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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Delayed hospital admission after hip fracture raises mortality risk
a retrospective, observational study suggests.
Among 867 elderly patients who underwent hip fracture surgery at a university hospital in China and who were available for follow-up, the proportion hospitalized on the day of injury was 25.4%, and the proportion hospitalized on days 1, 2, and 7 after injury were 54.7%, 66.3%, and 12.6%, respectively, reported Wei He, MD, of the Second Affiliated Hospital of Zhejiang University, Hangzhou, China, and colleagues in the World Journal of Emergency Medicine.
The mean time from admission to surgery was 5.2 days. Mortality rates at 1 year, 3 months, and 1 month after surgery were 10.5%, 5.4%, and 3.3%, respectively. Hospitalization at 7 or more days after injury was an independent risk factor for 1-year mortality (odds ratio, 1.76), the authors found.
Although the influence of surgical delay on mortality and morbidity among hip fracture patients has been widely studied, most data focus on surgery timing among hospitalized patients and fail to consider preadmission waiting time, they noted.
The current study aimed to assess outcomes based on “actual preadmission waiting time” through an analysis of data and surgical outcomes from a hospital electronic medical record system and from postoperative telephone interviews. Study subjects were patients aged over 65 years who underwent hip fracture surgery between Jan. 1, 2014, and Dec. 31, 2017. The mean age was 81.4 years, 74.7% of the patients were women, 67.1% had femoral neck fracture, and 56.1% had hip replacement surgery.
The findings, though limited by the retrospective nature of the study and the single-center design, suggest that, under the current conditions in China, admission delay may increase 1-year mortality, they wrote, concluding that “[i]n addition to early surgery highlighted in the guidelines, we also advocate early admission.”
The authors reported having no disclosures.
SOURCE: He W et al. World J Emerg Med. 2020;11(1):27-32.
a retrospective, observational study suggests.
Among 867 elderly patients who underwent hip fracture surgery at a university hospital in China and who were available for follow-up, the proportion hospitalized on the day of injury was 25.4%, and the proportion hospitalized on days 1, 2, and 7 after injury were 54.7%, 66.3%, and 12.6%, respectively, reported Wei He, MD, of the Second Affiliated Hospital of Zhejiang University, Hangzhou, China, and colleagues in the World Journal of Emergency Medicine.
The mean time from admission to surgery was 5.2 days. Mortality rates at 1 year, 3 months, and 1 month after surgery were 10.5%, 5.4%, and 3.3%, respectively. Hospitalization at 7 or more days after injury was an independent risk factor for 1-year mortality (odds ratio, 1.76), the authors found.
Although the influence of surgical delay on mortality and morbidity among hip fracture patients has been widely studied, most data focus on surgery timing among hospitalized patients and fail to consider preadmission waiting time, they noted.
The current study aimed to assess outcomes based on “actual preadmission waiting time” through an analysis of data and surgical outcomes from a hospital electronic medical record system and from postoperative telephone interviews. Study subjects were patients aged over 65 years who underwent hip fracture surgery between Jan. 1, 2014, and Dec. 31, 2017. The mean age was 81.4 years, 74.7% of the patients were women, 67.1% had femoral neck fracture, and 56.1% had hip replacement surgery.
The findings, though limited by the retrospective nature of the study and the single-center design, suggest that, under the current conditions in China, admission delay may increase 1-year mortality, they wrote, concluding that “[i]n addition to early surgery highlighted in the guidelines, we also advocate early admission.”
The authors reported having no disclosures.
SOURCE: He W et al. World J Emerg Med. 2020;11(1):27-32.
a retrospective, observational study suggests.
Among 867 elderly patients who underwent hip fracture surgery at a university hospital in China and who were available for follow-up, the proportion hospitalized on the day of injury was 25.4%, and the proportion hospitalized on days 1, 2, and 7 after injury were 54.7%, 66.3%, and 12.6%, respectively, reported Wei He, MD, of the Second Affiliated Hospital of Zhejiang University, Hangzhou, China, and colleagues in the World Journal of Emergency Medicine.
The mean time from admission to surgery was 5.2 days. Mortality rates at 1 year, 3 months, and 1 month after surgery were 10.5%, 5.4%, and 3.3%, respectively. Hospitalization at 7 or more days after injury was an independent risk factor for 1-year mortality (odds ratio, 1.76), the authors found.
Although the influence of surgical delay on mortality and morbidity among hip fracture patients has been widely studied, most data focus on surgery timing among hospitalized patients and fail to consider preadmission waiting time, they noted.
The current study aimed to assess outcomes based on “actual preadmission waiting time” through an analysis of data and surgical outcomes from a hospital electronic medical record system and from postoperative telephone interviews. Study subjects were patients aged over 65 years who underwent hip fracture surgery between Jan. 1, 2014, and Dec. 31, 2017. The mean age was 81.4 years, 74.7% of the patients were women, 67.1% had femoral neck fracture, and 56.1% had hip replacement surgery.
The findings, though limited by the retrospective nature of the study and the single-center design, suggest that, under the current conditions in China, admission delay may increase 1-year mortality, they wrote, concluding that “[i]n addition to early surgery highlighted in the guidelines, we also advocate early admission.”
The authors reported having no disclosures.
SOURCE: He W et al. World J Emerg Med. 2020;11(1):27-32.
FROM THE WORLD JOURNAL OF EMERGENCY MEDICINE
Oral paclitaxel bests IV version for tumor response, neuropathy incidence in mBC
SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.
The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.
In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.
Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.
Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.
Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.
Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”
The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.
Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.
Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.
Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m2 of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m2 over a 3-hour infusion every 3 weeks.
Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.
The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.
The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.
“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.
Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m2, but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.
In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.
The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.
“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.
He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”
The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.
During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”
“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.
The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.
SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.
SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.
The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.
In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.
Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.
Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.
Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.
Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”
The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.
Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.
Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.
Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m2 of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m2 over a 3-hour infusion every 3 weeks.
Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.
The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.
The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.
“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.
Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m2, but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.
In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.
The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.
“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.
He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”
The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.
During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”
“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.
The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.
SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.
SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.
The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.
In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.
Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.
Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.
Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.
Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”
The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.
Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.
Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.
Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m2 of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m2 over a 3-hour infusion every 3 weeks.
Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.
The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.
The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.
“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.
Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m2, but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.
In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.
The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.
“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.
He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”
The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.
During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”
“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.
The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.
SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.
REPORTING FROM SABCS 2019
First report from NeoTRIPaPDL1: No pCR benefit with atezolizumab in TNBC
SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.
A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.
“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.
Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.
On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).
“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.
The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.
The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m2 on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.
The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.
Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”
“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.
Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.
“All other toxicities were either mild or very rare,” he noted.
TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.
Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.
Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.
In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”
“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.
Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.
Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.
This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.
SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.
SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.
A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.
“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.
Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.
On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).
“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.
The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.
The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m2 on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.
The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.
Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”
“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.
Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.
“All other toxicities were either mild or very rare,” he noted.
TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.
Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.
Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.
In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”
“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.
Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.
Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.
This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.
SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.
SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.
A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.
“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.
Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.
On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).
“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.
The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.
The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m2 on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.
The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.
Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”
“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.
Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.
“All other toxicities were either mild or very rare,” he noted.
TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.
Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.
Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.
In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”
“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.
Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.
Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.
This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.
SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.
REPORTING FROM SABCS 2019
ASH releases guidelines on managing cardiopulmonary and kidney disease in SCD
ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.
That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.
The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.
The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.
At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.
The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.
For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.
For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).
Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.
Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.
This is in part because of technical factors, Dr. Desai said.
“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.
As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.
“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.
The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.
Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.
Dr. Liem and Dr. Desai reported having no conflicts of interest.
ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.
That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.
The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.
The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.
At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.
The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.
For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.
For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).
Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.
Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.
This is in part because of technical factors, Dr. Desai said.
“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.
As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.
“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.
The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.
Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.
Dr. Liem and Dr. Desai reported having no conflicts of interest.
ORLANDO – It is good practice to consult with a pulmonary hypertension (PH) expert before referring a patient with sickle cell disease (SCD) for right-heart catheterization or PH evaluation, according to new American Society of Hematology guidelines for the screening and management of cardiopulmonary and kidney disease in patients with SCD.
That “Good Practice” recommendation is one of several included in the evidence-based guidelines published Dec. 10 in Blood Advances and highlighted during a Special Education Session at the annual ASH meeting.
The guidelines provide 10 main recommendations intended to “support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD,” wrote Robert I. Liem, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues.
The recommendations, agreed upon by a multidisciplinary guideline panel, relate to screening, diagnosis, and management of PH, pulmonary arterial hypertension (PAH), hypertension, proteinuria and chronic kidney disease, and venous thromboembolism (VTE). Most are “conditional,” as opposed to “strong,” because of a paucity of direct, high-quality outcomes data, and they are accompanied by the Good Practice Statements, descriptive remarks and caveats based on the available data, as well as suggestions for future research.
At the special ASH session, Ankit A. Desai, MD, highlighted some of the recommendations and discussed considerations for their practical application.
The Good Practice Statement on consulting a specialist before referring a patient for PH relates specifically to Recommendations 2a and 2b on the management of abnormal echocardiography, explained Dr. Desai of Indiana University, Indianapolis.
For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of at least 2.5-2.9 m/s on echocardiography, the panel recommends against right-heart catheterization (Recommendation 2a, conditional), he said.
For children and adults with SCD and a peak TRJV of at least 2.5 m/s who also have a reduced 6-minute walk distance (6MWD) and/or elevated N-terminal proB-type natriuretic peptide (NT-proBNP), the panel supports right-heart catheterization (Recommendation 2b, conditional).
Dr. Desai noted that the 2.5 m/s threshold was found to be suboptimal when used as the sole criteria for right-heart catheterization. Using that threshold alone is associated with “moderate to large” harms, such as starting inappropriate PH-specific therapies and/or performing unnecessary right-heart catheterization. However, when used in combination with 6MWD, the predictive capacity improved significantly, and the risk for potential harm was low, he explained.
Another Good Practice Statement included in the guidelines, and relevant to these recommendations on managing abnormal echocardiography, addresses the importance of basing decisions about the need for right-heart catheterization on echocardiograms obtained at steady state rather than during acute illness, such as during hospitalization for pain or acute chest syndrome.
This is in part because of technical factors, Dr. Desai said.
“We know that repeating [echocardiography] is something that should be considered in patients because ... results vary – sometimes quite a bit – from study to study,” he said.
As for the cutoff values for 6MWD and NT-proBNP, “a decent amount of literature” suggests that less than 333 m and less than 160 pg/ml, respectively, are good thresholds, he said.
“Importantly, this should all be taken in the context of good clinical judgment ... along with discussion with a PH expert,” he added.
The full guidelines are available, along with additional ASH guidelines on immune thrombocytopenia and prevention of venous thromboembolism in surgical hospitalized patients, at the ASH publications website.
Of note, the SCD guidelines on cardiopulmonary disease and kidney disease are one of five sets of SCD guidelines that have been in development; these are the first of those to be published. The remaining four sets of guidelines will address pain, cerebrovascular complications, transfusion, and hematopoietic stem cell transplant. All will be published in Blood Advances, and according to Dr. Liem, the transfusion medicine guidelines have been accepted and should be published in January 2020, followed by those for cerebrovascular complications. Publication of the pain and transplant guidelines are anticipated later in 2020.
Dr. Liem and Dr. Desai reported having no conflicts of interest.
EXPERT ANALYSIS FROM ASH 2019
APHINITY 6-year data: Benefit ongoing in HER2+ early BC, no significant OS benefit
SAN ANTONIO – Adding pertuzumab to trastuzumab and chemotherapy after surgery for HER2-positive early breast cancer continued to show a slight, but statistically nonsignificant overall survival benefit, compared with placebo, at a preplanned 6-year interim analysis of the phase 3 APHINITY trial.
Invasive disease-free survival (IDFS) was significantly improved with pertuzumab at this second interim analysis, and node-positive patients continued to derive the greatest benefit, as was the case in the primary analysis reported in the New England Journal of Medicine in 2017, Martine Piccart, MD, PhD, reported at the San Antonio Breast Cancer Symposium.
At a median of 74.1 months of follow-up, overall survival (OS) was 94.8% in 2,400 patients in the pertuzumab arm, compared with 93.9% in 2,405 patients in the placebo arm (hazard ratio, 0.85), said Dr. Piccart of Institut Jules Bordet, Brussels.
She noted that a “very stringent” P value of.0012 was required for statistical significance in this interim OS analysis.
IDFS rates at follow-up were 90.6% vs. 87.8% in the intent-to-treat population, a difference caused mainly by a reduction in distant and loco-regional recurrence, she noted.
“[That translates] to a 2.8% absolute improvement with pertuzumab at 6 years,” she said, adding that the risk of both distant and loco-regional recurrences was reduced with pertuzumab. “The rate of [central nervous system] metastases, contralateral invasive breast cancers, and death without a prior event – not different between the two treatment groups.”
In the node-positive cohort, the 6-year IDFS rates were 87.9% vs. 83.4% with pertuzumab vs. placebo (4.5% absolute benefit; HR, 0.72), showing a clear benefit.
“In contrast, no treatment effect is detected in the node-negative population [95.0% and 94.9%, respectively; HR, 1.02],” she said.
Importantly, the clinical benefits were seen regardless of hormone receptor status (HRs, 0.73 and 0.83 for hormone receptor–positive and –negative disease, respectively), she said, noting that this finding differs from the 3-year analysis, which suggested an enhanced benefit only in the hormone receptor–negative cohort.
“These [hormone receptor–negative] patients still benefit from pertuzumab ... but interestingly, now the curves are diverging in the hormone receptor–positive population, and there is a benefit emerging,” she said.
An updated descriptive analysis of cardiac safety was also performed, and no new safety concerns emerged, Dr. Piccart said.
“What is important to remember is the rate of severe cardiac events is below 1% in both groups (0.8% and 0.3% with pertuzumab and placebo),” she said.
APHINITY is a randomized, multicenter, double-blind, placebo-controlled trial which previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest but statistically significant improvement in IDFS, compared with placebo and chemotherapy plus trastuzumab (HR, 0.81; P = .04).
The effect was more pronounced in node-negative patients (HR, 0.77) and hormone receptor–negative patients (HR, 0.76).
Patients with node-positive or high-risk node-negative, HER2-positive, operable early breast cancer were enrolled between November 2011 and August 2013, and the primary analysis was conducted at 45.4 months of follow-up. Based on those findings, pertuzumab in combination with trastuzumab was approved for high-risk early HER2-positive breast cancer patients.
The first interim OS analysis was conducted at that time, and no significant treatment effect was observed, Dr. Piccart said.
The 6-year findings demonstrate that the small OS benefit and the statistically significant IDFS benefit with pertuzumab in this setting is maintained, with the node-positive population deriving the greatest benefit.
“Further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2-positive breast cancer,” she said, noting that a calendar-driven third interim OS analysis is planned in 2.5 years.
The APHINITY trial is funded by Roche. Dr. Piccart reported receiving consulting fees from Roche and research funding to her institution from Roche and several other companies. She also is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, and Immunomedics.
SOURCE: Piccart M et al. SABCS 2019, Abstract GS1-04.
SAN ANTONIO – Adding pertuzumab to trastuzumab and chemotherapy after surgery for HER2-positive early breast cancer continued to show a slight, but statistically nonsignificant overall survival benefit, compared with placebo, at a preplanned 6-year interim analysis of the phase 3 APHINITY trial.
Invasive disease-free survival (IDFS) was significantly improved with pertuzumab at this second interim analysis, and node-positive patients continued to derive the greatest benefit, as was the case in the primary analysis reported in the New England Journal of Medicine in 2017, Martine Piccart, MD, PhD, reported at the San Antonio Breast Cancer Symposium.
At a median of 74.1 months of follow-up, overall survival (OS) was 94.8% in 2,400 patients in the pertuzumab arm, compared with 93.9% in 2,405 patients in the placebo arm (hazard ratio, 0.85), said Dr. Piccart of Institut Jules Bordet, Brussels.
She noted that a “very stringent” P value of.0012 was required for statistical significance in this interim OS analysis.
IDFS rates at follow-up were 90.6% vs. 87.8% in the intent-to-treat population, a difference caused mainly by a reduction in distant and loco-regional recurrence, she noted.
“[That translates] to a 2.8% absolute improvement with pertuzumab at 6 years,” she said, adding that the risk of both distant and loco-regional recurrences was reduced with pertuzumab. “The rate of [central nervous system] metastases, contralateral invasive breast cancers, and death without a prior event – not different between the two treatment groups.”
In the node-positive cohort, the 6-year IDFS rates were 87.9% vs. 83.4% with pertuzumab vs. placebo (4.5% absolute benefit; HR, 0.72), showing a clear benefit.
“In contrast, no treatment effect is detected in the node-negative population [95.0% and 94.9%, respectively; HR, 1.02],” she said.
Importantly, the clinical benefits were seen regardless of hormone receptor status (HRs, 0.73 and 0.83 for hormone receptor–positive and –negative disease, respectively), she said, noting that this finding differs from the 3-year analysis, which suggested an enhanced benefit only in the hormone receptor–negative cohort.
“These [hormone receptor–negative] patients still benefit from pertuzumab ... but interestingly, now the curves are diverging in the hormone receptor–positive population, and there is a benefit emerging,” she said.
An updated descriptive analysis of cardiac safety was also performed, and no new safety concerns emerged, Dr. Piccart said.
“What is important to remember is the rate of severe cardiac events is below 1% in both groups (0.8% and 0.3% with pertuzumab and placebo),” she said.
APHINITY is a randomized, multicenter, double-blind, placebo-controlled trial which previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest but statistically significant improvement in IDFS, compared with placebo and chemotherapy plus trastuzumab (HR, 0.81; P = .04).
The effect was more pronounced in node-negative patients (HR, 0.77) and hormone receptor–negative patients (HR, 0.76).
Patients with node-positive or high-risk node-negative, HER2-positive, operable early breast cancer were enrolled between November 2011 and August 2013, and the primary analysis was conducted at 45.4 months of follow-up. Based on those findings, pertuzumab in combination with trastuzumab was approved for high-risk early HER2-positive breast cancer patients.
The first interim OS analysis was conducted at that time, and no significant treatment effect was observed, Dr. Piccart said.
The 6-year findings demonstrate that the small OS benefit and the statistically significant IDFS benefit with pertuzumab in this setting is maintained, with the node-positive population deriving the greatest benefit.
“Further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2-positive breast cancer,” she said, noting that a calendar-driven third interim OS analysis is planned in 2.5 years.
The APHINITY trial is funded by Roche. Dr. Piccart reported receiving consulting fees from Roche and research funding to her institution from Roche and several other companies. She also is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, and Immunomedics.
SOURCE: Piccart M et al. SABCS 2019, Abstract GS1-04.
SAN ANTONIO – Adding pertuzumab to trastuzumab and chemotherapy after surgery for HER2-positive early breast cancer continued to show a slight, but statistically nonsignificant overall survival benefit, compared with placebo, at a preplanned 6-year interim analysis of the phase 3 APHINITY trial.
Invasive disease-free survival (IDFS) was significantly improved with pertuzumab at this second interim analysis, and node-positive patients continued to derive the greatest benefit, as was the case in the primary analysis reported in the New England Journal of Medicine in 2017, Martine Piccart, MD, PhD, reported at the San Antonio Breast Cancer Symposium.
At a median of 74.1 months of follow-up, overall survival (OS) was 94.8% in 2,400 patients in the pertuzumab arm, compared with 93.9% in 2,405 patients in the placebo arm (hazard ratio, 0.85), said Dr. Piccart of Institut Jules Bordet, Brussels.
She noted that a “very stringent” P value of.0012 was required for statistical significance in this interim OS analysis.
IDFS rates at follow-up were 90.6% vs. 87.8% in the intent-to-treat population, a difference caused mainly by a reduction in distant and loco-regional recurrence, she noted.
“[That translates] to a 2.8% absolute improvement with pertuzumab at 6 years,” she said, adding that the risk of both distant and loco-regional recurrences was reduced with pertuzumab. “The rate of [central nervous system] metastases, contralateral invasive breast cancers, and death without a prior event – not different between the two treatment groups.”
In the node-positive cohort, the 6-year IDFS rates were 87.9% vs. 83.4% with pertuzumab vs. placebo (4.5% absolute benefit; HR, 0.72), showing a clear benefit.
“In contrast, no treatment effect is detected in the node-negative population [95.0% and 94.9%, respectively; HR, 1.02],” she said.
Importantly, the clinical benefits were seen regardless of hormone receptor status (HRs, 0.73 and 0.83 for hormone receptor–positive and –negative disease, respectively), she said, noting that this finding differs from the 3-year analysis, which suggested an enhanced benefit only in the hormone receptor–negative cohort.
“These [hormone receptor–negative] patients still benefit from pertuzumab ... but interestingly, now the curves are diverging in the hormone receptor–positive population, and there is a benefit emerging,” she said.
An updated descriptive analysis of cardiac safety was also performed, and no new safety concerns emerged, Dr. Piccart said.
“What is important to remember is the rate of severe cardiac events is below 1% in both groups (0.8% and 0.3% with pertuzumab and placebo),” she said.
APHINITY is a randomized, multicenter, double-blind, placebo-controlled trial which previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest but statistically significant improvement in IDFS, compared with placebo and chemotherapy plus trastuzumab (HR, 0.81; P = .04).
The effect was more pronounced in node-negative patients (HR, 0.77) and hormone receptor–negative patients (HR, 0.76).
Patients with node-positive or high-risk node-negative, HER2-positive, operable early breast cancer were enrolled between November 2011 and August 2013, and the primary analysis was conducted at 45.4 months of follow-up. Based on those findings, pertuzumab in combination with trastuzumab was approved for high-risk early HER2-positive breast cancer patients.
The first interim OS analysis was conducted at that time, and no significant treatment effect was observed, Dr. Piccart said.
The 6-year findings demonstrate that the small OS benefit and the statistically significant IDFS benefit with pertuzumab in this setting is maintained, with the node-positive population deriving the greatest benefit.
“Further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2-positive breast cancer,” she said, noting that a calendar-driven third interim OS analysis is planned in 2.5 years.
The APHINITY trial is funded by Roche. Dr. Piccart reported receiving consulting fees from Roche and research funding to her institution from Roche and several other companies. She also is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, and Immunomedics.
SOURCE: Piccart M et al. SABCS 2019, Abstract GS1-04.
REPORTING FROM SABCS 2019
Oral arginine emerges as potential adjuvant for vaso-occlusive crisis management
ORLANDO – Oral arginine supplementation significantly increased plasma arginine levels and improved acute pain-related outcomes in Nigerian children with sickle cell disease in a randomized, placebo-controlled, phase 2 trial.
Of 68 children with a mean age of 10 years who were hospitalized with vaso-occlusive crisis involving severe pain and treated with standard pain management, 35 were randomized to receive adjuvant oral L-arginine at a dose of 100 mg/kg every 8 hours for 5 days or until discharge, and 33 received placebo. Those in the arginine arm experienced a 125% increase in their plasma arginine level, compared with a 29% increase in the placebo arm, Richard Onalo, FC Paed, reported during a press briefing at the annual meeting of the American Society of Hematology.
“This was statistically significant,” Dr. Onalo, of the department of pediatrics at the University of Abuja, Nigeria, said of the difference between the two arms. “Also, the global bioavailability ratio increased by 59% in the arginine arm.”
Low plasma arginine levels are associated with acute pain requiring hospitalization in Nigerian children with sickle cell disease, and have also been shown in a prior study in the United States to predict pediatric vaso-occlusion, Dr. Onalo said, adding that arginine supplementation, which has known opioid-sparing effects, was found in another phase 2, randomized, placebo-controlled U.S. study to significantly decrease pain scores.
In the current study, the increase in arginine bioavailability inversely correlated with Medication Quantification Scale scores, which were 73 vs. 120 in the arginine and placebo arms, respectively (r = -0.35; P = .02), indicating reduced analgesic use in the arginine arm, he said.
“Clinically, the patients in the arginine arm also tended to have a faster resolution in their pain score,” he said.
Despite similar baseline Numerical Pain Scale (PS) scores (8.7 and 8.4 on a 0-10 scale), day 5 pain scores were 1.2 vs. 2.0, and the mean daily rate of decline was 1.5 vs. 1.1 cm/day.
Crisis resolution was achieved by 25% of the patients in the arginine arm in about 72 hours, compared with about 120 hours in the placebo arms.
“By day 5, 54% of patients on arginine were already home, as compared with just 24% in the placebo arm, and this was found to be clinically and statistically significant,” Dr. Onalo said, noting that mean hospital length of stay was 110 hours vs. 156 hours in the arginine and placebo arms, respectively.
A non–statistically significant decrease in mean total opioid dose was also observed in the arginine vs. placebo arms (3.8 vs 5.1 mg/kg; P = .11).
Arginine supplementation in this study was safe; no serious treatment-related adverse events occurred, and there were no significant differences between the groups in the incidence of adverse events. Dr. Onalo noted, however, that a trend toward more vomiting was observed in the arginine versus the placebo arm (20% vs. 3%, P = .07).
Severe vaso-occlusive pain episodes are a major cause of morbidity and mortality in sickle cell disease, and based on the prior findings – and the lack of data regarding the role of arginine for treating acute sickle cell-related vaso-occlusive pain episodes in sub-Saharan Africa – Dr. Onalo and colleagues set out to assess its role in that setting.
“Also, we are interested in finding a molecule that can be used easily by the patient at home, and also can be [self-administered],” he said.
Children enrolled in the double-blind study had a severe vaso-occlusive pain episode, defined by a PS score of at least 7 on a scale of 0-10, at one of two major hospitals in Abuja, Nigeria. All patients received pain management, including opioid and nonopioid analgesics, per institutional practice.
The findings reinforce the role of arginine in vaso-occlusive pain episodes, and suggest that oral arginine is a promising adjuvant therapy for vaso-occlusive crisis management in patients with sickle cell disease, he said.
“We recommend a phase 3 multicenter clinical trial,” he added.
As for a potential role for arginine in this setting in the United States, prevention trials in the U.S. have thus far been negative, said Julie Panepinto, MD, the press briefing moderator and a pediatric hematologist-oncologist at Children’s Hospital of Wisconsin, Milwaukee.
“This is my first knowledge of use in the acute setting,” said Dr. Panepinto, also a professor at the Medical College of Wisconsin in Milwaukee. “There is going to be some future work looking at use of arginine in the U.S. for patients presenting with pain.”
For now, however, it’s too early to say that all patients should be started on arginine, she said, adding that more information is needed, including about appropriate dosing.
Nonetheless, it’s encouraging to see positive findings, she noted.
“We’ve been looking at and thinking about arginine for a long time, so I think this is a really exciting study ... that should lead us to future work to really understand better how to use the medication,” she said.
Dr. Onalo reported having no disclosures. Dr. Panepinto has received research funding from the National Institutes of Health and the Health Resources and Services Administration.
SOURCE: Onalo R et al. ASH 2019, Abstract 613.
ORLANDO – Oral arginine supplementation significantly increased plasma arginine levels and improved acute pain-related outcomes in Nigerian children with sickle cell disease in a randomized, placebo-controlled, phase 2 trial.
Of 68 children with a mean age of 10 years who were hospitalized with vaso-occlusive crisis involving severe pain and treated with standard pain management, 35 were randomized to receive adjuvant oral L-arginine at a dose of 100 mg/kg every 8 hours for 5 days or until discharge, and 33 received placebo. Those in the arginine arm experienced a 125% increase in their plasma arginine level, compared with a 29% increase in the placebo arm, Richard Onalo, FC Paed, reported during a press briefing at the annual meeting of the American Society of Hematology.
“This was statistically significant,” Dr. Onalo, of the department of pediatrics at the University of Abuja, Nigeria, said of the difference between the two arms. “Also, the global bioavailability ratio increased by 59% in the arginine arm.”
Low plasma arginine levels are associated with acute pain requiring hospitalization in Nigerian children with sickle cell disease, and have also been shown in a prior study in the United States to predict pediatric vaso-occlusion, Dr. Onalo said, adding that arginine supplementation, which has known opioid-sparing effects, was found in another phase 2, randomized, placebo-controlled U.S. study to significantly decrease pain scores.
In the current study, the increase in arginine bioavailability inversely correlated with Medication Quantification Scale scores, which were 73 vs. 120 in the arginine and placebo arms, respectively (r = -0.35; P = .02), indicating reduced analgesic use in the arginine arm, he said.
“Clinically, the patients in the arginine arm also tended to have a faster resolution in their pain score,” he said.
Despite similar baseline Numerical Pain Scale (PS) scores (8.7 and 8.4 on a 0-10 scale), day 5 pain scores were 1.2 vs. 2.0, and the mean daily rate of decline was 1.5 vs. 1.1 cm/day.
Crisis resolution was achieved by 25% of the patients in the arginine arm in about 72 hours, compared with about 120 hours in the placebo arms.
“By day 5, 54% of patients on arginine were already home, as compared with just 24% in the placebo arm, and this was found to be clinically and statistically significant,” Dr. Onalo said, noting that mean hospital length of stay was 110 hours vs. 156 hours in the arginine and placebo arms, respectively.
A non–statistically significant decrease in mean total opioid dose was also observed in the arginine vs. placebo arms (3.8 vs 5.1 mg/kg; P = .11).
Arginine supplementation in this study was safe; no serious treatment-related adverse events occurred, and there were no significant differences between the groups in the incidence of adverse events. Dr. Onalo noted, however, that a trend toward more vomiting was observed in the arginine versus the placebo arm (20% vs. 3%, P = .07).
Severe vaso-occlusive pain episodes are a major cause of morbidity and mortality in sickle cell disease, and based on the prior findings – and the lack of data regarding the role of arginine for treating acute sickle cell-related vaso-occlusive pain episodes in sub-Saharan Africa – Dr. Onalo and colleagues set out to assess its role in that setting.
“Also, we are interested in finding a molecule that can be used easily by the patient at home, and also can be [self-administered],” he said.
Children enrolled in the double-blind study had a severe vaso-occlusive pain episode, defined by a PS score of at least 7 on a scale of 0-10, at one of two major hospitals in Abuja, Nigeria. All patients received pain management, including opioid and nonopioid analgesics, per institutional practice.
The findings reinforce the role of arginine in vaso-occlusive pain episodes, and suggest that oral arginine is a promising adjuvant therapy for vaso-occlusive crisis management in patients with sickle cell disease, he said.
“We recommend a phase 3 multicenter clinical trial,” he added.
As for a potential role for arginine in this setting in the United States, prevention trials in the U.S. have thus far been negative, said Julie Panepinto, MD, the press briefing moderator and a pediatric hematologist-oncologist at Children’s Hospital of Wisconsin, Milwaukee.
“This is my first knowledge of use in the acute setting,” said Dr. Panepinto, also a professor at the Medical College of Wisconsin in Milwaukee. “There is going to be some future work looking at use of arginine in the U.S. for patients presenting with pain.”
For now, however, it’s too early to say that all patients should be started on arginine, she said, adding that more information is needed, including about appropriate dosing.
Nonetheless, it’s encouraging to see positive findings, she noted.
“We’ve been looking at and thinking about arginine for a long time, so I think this is a really exciting study ... that should lead us to future work to really understand better how to use the medication,” she said.
Dr. Onalo reported having no disclosures. Dr. Panepinto has received research funding from the National Institutes of Health and the Health Resources and Services Administration.
SOURCE: Onalo R et al. ASH 2019, Abstract 613.
ORLANDO – Oral arginine supplementation significantly increased plasma arginine levels and improved acute pain-related outcomes in Nigerian children with sickle cell disease in a randomized, placebo-controlled, phase 2 trial.
Of 68 children with a mean age of 10 years who were hospitalized with vaso-occlusive crisis involving severe pain and treated with standard pain management, 35 were randomized to receive adjuvant oral L-arginine at a dose of 100 mg/kg every 8 hours for 5 days or until discharge, and 33 received placebo. Those in the arginine arm experienced a 125% increase in their plasma arginine level, compared with a 29% increase in the placebo arm, Richard Onalo, FC Paed, reported during a press briefing at the annual meeting of the American Society of Hematology.
“This was statistically significant,” Dr. Onalo, of the department of pediatrics at the University of Abuja, Nigeria, said of the difference between the two arms. “Also, the global bioavailability ratio increased by 59% in the arginine arm.”
Low plasma arginine levels are associated with acute pain requiring hospitalization in Nigerian children with sickle cell disease, and have also been shown in a prior study in the United States to predict pediatric vaso-occlusion, Dr. Onalo said, adding that arginine supplementation, which has known opioid-sparing effects, was found in another phase 2, randomized, placebo-controlled U.S. study to significantly decrease pain scores.
In the current study, the increase in arginine bioavailability inversely correlated with Medication Quantification Scale scores, which were 73 vs. 120 in the arginine and placebo arms, respectively (r = -0.35; P = .02), indicating reduced analgesic use in the arginine arm, he said.
“Clinically, the patients in the arginine arm also tended to have a faster resolution in their pain score,” he said.
Despite similar baseline Numerical Pain Scale (PS) scores (8.7 and 8.4 on a 0-10 scale), day 5 pain scores were 1.2 vs. 2.0, and the mean daily rate of decline was 1.5 vs. 1.1 cm/day.
Crisis resolution was achieved by 25% of the patients in the arginine arm in about 72 hours, compared with about 120 hours in the placebo arms.
“By day 5, 54% of patients on arginine were already home, as compared with just 24% in the placebo arm, and this was found to be clinically and statistically significant,” Dr. Onalo said, noting that mean hospital length of stay was 110 hours vs. 156 hours in the arginine and placebo arms, respectively.
A non–statistically significant decrease in mean total opioid dose was also observed in the arginine vs. placebo arms (3.8 vs 5.1 mg/kg; P = .11).
Arginine supplementation in this study was safe; no serious treatment-related adverse events occurred, and there were no significant differences between the groups in the incidence of adverse events. Dr. Onalo noted, however, that a trend toward more vomiting was observed in the arginine versus the placebo arm (20% vs. 3%, P = .07).
Severe vaso-occlusive pain episodes are a major cause of morbidity and mortality in sickle cell disease, and based on the prior findings – and the lack of data regarding the role of arginine for treating acute sickle cell-related vaso-occlusive pain episodes in sub-Saharan Africa – Dr. Onalo and colleagues set out to assess its role in that setting.
“Also, we are interested in finding a molecule that can be used easily by the patient at home, and also can be [self-administered],” he said.
Children enrolled in the double-blind study had a severe vaso-occlusive pain episode, defined by a PS score of at least 7 on a scale of 0-10, at one of two major hospitals in Abuja, Nigeria. All patients received pain management, including opioid and nonopioid analgesics, per institutional practice.
The findings reinforce the role of arginine in vaso-occlusive pain episodes, and suggest that oral arginine is a promising adjuvant therapy for vaso-occlusive crisis management in patients with sickle cell disease, he said.
“We recommend a phase 3 multicenter clinical trial,” he added.
As for a potential role for arginine in this setting in the United States, prevention trials in the U.S. have thus far been negative, said Julie Panepinto, MD, the press briefing moderator and a pediatric hematologist-oncologist at Children’s Hospital of Wisconsin, Milwaukee.
“This is my first knowledge of use in the acute setting,” said Dr. Panepinto, also a professor at the Medical College of Wisconsin in Milwaukee. “There is going to be some future work looking at use of arginine in the U.S. for patients presenting with pain.”
For now, however, it’s too early to say that all patients should be started on arginine, she said, adding that more information is needed, including about appropriate dosing.
Nonetheless, it’s encouraging to see positive findings, she noted.
“We’ve been looking at and thinking about arginine for a long time, so I think this is a really exciting study ... that should lead us to future work to really understand better how to use the medication,” she said.
Dr. Onalo reported having no disclosures. Dr. Panepinto has received research funding from the National Institutes of Health and the Health Resources and Services Administration.
SOURCE: Onalo R et al. ASH 2019, Abstract 613.
REPORTING FROM ASH 2019
Aspirin plus a DOAC may do more harm than good in some
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
REPORTING FROM ASH 2019
Certolizumab may reduce uveitis flares, axSpA disease activity
ATLANTA – Certolizumab pegol, a PEGylated, monoclonal, anti–tumor necrosis factor antibody, reduces recurrent acute anterior uveitis flares and improves disease activity in patients with axial spondyloarthritis, according to findings from the open-label, 96-week, phase 4 C-VIEW study.
When given earlier in the course of disease, the treatment, which is the only Food and Drug Administration–approved tumor necrosis factor inhibitor (TNFi) for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA), also shortens symptom duration, a post hoc analysis of data from the multicenter, phase 3 C-axSpAnd study suggests. The findings from both studies were presented during a session at the annual meeting of the American College of Rheumatology.
C-VIEW
In 85 patients with active axSpA who completed 48 weeks of certolizumab pegol therapy in the C-VIEW study, the acute anterior uveitis (AAU) flare incidence over 48 weeks was a mean of 0.2, compared with 1.5 flares per person in the 48 weeks prior to treatment initiation, reported Irene E. van der Horst-Bruinsma, MD, PhD, of Amsterdam University Medical Center. The comparison was adjusted for possible within-patient correlations, flare period (pre- and post baseline), and axSpA disease duration.
This finding, from a preplanned interim analysis, represented a flare incidence of 18.7 versus 146.6 per 100 patient-years, during treatment versus prior to treatment – an 87% reduction – and the difference was statistically significant (P less than .001), Dr. van der Horst-Bruinsma said.
The percentage of patients experiencing one flare was 12.4% during therapy, compared with 64% prior to therapy, and the percentage experiencing two or more flares was 2.2% versus 24.7%, respectively, she said, adding that, in the 13 patients who experienced flares both before and during treatment, the mean flare duration was reduced during treatment (58.4 vs. 97.4 days). A comparison of radiographic and nr-axSpA patients showed similar reductions in flares during versus prior to treatment, going from 144.5 to 19.0 flares per 100 patient-years with radiographic disease and from 158.9 to 17.2 flares per 100 patient-years in nr-axSpA.
Furthermore, after 48 weeks of treatment, disease activity had improved substantially, with mean Ankylosing Spondylitis Disease Activity Score (ASDAS) improving from 3.5 to 2.0 at week 48, 94.2% of patients reaching ASDAS clinical improvement at week 48, and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreasing significantly from 6.5 to 3.3 at week 48.
“ASDAS 20 was reached by 75% of the patients, the ASDAS 40 by 54%, and the ASDAS partial remission criteria were reached by 31% of the patients,” she said.
Study participants were adults with a mean age of 46.5 years and active disease according to Assessment of Spondyloarthritis International Society (ASAS) criteria and a history of recurrent AAU flares (either two or more in total, or one or more in the year prior to study entry). They were HLA-B27 positive, eligible for anti-TNF therapy because they had an inadequate response (or contraindication) to at least two prior NSAIDs, were biologic naive, or had failed to respond to no more than one prior anti-TNF agent. Both radiographic and nr-axSpA patients were included, and of 115 who enrolled, 89 initiated treatment, including 76 with radiographic disease and 13 with nonradiographic disease; 85 completed week 48 of treatment.
Certolizumab pegol was given at a loading dose of 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through week 96, and was well tolerated. No new safety signals were identified, Dr. van der Horst-Bruinsma said.
“We know that acute anterior uveitis, an inflammation of ... the uveal tract, is the most common extra-articular manifestation in axial spondyloarthritis,” she said. “It is reported in up to 40% of patients and is associated with significant clinical burden.”
AAU is also strongly associated with the HLA-B27 antigen, therefore patients who do not have ankylosing spondylitis but who are HLA-B27 positive also are at risk, she said, noting that previous studies have shown that TNF inhibitors reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis), but that data in nr-axSpA are scarce.
The aim of C-VIEW was to analyze the impact of certolizumab pegol treatment on AAU flares in patients with active radiographic or nr-axSpA and a recent history of AAU, she said.
“C-VIEW was the first study to examine the impact of certolizumab on the incidence of acute anterior uveitis flares in HLA-B27-positive patients with a recent history of acute anterior uveitis, including patients with nr-axSpA ... and in conclusion we can say that these results indicate that certolizumab is a suitable treatment option for patients with axSpA and a history of recurrent acute anterior uveitis,” she said.
C-axSpAnd
In the pivotal 3-year C-axSpAnd study, which included a 52‑week, double-blind, placebo-controlled period, 159 patients with active nr-axSpA, objective signs of inflammation, and previous failure of at least two NSAIDS were treated with certolizumab pegol, and 158 similar patients received placebo. Both groups received nonbiologic background medication.
The results of the trial, published in Arthritis & Rheumatology in March 2019, showed that adding certolizumab pegol to background medication is superior to adding placebo in patients with active nr-axSpA and led to its FDA approval for axSpA in March 2019, but the effects of symptom duration on outcomes with certolizumab pegol have not been well studied, Jonathan Kay, MD, said at the ACR meeting.
The current post hoc analysis stratified patients based on symptom duration and showed that certolizumab pegol recipients with less than 5 years of symptoms at baseline had improved outcomes at weeks 12 and 52, compared with those who had 5 or more years of symptoms at baseline, said Dr. Kay of UMass Memorial Medical Center and the University of Massachusetts, Worcester.
For example, major improvement in ASDAS at week 52, the primary outcome measure, was achieved by 55% of 80 patients with shorter symptom duration, compared with 39.2% of 79 patients with longer symptom duration, and the ASAS 40 responder rates in the groups, respectively, were 58.5% and 36.7% at 12 weeks and 65% and 48.1% at 52 weeks, he said.
Certolizumab pegol recipients with shorter symptom duration also had greater improvement in BASDAI score, nocturnal spinal pain, fatigue, morning stiffness, and the 36-item Short Form Survey physical component score, he noted.
Using a cutoff of 3 years rather than 5 years, responder rates for major improvement in ASDAS and ASAS 40 were still greater in certolizumab pegol–treated patients with shorter symptom duration: At 52 weeks, 56.4% of 55 patients with less than 3 years of symptoms, compared with 42.3% of 104 with 3 or more years of symptoms, achieved major improvement in ASDAS, and ASAS 40 responder rates were 65.5%, compared with 51.9%, respectively.
Response rates in the placebo arm were low, compared with both certolizumab pegol groups, and no consistent trend in outcomes was observed based on symptom duration in that arm, Dr. Kay noted.
Study subjects were adults with a diagnosis of axSpA, active disease, fulfillment of ASAS classification criteria, and at least 12 months of inflammatory back pain. The trial excluded those with radiographic sacroiliitis meeting the modified New York classification criteria and who had exposure to more than one TNFi prior to baseline or primary failure of any TNFi. As in the C-VIEW study, participants were randomized to receive 400 mg certolizumab pegol at weeks 0, 2, and 4, and then 200 mg every 2 weeks thereafter through week 52.
The findings are notable because patients with axSpA – including radiographic disease and nr-axSpA – often experience delays in diagnosis, which can lead to a delay in treatment and a reduced quality of life because of the back pain, fatigue, and morning stiffness that commonly occur with the disease.
“Women, especially, with axial spondyloarthritis experience a longer delay in diagnosis than do male patients,” Dr. Kay noted.
The findings of this post hoc analysis underscore the risks associated with such a delay. “These results imply that early diagnosis enabling earlier treatment is important for patients with nonradiographic axSpA, as it is for patients with radiographic axSpA,” he concluded.
The C-VIEW and C-axSpAnd studies were funded by UCB. Dr. van der Horst-Bruinsma reported receiving honoraria, consulting fees, and/or research grants from UCB as well as from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Pfizer. Dr. Kay reported receiving grant/research support from Gilead, Pfizer, and UCB, and consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion, Merck, Novartis, Samsung Bioepis, Sandoz, and UCB.
SOURCES: van der Horst-Bruinsma I et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 935; Kay J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 936.
ATLANTA – Certolizumab pegol, a PEGylated, monoclonal, anti–tumor necrosis factor antibody, reduces recurrent acute anterior uveitis flares and improves disease activity in patients with axial spondyloarthritis, according to findings from the open-label, 96-week, phase 4 C-VIEW study.
When given earlier in the course of disease, the treatment, which is the only Food and Drug Administration–approved tumor necrosis factor inhibitor (TNFi) for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA), also shortens symptom duration, a post hoc analysis of data from the multicenter, phase 3 C-axSpAnd study suggests. The findings from both studies were presented during a session at the annual meeting of the American College of Rheumatology.
C-VIEW
In 85 patients with active axSpA who completed 48 weeks of certolizumab pegol therapy in the C-VIEW study, the acute anterior uveitis (AAU) flare incidence over 48 weeks was a mean of 0.2, compared with 1.5 flares per person in the 48 weeks prior to treatment initiation, reported Irene E. van der Horst-Bruinsma, MD, PhD, of Amsterdam University Medical Center. The comparison was adjusted for possible within-patient correlations, flare period (pre- and post baseline), and axSpA disease duration.
This finding, from a preplanned interim analysis, represented a flare incidence of 18.7 versus 146.6 per 100 patient-years, during treatment versus prior to treatment – an 87% reduction – and the difference was statistically significant (P less than .001), Dr. van der Horst-Bruinsma said.
The percentage of patients experiencing one flare was 12.4% during therapy, compared with 64% prior to therapy, and the percentage experiencing two or more flares was 2.2% versus 24.7%, respectively, she said, adding that, in the 13 patients who experienced flares both before and during treatment, the mean flare duration was reduced during treatment (58.4 vs. 97.4 days). A comparison of radiographic and nr-axSpA patients showed similar reductions in flares during versus prior to treatment, going from 144.5 to 19.0 flares per 100 patient-years with radiographic disease and from 158.9 to 17.2 flares per 100 patient-years in nr-axSpA.
Furthermore, after 48 weeks of treatment, disease activity had improved substantially, with mean Ankylosing Spondylitis Disease Activity Score (ASDAS) improving from 3.5 to 2.0 at week 48, 94.2% of patients reaching ASDAS clinical improvement at week 48, and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreasing significantly from 6.5 to 3.3 at week 48.
“ASDAS 20 was reached by 75% of the patients, the ASDAS 40 by 54%, and the ASDAS partial remission criteria were reached by 31% of the patients,” she said.
Study participants were adults with a mean age of 46.5 years and active disease according to Assessment of Spondyloarthritis International Society (ASAS) criteria and a history of recurrent AAU flares (either two or more in total, or one or more in the year prior to study entry). They were HLA-B27 positive, eligible for anti-TNF therapy because they had an inadequate response (or contraindication) to at least two prior NSAIDs, were biologic naive, or had failed to respond to no more than one prior anti-TNF agent. Both radiographic and nr-axSpA patients were included, and of 115 who enrolled, 89 initiated treatment, including 76 with radiographic disease and 13 with nonradiographic disease; 85 completed week 48 of treatment.
Certolizumab pegol was given at a loading dose of 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through week 96, and was well tolerated. No new safety signals were identified, Dr. van der Horst-Bruinsma said.
“We know that acute anterior uveitis, an inflammation of ... the uveal tract, is the most common extra-articular manifestation in axial spondyloarthritis,” she said. “It is reported in up to 40% of patients and is associated with significant clinical burden.”
AAU is also strongly associated with the HLA-B27 antigen, therefore patients who do not have ankylosing spondylitis but who are HLA-B27 positive also are at risk, she said, noting that previous studies have shown that TNF inhibitors reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis), but that data in nr-axSpA are scarce.
The aim of C-VIEW was to analyze the impact of certolizumab pegol treatment on AAU flares in patients with active radiographic or nr-axSpA and a recent history of AAU, she said.
“C-VIEW was the first study to examine the impact of certolizumab on the incidence of acute anterior uveitis flares in HLA-B27-positive patients with a recent history of acute anterior uveitis, including patients with nr-axSpA ... and in conclusion we can say that these results indicate that certolizumab is a suitable treatment option for patients with axSpA and a history of recurrent acute anterior uveitis,” she said.
C-axSpAnd
In the pivotal 3-year C-axSpAnd study, which included a 52‑week, double-blind, placebo-controlled period, 159 patients with active nr-axSpA, objective signs of inflammation, and previous failure of at least two NSAIDS were treated with certolizumab pegol, and 158 similar patients received placebo. Both groups received nonbiologic background medication.
The results of the trial, published in Arthritis & Rheumatology in March 2019, showed that adding certolizumab pegol to background medication is superior to adding placebo in patients with active nr-axSpA and led to its FDA approval for axSpA in March 2019, but the effects of symptom duration on outcomes with certolizumab pegol have not been well studied, Jonathan Kay, MD, said at the ACR meeting.
The current post hoc analysis stratified patients based on symptom duration and showed that certolizumab pegol recipients with less than 5 years of symptoms at baseline had improved outcomes at weeks 12 and 52, compared with those who had 5 or more years of symptoms at baseline, said Dr. Kay of UMass Memorial Medical Center and the University of Massachusetts, Worcester.
For example, major improvement in ASDAS at week 52, the primary outcome measure, was achieved by 55% of 80 patients with shorter symptom duration, compared with 39.2% of 79 patients with longer symptom duration, and the ASAS 40 responder rates in the groups, respectively, were 58.5% and 36.7% at 12 weeks and 65% and 48.1% at 52 weeks, he said.
Certolizumab pegol recipients with shorter symptom duration also had greater improvement in BASDAI score, nocturnal spinal pain, fatigue, morning stiffness, and the 36-item Short Form Survey physical component score, he noted.
Using a cutoff of 3 years rather than 5 years, responder rates for major improvement in ASDAS and ASAS 40 were still greater in certolizumab pegol–treated patients with shorter symptom duration: At 52 weeks, 56.4% of 55 patients with less than 3 years of symptoms, compared with 42.3% of 104 with 3 or more years of symptoms, achieved major improvement in ASDAS, and ASAS 40 responder rates were 65.5%, compared with 51.9%, respectively.
Response rates in the placebo arm were low, compared with both certolizumab pegol groups, and no consistent trend in outcomes was observed based on symptom duration in that arm, Dr. Kay noted.
Study subjects were adults with a diagnosis of axSpA, active disease, fulfillment of ASAS classification criteria, and at least 12 months of inflammatory back pain. The trial excluded those with radiographic sacroiliitis meeting the modified New York classification criteria and who had exposure to more than one TNFi prior to baseline or primary failure of any TNFi. As in the C-VIEW study, participants were randomized to receive 400 mg certolizumab pegol at weeks 0, 2, and 4, and then 200 mg every 2 weeks thereafter through week 52.
The findings are notable because patients with axSpA – including radiographic disease and nr-axSpA – often experience delays in diagnosis, which can lead to a delay in treatment and a reduced quality of life because of the back pain, fatigue, and morning stiffness that commonly occur with the disease.
“Women, especially, with axial spondyloarthritis experience a longer delay in diagnosis than do male patients,” Dr. Kay noted.
The findings of this post hoc analysis underscore the risks associated with such a delay. “These results imply that early diagnosis enabling earlier treatment is important for patients with nonradiographic axSpA, as it is for patients with radiographic axSpA,” he concluded.
The C-VIEW and C-axSpAnd studies were funded by UCB. Dr. van der Horst-Bruinsma reported receiving honoraria, consulting fees, and/or research grants from UCB as well as from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Pfizer. Dr. Kay reported receiving grant/research support from Gilead, Pfizer, and UCB, and consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion, Merck, Novartis, Samsung Bioepis, Sandoz, and UCB.
SOURCES: van der Horst-Bruinsma I et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 935; Kay J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 936.
ATLANTA – Certolizumab pegol, a PEGylated, monoclonal, anti–tumor necrosis factor antibody, reduces recurrent acute anterior uveitis flares and improves disease activity in patients with axial spondyloarthritis, according to findings from the open-label, 96-week, phase 4 C-VIEW study.
When given earlier in the course of disease, the treatment, which is the only Food and Drug Administration–approved tumor necrosis factor inhibitor (TNFi) for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA), also shortens symptom duration, a post hoc analysis of data from the multicenter, phase 3 C-axSpAnd study suggests. The findings from both studies were presented during a session at the annual meeting of the American College of Rheumatology.
C-VIEW
In 85 patients with active axSpA who completed 48 weeks of certolizumab pegol therapy in the C-VIEW study, the acute anterior uveitis (AAU) flare incidence over 48 weeks was a mean of 0.2, compared with 1.5 flares per person in the 48 weeks prior to treatment initiation, reported Irene E. van der Horst-Bruinsma, MD, PhD, of Amsterdam University Medical Center. The comparison was adjusted for possible within-patient correlations, flare period (pre- and post baseline), and axSpA disease duration.
This finding, from a preplanned interim analysis, represented a flare incidence of 18.7 versus 146.6 per 100 patient-years, during treatment versus prior to treatment – an 87% reduction – and the difference was statistically significant (P less than .001), Dr. van der Horst-Bruinsma said.
The percentage of patients experiencing one flare was 12.4% during therapy, compared with 64% prior to therapy, and the percentage experiencing two or more flares was 2.2% versus 24.7%, respectively, she said, adding that, in the 13 patients who experienced flares both before and during treatment, the mean flare duration was reduced during treatment (58.4 vs. 97.4 days). A comparison of radiographic and nr-axSpA patients showed similar reductions in flares during versus prior to treatment, going from 144.5 to 19.0 flares per 100 patient-years with radiographic disease and from 158.9 to 17.2 flares per 100 patient-years in nr-axSpA.
Furthermore, after 48 weeks of treatment, disease activity had improved substantially, with mean Ankylosing Spondylitis Disease Activity Score (ASDAS) improving from 3.5 to 2.0 at week 48, 94.2% of patients reaching ASDAS clinical improvement at week 48, and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreasing significantly from 6.5 to 3.3 at week 48.
“ASDAS 20 was reached by 75% of the patients, the ASDAS 40 by 54%, and the ASDAS partial remission criteria were reached by 31% of the patients,” she said.
Study participants were adults with a mean age of 46.5 years and active disease according to Assessment of Spondyloarthritis International Society (ASAS) criteria and a history of recurrent AAU flares (either two or more in total, or one or more in the year prior to study entry). They were HLA-B27 positive, eligible for anti-TNF therapy because they had an inadequate response (or contraindication) to at least two prior NSAIDs, were biologic naive, or had failed to respond to no more than one prior anti-TNF agent. Both radiographic and nr-axSpA patients were included, and of 115 who enrolled, 89 initiated treatment, including 76 with radiographic disease and 13 with nonradiographic disease; 85 completed week 48 of treatment.
Certolizumab pegol was given at a loading dose of 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through week 96, and was well tolerated. No new safety signals were identified, Dr. van der Horst-Bruinsma said.
“We know that acute anterior uveitis, an inflammation of ... the uveal tract, is the most common extra-articular manifestation in axial spondyloarthritis,” she said. “It is reported in up to 40% of patients and is associated with significant clinical burden.”
AAU is also strongly associated with the HLA-B27 antigen, therefore patients who do not have ankylosing spondylitis but who are HLA-B27 positive also are at risk, she said, noting that previous studies have shown that TNF inhibitors reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis), but that data in nr-axSpA are scarce.
The aim of C-VIEW was to analyze the impact of certolizumab pegol treatment on AAU flares in patients with active radiographic or nr-axSpA and a recent history of AAU, she said.
“C-VIEW was the first study to examine the impact of certolizumab on the incidence of acute anterior uveitis flares in HLA-B27-positive patients with a recent history of acute anterior uveitis, including patients with nr-axSpA ... and in conclusion we can say that these results indicate that certolizumab is a suitable treatment option for patients with axSpA and a history of recurrent acute anterior uveitis,” she said.
C-axSpAnd
In the pivotal 3-year C-axSpAnd study, which included a 52‑week, double-blind, placebo-controlled period, 159 patients with active nr-axSpA, objective signs of inflammation, and previous failure of at least two NSAIDS were treated with certolizumab pegol, and 158 similar patients received placebo. Both groups received nonbiologic background medication.
The results of the trial, published in Arthritis & Rheumatology in March 2019, showed that adding certolizumab pegol to background medication is superior to adding placebo in patients with active nr-axSpA and led to its FDA approval for axSpA in March 2019, but the effects of symptom duration on outcomes with certolizumab pegol have not been well studied, Jonathan Kay, MD, said at the ACR meeting.
The current post hoc analysis stratified patients based on symptom duration and showed that certolizumab pegol recipients with less than 5 years of symptoms at baseline had improved outcomes at weeks 12 and 52, compared with those who had 5 or more years of symptoms at baseline, said Dr. Kay of UMass Memorial Medical Center and the University of Massachusetts, Worcester.
For example, major improvement in ASDAS at week 52, the primary outcome measure, was achieved by 55% of 80 patients with shorter symptom duration, compared with 39.2% of 79 patients with longer symptom duration, and the ASAS 40 responder rates in the groups, respectively, were 58.5% and 36.7% at 12 weeks and 65% and 48.1% at 52 weeks, he said.
Certolizumab pegol recipients with shorter symptom duration also had greater improvement in BASDAI score, nocturnal spinal pain, fatigue, morning stiffness, and the 36-item Short Form Survey physical component score, he noted.
Using a cutoff of 3 years rather than 5 years, responder rates for major improvement in ASDAS and ASAS 40 were still greater in certolizumab pegol–treated patients with shorter symptom duration: At 52 weeks, 56.4% of 55 patients with less than 3 years of symptoms, compared with 42.3% of 104 with 3 or more years of symptoms, achieved major improvement in ASDAS, and ASAS 40 responder rates were 65.5%, compared with 51.9%, respectively.
Response rates in the placebo arm were low, compared with both certolizumab pegol groups, and no consistent trend in outcomes was observed based on symptom duration in that arm, Dr. Kay noted.
Study subjects were adults with a diagnosis of axSpA, active disease, fulfillment of ASAS classification criteria, and at least 12 months of inflammatory back pain. The trial excluded those with radiographic sacroiliitis meeting the modified New York classification criteria and who had exposure to more than one TNFi prior to baseline or primary failure of any TNFi. As in the C-VIEW study, participants were randomized to receive 400 mg certolizumab pegol at weeks 0, 2, and 4, and then 200 mg every 2 weeks thereafter through week 52.
The findings are notable because patients with axSpA – including radiographic disease and nr-axSpA – often experience delays in diagnosis, which can lead to a delay in treatment and a reduced quality of life because of the back pain, fatigue, and morning stiffness that commonly occur with the disease.
“Women, especially, with axial spondyloarthritis experience a longer delay in diagnosis than do male patients,” Dr. Kay noted.
The findings of this post hoc analysis underscore the risks associated with such a delay. “These results imply that early diagnosis enabling earlier treatment is important for patients with nonradiographic axSpA, as it is for patients with radiographic axSpA,” he concluded.
The C-VIEW and C-axSpAnd studies were funded by UCB. Dr. van der Horst-Bruinsma reported receiving honoraria, consulting fees, and/or research grants from UCB as well as from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Pfizer. Dr. Kay reported receiving grant/research support from Gilead, Pfizer, and UCB, and consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion, Merck, Novartis, Samsung Bioepis, Sandoz, and UCB.
SOURCES: van der Horst-Bruinsma I et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 935; Kay J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 936.
REPORTING FROM ACR 2019
TULIP trials show clinical benefit of anifrolumab for SLE
ATLANTA –
In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.
The findings were published online Nov. 11 in Lancet Rheumatology.
TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.
The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.
The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.
“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”
Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.
In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.
TULIP-1
The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.
The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.
Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.
BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.
The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.
“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”
The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.
“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.
The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.
However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).
“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.
Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.
The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.
Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).
“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.
The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”
Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.
“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”
TULIP-2
BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.
“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”
Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).
“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).
Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.
Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.
Serum anti–double stranded DNA also trended toward normalization with anifrolumab.
The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”
Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.
No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”
“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.
The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.
SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
ATLANTA –
In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.
The findings were published online Nov. 11 in Lancet Rheumatology.
TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.
The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.
The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.
“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”
Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.
In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.
TULIP-1
The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.
The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.
Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.
BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.
The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.
“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”
The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.
“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.
The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.
However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).
“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.
Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.
The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.
Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).
“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.
The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”
Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.
“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”
TULIP-2
BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.
“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”
Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).
“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).
Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.
Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.
Serum anti–double stranded DNA also trended toward normalization with anifrolumab.
The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”
Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.
No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”
“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.
The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.
SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
ATLANTA –
In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.
The findings were published online Nov. 11 in Lancet Rheumatology.
TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.
The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.
The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.
“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”
Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.
In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.
TULIP-1
The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.
The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.
Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.
BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.
The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.
“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”
The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.
“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.
The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.
However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).
“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.
Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.
The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.
Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).
“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.
The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”
Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.
“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”
TULIP-2
BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.
“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”
Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).
“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).
Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.
Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.
Serum anti–double stranded DNA also trended toward normalization with anifrolumab.
The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”
Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.
No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”
“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.
The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.
SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
REPORTING FROM ACR 2019
Upadacitinib doubles ASAS 40 response vs. placebo in ankylosing spondylitis
ATLANTA – in the randomized, placebo-controlled, phase 2/3 SELECT-AXIS 1 study.
Physical functioning and imaging measures also were improved with upadacitinib in the double-blind, multicenter study, Désirée van der Heijde, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
The findings are notable because patients with ankylosing spondylitis (AS) who have an inadequate response or contraindication to NSAIDs have limited treatment options other than biologic disease-modifying antirheumatic drugs (bDMARDs). The JAK pathway has emerged as a potential therapeutic target in AS, and given its recent approval for the treatment of RA as well as ongoing studies of the agent for several other chronic immune-mediated inflammatory diseases, Dr. van der Heijde and colleagues sought to assess its efficacy and safety in bDMARD-naive patients with active AS.
Of 93 AS patients aged 18 years and older who were randomized to receive 15 mg of upadacitinib daily, 51.6% achieved the primary study endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 14, compared with 25.5% of 94 patients who received placebo, said Dr. van der Heijde, professor of rheumatology at Leiden (the Netherlands) University Medical Center.
The effect was rapid, with a clear difference emerging between the treatment and placebo groups within 2 weeks, she noted.
Significant improvements were also seen with upadacitinib for several key secondary endpoints including change from baseline to week 14 in the Ankylosing Spondylitis Disease Activity Score, Spondyloarthritis Research Consortium of Canada MRI Spine, a 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), ASAS partial remission, and Bath Ankylosing Spondylitis Functional Index.
SELECT-AXIS 1 patients were adults with a mean age of 45 years who were enrolled from 60 sites in 20 countries. All met modified New York criteria for AS based on central reading of radiographs, had a BASDAI score of at least 4, had a patient assessment of total back pain of 4 or greater on a 0-10 scale at screening and baseline, were naive to bDMARDs, and had either an inadequate response to at least two NSAIDs or an intolerance/contraindication to NSAIDs.
Most patients (70.6%) were men, and 76.5% were HLA-B27 positive. Mean symptom duration was 14-15 years, and mean disease duration was 7-8 years, Dr. van der Heijde said, adding that baseline disease characteristics were balanced between the two arms.
All randomized patients received their assigned treatment, and 95.7% completed the study through week 14, including 90 of 94 placebo group patients and 89 of 93 upadacitinib patients.
“Treatment was generally well tolerated,” she said.
The proportions of patients in the treatment and placebo groups, respectively, were similar with respect to adverse events leading to discontinuation (2.2% vs. 3.2%), serious adverse events (1.1% in each group), and infections (20.4% vs. 27.7%). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported. Also, no differences were seen between the groups in relevant laboratory abnormalities, and no new safety finding were observed in comparison with previous upadacitinib studies in other diseases, she noted.
Dr. van der Heijde concluded that “these results support further investigation of upadacitinib for the treatment of ankylosing spondyloarthritis.”
AbbVie, which markets upadacitinib, funded the study. Dr. van der Heijde disclosed financial relationships with AbbVie and 20 other pharmaceutical companies. Many other authors also reported financial relationships with industry, including AbbVie.
SOURCE: van der Heijde D et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2728.
ATLANTA – in the randomized, placebo-controlled, phase 2/3 SELECT-AXIS 1 study.
Physical functioning and imaging measures also were improved with upadacitinib in the double-blind, multicenter study, Désirée van der Heijde, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
The findings are notable because patients with ankylosing spondylitis (AS) who have an inadequate response or contraindication to NSAIDs have limited treatment options other than biologic disease-modifying antirheumatic drugs (bDMARDs). The JAK pathway has emerged as a potential therapeutic target in AS, and given its recent approval for the treatment of RA as well as ongoing studies of the agent for several other chronic immune-mediated inflammatory diseases, Dr. van der Heijde and colleagues sought to assess its efficacy and safety in bDMARD-naive patients with active AS.
Of 93 AS patients aged 18 years and older who were randomized to receive 15 mg of upadacitinib daily, 51.6% achieved the primary study endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 14, compared with 25.5% of 94 patients who received placebo, said Dr. van der Heijde, professor of rheumatology at Leiden (the Netherlands) University Medical Center.
The effect was rapid, with a clear difference emerging between the treatment and placebo groups within 2 weeks, she noted.
Significant improvements were also seen with upadacitinib for several key secondary endpoints including change from baseline to week 14 in the Ankylosing Spondylitis Disease Activity Score, Spondyloarthritis Research Consortium of Canada MRI Spine, a 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), ASAS partial remission, and Bath Ankylosing Spondylitis Functional Index.
SELECT-AXIS 1 patients were adults with a mean age of 45 years who were enrolled from 60 sites in 20 countries. All met modified New York criteria for AS based on central reading of radiographs, had a BASDAI score of at least 4, had a patient assessment of total back pain of 4 or greater on a 0-10 scale at screening and baseline, were naive to bDMARDs, and had either an inadequate response to at least two NSAIDs or an intolerance/contraindication to NSAIDs.
Most patients (70.6%) were men, and 76.5% were HLA-B27 positive. Mean symptom duration was 14-15 years, and mean disease duration was 7-8 years, Dr. van der Heijde said, adding that baseline disease characteristics were balanced between the two arms.
All randomized patients received their assigned treatment, and 95.7% completed the study through week 14, including 90 of 94 placebo group patients and 89 of 93 upadacitinib patients.
“Treatment was generally well tolerated,” she said.
The proportions of patients in the treatment and placebo groups, respectively, were similar with respect to adverse events leading to discontinuation (2.2% vs. 3.2%), serious adverse events (1.1% in each group), and infections (20.4% vs. 27.7%). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported. Also, no differences were seen between the groups in relevant laboratory abnormalities, and no new safety finding were observed in comparison with previous upadacitinib studies in other diseases, she noted.
Dr. van der Heijde concluded that “these results support further investigation of upadacitinib for the treatment of ankylosing spondyloarthritis.”
AbbVie, which markets upadacitinib, funded the study. Dr. van der Heijde disclosed financial relationships with AbbVie and 20 other pharmaceutical companies. Many other authors also reported financial relationships with industry, including AbbVie.
SOURCE: van der Heijde D et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2728.
ATLANTA – in the randomized, placebo-controlled, phase 2/3 SELECT-AXIS 1 study.
Physical functioning and imaging measures also were improved with upadacitinib in the double-blind, multicenter study, Désirée van der Heijde, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
The findings are notable because patients with ankylosing spondylitis (AS) who have an inadequate response or contraindication to NSAIDs have limited treatment options other than biologic disease-modifying antirheumatic drugs (bDMARDs). The JAK pathway has emerged as a potential therapeutic target in AS, and given its recent approval for the treatment of RA as well as ongoing studies of the agent for several other chronic immune-mediated inflammatory diseases, Dr. van der Heijde and colleagues sought to assess its efficacy and safety in bDMARD-naive patients with active AS.
Of 93 AS patients aged 18 years and older who were randomized to receive 15 mg of upadacitinib daily, 51.6% achieved the primary study endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 14, compared with 25.5% of 94 patients who received placebo, said Dr. van der Heijde, professor of rheumatology at Leiden (the Netherlands) University Medical Center.
The effect was rapid, with a clear difference emerging between the treatment and placebo groups within 2 weeks, she noted.
Significant improvements were also seen with upadacitinib for several key secondary endpoints including change from baseline to week 14 in the Ankylosing Spondylitis Disease Activity Score, Spondyloarthritis Research Consortium of Canada MRI Spine, a 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), ASAS partial remission, and Bath Ankylosing Spondylitis Functional Index.
SELECT-AXIS 1 patients were adults with a mean age of 45 years who were enrolled from 60 sites in 20 countries. All met modified New York criteria for AS based on central reading of radiographs, had a BASDAI score of at least 4, had a patient assessment of total back pain of 4 or greater on a 0-10 scale at screening and baseline, were naive to bDMARDs, and had either an inadequate response to at least two NSAIDs or an intolerance/contraindication to NSAIDs.
Most patients (70.6%) were men, and 76.5% were HLA-B27 positive. Mean symptom duration was 14-15 years, and mean disease duration was 7-8 years, Dr. van der Heijde said, adding that baseline disease characteristics were balanced between the two arms.
All randomized patients received their assigned treatment, and 95.7% completed the study through week 14, including 90 of 94 placebo group patients and 89 of 93 upadacitinib patients.
“Treatment was generally well tolerated,” she said.
The proportions of patients in the treatment and placebo groups, respectively, were similar with respect to adverse events leading to discontinuation (2.2% vs. 3.2%), serious adverse events (1.1% in each group), and infections (20.4% vs. 27.7%). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported. Also, no differences were seen between the groups in relevant laboratory abnormalities, and no new safety finding were observed in comparison with previous upadacitinib studies in other diseases, she noted.
Dr. van der Heijde concluded that “these results support further investigation of upadacitinib for the treatment of ankylosing spondyloarthritis.”
AbbVie, which markets upadacitinib, funded the study. Dr. van der Heijde disclosed financial relationships with AbbVie and 20 other pharmaceutical companies. Many other authors also reported financial relationships with industry, including AbbVie.
SOURCE: van der Heijde D et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2728.
REPORTING FROM ACR 2019
