of the American College of Rheumatology.
This increased score represented improvements in its four components: measuring disease activity, using a disease activity score in treatment decision making, documenting evidence for creating a treatment goal, and making shared decisions, Dr. Leatherwood explained in a video interview. Some of Dr. Leatherwood’s collaborators in this study from Brigham and Women’s Hospital in Boston developed and first introduced the treat-to-target implementation score a few years ago (Arthritis Rheum. 2017 July;69[7]:1374-80).
The major interventions used in this program included having patients complete the Routine Assessment of Patient Index Data 3 index (Rheum Dis Clin North Am. 2009 Nov;35[4]:773-8) at every clinic encounter, focus-group discussions with panels of patients both prior to and during the year-long program, and monthly “learning collaborative sessions” for the nine rheumatologists in the intervention arm to discuss and develop treat-to-target practices, said Dr. Leatherwood, a rheumatologist at Kaiser Permanente in Oakland, Calif. The physicians in the intervention group also received frequent email reminders about adopting a treat-to-target approach. The control arm of the study included 11 rheumatologists who did not participate in these sessions or receive the reminders.
Dr. Leatherwood expressed confidence that other health systems could now adapt and use the treatment model she and her associates developed and tested after tailoring it to better match their local conditions.
The study received partial funding from Pfizer. Dr. Leatherwood had no disclosures to report.
SOURCE: Leatherwood CL et al. ACR Annual Meeting, Abstract 326.
CHICAGO – A novel disease-management approach that paired routine monitoring of the clinical status of patients with RA and training for their rheumatologists on how to refine their treat-to-target practices led to a modest but meaningful boost in the achievement of treat-to-target goals in a single-center study with 2,549 patients.
After 1 year, patients assigned to the intervention program had a 12% improvement in their treat-to-target implementation score, compared with patients who received standard care, an increase that was “clinically meaningful,” Cianna L. Leatherwood, MD, said while presenting a poster at the annual meeting of the American College of Rheumatology.
This increased score represented improvements in its four components: measuring disease activity, using a disease activity score in treatment decision making, documenting evidence for creating a treatment goal, and making shared decisions, Dr. Leatherwood explained in a video interview. Some of Dr. Leatherwood’s collaborators in this study from Brigham and Women’s Hospital in Boston developed and first introduced the treat-to-target implementation score a few years ago (Arthritis Rheum. 2017 July;69[7]:1374-80).
The major interventions used in this program included having patients complete the Routine Assessment of Patient Index Data 3 index (Rheum Dis Clin North Am. 2009 Nov;35[4]:773-8) at every clinic encounter, focus-group discussions with panels of patients both prior to and during the year-long program, and monthly “learning collaborative sessions” for the nine rheumatologists in the intervention arm to discuss and develop treat-to-target practices, said Dr. Leatherwood, a rheumatologist at Kaiser Permanente in Oakland, Calif. The physicians in the intervention group also received frequent email reminders about adopting a treat-to-target approach. The control arm of the study included 11 rheumatologists who did not participate in these sessions or receive the reminders.
Dr. Leatherwood expressed confidence that other health systems could now adapt and use the treatment model she and her associates developed and tested after tailoring it to better match their local conditions.
The study received partial funding from Pfizer. Dr. Leatherwood had no disclosures to report.
SOURCE: Leatherwood CL et al. ACR Annual Meeting, Abstract 326.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: After 1 year, the treat-to-target implementation score in the intervention patients was 12% higher than among the control patients.
Study details: A single-center, controlled study with 2,549 RA patients and 22 rheumatologists.
Disclosures: The study received partial funding from Pfizer. Dr. Leatherwood had no disclosures to report.
Source: Leatherwood CL et al. ACR Annual Meeting, Abstract 326.
Travel Advocacy Scholarship Deadline Approaching
Applications are due by October 31 for the SVS Vascular Surgery Trainee Advocacy Travel Scholarship. The scholarship is designed to enhance the trainee’s health policy and advocacy development. The recipient gets the chance to participate in Capitol Hill visits and learn more about the SVS’ health policy and advocacy activities. Applicants must be an SVS Candidate Member currently enrolled in or accepted into a vascular surgery training program and have interest in health policy and advocacy issues related to vascular surgery.
Applications are due by October 31 for the SVS Vascular Surgery Trainee Advocacy Travel Scholarship. The scholarship is designed to enhance the trainee’s health policy and advocacy development. The recipient gets the chance to participate in Capitol Hill visits and learn more about the SVS’ health policy and advocacy activities. Applicants must be an SVS Candidate Member currently enrolled in or accepted into a vascular surgery training program and have interest in health policy and advocacy issues related to vascular surgery.
Applications are due by October 31 for the SVS Vascular Surgery Trainee Advocacy Travel Scholarship. The scholarship is designed to enhance the trainee’s health policy and advocacy development. The recipient gets the chance to participate in Capitol Hill visits and learn more about the SVS’ health policy and advocacy activities. Applicants must be an SVS Candidate Member currently enrolled in or accepted into a vascular surgery training program and have interest in health policy and advocacy issues related to vascular surgery.
PET/CT has good accuracy for diagnosing GCA
CHICAGO – Combined PET/CT has good diagnostic accuracy, including a 98% negative predictive value, when compared with temporal artery biopsy for suspected giant cell arteritis, according to findings from a study of 64 patients.
Study participants included patients with newly suspected giant cell arteritis (GCA) and all underwent PET/CT from the vertex to the diaphragm within 72 hours of starting corticosteroid therapy and prior to undergoing temporal artery biopsy (TAB). Two nuclear medicine physicians blinded to clinical and biopsy data identified GCA in the scans of 12 of 58 patients (21%) who ultimately underwent both PET/CT and TAB, Anthony M. Sammel, MBBS, reported at the annual meeting of the American College of Rheumatology.
Compared with TAB, which is the standard of care for diagnosing GCA in most centers, global GCA assessment by PET/CT had a sensitivity of 92%, specificity of 85%, and positive predictive value of 61%, said Dr. Sammel, a rheumatologist at Royal North Shore Hospital in Sydney.
The findings, and particularly the 98% negative predictive value, suggest that PET/CT could be used first line to rule out suspected GCA, although the sample size in the study was modest, he noted.
“I believe [the findings] would support PET/CT, when we include the head, neck, and chest, as a first-line test for patients newly suspected of having giant cell arteritis. I think we do need to be mindful that it’s not perfect,” he said, explaining that a TAB is warranted in a patient with a negative scan despite a clinician’s sense that there is a high likelihood of GCA.
However, the findings suggest that a negative study in a low to moderate risk patient would be “very, very reassuring,” and as such patients probably do not need a biopsy, he said in a video interview in which he also discussed cost-benefit issues with respect to PET/CT in this setting.
Of note, PET/CT diagnosed alternative conditions, including cancer and infections, that can mimic GCA in 13 study participants. At least one of those patients “may well have come to serious harm” on immunosuppressive therapy had his cervical spine infection gone undiagnosed, he said.
This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
SOURCE: Sammel AM et al. ACR Annual Meeting, Abstract L15.
CHICAGO – Combined PET/CT has good diagnostic accuracy, including a 98% negative predictive value, when compared with temporal artery biopsy for suspected giant cell arteritis, according to findings from a study of 64 patients.
Study participants included patients with newly suspected giant cell arteritis (GCA) and all underwent PET/CT from the vertex to the diaphragm within 72 hours of starting corticosteroid therapy and prior to undergoing temporal artery biopsy (TAB). Two nuclear medicine physicians blinded to clinical and biopsy data identified GCA in the scans of 12 of 58 patients (21%) who ultimately underwent both PET/CT and TAB, Anthony M. Sammel, MBBS, reported at the annual meeting of the American College of Rheumatology.
Compared with TAB, which is the standard of care for diagnosing GCA in most centers, global GCA assessment by PET/CT had a sensitivity of 92%, specificity of 85%, and positive predictive value of 61%, said Dr. Sammel, a rheumatologist at Royal North Shore Hospital in Sydney.
The findings, and particularly the 98% negative predictive value, suggest that PET/CT could be used first line to rule out suspected GCA, although the sample size in the study was modest, he noted.
“I believe [the findings] would support PET/CT, when we include the head, neck, and chest, as a first-line test for patients newly suspected of having giant cell arteritis. I think we do need to be mindful that it’s not perfect,” he said, explaining that a TAB is warranted in a patient with a negative scan despite a clinician’s sense that there is a high likelihood of GCA.
However, the findings suggest that a negative study in a low to moderate risk patient would be “very, very reassuring,” and as such patients probably do not need a biopsy, he said in a video interview in which he also discussed cost-benefit issues with respect to PET/CT in this setting.
Of note, PET/CT diagnosed alternative conditions, including cancer and infections, that can mimic GCA in 13 study participants. At least one of those patients “may well have come to serious harm” on immunosuppressive therapy had his cervical spine infection gone undiagnosed, he said.
This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
SOURCE: Sammel AM et al. ACR Annual Meeting, Abstract L15.
CHICAGO – Combined PET/CT has good diagnostic accuracy, including a 98% negative predictive value, when compared with temporal artery biopsy for suspected giant cell arteritis, according to findings from a study of 64 patients.
Study participants included patients with newly suspected giant cell arteritis (GCA) and all underwent PET/CT from the vertex to the diaphragm within 72 hours of starting corticosteroid therapy and prior to undergoing temporal artery biopsy (TAB). Two nuclear medicine physicians blinded to clinical and biopsy data identified GCA in the scans of 12 of 58 patients (21%) who ultimately underwent both PET/CT and TAB, Anthony M. Sammel, MBBS, reported at the annual meeting of the American College of Rheumatology.
Compared with TAB, which is the standard of care for diagnosing GCA in most centers, global GCA assessment by PET/CT had a sensitivity of 92%, specificity of 85%, and positive predictive value of 61%, said Dr. Sammel, a rheumatologist at Royal North Shore Hospital in Sydney.
The findings, and particularly the 98% negative predictive value, suggest that PET/CT could be used first line to rule out suspected GCA, although the sample size in the study was modest, he noted.
“I believe [the findings] would support PET/CT, when we include the head, neck, and chest, as a first-line test for patients newly suspected of having giant cell arteritis. I think we do need to be mindful that it’s not perfect,” he said, explaining that a TAB is warranted in a patient with a negative scan despite a clinician’s sense that there is a high likelihood of GCA.
However, the findings suggest that a negative study in a low to moderate risk patient would be “very, very reassuring,” and as such patients probably do not need a biopsy, he said in a video interview in which he also discussed cost-benefit issues with respect to PET/CT in this setting.
Of note, PET/CT diagnosed alternative conditions, including cancer and infections, that can mimic GCA in 13 study participants. At least one of those patients “may well have come to serious harm” on immunosuppressive therapy had his cervical spine infection gone undiagnosed, he said.
This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
SOURCE: Sammel AM et al. ACR Annual Meeting, Abstract L15.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: PET/CT had 92% sensitivity, 85% specificity, 61% positive predictive value, and 98% negative predictive value.
Study details: A study of diagnostic accuracy of PET/CT for giant cell arteritis in 64 patients.
Disclosures: This study was funded by Arthritis Australia. Dr. Sammel reported having no relevant disclosures.
Source: Sammel AM et al. ACR Annual Meeting, Abstract L15.
Dermatology Residency Match: Data on Who Matched in 2018
Form CMS Virtual MIPS Group
The election period to form a virtual group for the 2019 Merit-based Incentive Payment System (MIPS) performance year is now open. These groups give participants the opportunity to coordinate resources that can help achieve and meet requirements under each MIPS performance category. A virtual group may be formed by location, specialty or shared patient population. If you fall within the criteria of those who can participate, apply today. More information can be found in the 2019 Toolkit, which includes a fact sheet, information on the election process, an agreement template and a sample email for election submission. The application deadline for a virtual group and its members is Dec. 31, 2018.
The election period to form a virtual group for the 2019 Merit-based Incentive Payment System (MIPS) performance year is now open. These groups give participants the opportunity to coordinate resources that can help achieve and meet requirements under each MIPS performance category. A virtual group may be formed by location, specialty or shared patient population. If you fall within the criteria of those who can participate, apply today. More information can be found in the 2019 Toolkit, which includes a fact sheet, information on the election process, an agreement template and a sample email for election submission. The application deadline for a virtual group and its members is Dec. 31, 2018.
The election period to form a virtual group for the 2019 Merit-based Incentive Payment System (MIPS) performance year is now open. These groups give participants the opportunity to coordinate resources that can help achieve and meet requirements under each MIPS performance category. A virtual group may be formed by location, specialty or shared patient population. If you fall within the criteria of those who can participate, apply today. More information can be found in the 2019 Toolkit, which includes a fact sheet, information on the election process, an agreement template and a sample email for election submission. The application deadline for a virtual group and its members is Dec. 31, 2018.
Novel blood test brings RA prevention closer to reality
CHICAGO – A positive B cell clonality test in a peripheral blood sample predicts imminent onset of rheumatoid arthritis with a high degree of accuracy in at-risk individuals, Niek de Vries, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
This finding, now confirmed twice over in separate validation studies, opens the door to trials of pharmacologic treatment aimed at preventing rheumatoid arthritis (RA).
“In my view, a positive test might be an indication for preventive treatment and retesting at 1 year to evaluate the treatment effect,” said Dr. de Vries, professor of rheumatology at the University of Amsterdam.
Many patients with RA experience a pre-RA phase marked by joint pain, the presence of RA-specific autoantibodies, IgM rheumatoid factor, and/or anticitrullinated protein antibodies, but no synovial inflammation. The challenge in attempting to develop RA preventive strategies targeting this population is that only about 28% of them go on to develop RA within 3 years. Exposing the entire preclinical-phase population to powerful antirheumatic drugs to try to prevent RA in the minority who are actually headed for overt disease is not an attractive strategy.
That’s why Dr. de Vries and his coinvestigators developed a method of B cell receptor (BCR) analysis using PCR and next-generation sequencing techniques. They determined that when a clone comprised more than 0.5% of the total B cell receptor population, it can be considered an expanded or dominant clone. They then demonstrated that when a patient in the pre-RA phase has five or more dominant clones in a peripheral blood sample, that can be considered a positive BCR test. In two published studies, they showed that a positive BCR test in the pre-RA stage accurately predicts onset of overt RA within the next several years (Ann Rheum Dis. 2017 Nov;76[11]:1924-30 and Ann Rheum Dis. 2018;77:151). They have also shown that at the time of RA onset, the BCR clones disappear from peripheral blood and reappear in the synovium.
At the ACR annual meeting, Dr. de Vries presented the results of a new BCR test validation study, this one involving 129 pre–RA-phase Dutch patients. The purpose of this study was to learn whether the BCR test is more predictive than clinical predictors such as the Risk Rule Model, and also to determine whether a higher number of dominant clones predicts RA onset even more accurately than the five-or-more clone threshold the investigators had been using. The answer to both questions proved to be yes.
Thirty-five percent of the 129 pre-RA subjects had a positive BCR test as defined by the presence of five or more expanded clones. A total of 75% of them went on to develop RA within the next 3 years. None of the BCR test-negative patients did. That result translated to a test sensitivity of 100%, a specificity of 87%, a positive predictive value of 71%, and a negative predictive value of 100%. A positive BCR blood test was associated with a 120-fold increased risk of an RA diagnosis within 3 years.
The investigators also compared outcomes in the 17% of study participants with a high degree of BCR test positivity, defined as the presence of nine or more expanded clones, versus the 18% of subjects whose positive BCR test had five to eight clones. Overall, 91% with a highly positive BCR test featuring nine or more clones developed RA within 3 years, compared with 55% of those with five to eight clones.
These findings permit categorization of pre-RA patients into three groups. Those with a negative BCR test can be reassured that their 3-year risk of developing RA is similar to the background risk in the general population. Those with a mid-range positive BCR test – that is, five to eight dominant clones – should probably be retested periodically, although the optimum interval is still under study. And patients with a highly positive BCR test might be candidates for preventive therapy.
Before RA-preventive therapy during the high-risk pre-RA phase can be introduced into routine clinical practice, however, several issues need to be resolved, Dr. de Vries continued. Although a single dose of rituximab (Rituxan) showed efficacy in a proof-of-concept study, that was off-label therapy. There is as yet no approved agent for prevention of RA in high-risk patients. Also, the risk/benefit ratio of preventive therapy will need to be determined. And rheumatologists will have to figure out how to identify these high-risk pre-RA individuals early, when preventive therapy is likely to most effective.
Several audience members observed that the Dutch investigators’ BCR test using PCR and next-generation sequencing is technically complex. They asked if the BCR results might correlate with any far more readily available serologic tests. The answer is no, according to Dr. de Vries.
“I think it’s very important to realize that what we test is the migration of B cells or plasmablast-like cells through the blood at the moment that we’re testing. This is completely different from a serological assessment of antibody production by plasma cells which are present in the bone marrow, which changes very little despite effective treatment. In contrast, if we test B cell migration while a patient gets corticosteroids we see an immediate disappearance of all these cells. So it’s a different parameter,” the rheumatologist explained.
The Dutch Arthritis Association funded the study. Dr. de Vries noted that he is a coinventor of the BCR test, the intellectual property rights for which belong to the University of Amsterdam. He receives research funding from Pfizer, Roche, Janssen, and GlaxoSmithKline.
SOURCE: de Vries N et al. Arthritis Rheumatol. 2018;70(Suppl 10). Abstract 835.
CHICAGO – A positive B cell clonality test in a peripheral blood sample predicts imminent onset of rheumatoid arthritis with a high degree of accuracy in at-risk individuals, Niek de Vries, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
This finding, now confirmed twice over in separate validation studies, opens the door to trials of pharmacologic treatment aimed at preventing rheumatoid arthritis (RA).
“In my view, a positive test might be an indication for preventive treatment and retesting at 1 year to evaluate the treatment effect,” said Dr. de Vries, professor of rheumatology at the University of Amsterdam.
Many patients with RA experience a pre-RA phase marked by joint pain, the presence of RA-specific autoantibodies, IgM rheumatoid factor, and/or anticitrullinated protein antibodies, but no synovial inflammation. The challenge in attempting to develop RA preventive strategies targeting this population is that only about 28% of them go on to develop RA within 3 years. Exposing the entire preclinical-phase population to powerful antirheumatic drugs to try to prevent RA in the minority who are actually headed for overt disease is not an attractive strategy.
That’s why Dr. de Vries and his coinvestigators developed a method of B cell receptor (BCR) analysis using PCR and next-generation sequencing techniques. They determined that when a clone comprised more than 0.5% of the total B cell receptor population, it can be considered an expanded or dominant clone. They then demonstrated that when a patient in the pre-RA phase has five or more dominant clones in a peripheral blood sample, that can be considered a positive BCR test. In two published studies, they showed that a positive BCR test in the pre-RA stage accurately predicts onset of overt RA within the next several years (Ann Rheum Dis. 2017 Nov;76[11]:1924-30 and Ann Rheum Dis. 2018;77:151). They have also shown that at the time of RA onset, the BCR clones disappear from peripheral blood and reappear in the synovium.
At the ACR annual meeting, Dr. de Vries presented the results of a new BCR test validation study, this one involving 129 pre–RA-phase Dutch patients. The purpose of this study was to learn whether the BCR test is more predictive than clinical predictors such as the Risk Rule Model, and also to determine whether a higher number of dominant clones predicts RA onset even more accurately than the five-or-more clone threshold the investigators had been using. The answer to both questions proved to be yes.
Thirty-five percent of the 129 pre-RA subjects had a positive BCR test as defined by the presence of five or more expanded clones. A total of 75% of them went on to develop RA within the next 3 years. None of the BCR test-negative patients did. That result translated to a test sensitivity of 100%, a specificity of 87%, a positive predictive value of 71%, and a negative predictive value of 100%. A positive BCR blood test was associated with a 120-fold increased risk of an RA diagnosis within 3 years.
The investigators also compared outcomes in the 17% of study participants with a high degree of BCR test positivity, defined as the presence of nine or more expanded clones, versus the 18% of subjects whose positive BCR test had five to eight clones. Overall, 91% with a highly positive BCR test featuring nine or more clones developed RA within 3 years, compared with 55% of those with five to eight clones.
These findings permit categorization of pre-RA patients into three groups. Those with a negative BCR test can be reassured that their 3-year risk of developing RA is similar to the background risk in the general population. Those with a mid-range positive BCR test – that is, five to eight dominant clones – should probably be retested periodically, although the optimum interval is still under study. And patients with a highly positive BCR test might be candidates for preventive therapy.
Before RA-preventive therapy during the high-risk pre-RA phase can be introduced into routine clinical practice, however, several issues need to be resolved, Dr. de Vries continued. Although a single dose of rituximab (Rituxan) showed efficacy in a proof-of-concept study, that was off-label therapy. There is as yet no approved agent for prevention of RA in high-risk patients. Also, the risk/benefit ratio of preventive therapy will need to be determined. And rheumatologists will have to figure out how to identify these high-risk pre-RA individuals early, when preventive therapy is likely to most effective.
Several audience members observed that the Dutch investigators’ BCR test using PCR and next-generation sequencing is technically complex. They asked if the BCR results might correlate with any far more readily available serologic tests. The answer is no, according to Dr. de Vries.
“I think it’s very important to realize that what we test is the migration of B cells or plasmablast-like cells through the blood at the moment that we’re testing. This is completely different from a serological assessment of antibody production by plasma cells which are present in the bone marrow, which changes very little despite effective treatment. In contrast, if we test B cell migration while a patient gets corticosteroids we see an immediate disappearance of all these cells. So it’s a different parameter,” the rheumatologist explained.
The Dutch Arthritis Association funded the study. Dr. de Vries noted that he is a coinventor of the BCR test, the intellectual property rights for which belong to the University of Amsterdam. He receives research funding from Pfizer, Roche, Janssen, and GlaxoSmithKline.
SOURCE: de Vries N et al. Arthritis Rheumatol. 2018;70(Suppl 10). Abstract 835.
CHICAGO – A positive B cell clonality test in a peripheral blood sample predicts imminent onset of rheumatoid arthritis with a high degree of accuracy in at-risk individuals, Niek de Vries, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
This finding, now confirmed twice over in separate validation studies, opens the door to trials of pharmacologic treatment aimed at preventing rheumatoid arthritis (RA).
“In my view, a positive test might be an indication for preventive treatment and retesting at 1 year to evaluate the treatment effect,” said Dr. de Vries, professor of rheumatology at the University of Amsterdam.
Many patients with RA experience a pre-RA phase marked by joint pain, the presence of RA-specific autoantibodies, IgM rheumatoid factor, and/or anticitrullinated protein antibodies, but no synovial inflammation. The challenge in attempting to develop RA preventive strategies targeting this population is that only about 28% of them go on to develop RA within 3 years. Exposing the entire preclinical-phase population to powerful antirheumatic drugs to try to prevent RA in the minority who are actually headed for overt disease is not an attractive strategy.
That’s why Dr. de Vries and his coinvestigators developed a method of B cell receptor (BCR) analysis using PCR and next-generation sequencing techniques. They determined that when a clone comprised more than 0.5% of the total B cell receptor population, it can be considered an expanded or dominant clone. They then demonstrated that when a patient in the pre-RA phase has five or more dominant clones in a peripheral blood sample, that can be considered a positive BCR test. In two published studies, they showed that a positive BCR test in the pre-RA stage accurately predicts onset of overt RA within the next several years (Ann Rheum Dis. 2017 Nov;76[11]:1924-30 and Ann Rheum Dis. 2018;77:151). They have also shown that at the time of RA onset, the BCR clones disappear from peripheral blood and reappear in the synovium.
At the ACR annual meeting, Dr. de Vries presented the results of a new BCR test validation study, this one involving 129 pre–RA-phase Dutch patients. The purpose of this study was to learn whether the BCR test is more predictive than clinical predictors such as the Risk Rule Model, and also to determine whether a higher number of dominant clones predicts RA onset even more accurately than the five-or-more clone threshold the investigators had been using. The answer to both questions proved to be yes.
Thirty-five percent of the 129 pre-RA subjects had a positive BCR test as defined by the presence of five or more expanded clones. A total of 75% of them went on to develop RA within the next 3 years. None of the BCR test-negative patients did. That result translated to a test sensitivity of 100%, a specificity of 87%, a positive predictive value of 71%, and a negative predictive value of 100%. A positive BCR blood test was associated with a 120-fold increased risk of an RA diagnosis within 3 years.
The investigators also compared outcomes in the 17% of study participants with a high degree of BCR test positivity, defined as the presence of nine or more expanded clones, versus the 18% of subjects whose positive BCR test had five to eight clones. Overall, 91% with a highly positive BCR test featuring nine or more clones developed RA within 3 years, compared with 55% of those with five to eight clones.
These findings permit categorization of pre-RA patients into three groups. Those with a negative BCR test can be reassured that their 3-year risk of developing RA is similar to the background risk in the general population. Those with a mid-range positive BCR test – that is, five to eight dominant clones – should probably be retested periodically, although the optimum interval is still under study. And patients with a highly positive BCR test might be candidates for preventive therapy.
Before RA-preventive therapy during the high-risk pre-RA phase can be introduced into routine clinical practice, however, several issues need to be resolved, Dr. de Vries continued. Although a single dose of rituximab (Rituxan) showed efficacy in a proof-of-concept study, that was off-label therapy. There is as yet no approved agent for prevention of RA in high-risk patients. Also, the risk/benefit ratio of preventive therapy will need to be determined. And rheumatologists will have to figure out how to identify these high-risk pre-RA individuals early, when preventive therapy is likely to most effective.
Several audience members observed that the Dutch investigators’ BCR test using PCR and next-generation sequencing is technically complex. They asked if the BCR results might correlate with any far more readily available serologic tests. The answer is no, according to Dr. de Vries.
“I think it’s very important to realize that what we test is the migration of B cells or plasmablast-like cells through the blood at the moment that we’re testing. This is completely different from a serological assessment of antibody production by plasma cells which are present in the bone marrow, which changes very little despite effective treatment. In contrast, if we test B cell migration while a patient gets corticosteroids we see an immediate disappearance of all these cells. So it’s a different parameter,” the rheumatologist explained.
The Dutch Arthritis Association funded the study. Dr. de Vries noted that he is a coinventor of the BCR test, the intellectual property rights for which belong to the University of Amsterdam. He receives research funding from Pfizer, Roche, Janssen, and GlaxoSmithKline.
SOURCE: de Vries N et al. Arthritis Rheumatol. 2018;70(Suppl 10). Abstract 835.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: A peripheral blood sample showing a high level of expanded B cell receptor clones accurately predicts looming onset of rheumatoid arthritis.
Major finding: Ninety-one percent of patients with a highly positive B cell receptor clonality blood test developed rheumatoid arthritis within the next 3 years.
Study details: This study included 129 patients deemed at high risk for developing rheumatoid arthritis who were followed for 3 years.
Disclosures: The Dutch Arthritis Association funded the study. The presenter noted that he is a coinventor of the B cell receptor blood test, the intellectual property rights for which belong to the University of Amsterdam.
Source: De Vries N et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 835.