Susan London

CHICAGO – The oral cell cycle inhibitor abemaciclib is active in refractory metastatic breast cancer that is positive for hormone receptors and negative for HER2, according to results of the MONARCH 1 trial.

Nearly a fifth of the 132 women studied experienced a tumor response to this investigational agent on the phase II trial, lead author Dr. Maura N. Dickler of Memorial Sloan Kettering Cancer Center, New York, reported at the annual meeting of the American Society of Clinical Oncology.

“MONARCH 1 confirms single-agent activity of abemaciclib in heavily pretreated patients with hormone receptor–positive, HER2-negative metastatic breast cancer,” she summarized. “The safety and toxicity profile is consistent with previous experience. Twice-daily continuous dosing was feasible, and few patients discontinued treatment due to adverse events.”

“Phase III studies of abemaciclib in combination with endocrine therapies are ongoing,” Dr. Dickler added, referring to MONARCH 2, which is testing the drug in combination with fulvestrant in endocrine-pretreated disease, and MONARCH 3, which is testing the drug in combination with nonsteroidal aromatase inhibitors as initial treatment for metastatic disease.

“This is another piece of evidence that suggests that CDK4 is a very good therapeutic target in breast cancer,” according to session comoderator Dr. Carlos Arteaga, associate director for clinical research and co-leader of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

The toxicity profile of abemaciclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, differs somewhat from that of palbociclib (Ibrance), a similar agent already approved for combination therapy in this setting, he noted in an interview. Specifically, abemaciclib causes somewhat less neutropenia and more diarrhea, possibly because it has less activity against CDK6 (which also plays a role in hematopoiesis) than against CDK4, while palbociclib inhibits the two kinases equally.

The efficacy seen in the trial “is an encouraging result. I think that it begs the question as to whether in patients who are ER positive, maybe the anti-estrogen can be dispensed with by a drug like abemaciclib. The randomized studies that are ongoing of endocrine therapies, plus-minus abemaciclib, will tell us the answer to that I think,” Dr. Arteaga further commented. “And for patients, this represents, in my opinion, progress because it’s just one more drug, one more therapeutic that we can add to the armamentarium. And in the end, patients will win because the drugs will be equally effective with different toxicity profiles, which may allow us to make deliberate recommendations for one versus the other, or to go from one to the other.”

Last year, the Food and Drug Administration awarded abemaciclib Breakthrough Therapy Designation for the treatment of hormone receptor–positive advanced or metastatic breast cancer on the basis of findings from a phase I trial. This designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates a possible substantial improvement over available therapy on a clinically significant endpoint.

Women with metastatic hormone receptor–positive, HER2-negative breast cancer were eligible for MONARCH 1 if they had received at least two chemotherapy regimens (including one containing a taxane) for their disease and had experienced progression on or after endocrine therapy.

Those enrolled were a heavily pretreated population, having received a median of three prior systemic regimens specifically for metastatic disease and five in total, Dr. Dickler reported. All were treated with abemaciclib (LY2835219) 200 mg twice daily on a continuous basis.

Results of the trial showed that the investigator-assessed overall response rate, reflecting patients with partial or complete response, was 19.7%. “This response rate is similar to that of chemotherapy in a taxane-pretreated patient population,” she noted. Findings were similar when responses were instead assessed by blinded reviewers.

The lower bound of the 95% confidence interval, 13.3%, did not exclude the 15% predefined lower bound that had been set in trial planning, Dr. Dickler acknowledged. At the same time, however, the upper bound was 27.5%.

The clinical benefit rate with abemaciclib, adding to the responders the patients who achieved stable disease for at least 6 months, was 42.4%.

The median time to response was 3.7 months, and the median duration of response was 8.6 months. Ultimately, patients had a median progression-free survival of 6.0 months and a median overall survival of 17.7 months.

The most common grade 3 clinical adverse events were diarrhea (seen in 19.7%) and fatigue (12.9%), while none of the patients experienced grade 4 clinical events.

“Generally, the diarrhea was experienced during the first cycle of treatment and resolved quickly,” Dr. Dickler noted. “It was manageable in the majority of patients, responsive to a temporary suspension of study drug, antidiarrheal agents, and dose reductions for grade 3 events. One patient discontinued study therapy due to diarrhea.”

The leading laboratory abnormalities of grade 3 or 4 were a reduction in white blood cell count (27.7%) and a reduction in neutrophil count (26.9%).

The rate of serious adverse events was 24.2%. Three patients died while on therapy or within a month of stopping.

Overall, 49.2% of patients needed a dose reduction, most commonly because of diarrhea, prompting a session attendee to ask whether perhaps a lower starting dose of abemaciclib “would be better tolerated and just as effective.”

The dose used in MONARCH 1 was the maximal tolerated dose established by the phase I trial, Dr. Dickler replied. “Diarrhea obviously was common, but 50% of patients did not require a dose reduction. And when diarrhea did develop, it was really manageable.”

“So I think as a single agent, it’s not unreasonable to start at 200 mg twice daily. In combination with endocrine therapy, in the studies MONARCH 2 and 3, the concurrent dose is 150 mg twice daily,” she pointed out.

The investigators are currently analyzing biomarkers in tumor tissue and plasma to ascertain any predictors of response, according to Dr. Dickler.

Patients with brain metastases were excluded from the trial, she noted. However, “abemaciclib appears to cross the blood-brain barrier, so there is a lot of interest in looking at abemaciclib in patients with brain metastases, and there is a trial that’s ongoing specifically for that.”

Dr. Dickler disclosed that she has a consulting or advisory role with AstraZeneca, Bristol-Myers Squibb, Eisai, Genentech/Roche, Merrimack, Novartis, Pfizer, and Syndax, and that she receives research funding (institutional) from Genentech/Roche, Lilly, and Novartis. The trial was sponsored by Eli Lilly and Company.

CHICAGO – The oral cell cycle inhibitor abemaciclib is active in refractory metastatic breast cancer that is positive for hormone receptors and negative for HER2, according to results of the MONARCH 1 trial.

Nearly a fifth of the 132 women studied experienced a tumor response to this investigational agent on the phase II trial, lead author Dr. Maura N. Dickler of Memorial Sloan Kettering Cancer Center, New York, reported at the annual meeting of the American Society of Clinical Oncology.

“MONARCH 1 confirms single-agent activity of abemaciclib in heavily pretreated patients with hormone receptor–positive, HER2-negative metastatic breast cancer,” she summarized. “The safety and toxicity profile is consistent with previous experience. Twice-daily continuous dosing was feasible, and few patients discontinued treatment due to adverse events.”

“Phase III studies of abemaciclib in combination with endocrine therapies are ongoing,” Dr. Dickler added, referring to MONARCH 2, which is testing the drug in combination with fulvestrant in endocrine-pretreated disease, and MONARCH 3, which is testing the drug in combination with nonsteroidal aromatase inhibitors as initial treatment for metastatic disease.

“This is another piece of evidence that suggests that CDK4 is a very good therapeutic target in breast cancer,” according to session comoderator Dr. Carlos Arteaga, associate director for clinical research and co-leader of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

The toxicity profile of abemaciclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, differs somewhat from that of palbociclib (Ibrance), a similar agent already approved for combination therapy in this setting, he noted in an interview. Specifically, abemaciclib causes somewhat less neutropenia and more diarrhea, possibly because it has less activity against CDK6 (which also plays a role in hematopoiesis) than against CDK4, while palbociclib inhibits the two kinases equally.

The efficacy seen in the trial “is an encouraging result. I think that it begs the question as to whether in patients who are ER positive, maybe the anti-estrogen can be dispensed with by a drug like abemaciclib. The randomized studies that are ongoing of endocrine therapies, plus-minus abemaciclib, will tell us the answer to that I think,” Dr. Arteaga further commented. “And for patients, this represents, in my opinion, progress because it’s just one more drug, one more therapeutic that we can add to the armamentarium. And in the end, patients will win because the drugs will be equally effective with different toxicity profiles, which may allow us to make deliberate recommendations for one versus the other, or to go from one to the other.”

Last year, the Food and Drug Administration awarded abemaciclib Breakthrough Therapy Designation for the treatment of hormone receptor–positive advanced or metastatic breast cancer on the basis of findings from a phase I trial. This designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates a possible substantial improvement over available therapy on a clinically significant endpoint.

Women with metastatic hormone receptor–positive, HER2-negative breast cancer were eligible for MONARCH 1 if they had received at least two chemotherapy regimens (including one containing a taxane) for their disease and had experienced progression on or after endocrine therapy.

Those enrolled were a heavily pretreated population, having received a median of three prior systemic regimens specifically for metastatic disease and five in total, Dr. Dickler reported. All were treated with abemaciclib (LY2835219) 200 mg twice daily on a continuous basis.

Results of the trial showed that the investigator-assessed overall response rate, reflecting patients with partial or complete response, was 19.7%. “This response rate is similar to that of chemotherapy in a taxane-pretreated patient population,” she noted. Findings were similar when responses were instead assessed by blinded reviewers.

The lower bound of the 95% confidence interval, 13.3%, did not exclude the 15% predefined lower bound that had been set in trial planning, Dr. Dickler acknowledged. At the same time, however, the upper bound was 27.5%.

The clinical benefit rate with abemaciclib, adding to the responders the patients who achieved stable disease for at least 6 months, was 42.4%.

The median time to response was 3.7 months, and the median duration of response was 8.6 months. Ultimately, patients had a median progression-free survival of 6.0 months and a median overall survival of 17.7 months.

The most common grade 3 clinical adverse events were diarrhea (seen in 19.7%) and fatigue (12.9%), while none of the patients experienced grade 4 clinical events.

“Generally, the diarrhea was experienced during the first cycle of treatment and resolved quickly,” Dr. Dickler noted. “It was manageable in the majority of patients, responsive to a temporary suspension of study drug, antidiarrheal agents, and dose reductions for grade 3 events. One patient discontinued study therapy due to diarrhea.”

The leading laboratory abnormalities of grade 3 or 4 were a reduction in white blood cell count (27.7%) and a reduction in neutrophil count (26.9%).

The rate of serious adverse events was 24.2%. Three patients died while on therapy or within a month of stopping.

Overall, 49.2% of patients needed a dose reduction, most commonly because of diarrhea, prompting a session attendee to ask whether perhaps a lower starting dose of abemaciclib “would be better tolerated and just as effective.”

The dose used in MONARCH 1 was the maximal tolerated dose established by the phase I trial, Dr. Dickler replied. “Diarrhea obviously was common, but 50% of patients did not require a dose reduction. And when diarrhea did develop, it was really manageable.”

“So I think as a single agent, it’s not unreasonable to start at 200 mg twice daily. In combination with endocrine therapy, in the studies MONARCH 2 and 3, the concurrent dose is 150 mg twice daily,” she pointed out.

The investigators are currently analyzing biomarkers in tumor tissue and plasma to ascertain any predictors of response, according to Dr. Dickler.

Patients with brain metastases were excluded from the trial, she noted. However, “abemaciclib appears to cross the blood-brain barrier, so there is a lot of interest in looking at abemaciclib in patients with brain metastases, and there is a trial that’s ongoing specifically for that.”

Dr. Dickler disclosed that she has a consulting or advisory role with AstraZeneca, Bristol-Myers Squibb, Eisai, Genentech/Roche, Merrimack, Novartis, Pfizer, and Syndax, and that she receives research funding (institutional) from Genentech/Roche, Lilly, and Novartis. The trial was sponsored by Eli Lilly and Company.

CHICAGO – The oral cell cycle inhibitor abemaciclib is active in refractory metastatic breast cancer that is positive for hormone receptors and negative for HER2, according to results of the MONARCH 1 trial.

Nearly a fifth of the 132 women studied experienced a tumor response to this investigational agent on the phase II trial, lead author Dr. Maura N. Dickler of Memorial Sloan Kettering Cancer Center, New York, reported at the annual meeting of the American Society of Clinical Oncology.

“MONARCH 1 confirms single-agent activity of abemaciclib in heavily pretreated patients with hormone receptor–positive, HER2-negative metastatic breast cancer,” she summarized. “The safety and toxicity profile is consistent with previous experience. Twice-daily continuous dosing was feasible, and few patients discontinued treatment due to adverse events.”

“Phase III studies of abemaciclib in combination with endocrine therapies are ongoing,” Dr. Dickler added, referring to MONARCH 2, which is testing the drug in combination with fulvestrant in endocrine-pretreated disease, and MONARCH 3, which is testing the drug in combination with nonsteroidal aromatase inhibitors as initial treatment for metastatic disease.

“This is another piece of evidence that suggests that CDK4 is a very good therapeutic target in breast cancer,” according to session comoderator Dr. Carlos Arteaga, associate director for clinical research and co-leader of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

The toxicity profile of abemaciclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, differs somewhat from that of palbociclib (Ibrance), a similar agent already approved for combination therapy in this setting, he noted in an interview. Specifically, abemaciclib causes somewhat less neutropenia and more diarrhea, possibly because it has less activity against CDK6 (which also plays a role in hematopoiesis) than against CDK4, while palbociclib inhibits the two kinases equally.

The efficacy seen in the trial “is an encouraging result. I think that it begs the question as to whether in patients who are ER positive, maybe the anti-estrogen can be dispensed with by a drug like abemaciclib. The randomized studies that are ongoing of endocrine therapies, plus-minus abemaciclib, will tell us the answer to that I think,” Dr. Arteaga further commented. “And for patients, this represents, in my opinion, progress because it’s just one more drug, one more therapeutic that we can add to the armamentarium. And in the end, patients will win because the drugs will be equally effective with different toxicity profiles, which may allow us to make deliberate recommendations for one versus the other, or to go from one to the other.”

Last year, the Food and Drug Administration awarded abemaciclib Breakthrough Therapy Designation for the treatment of hormone receptor–positive advanced or metastatic breast cancer on the basis of findings from a phase I trial. This designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates a possible substantial improvement over available therapy on a clinically significant endpoint.

Women with metastatic hormone receptor–positive, HER2-negative breast cancer were eligible for MONARCH 1 if they had received at least two chemotherapy regimens (including one containing a taxane) for their disease and had experienced progression on or after endocrine therapy.

Those enrolled were a heavily pretreated population, having received a median of three prior systemic regimens specifically for metastatic disease and five in total, Dr. Dickler reported. All were treated with abemaciclib (LY2835219) 200 mg twice daily on a continuous basis.

Results of the trial showed that the investigator-assessed overall response rate, reflecting patients with partial or complete response, was 19.7%. “This response rate is similar to that of chemotherapy in a taxane-pretreated patient population,” she noted. Findings were similar when responses were instead assessed by blinded reviewers.

The lower bound of the 95% confidence interval, 13.3%, did not exclude the 15% predefined lower bound that had been set in trial planning, Dr. Dickler acknowledged. At the same time, however, the upper bound was 27.5%.

The clinical benefit rate with abemaciclib, adding to the responders the patients who achieved stable disease for at least 6 months, was 42.4%.

The median time to response was 3.7 months, and the median duration of response was 8.6 months. Ultimately, patients had a median progression-free survival of 6.0 months and a median overall survival of 17.7 months.

The most common grade 3 clinical adverse events were diarrhea (seen in 19.7%) and fatigue (12.9%), while none of the patients experienced grade 4 clinical events.

“Generally, the diarrhea was experienced during the first cycle of treatment and resolved quickly,” Dr. Dickler noted. “It was manageable in the majority of patients, responsive to a temporary suspension of study drug, antidiarrheal agents, and dose reductions for grade 3 events. One patient discontinued study therapy due to diarrhea.”

The leading laboratory abnormalities of grade 3 or 4 were a reduction in white blood cell count (27.7%) and a reduction in neutrophil count (26.9%).

The rate of serious adverse events was 24.2%. Three patients died while on therapy or within a month of stopping.

Overall, 49.2% of patients needed a dose reduction, most commonly because of diarrhea, prompting a session attendee to ask whether perhaps a lower starting dose of abemaciclib “would be better tolerated and just as effective.”

The dose used in MONARCH 1 was the maximal tolerated dose established by the phase I trial, Dr. Dickler replied. “Diarrhea obviously was common, but 50% of patients did not require a dose reduction. And when diarrhea did develop, it was really manageable.”

“So I think as a single agent, it’s not unreasonable to start at 200 mg twice daily. In combination with endocrine therapy, in the studies MONARCH 2 and 3, the concurrent dose is 150 mg twice daily,” she pointed out.

The investigators are currently analyzing biomarkers in tumor tissue and plasma to ascertain any predictors of response, according to Dr. Dickler.

Patients with brain metastases were excluded from the trial, she noted. However, “abemaciclib appears to cross the blood-brain barrier, so there is a lot of interest in looking at abemaciclib in patients with brain metastases, and there is a trial that’s ongoing specifically for that.”

Dr. Dickler disclosed that she has a consulting or advisory role with AstraZeneca, Bristol-Myers Squibb, Eisai, Genentech/Roche, Merrimack, Novartis, Pfizer, and Syndax, and that she receives research funding (institutional) from Genentech/Roche, Lilly, and Novartis. The trial was sponsored by Eli Lilly and Company.

CHICAGO – Lead author Dr. John P. Neoptolemos presented results of the European Study Group for Pancreatic Cancer’s Trial 4 (ESPAC-4), results he said would likely change the standard of care for resected pancreatic cancer.

Adding capecitabine to gemcitabine as adjuvant therapy prolonged survival among patients who have undergone resection of pancreatic cancer with curative intent, he reported at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, Dr. Neoptolemos discusses the efficacy results, toxicities and implications for practice. Dr. Neoptolemos is chair of surgery in the department of molecular and clinical cancer medicine at the University of Liverpool, United Kingdom.

CHICAGO – Lead author Dr. John P. Neoptolemos presented results of the European Study Group for Pancreatic Cancer’s Trial 4 (ESPAC-4), results he said would likely change the standard of care for resected pancreatic cancer.

Adding capecitabine to gemcitabine as adjuvant therapy prolonged survival among patients who have undergone resection of pancreatic cancer with curative intent, he reported at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, Dr. Neoptolemos discusses the efficacy results, toxicities and implications for practice. Dr. Neoptolemos is chair of surgery in the department of molecular and clinical cancer medicine at the University of Liverpool, United Kingdom.

CHICAGO – Lead author Dr. John P. Neoptolemos presented results of the European Study Group for Pancreatic Cancer’s Trial 4 (ESPAC-4), results he said would likely change the standard of care for resected pancreatic cancer.

Adding capecitabine to gemcitabine as adjuvant therapy prolonged survival among patients who have undergone resection of pancreatic cancer with curative intent, he reported at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, Dr. Neoptolemos discusses the efficacy results, toxicities and implications for practice. Dr. Neoptolemos is chair of surgery in the department of molecular and clinical cancer medicine at the University of Liverpool, United Kingdom.

CHICAGO – Adding capecitabine to gemcitabine as adjuvant therapy prolongs survival in patients who have undergone resection of pancreatic cancer with curative intent, according to results of the European Study Group for Pancreatic Cancer’s Trial 4 (ESPAC-4).

The international phase III trial is the second largest to be conducted in this patient population, randomizing 722 patients to open-label treatment with gemcitabine monotherapy or gemcitabine-capecitabine combination therapy.

Main results showed that compared with gemcitabine alone—the standard of care worldwide—the combination gave patients an additional 2.5 months of life, reducing the risk of death by 18%, investigators reported in a session and press conference at the annual meeting of the American Society of Clinical Oncology. Moreover, this benefit was achieved without an increase in serious toxicity.

Susan London

“Adjuvant gemcitabine with capecitabine is the second-step change that we can now observe for resected pancreas cancer,” lead author Dr. John P. Neoptolemos said, noting that the earlier ESPAC-2 and -3 trials represented the first-step change by establishing a survival benefit of adjuvant chemotherapy. “This is now the standard of care for resected pancreatic cancer.”

The findings of ESPAC-4 will not put adjuvant therapy in competition with neoadjuvant therapy, according to Dr. Neoptolemos, chair of surgery in the department of molecular and clinical cancer medicine at the University of Liverpool, United Kingdom.

“There are no trials showing that patients benefit from neoadjuvant therapy, so the fact that it’s used is not based on randomized trials,” he commented. “There is a trial called ESPAC-5 which is comparing straight-to-surgery with neoadjuvant therapies. One arm includes the same combination we see here, gemcitabine-capecitabine, also FOLFIRINOX, which is more toxic regimen, and also chemoradiation. I think the use of neoadjuvant therapy really requires randomized trials to determine which patients should have it and which patients will benefit from other approaches.”

“The findings from ESPAC-4 are welcome findings for our patients with pancreatic cancer,” ASCO Expert Dr. Smitha S. Krishnamurthi said in an interview. “As you know, it’s a very difficult disease to treat; most patients do succumb to this disease. But this combination has shown improved survival without increasing the rate of serious toxicity. So for patients to take an additional approved oral chemotherapy for 6 months along with the gemcitabine to potentially have improved survival I think is a very welcome finding.”

There will likely be good uptake of this combination regimen in the United States for patients who are candidates for adjuvant therapy and being treated outside of trials, she predicted.

Susan London

“I definitely will be offering this to patients who are not going on clinical trial. Right now, we are participating in a neoadjuvant study. There is a lot of interest in neoadjuvant therapy, but it is not standard of care,” explained Dr. Krishnamurthi of UH Case Medical Center, and an associate professor of medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.

“So for patients who have had a potentially curative resection, gemcitabine-capecitabine represents a new standard adjuvant treatment,” she said.

In ESPAC-4, patients who no more than 12 weeks out from surgery were randomized to have six 4-week cycles of intravenous gemcitabine (Gemzar) either alone or with the addition of oral capecitabine (Xeloda).

The investigators opted to use an open-label design and not to use a placebo for several reasons, according to Dr. Neoptolemos.

“The primary endpoint is death. This is hard endpoint that would not be influenced by placebo. Toxicity is reported according to [Common Terminology Criteria for Adverse Events (CTCAE)] version 4. Every time there was a toxicity event and/or serious adverse event, the arm would need to be unblinded to determine whether or not dose reduction was required. This would involve most patients and become impracticable,” he explained in an interview. “Organizing a placebo would be very expensive with no gain.”

The trial accrued very quickly, and its steering committee asked the investigators to conduct a full analysis ahead of schedule.

Results showed that median survival was 28.0 months with the gemcitabine-capecitabine combination and 25.5 month with gemcitabine alone (hazard ratio, 0.82; P = .032). The corresponding estimated 5-year survival rates were 28.8% and 16.3%. Efficacy findings were similar across patient subgroups.

The gemcitabine-capecitabine and gemcitabine groups did not differ significantly with respect to the rate of serious adverse events (30% vs. 30%) or treatment-related serious adverse events (24% vs. 26%), although the combination was more often associated with severe diarrhea (14 vs. 5 patients). Quality of life was essentially the same for the two groups.

Dr. Neoptolemos disclosed that he receives grant and research support from Taiho Pharmaceutical, Kael-Gemvax, AstraZeneca, Clovis Oncology, Ventana, and Merck, and that he receives educational travel grants from NuCana BioMed.

CHICAGO – Adding capecitabine to gemcitabine as adjuvant therapy prolongs survival in patients who have undergone resection of pancreatic cancer with curative intent, according to results of the European Study Group for Pancreatic Cancer’s Trial 4 (ESPAC-4).

The international phase III trial is the second largest to be conducted in this patient population, randomizing 722 patients to open-label treatment with gemcitabine monotherapy or gemcitabine-capecitabine combination therapy.

Main results showed that compared with gemcitabine alone—the standard of care worldwide—the combination gave patients an additional 2.5 months of life, reducing the risk of death by 18%, investigators reported in a session and press conference at the annual meeting of the American Society of Clinical Oncology. Moreover, this benefit was achieved without an increase in serious toxicity.

Susan London

“Adjuvant gemcitabine with capecitabine is the second-step change that we can now observe for resected pancreas cancer,” lead author Dr. John P. Neoptolemos said, noting that the earlier ESPAC-2 and -3 trials represented the first-step change by establishing a survival benefit of adjuvant chemotherapy. “This is now the standard of care for resected pancreatic cancer.”

The findings of ESPAC-4 will not put adjuvant therapy in competition with neoadjuvant therapy, according to Dr. Neoptolemos, chair of surgery in the department of molecular and clinical cancer medicine at the University of Liverpool, United Kingdom.

“There are no trials showing that patients benefit from neoadjuvant therapy, so the fact that it’s used is not based on randomized trials,” he commented. “There is a trial called ESPAC-5 which is comparing straight-to-surgery with neoadjuvant therapies. One arm includes the same combination we see here, gemcitabine-capecitabine, also FOLFIRINOX, which is more toxic regimen, and also chemoradiation. I think the use of neoadjuvant therapy really requires randomized trials to determine which patients should have it and which patients will benefit from other approaches.”

“The findings from ESPAC-4 are welcome findings for our patients with pancreatic cancer,” ASCO Expert Dr. Smitha S. Krishnamurthi said in an interview. “As you know, it’s a very difficult disease to treat; most patients do succumb to this disease. But this combination has shown improved survival without increasing the rate of serious toxicity. So for patients to take an additional approved oral chemotherapy for 6 months along with the gemcitabine to potentially have improved survival I think is a very welcome finding.”

There will likely be good uptake of this combination regimen in the United States for patients who are candidates for adjuvant therapy and being treated outside of trials, she predicted.

Susan London

“I definitely will be offering this to patients who are not going on clinical trial. Right now, we are participating in a neoadjuvant study. There is a lot of interest in neoadjuvant therapy, but it is not standard of care,” explained Dr. Krishnamurthi of UH Case Medical Center, and an associate professor of medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.

“So for patients who have had a potentially curative resection, gemcitabine-capecitabine represents a new standard adjuvant treatment,” she said.

In ESPAC-4, patients who no more than 12 weeks out from surgery were randomized to have six 4-week cycles of intravenous gemcitabine (Gemzar) either alone or with the addition of oral capecitabine (Xeloda).

The investigators opted to use an open-label design and not to use a placebo for several reasons, according to Dr. Neoptolemos.

“The primary endpoint is death. This is hard endpoint that would not be influenced by placebo. Toxicity is reported according to [Common Terminology Criteria for Adverse Events (CTCAE)] version 4. Every time there was a toxicity event and/or serious adverse event, the arm would need to be unblinded to determine whether or not dose reduction was required. This would involve most patients and become impracticable,” he explained in an interview. “Organizing a placebo would be very expensive with no gain.”

The trial accrued very quickly, and its steering committee asked the investigators to conduct a full analysis ahead of schedule.

Results showed that median survival was 28.0 months with the gemcitabine-capecitabine combination and 25.5 month with gemcitabine alone (hazard ratio, 0.82; P = .032). The corresponding estimated 5-year survival rates were 28.8% and 16.3%. Efficacy findings were similar across patient subgroups.

The gemcitabine-capecitabine and gemcitabine groups did not differ significantly with respect to the rate of serious adverse events (30% vs. 30%) or treatment-related serious adverse events (24% vs. 26%), although the combination was more often associated with severe diarrhea (14 vs. 5 patients). Quality of life was essentially the same for the two groups.

Dr. Neoptolemos disclosed that he receives grant and research support from Taiho Pharmaceutical, Kael-Gemvax, AstraZeneca, Clovis Oncology, Ventana, and Merck, and that he receives educational travel grants from NuCana BioMed.

CHICAGO – Adding capecitabine to gemcitabine as adjuvant therapy prolongs survival in patients who have undergone resection of pancreatic cancer with curative intent, according to results of the European Study Group for Pancreatic Cancer’s Trial 4 (ESPAC-4).

The international phase III trial is the second largest to be conducted in this patient population, randomizing 722 patients to open-label treatment with gemcitabine monotherapy or gemcitabine-capecitabine combination therapy.

Main results showed that compared with gemcitabine alone—the standard of care worldwide—the combination gave patients an additional 2.5 months of life, reducing the risk of death by 18%, investigators reported in a session and press conference at the annual meeting of the American Society of Clinical Oncology. Moreover, this benefit was achieved without an increase in serious toxicity.

Susan London

“Adjuvant gemcitabine with capecitabine is the second-step change that we can now observe for resected pancreas cancer,” lead author Dr. John P. Neoptolemos said, noting that the earlier ESPAC-2 and -3 trials represented the first-step change by establishing a survival benefit of adjuvant chemotherapy. “This is now the standard of care for resected pancreatic cancer.”

The findings of ESPAC-4 will not put adjuvant therapy in competition with neoadjuvant therapy, according to Dr. Neoptolemos, chair of surgery in the department of molecular and clinical cancer medicine at the University of Liverpool, United Kingdom.

“There are no trials showing that patients benefit from neoadjuvant therapy, so the fact that it’s used is not based on randomized trials,” he commented. “There is a trial called ESPAC-5 which is comparing straight-to-surgery with neoadjuvant therapies. One arm includes the same combination we see here, gemcitabine-capecitabine, also FOLFIRINOX, which is more toxic regimen, and also chemoradiation. I think the use of neoadjuvant therapy really requires randomized trials to determine which patients should have it and which patients will benefit from other approaches.”

“The findings from ESPAC-4 are welcome findings for our patients with pancreatic cancer,” ASCO Expert Dr. Smitha S. Krishnamurthi said in an interview. “As you know, it’s a very difficult disease to treat; most patients do succumb to this disease. But this combination has shown improved survival without increasing the rate of serious toxicity. So for patients to take an additional approved oral chemotherapy for 6 months along with the gemcitabine to potentially have improved survival I think is a very welcome finding.”

There will likely be good uptake of this combination regimen in the United States for patients who are candidates for adjuvant therapy and being treated outside of trials, she predicted.

Susan London

“I definitely will be offering this to patients who are not going on clinical trial. Right now, we are participating in a neoadjuvant study. There is a lot of interest in neoadjuvant therapy, but it is not standard of care,” explained Dr. Krishnamurthi of UH Case Medical Center, and an associate professor of medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.

“So for patients who have had a potentially curative resection, gemcitabine-capecitabine represents a new standard adjuvant treatment,” she said.

In ESPAC-4, patients who no more than 12 weeks out from surgery were randomized to have six 4-week cycles of intravenous gemcitabine (Gemzar) either alone or with the addition of oral capecitabine (Xeloda).

The investigators opted to use an open-label design and not to use a placebo for several reasons, according to Dr. Neoptolemos.

“The primary endpoint is death. This is hard endpoint that would not be influenced by placebo. Toxicity is reported according to [Common Terminology Criteria for Adverse Events (CTCAE)] version 4. Every time there was a toxicity event and/or serious adverse event, the arm would need to be unblinded to determine whether or not dose reduction was required. This would involve most patients and become impracticable,” he explained in an interview. “Organizing a placebo would be very expensive with no gain.”

The trial accrued very quickly, and its steering committee asked the investigators to conduct a full analysis ahead of schedule.

Results showed that median survival was 28.0 months with the gemcitabine-capecitabine combination and 25.5 month with gemcitabine alone (hazard ratio, 0.82; P = .032). The corresponding estimated 5-year survival rates were 28.8% and 16.3%. Efficacy findings were similar across patient subgroups.

The gemcitabine-capecitabine and gemcitabine groups did not differ significantly with respect to the rate of serious adverse events (30% vs. 30%) or treatment-related serious adverse events (24% vs. 26%), although the combination was more often associated with severe diarrhea (14 vs. 5 patients). Quality of life was essentially the same for the two groups.

Dr. Neoptolemos disclosed that he receives grant and research support from Taiho Pharmaceutical, Kael-Gemvax, AstraZeneca, Clovis Oncology, Ventana, and Merck, and that he receives educational travel grants from NuCana BioMed.

SAN FRANCISCO – Pulmonologists generally have a high level of knowledge about inhalational devices used in the treatment of chronic obstructive pulmonary disease (COPD), but there are areas where more education would be welcomed, according to a survey conducted by the American Thoracic Society and sponsored by Sunovion Pharmaceuticals.

More than half of respondents believed that they were at least very knowledgeable about medications used to treat COPD and the devices as a whole, Dr. Sidney S. Braman reported in a press conference and poster session at an international conference of the American Thoracic Society. But only a third knew what hand-held small-volume nebulizers were intended for or how to use them, and respondents varied in their views regarding which patients are candidates for use.

The survey assessed knowledge, attitudes, and practices regarding the management of COPD, including the use of metered-dose inhalers, dry powder inhalers, and handheld small-volume nebulizers. In all, 205 U.S. pulmonologists and pulmonology fellows participated.

Overall, 79% and 54% of respondents indicated that they were extremely or very knowledgeable about medications used to manage COPD and about the inhalational devices, respectively, lead author Dr. Braman, a professor of medicine; pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai in New York, reported. Additionally, 68% had this level of knowledge when it came to preventing exacerbations, and 43% and 22% did when it came to teaching patients how to use the devices and how to clean and store them, respectively. Large proportions – 72%-89%, depending on the topic – were somewhat or very interested in receiving additional education.

Only a minority of respondents reported being extremely or very knowledgeable specifically about handheld small-volume nebulizers. Just 34% knew well their intended use, 33% when to use them, 32% how to use them, 31% who should use them, and 20% how to clean and maintain them.

As expected, respondents were increasing likely to say that they typically recommended a nebulized medication as the severity of the disease increased. Some 52% recommended it early in treatment for patients with the most severe dyspnea (modified Medical Research Council scale grade 4), and 69% did so early in treatment after acute exacerbations.

Similarly, respondents were increasing likely to say that they found handheld small-volume nebulizers more effective than the inhalers as the severity of disease rose. Overall, 63% endorsed this viewpoint for patients with grade 4 disease, and 70% did so for patients who had experienced acute exacerbations.

“The results I think were somewhat expected and somewhat not expected,” commented Dr. Braman. “I think this all tells us that we really need better education. And for us at the ATS, this is so important, because what it’s saying is we need to get out there, we need to have better studies in terms of what are the appropriate uses, and then turn around and give our members and others around the world education about the small-volume nebulizer use.”

While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline “gives clinicians a wonderful road map on how to approach COPD,” by explaining what medications to deliver as the disease progresses, the guideline is lacking information about the devices, particularly the small-volume nebulizer.

During an interview, press conference moderator Dr. David Mannino, professor and chair of preventive medicine & environmental health at the University of Kentucky College of Public Health in Lexington, said he was not surprised by the survey’s results.

“Years ago and certainly when I was going through training as a resident, there was this body of literature being developed showing that respiratory therapists working with patients in hospitals with the use of metered-dose inhalers and spacers got results that equaled that of the nebulizer, which I frankly never bought because although the data may have supported that, people don’t take respiratory therapists home with them. … I know my sick patients cling to their nebulized therapies very stringently.

“Ultimately, we have patients who very much would benefit by having a truly very small nebulizer that they could take with them because the problem with inhaled therapies in COPD – your metered-dose inhalers, your dry powder inhalers, and all these other devices – is that you basically get one opportunity in somewhere between about half a second and 2 seconds to get your dose of medication in,” Dr. Mannino said. “Even when you throw a spacer on, it does not pass what I would call the ‘my mom test,’” meaning that use would be difficult for an older adult with suboptimal hand-eye-breathing coordination and possibly comorbidities such as arthritis and cognitive impairment.

In contrast, nebulizers deliver medication during a full 2-3 minutes of tidal breathing. “That’s why nebulizers work better for patients, because they have more of an opportunity to get the medication,” Dr. Mannino maintained. “Once we get to the point where we actually can figure out how to get nebulized therapy in a truly easily transportable form – and I think there is some technology that is being developed – ultimately, what I’d love to see is a nebulizer that is truly the size of a little metered-dose inhaler. That will then be the game changer, I think.”

The online survey was designed by a steering committee of ATS clinicians and scientists and was conducted by Harris Poll during January 2016. Pulmonologists and fellows with an interest in COPD from the ATS membership roster who had attended recent conferences were invited to participate.

Dr. Braman disclosed that he had no relevant conflicts of interest. The study was sponsored by Sunovion Pharmaceuticals, and the survey data were provided by Harris Poll.

SAN FRANCISCO – Pulmonologists generally have a high level of knowledge about inhalational devices used in the treatment of chronic obstructive pulmonary disease (COPD), but there are areas where more education would be welcomed, according to a survey conducted by the American Thoracic Society and sponsored by Sunovion Pharmaceuticals.

More than half of respondents believed that they were at least very knowledgeable about medications used to treat COPD and the devices as a whole, Dr. Sidney S. Braman reported in a press conference and poster session at an international conference of the American Thoracic Society. But only a third knew what hand-held small-volume nebulizers were intended for or how to use them, and respondents varied in their views regarding which patients are candidates for use.

The survey assessed knowledge, attitudes, and practices regarding the management of COPD, including the use of metered-dose inhalers, dry powder inhalers, and handheld small-volume nebulizers. In all, 205 U.S. pulmonologists and pulmonology fellows participated.

Overall, 79% and 54% of respondents indicated that they were extremely or very knowledgeable about medications used to manage COPD and about the inhalational devices, respectively, lead author Dr. Braman, a professor of medicine; pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai in New York, reported. Additionally, 68% had this level of knowledge when it came to preventing exacerbations, and 43% and 22% did when it came to teaching patients how to use the devices and how to clean and store them, respectively. Large proportions – 72%-89%, depending on the topic – were somewhat or very interested in receiving additional education.

Only a minority of respondents reported being extremely or very knowledgeable specifically about handheld small-volume nebulizers. Just 34% knew well their intended use, 33% when to use them, 32% how to use them, 31% who should use them, and 20% how to clean and maintain them.

As expected, respondents were increasing likely to say that they typically recommended a nebulized medication as the severity of the disease increased. Some 52% recommended it early in treatment for patients with the most severe dyspnea (modified Medical Research Council scale grade 4), and 69% did so early in treatment after acute exacerbations.

Similarly, respondents were increasing likely to say that they found handheld small-volume nebulizers more effective than the inhalers as the severity of disease rose. Overall, 63% endorsed this viewpoint for patients with grade 4 disease, and 70% did so for patients who had experienced acute exacerbations.

“The results I think were somewhat expected and somewhat not expected,” commented Dr. Braman. “I think this all tells us that we really need better education. And for us at the ATS, this is so important, because what it’s saying is we need to get out there, we need to have better studies in terms of what are the appropriate uses, and then turn around and give our members and others around the world education about the small-volume nebulizer use.”

While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline “gives clinicians a wonderful road map on how to approach COPD,” by explaining what medications to deliver as the disease progresses, the guideline is lacking information about the devices, particularly the small-volume nebulizer.

During an interview, press conference moderator Dr. David Mannino, professor and chair of preventive medicine & environmental health at the University of Kentucky College of Public Health in Lexington, said he was not surprised by the survey’s results.

“Years ago and certainly when I was going through training as a resident, there was this body of literature being developed showing that respiratory therapists working with patients in hospitals with the use of metered-dose inhalers and spacers got results that equaled that of the nebulizer, which I frankly never bought because although the data may have supported that, people don’t take respiratory therapists home with them. … I know my sick patients cling to their nebulized therapies very stringently.

“Ultimately, we have patients who very much would benefit by having a truly very small nebulizer that they could take with them because the problem with inhaled therapies in COPD – your metered-dose inhalers, your dry powder inhalers, and all these other devices – is that you basically get one opportunity in somewhere between about half a second and 2 seconds to get your dose of medication in,” Dr. Mannino said. “Even when you throw a spacer on, it does not pass what I would call the ‘my mom test,’” meaning that use would be difficult for an older adult with suboptimal hand-eye-breathing coordination and possibly comorbidities such as arthritis and cognitive impairment.

In contrast, nebulizers deliver medication during a full 2-3 minutes of tidal breathing. “That’s why nebulizers work better for patients, because they have more of an opportunity to get the medication,” Dr. Mannino maintained. “Once we get to the point where we actually can figure out how to get nebulized therapy in a truly easily transportable form – and I think there is some technology that is being developed – ultimately, what I’d love to see is a nebulizer that is truly the size of a little metered-dose inhaler. That will then be the game changer, I think.”

The online survey was designed by a steering committee of ATS clinicians and scientists and was conducted by Harris Poll during January 2016. Pulmonologists and fellows with an interest in COPD from the ATS membership roster who had attended recent conferences were invited to participate.

Dr. Braman disclosed that he had no relevant conflicts of interest. The study was sponsored by Sunovion Pharmaceuticals, and the survey data were provided by Harris Poll.

SAN FRANCISCO – Pulmonologists generally have a high level of knowledge about inhalational devices used in the treatment of chronic obstructive pulmonary disease (COPD), but there are areas where more education would be welcomed, according to a survey conducted by the American Thoracic Society and sponsored by Sunovion Pharmaceuticals.

More than half of respondents believed that they were at least very knowledgeable about medications used to treat COPD and the devices as a whole, Dr. Sidney S. Braman reported in a press conference and poster session at an international conference of the American Thoracic Society. But only a third knew what hand-held small-volume nebulizers were intended for or how to use them, and respondents varied in their views regarding which patients are candidates for use.

The survey assessed knowledge, attitudes, and practices regarding the management of COPD, including the use of metered-dose inhalers, dry powder inhalers, and handheld small-volume nebulizers. In all, 205 U.S. pulmonologists and pulmonology fellows participated.

Overall, 79% and 54% of respondents indicated that they were extremely or very knowledgeable about medications used to manage COPD and about the inhalational devices, respectively, lead author Dr. Braman, a professor of medicine; pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai in New York, reported. Additionally, 68% had this level of knowledge when it came to preventing exacerbations, and 43% and 22% did when it came to teaching patients how to use the devices and how to clean and store them, respectively. Large proportions – 72%-89%, depending on the topic – were somewhat or very interested in receiving additional education.

Only a minority of respondents reported being extremely or very knowledgeable specifically about handheld small-volume nebulizers. Just 34% knew well their intended use, 33% when to use them, 32% how to use them, 31% who should use them, and 20% how to clean and maintain them.

As expected, respondents were increasing likely to say that they typically recommended a nebulized medication as the severity of the disease increased. Some 52% recommended it early in treatment for patients with the most severe dyspnea (modified Medical Research Council scale grade 4), and 69% did so early in treatment after acute exacerbations.

Similarly, respondents were increasing likely to say that they found handheld small-volume nebulizers more effective than the inhalers as the severity of disease rose. Overall, 63% endorsed this viewpoint for patients with grade 4 disease, and 70% did so for patients who had experienced acute exacerbations.

“The results I think were somewhat expected and somewhat not expected,” commented Dr. Braman. “I think this all tells us that we really need better education. And for us at the ATS, this is so important, because what it’s saying is we need to get out there, we need to have better studies in terms of what are the appropriate uses, and then turn around and give our members and others around the world education about the small-volume nebulizer use.”

While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline “gives clinicians a wonderful road map on how to approach COPD,” by explaining what medications to deliver as the disease progresses, the guideline is lacking information about the devices, particularly the small-volume nebulizer.

During an interview, press conference moderator Dr. David Mannino, professor and chair of preventive medicine & environmental health at the University of Kentucky College of Public Health in Lexington, said he was not surprised by the survey’s results.

“Years ago and certainly when I was going through training as a resident, there was this body of literature being developed showing that respiratory therapists working with patients in hospitals with the use of metered-dose inhalers and spacers got results that equaled that of the nebulizer, which I frankly never bought because although the data may have supported that, people don’t take respiratory therapists home with them. … I know my sick patients cling to their nebulized therapies very stringently.

“Ultimately, we have patients who very much would benefit by having a truly very small nebulizer that they could take with them because the problem with inhaled therapies in COPD – your metered-dose inhalers, your dry powder inhalers, and all these other devices – is that you basically get one opportunity in somewhere between about half a second and 2 seconds to get your dose of medication in,” Dr. Mannino said. “Even when you throw a spacer on, it does not pass what I would call the ‘my mom test,’” meaning that use would be difficult for an older adult with suboptimal hand-eye-breathing coordination and possibly comorbidities such as arthritis and cognitive impairment.

In contrast, nebulizers deliver medication during a full 2-3 minutes of tidal breathing. “That’s why nebulizers work better for patients, because they have more of an opportunity to get the medication,” Dr. Mannino maintained. “Once we get to the point where we actually can figure out how to get nebulized therapy in a truly easily transportable form – and I think there is some technology that is being developed – ultimately, what I’d love to see is a nebulizer that is truly the size of a little metered-dose inhaler. That will then be the game changer, I think.”

The online survey was designed by a steering committee of ATS clinicians and scientists and was conducted by Harris Poll during January 2016. Pulmonologists and fellows with an interest in COPD from the ATS membership roster who had attended recent conferences were invited to participate.

Dr. Braman disclosed that he had no relevant conflicts of interest. The study was sponsored by Sunovion Pharmaceuticals, and the survey data were provided by Harris Poll.

SAN FRANCISCO – Compressing damaged lung tissue with endobronchial coils improves exercise tolerance in patients with severe emphysema, albeit with the tradeoff of more adverse events, concludes the phase 3 RENEW trial.

After a year of treatment, the 6-minute walk distance had improved in patients given coils, whereas it had worsened in patients managed with usual care, with a difference of nearly 15 meters between groups, investigators reported at an international conference of the American Thoracic Society and simultaneously published (JAMA. doi:10.1001/jama.2016.6261. Published online May 15, 2016).

However, the median gain with coils fell short of the study’s predefined minimal clinically important difference of 25 meters. Additionally, major complications, mainly lower respiratory tract infections, were more common with the coils, although they resolved with time.

“Participants in the RENEW trial had advanced disease. Seventy-seven percent had homogeneous emphysema. This is a group that has very few therapeutic options,” commented lead investigator Dr. Frank C. Sciurba, director of both the Emphysema Research Center and the Pulmonary Function Exercise Physiology Laboratory at the University of Pittsburgh.

“The response rates of endobronchial coils to improve quality of life and exercise tolerance in these severely symptomatic patients balanced against peri-procedural adverse events in this population provides an evidence-based choice for symptomatic patients and treating physicians when there are few other options in these patients,” he said.

RENEW (Lung Volume Reduction Coil Treatment in Patients With Emphysema) was conducted among 315 patients from the United States, Canada, the United Kingdom, Germany, the Netherlands, and France who had emphysema with severe air trapping.

“This was a very inclusive study. In contrast to the surgical and valvular studies, we randomized nearly half of those screened because we allowed patients with homogeneous disease and of course didn’t select based on fissure integrity, which is a selection criterion for other studies,” Dr. Sciurba commented.

The patients received either guideline-based usual care alone (including pulmonary rehabilitation and bronchodilators) or with the addition of bilateral, bronchoscopically placed coils (RePneu Lung Volume Reduction Coil System, currently investigational in the United States).

At 12 months, the median 6-minute walk distance had improved by 10.3 meters with coil treatment but worsened by 7.6 meters with usual care (P = .02). The proportion of patients attaining an improvement of at least 25 meters was higher in the coil group (40.0% vs. 26.9%; P = .01).

In exploratory analyses, patients having more nonpulmonary comorbidities at baseline derived lesser benefit in walk distance from coil treatment, Dr. Sciurba noted.

The coils also netted greater improvement in the median change in forced exploratory volume in 1 second (FEV1) (difference between groups, 7.0%; P < .001) and in scores on the St. George’s Respiratory Questionnaire (difference between groups, −8.9 points).

At the same time, patients in the coil group had higher rates of major complications such as pneumonia requiring hospitalization and other potentially life-threatening or fatal events (34.8% vs. 19.1%, P = .002) and of other serious adverse events such as pneumonia (20% vs. 4.5%) and pneumothorax (9.7% vs. 0.6%).

“All of these adverse events returned to baseline at 9 to 12 months,” Dr. Sciurba reported. Additionally, there was no significant difference between groups in mortality rate.

Of note, 35% of the 40 cases of coil-associated opacities initially thought to be pneumonia were in fact determined to likely be a noninfectious inflammatory reaction to the coils. “These adjudicated noninfectious coil-associated opacities were associated with a better response,” he noted.

Finally, in stratified analyses, patients with greater air trapping at baseline had better-than-average improvements in outcomes with the coils, regardless of whether they had homogeneous or heterogeneous disease. Among patients with lesser air trapping, those with homogeneous disease derived much less benefit than the average from coils, while the group with heterogeneous disease was too small to draw any conclusions.

Dr. Sciurba disclosed that he receives institutional support from PneumRx and Pulmonx. The study was sponsored by PneumRx.

SAN FRANCISCO – Compressing damaged lung tissue with endobronchial coils improves exercise tolerance in patients with severe emphysema, albeit with the tradeoff of more adverse events, concludes the phase 3 RENEW trial.

After a year of treatment, the 6-minute walk distance had improved in patients given coils, whereas it had worsened in patients managed with usual care, with a difference of nearly 15 meters between groups, investigators reported at an international conference of the American Thoracic Society and simultaneously published (JAMA. doi:10.1001/jama.2016.6261. Published online May 15, 2016).

However, the median gain with coils fell short of the study’s predefined minimal clinically important difference of 25 meters. Additionally, major complications, mainly lower respiratory tract infections, were more common with the coils, although they resolved with time.

“Participants in the RENEW trial had advanced disease. Seventy-seven percent had homogeneous emphysema. This is a group that has very few therapeutic options,” commented lead investigator Dr. Frank C. Sciurba, director of both the Emphysema Research Center and the Pulmonary Function Exercise Physiology Laboratory at the University of Pittsburgh.

“The response rates of endobronchial coils to improve quality of life and exercise tolerance in these severely symptomatic patients balanced against peri-procedural adverse events in this population provides an evidence-based choice for symptomatic patients and treating physicians when there are few other options in these patients,” he said.

RENEW (Lung Volume Reduction Coil Treatment in Patients With Emphysema) was conducted among 315 patients from the United States, Canada, the United Kingdom, Germany, the Netherlands, and France who had emphysema with severe air trapping.

“This was a very inclusive study. In contrast to the surgical and valvular studies, we randomized nearly half of those screened because we allowed patients with homogeneous disease and of course didn’t select based on fissure integrity, which is a selection criterion for other studies,” Dr. Sciurba commented.

The patients received either guideline-based usual care alone (including pulmonary rehabilitation and bronchodilators) or with the addition of bilateral, bronchoscopically placed coils (RePneu Lung Volume Reduction Coil System, currently investigational in the United States).

At 12 months, the median 6-minute walk distance had improved by 10.3 meters with coil treatment but worsened by 7.6 meters with usual care (P = .02). The proportion of patients attaining an improvement of at least 25 meters was higher in the coil group (40.0% vs. 26.9%; P = .01).

In exploratory analyses, patients having more nonpulmonary comorbidities at baseline derived lesser benefit in walk distance from coil treatment, Dr. Sciurba noted.

The coils also netted greater improvement in the median change in forced exploratory volume in 1 second (FEV1) (difference between groups, 7.0%; P < .001) and in scores on the St. George’s Respiratory Questionnaire (difference between groups, −8.9 points).

At the same time, patients in the coil group had higher rates of major complications such as pneumonia requiring hospitalization and other potentially life-threatening or fatal events (34.8% vs. 19.1%, P = .002) and of other serious adverse events such as pneumonia (20% vs. 4.5%) and pneumothorax (9.7% vs. 0.6%).

“All of these adverse events returned to baseline at 9 to 12 months,” Dr. Sciurba reported. Additionally, there was no significant difference between groups in mortality rate.

Of note, 35% of the 40 cases of coil-associated opacities initially thought to be pneumonia were in fact determined to likely be a noninfectious inflammatory reaction to the coils. “These adjudicated noninfectious coil-associated opacities were associated with a better response,” he noted.

Finally, in stratified analyses, patients with greater air trapping at baseline had better-than-average improvements in outcomes with the coils, regardless of whether they had homogeneous or heterogeneous disease. Among patients with lesser air trapping, those with homogeneous disease derived much less benefit than the average from coils, while the group with heterogeneous disease was too small to draw any conclusions.

Dr. Sciurba disclosed that he receives institutional support from PneumRx and Pulmonx. The study was sponsored by PneumRx.

SAN FRANCISCO – Compressing damaged lung tissue with endobronchial coils improves exercise tolerance in patients with severe emphysema, albeit with the tradeoff of more adverse events, concludes the phase 3 RENEW trial.

After a year of treatment, the 6-minute walk distance had improved in patients given coils, whereas it had worsened in patients managed with usual care, with a difference of nearly 15 meters between groups, investigators reported at an international conference of the American Thoracic Society and simultaneously published (JAMA. doi:10.1001/jama.2016.6261. Published online May 15, 2016).

However, the median gain with coils fell short of the study’s predefined minimal clinically important difference of 25 meters. Additionally, major complications, mainly lower respiratory tract infections, were more common with the coils, although they resolved with time.

“Participants in the RENEW trial had advanced disease. Seventy-seven percent had homogeneous emphysema. This is a group that has very few therapeutic options,” commented lead investigator Dr. Frank C. Sciurba, director of both the Emphysema Research Center and the Pulmonary Function Exercise Physiology Laboratory at the University of Pittsburgh.

“The response rates of endobronchial coils to improve quality of life and exercise tolerance in these severely symptomatic patients balanced against peri-procedural adverse events in this population provides an evidence-based choice for symptomatic patients and treating physicians when there are few other options in these patients,” he said.

RENEW (Lung Volume Reduction Coil Treatment in Patients With Emphysema) was conducted among 315 patients from the United States, Canada, the United Kingdom, Germany, the Netherlands, and France who had emphysema with severe air trapping.

“This was a very inclusive study. In contrast to the surgical and valvular studies, we randomized nearly half of those screened because we allowed patients with homogeneous disease and of course didn’t select based on fissure integrity, which is a selection criterion for other studies,” Dr. Sciurba commented.

The patients received either guideline-based usual care alone (including pulmonary rehabilitation and bronchodilators) or with the addition of bilateral, bronchoscopically placed coils (RePneu Lung Volume Reduction Coil System, currently investigational in the United States).

At 12 months, the median 6-minute walk distance had improved by 10.3 meters with coil treatment but worsened by 7.6 meters with usual care (P = .02). The proportion of patients attaining an improvement of at least 25 meters was higher in the coil group (40.0% vs. 26.9%; P = .01).

In exploratory analyses, patients having more nonpulmonary comorbidities at baseline derived lesser benefit in walk distance from coil treatment, Dr. Sciurba noted.

The coils also netted greater improvement in the median change in forced exploratory volume in 1 second (FEV1) (difference between groups, 7.0%; P < .001) and in scores on the St. George’s Respiratory Questionnaire (difference between groups, −8.9 points).

At the same time, patients in the coil group had higher rates of major complications such as pneumonia requiring hospitalization and other potentially life-threatening or fatal events (34.8% vs. 19.1%, P = .002) and of other serious adverse events such as pneumonia (20% vs. 4.5%) and pneumothorax (9.7% vs. 0.6%).

“All of these adverse events returned to baseline at 9 to 12 months,” Dr. Sciurba reported. Additionally, there was no significant difference between groups in mortality rate.

Of note, 35% of the 40 cases of coil-associated opacities initially thought to be pneumonia were in fact determined to likely be a noninfectious inflammatory reaction to the coils. “These adjudicated noninfectious coil-associated opacities were associated with a better response,” he noted.

Finally, in stratified analyses, patients with greater air trapping at baseline had better-than-average improvements in outcomes with the coils, regardless of whether they had homogeneous or heterogeneous disease. Among patients with lesser air trapping, those with homogeneous disease derived much less benefit than the average from coils, while the group with heterogeneous disease was too small to draw any conclusions.

Dr. Sciurba disclosed that he receives institutional support from PneumRx and Pulmonx. The study was sponsored by PneumRx.

SAN FRANCISCO – It may be time to revise guidelines when it comes to initial treatment of chronic obstructive pulmonary disease (COPD) complicated by exacerbations, based on data from a phase III trial reported at an international conference of the American Thoracic Society.

The trial, known as FLAME, undertook a head-to-head comparison of two inhaled drug combinations among more than 3,300 patients from 43 countries. Patients were randomized to once-daily indacaterol (a long-acting beta-agonist, or LABA, bronchodilator) and glycopyrronium (a long-acting muscarinic antagonist, or LAMA, bronchodilator), or to twice-daily salmeterol, also a LABA bronchodilator, and the inhaled glucocorticoid fluticasone.

After a year, the annual rate of exacerbations was 11% lower with indacaterol-glycopyrronium than with salmeterol-fluticasone, according to results reported in a press conference and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1516385). The difference not only met the trial’s primary endpoint of noninferiority, but also established superiority.

The dual bronchodilator combination was also superior to salmeterol-fluticasone when it came to other outcomes, such as respiratory-related health status and rescue medication use, and it had a good safety profile.

“I think we can say that... a dual bronchodilator is the first-choice combination that can be used in patients with COPD,” commented lead author Dr. Jadwiga A. Wedzicha, a professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

“This has a lot of implications. We are going to have to rewrite the guidelines and change our algorithms,” she said, noting that they currently recommend a LABA with an inhaled corticosteroid (the latter of which has adverse effects, especially in an aging population) or single-agent LAMA. “I’m pretty convinced by the data. We’ve got basically four LABA-LAMAs out there; we need to see other studies and look at different patient populations. But I think the data is pretty persuasive, so that we can now change our algorithms.”

Several ongoing studies are looking at triple therapy of a LABA-LAMA plus an inhaled corticosteroid, which may be useful in patients who continue to have exacerbations on dual bronchodilator therapy, according to Dr. Wedzicha. “I think we’ll move to the triple [therapy], because breathlessness is a problem,” she predicted, noting that bronchodilators address that symptom well. “As you get more severe, you are going to get short of breath. So I think the LABA-LAMA will stay and the inhaled corticosteroid will be added on top. That’s what I think COPD treatment will look like.”

Press conference moderator Dr. David Mannino, professor & chair (Preventive Medicine & Environmental Health) at the University of Kentucky College of Public Health in Lexington, praised the research but disagreed about its implications. “I think one very good study is just that – one very good study. Is that enough to change guidelines? I don’t think so,” he said in an interview. “I’d like to see this replicated, because in the U.S., for example, this medication isn’t even available. And if I write [a prescription] for one LABA-LAMA, what a patient actually gets may be dictated by their insurance and coverage and other things.”

“So I would like to see this done with other LABA-LAMAs, and see other head-to-head trials,” he elaborated. “And there is a great deal of boldness and risk on the part of drug companies to do head-to-head trials because they might not get a win. They lucked out in this one. You could do the same trial with products from different companies and not get the same results. And then you are left wondering what was wrong, was it patient characteristics or other things.”

The 3,362 patients studied in FLAME had disabling, symptomatic COPD and had experienced at least one exacerbation in the past year. They were randomized evenly to once-daily indacaterol-glycopyrronium (marketed outside the United States) or twice-daily salmeterol-fluticasone.

Results showed that the annual rate of any exacerbation was significantly lower with indacaterol-glycopyrronium than with salmeterol-fluticasone in the per protocol population (3.59 vs. 4.03; rate ratio, 0.89), with similar findings in the intent-to-treat population. Additionally, in a preplanned analysis, the findings were consistent regardless of patients’ blood levels of eosinophils, a possible marker of steroid sensitivity.

Indacaterol-glycopyrronium was also associated with a longer time to first exacerbation (71 vs. 51 days; hazard ratio, 0.84) and a lower annual rate of moderate or severe exacerbations (0.98 vs. 1.19; rate ratio, 0.83).

There was no difference between groups in the risk of death, but the study lasted only a year and was not powered for that endpoint, Dr. Wedzicha pointed out. “We are seeing less deaths in patients generally in COPD because we are monitoring them very carefully,” she added.

Indacaterol-glycopyrronium was also superior to salmeterol-fluticasone when it came to improvements in health status (assessed with the St. George’s Respiratory Questionnaire), use of rescue medication, and lung function.

The adverse event profiles of both drug combinations were essentially as expected, Dr. Wedzicha reported. Pneumonia was less common with indacaterol-glycopyrronium (3.2% vs. 4.8%).

The indacaterol-glycopyrronium formulation available in the United States, which contains lower doses of the drugs and is used twice-daily, would likely net results similar to those seen in the trial, she speculated. However, once-daily treatment is generally associated with better compliance.

The inflammatory component of COPD still needs attention, according to Dr. Wedzicha. “There is no good evidence that a LABA-LAMA is doing anything to the underlying airway inflammation ... I think a major unmet need now is novel anti-inflammatory agents,” she said.

Dr. Wedzicha disclosed that she received nonfinancial support from Novartis during the conduct of the study; grant support and personal fees from Johnson and Johnson and Vifor Pharma; grant support, personal fees, and nonfinancial support from GlaxoSmithKline, and Takeda; personal fees from Pfizer, Bayer, Chiesi, and Napp; and personal fees and nonfinancial support from Novartis, AstraZeneca, and Boehringer Ingelheim outside the trial. The trial was sponsored by Novartis.

SAN FRANCISCO – It may be time to revise guidelines when it comes to initial treatment of chronic obstructive pulmonary disease (COPD) complicated by exacerbations, based on data from a phase III trial reported at an international conference of the American Thoracic Society.

The trial, known as FLAME, undertook a head-to-head comparison of two inhaled drug combinations among more than 3,300 patients from 43 countries. Patients were randomized to once-daily indacaterol (a long-acting beta-agonist, or LABA, bronchodilator) and glycopyrronium (a long-acting muscarinic antagonist, or LAMA, bronchodilator), or to twice-daily salmeterol, also a LABA bronchodilator, and the inhaled glucocorticoid fluticasone.

After a year, the annual rate of exacerbations was 11% lower with indacaterol-glycopyrronium than with salmeterol-fluticasone, according to results reported in a press conference and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1516385). The difference not only met the trial’s primary endpoint of noninferiority, but also established superiority.

The dual bronchodilator combination was also superior to salmeterol-fluticasone when it came to other outcomes, such as respiratory-related health status and rescue medication use, and it had a good safety profile.

“I think we can say that... a dual bronchodilator is the first-choice combination that can be used in patients with COPD,” commented lead author Dr. Jadwiga A. Wedzicha, a professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

“This has a lot of implications. We are going to have to rewrite the guidelines and change our algorithms,” she said, noting that they currently recommend a LABA with an inhaled corticosteroid (the latter of which has adverse effects, especially in an aging population) or single-agent LAMA. “I’m pretty convinced by the data. We’ve got basically four LABA-LAMAs out there; we need to see other studies and look at different patient populations. But I think the data is pretty persuasive, so that we can now change our algorithms.”

Several ongoing studies are looking at triple therapy of a LABA-LAMA plus an inhaled corticosteroid, which may be useful in patients who continue to have exacerbations on dual bronchodilator therapy, according to Dr. Wedzicha. “I think we’ll move to the triple [therapy], because breathlessness is a problem,” she predicted, noting that bronchodilators address that symptom well. “As you get more severe, you are going to get short of breath. So I think the LABA-LAMA will stay and the inhaled corticosteroid will be added on top. That’s what I think COPD treatment will look like.”

Press conference moderator Dr. David Mannino, professor & chair (Preventive Medicine & Environmental Health) at the University of Kentucky College of Public Health in Lexington, praised the research but disagreed about its implications. “I think one very good study is just that – one very good study. Is that enough to change guidelines? I don’t think so,” he said in an interview. “I’d like to see this replicated, because in the U.S., for example, this medication isn’t even available. And if I write [a prescription] for one LABA-LAMA, what a patient actually gets may be dictated by their insurance and coverage and other things.”

“So I would like to see this done with other LABA-LAMAs, and see other head-to-head trials,” he elaborated. “And there is a great deal of boldness and risk on the part of drug companies to do head-to-head trials because they might not get a win. They lucked out in this one. You could do the same trial with products from different companies and not get the same results. And then you are left wondering what was wrong, was it patient characteristics or other things.”

The 3,362 patients studied in FLAME had disabling, symptomatic COPD and had experienced at least one exacerbation in the past year. They were randomized evenly to once-daily indacaterol-glycopyrronium (marketed outside the United States) or twice-daily salmeterol-fluticasone.

Results showed that the annual rate of any exacerbation was significantly lower with indacaterol-glycopyrronium than with salmeterol-fluticasone in the per protocol population (3.59 vs. 4.03; rate ratio, 0.89), with similar findings in the intent-to-treat population. Additionally, in a preplanned analysis, the findings were consistent regardless of patients’ blood levels of eosinophils, a possible marker of steroid sensitivity.

Indacaterol-glycopyrronium was also associated with a longer time to first exacerbation (71 vs. 51 days; hazard ratio, 0.84) and a lower annual rate of moderate or severe exacerbations (0.98 vs. 1.19; rate ratio, 0.83).

There was no difference between groups in the risk of death, but the study lasted only a year and was not powered for that endpoint, Dr. Wedzicha pointed out. “We are seeing less deaths in patients generally in COPD because we are monitoring them very carefully,” she added.

Indacaterol-glycopyrronium was also superior to salmeterol-fluticasone when it came to improvements in health status (assessed with the St. George’s Respiratory Questionnaire), use of rescue medication, and lung function.

The adverse event profiles of both drug combinations were essentially as expected, Dr. Wedzicha reported. Pneumonia was less common with indacaterol-glycopyrronium (3.2% vs. 4.8%).

The indacaterol-glycopyrronium formulation available in the United States, which contains lower doses of the drugs and is used twice-daily, would likely net results similar to those seen in the trial, she speculated. However, once-daily treatment is generally associated with better compliance.

The inflammatory component of COPD still needs attention, according to Dr. Wedzicha. “There is no good evidence that a LABA-LAMA is doing anything to the underlying airway inflammation ... I think a major unmet need now is novel anti-inflammatory agents,” she said.

Dr. Wedzicha disclosed that she received nonfinancial support from Novartis during the conduct of the study; grant support and personal fees from Johnson and Johnson and Vifor Pharma; grant support, personal fees, and nonfinancial support from GlaxoSmithKline, and Takeda; personal fees from Pfizer, Bayer, Chiesi, and Napp; and personal fees and nonfinancial support from Novartis, AstraZeneca, and Boehringer Ingelheim outside the trial. The trial was sponsored by Novartis.

SAN FRANCISCO – It may be time to revise guidelines when it comes to initial treatment of chronic obstructive pulmonary disease (COPD) complicated by exacerbations, based on data from a phase III trial reported at an international conference of the American Thoracic Society.

The trial, known as FLAME, undertook a head-to-head comparison of two inhaled drug combinations among more than 3,300 patients from 43 countries. Patients were randomized to once-daily indacaterol (a long-acting beta-agonist, or LABA, bronchodilator) and glycopyrronium (a long-acting muscarinic antagonist, or LAMA, bronchodilator), or to twice-daily salmeterol, also a LABA bronchodilator, and the inhaled glucocorticoid fluticasone.

After a year, the annual rate of exacerbations was 11% lower with indacaterol-glycopyrronium than with salmeterol-fluticasone, according to results reported in a press conference and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1516385). The difference not only met the trial’s primary endpoint of noninferiority, but also established superiority.

The dual bronchodilator combination was also superior to salmeterol-fluticasone when it came to other outcomes, such as respiratory-related health status and rescue medication use, and it had a good safety profile.

“I think we can say that... a dual bronchodilator is the first-choice combination that can be used in patients with COPD,” commented lead author Dr. Jadwiga A. Wedzicha, a professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

“This has a lot of implications. We are going to have to rewrite the guidelines and change our algorithms,” she said, noting that they currently recommend a LABA with an inhaled corticosteroid (the latter of which has adverse effects, especially in an aging population) or single-agent LAMA. “I’m pretty convinced by the data. We’ve got basically four LABA-LAMAs out there; we need to see other studies and look at different patient populations. But I think the data is pretty persuasive, so that we can now change our algorithms.”

Several ongoing studies are looking at triple therapy of a LABA-LAMA plus an inhaled corticosteroid, which may be useful in patients who continue to have exacerbations on dual bronchodilator therapy, according to Dr. Wedzicha. “I think we’ll move to the triple [therapy], because breathlessness is a problem,” she predicted, noting that bronchodilators address that symptom well. “As you get more severe, you are going to get short of breath. So I think the LABA-LAMA will stay and the inhaled corticosteroid will be added on top. That’s what I think COPD treatment will look like.”

Press conference moderator Dr. David Mannino, professor & chair (Preventive Medicine & Environmental Health) at the University of Kentucky College of Public Health in Lexington, praised the research but disagreed about its implications. “I think one very good study is just that – one very good study. Is that enough to change guidelines? I don’t think so,” he said in an interview. “I’d like to see this replicated, because in the U.S., for example, this medication isn’t even available. And if I write [a prescription] for one LABA-LAMA, what a patient actually gets may be dictated by their insurance and coverage and other things.”

“So I would like to see this done with other LABA-LAMAs, and see other head-to-head trials,” he elaborated. “And there is a great deal of boldness and risk on the part of drug companies to do head-to-head trials because they might not get a win. They lucked out in this one. You could do the same trial with products from different companies and not get the same results. And then you are left wondering what was wrong, was it patient characteristics or other things.”

The 3,362 patients studied in FLAME had disabling, symptomatic COPD and had experienced at least one exacerbation in the past year. They were randomized evenly to once-daily indacaterol-glycopyrronium (marketed outside the United States) or twice-daily salmeterol-fluticasone.

Results showed that the annual rate of any exacerbation was significantly lower with indacaterol-glycopyrronium than with salmeterol-fluticasone in the per protocol population (3.59 vs. 4.03; rate ratio, 0.89), with similar findings in the intent-to-treat population. Additionally, in a preplanned analysis, the findings were consistent regardless of patients’ blood levels of eosinophils, a possible marker of steroid sensitivity.

Indacaterol-glycopyrronium was also associated with a longer time to first exacerbation (71 vs. 51 days; hazard ratio, 0.84) and a lower annual rate of moderate or severe exacerbations (0.98 vs. 1.19; rate ratio, 0.83).

There was no difference between groups in the risk of death, but the study lasted only a year and was not powered for that endpoint, Dr. Wedzicha pointed out. “We are seeing less deaths in patients generally in COPD because we are monitoring them very carefully,” she added.

Indacaterol-glycopyrronium was also superior to salmeterol-fluticasone when it came to improvements in health status (assessed with the St. George’s Respiratory Questionnaire), use of rescue medication, and lung function.

The adverse event profiles of both drug combinations were essentially as expected, Dr. Wedzicha reported. Pneumonia was less common with indacaterol-glycopyrronium (3.2% vs. 4.8%).

The indacaterol-glycopyrronium formulation available in the United States, which contains lower doses of the drugs and is used twice-daily, would likely net results similar to those seen in the trial, she speculated. However, once-daily treatment is generally associated with better compliance.

The inflammatory component of COPD still needs attention, according to Dr. Wedzicha. “There is no good evidence that a LABA-LAMA is doing anything to the underlying airway inflammation ... I think a major unmet need now is novel anti-inflammatory agents,” she said.

Dr. Wedzicha disclosed that she received nonfinancial support from Novartis during the conduct of the study; grant support and personal fees from Johnson and Johnson and Vifor Pharma; grant support, personal fees, and nonfinancial support from GlaxoSmithKline, and Takeda; personal fees from Pfizer, Bayer, Chiesi, and Napp; and personal fees and nonfinancial support from Novartis, AstraZeneca, and Boehringer Ingelheim outside the trial. The trial was sponsored by Novartis.

SAN FRANCISCO – Despite evidence implicating platelets in the development and resolution of acute respiratory distress syndrome (ARDS), the antiplatelet agent aspirin was not efficacious for prevention, according to the findings from a phase IIb trial reported at an international conference of the American Thoracic Society.

A total of 400 at-risk patients from emergency departments were enrolled in the trial, known as LIPS-A (Lung Injury Prevention Study With Aspirin), and randomized evenly to aspirin or placebo, started within 24 hours of presentation.

Overall, about 10% of patients developed ARDS by day 7, with no significant difference between the groups, according to results reported at the conference and simultaneously published in JAMA (2016 May 15. doi: 10.1001/jama.2016.6330).

“In patients at risk for ARDS, aspirin therapy administered within 24 hours of presentation to the emergency department was safe. However, it did not decrease the primary outcome of ARDS development or improve any of the secondary outcomes,” commented lead author Dr. Daryl J. Kor, an associate professor of anesthesiology at the Mayo Clinic, Rochester, Minn. “The results of this phase IIb trial do not support continuation to a larger phase III trial.”

Nonetheless, as the first large multicenter ARDS prevention trial, LIPS-A provided an abundance of information about research in this challenging area, he stressed. For example, the information gleaned will help inform future trials on issues related to timely enrollment, risk prediction, and work flow modifications.

“In terms of limitations, we should note that there was a very low rate of ARDS, much lower than we anticipated,” Dr. Kor said. Patients also had less severe disease than expected. “There are always questions about the dose and duration [of treatment], as well as whether or not the ED environment is early enough for an ARDS prevention trial. Almost 15% of our patient population had prevalent bilateral infiltrates by the time they presented to the emergency department,” he noted.

Despite the negative LIPS-A findings, there may still be a role for aspirin in the treatment of ARDS, according to conference attendee Dr. Ivor S. Douglas, chief of pulmonary sciences and critical care medicine, and director of the medical intensive care unit, at the Denver Health Medical Center and the University of Colorado.

ARDS lacks a good biomarker similar to the troponin used to identify and guide aspirin treatment in myocardial infarction, he explained in an interview.

“I continue to believe that there are several endophenotypes, subgroups of the disease where an endothelial vascular phenotype is predominant,” Dr. Douglas explained. “And as we understand more about the fundamental biology of the disease, I suspect that many of these things that have been shown in unselected populations not to have efficacy – you didn’t hear me say negative, but not to have efficacy – may well be revisited within the context of a more well defined phenotype for the disease.

“I think it’s imperative that we don’t just call the balls and strikes here,” Dr. Douglas added. “The idea is to move the science forward and to do it in a really thoughtful and rigorous way.”

LIPS-A enrolled adult patients from 16 U.S. academic hospitals who were at risk for ARDS, defined as having a Lung Injury Prediction Score of 4 or greater (corresponding to a risk of about 18%), in the emergency department and were planned to be hospitalized.

They were randomized to receive aspirin (a 325-mg loading dose, followed by 81 mg/day) or placebo within 24 hours of emergency department presentation, with continuation out to hospital day 7, discharge, or death.

On average, patients received their first dose of the study drug slightly less than 13 hours after randomization, Dr. Kor reported.

Incident ARDS by day 7 was seen in 10.3% of the aspirin group and 8.7% of the placebo group, a nonsignificant difference. Findings were similar for each study site individually.

The groups were also statistically indistinguishable with respect to mean number of ventilator-free days out to day 28 (24.9 vs. 25.2), mean intensive care unit length of stay (5.2 vs. 5.4 days), and the 28-day rate of survival (90% vs. 90%), among other secondary outcomes.

In terms of safety, the incidence of bleeding-related adverse events was not significantly greater with aspirin than with placebo (5.6% vs. 2.6%). Measures of renal function were also essentially the same.

Analyses of a host of biomarkers associated with injury, inflammation, and thrombosis generally showed no differences in levels between groups. The possible exception was a trend toward a higher level of interleukin-2 in the aspirin group.

Dr. Kor disclosed that he receives personal fees from UpToDate.

SAN FRANCISCO – Despite evidence implicating platelets in the development and resolution of acute respiratory distress syndrome (ARDS), the antiplatelet agent aspirin was not efficacious for prevention, according to the findings from a phase IIb trial reported at an international conference of the American Thoracic Society.

A total of 400 at-risk patients from emergency departments were enrolled in the trial, known as LIPS-A (Lung Injury Prevention Study With Aspirin), and randomized evenly to aspirin or placebo, started within 24 hours of presentation.

Overall, about 10% of patients developed ARDS by day 7, with no significant difference between the groups, according to results reported at the conference and simultaneously published in JAMA (2016 May 15. doi: 10.1001/jama.2016.6330).

“In patients at risk for ARDS, aspirin therapy administered within 24 hours of presentation to the emergency department was safe. However, it did not decrease the primary outcome of ARDS development or improve any of the secondary outcomes,” commented lead author Dr. Daryl J. Kor, an associate professor of anesthesiology at the Mayo Clinic, Rochester, Minn. “The results of this phase IIb trial do not support continuation to a larger phase III trial.”

Nonetheless, as the first large multicenter ARDS prevention trial, LIPS-A provided an abundance of information about research in this challenging area, he stressed. For example, the information gleaned will help inform future trials on issues related to timely enrollment, risk prediction, and work flow modifications.

“In terms of limitations, we should note that there was a very low rate of ARDS, much lower than we anticipated,” Dr. Kor said. Patients also had less severe disease than expected. “There are always questions about the dose and duration [of treatment], as well as whether or not the ED environment is early enough for an ARDS prevention trial. Almost 15% of our patient population had prevalent bilateral infiltrates by the time they presented to the emergency department,” he noted.

Despite the negative LIPS-A findings, there may still be a role for aspirin in the treatment of ARDS, according to conference attendee Dr. Ivor S. Douglas, chief of pulmonary sciences and critical care medicine, and director of the medical intensive care unit, at the Denver Health Medical Center and the University of Colorado.

ARDS lacks a good biomarker similar to the troponin used to identify and guide aspirin treatment in myocardial infarction, he explained in an interview.

“I continue to believe that there are several endophenotypes, subgroups of the disease where an endothelial vascular phenotype is predominant,” Dr. Douglas explained. “And as we understand more about the fundamental biology of the disease, I suspect that many of these things that have been shown in unselected populations not to have efficacy – you didn’t hear me say negative, but not to have efficacy – may well be revisited within the context of a more well defined phenotype for the disease.

“I think it’s imperative that we don’t just call the balls and strikes here,” Dr. Douglas added. “The idea is to move the science forward and to do it in a really thoughtful and rigorous way.”

LIPS-A enrolled adult patients from 16 U.S. academic hospitals who were at risk for ARDS, defined as having a Lung Injury Prediction Score of 4 or greater (corresponding to a risk of about 18%), in the emergency department and were planned to be hospitalized.

They were randomized to receive aspirin (a 325-mg loading dose, followed by 81 mg/day) or placebo within 24 hours of emergency department presentation, with continuation out to hospital day 7, discharge, or death.

On average, patients received their first dose of the study drug slightly less than 13 hours after randomization, Dr. Kor reported.

Incident ARDS by day 7 was seen in 10.3% of the aspirin group and 8.7% of the placebo group, a nonsignificant difference. Findings were similar for each study site individually.

The groups were also statistically indistinguishable with respect to mean number of ventilator-free days out to day 28 (24.9 vs. 25.2), mean intensive care unit length of stay (5.2 vs. 5.4 days), and the 28-day rate of survival (90% vs. 90%), among other secondary outcomes.

In terms of safety, the incidence of bleeding-related adverse events was not significantly greater with aspirin than with placebo (5.6% vs. 2.6%). Measures of renal function were also essentially the same.

Analyses of a host of biomarkers associated with injury, inflammation, and thrombosis generally showed no differences in levels between groups. The possible exception was a trend toward a higher level of interleukin-2 in the aspirin group.

Dr. Kor disclosed that he receives personal fees from UpToDate.

SAN FRANCISCO – Despite evidence implicating platelets in the development and resolution of acute respiratory distress syndrome (ARDS), the antiplatelet agent aspirin was not efficacious for prevention, according to the findings from a phase IIb trial reported at an international conference of the American Thoracic Society.

A total of 400 at-risk patients from emergency departments were enrolled in the trial, known as LIPS-A (Lung Injury Prevention Study With Aspirin), and randomized evenly to aspirin or placebo, started within 24 hours of presentation.

Overall, about 10% of patients developed ARDS by day 7, with no significant difference between the groups, according to results reported at the conference and simultaneously published in JAMA (2016 May 15. doi: 10.1001/jama.2016.6330).

“In patients at risk for ARDS, aspirin therapy administered within 24 hours of presentation to the emergency department was safe. However, it did not decrease the primary outcome of ARDS development or improve any of the secondary outcomes,” commented lead author Dr. Daryl J. Kor, an associate professor of anesthesiology at the Mayo Clinic, Rochester, Minn. “The results of this phase IIb trial do not support continuation to a larger phase III trial.”

Nonetheless, as the first large multicenter ARDS prevention trial, LIPS-A provided an abundance of information about research in this challenging area, he stressed. For example, the information gleaned will help inform future trials on issues related to timely enrollment, risk prediction, and work flow modifications.

“In terms of limitations, we should note that there was a very low rate of ARDS, much lower than we anticipated,” Dr. Kor said. Patients also had less severe disease than expected. “There are always questions about the dose and duration [of treatment], as well as whether or not the ED environment is early enough for an ARDS prevention trial. Almost 15% of our patient population had prevalent bilateral infiltrates by the time they presented to the emergency department,” he noted.

Despite the negative LIPS-A findings, there may still be a role for aspirin in the treatment of ARDS, according to conference attendee Dr. Ivor S. Douglas, chief of pulmonary sciences and critical care medicine, and director of the medical intensive care unit, at the Denver Health Medical Center and the University of Colorado.

ARDS lacks a good biomarker similar to the troponin used to identify and guide aspirin treatment in myocardial infarction, he explained in an interview.

“I continue to believe that there are several endophenotypes, subgroups of the disease where an endothelial vascular phenotype is predominant,” Dr. Douglas explained. “And as we understand more about the fundamental biology of the disease, I suspect that many of these things that have been shown in unselected populations not to have efficacy – you didn’t hear me say negative, but not to have efficacy – may well be revisited within the context of a more well defined phenotype for the disease.

“I think it’s imperative that we don’t just call the balls and strikes here,” Dr. Douglas added. “The idea is to move the science forward and to do it in a really thoughtful and rigorous way.”

LIPS-A enrolled adult patients from 16 U.S. academic hospitals who were at risk for ARDS, defined as having a Lung Injury Prediction Score of 4 or greater (corresponding to a risk of about 18%), in the emergency department and were planned to be hospitalized.

They were randomized to receive aspirin (a 325-mg loading dose, followed by 81 mg/day) or placebo within 24 hours of emergency department presentation, with continuation out to hospital day 7, discharge, or death.

On average, patients received their first dose of the study drug slightly less than 13 hours after randomization, Dr. Kor reported.

Incident ARDS by day 7 was seen in 10.3% of the aspirin group and 8.7% of the placebo group, a nonsignificant difference. Findings were similar for each study site individually.

The groups were also statistically indistinguishable with respect to mean number of ventilator-free days out to day 28 (24.9 vs. 25.2), mean intensive care unit length of stay (5.2 vs. 5.4 days), and the 28-day rate of survival (90% vs. 90%), among other secondary outcomes.

In terms of safety, the incidence of bleeding-related adverse events was not significantly greater with aspirin than with placebo (5.6% vs. 2.6%). Measures of renal function were also essentially the same.

Analyses of a host of biomarkers associated with injury, inflammation, and thrombosis generally showed no differences in levels between groups. The possible exception was a trend toward a higher level of interleukin-2 in the aspirin group.

Dr. Kor disclosed that he receives personal fees from UpToDate.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Mindfulness works as well as pharmacotherapy for prevention in patients who have chronic migraine with medication overuse, suggest initial findings of a trial reported at the annual meeting of the American Academy of Neurology.

Results at 6 months showed that both pharmacotherapy and a 6-week mindfulness training program netted 40% to 50% reductions in migraine days and medication uses per month, with no significant differences between these approaches.

Susan London/Frontline Medical News

“The effects of mindfulness alone seemed to be comparable to those obtained for medication alone in this particular group of patients,” commented lead author Dr. Licia Grazzi, a neurologist with the Headache Center, Carlo Besta Neurological Institute and Foundation, in Milan.

“We didn’t assess it specifically, but patients commented that mindfulness [produced no] side effects. Patients adhered very well to the treatment; they came to the sessions, so they could follow the treatment in an adequate way,” she added.

Giving some background, Dr. Grazzi noted that chronic migraine is especially disabling and hard to treatment in the context of medication overuse. Conventional management entails a period of medication weaning, followed by reintroduction of medication at appropriate levels plus adjunctive therapies as needed.

“Researchers have not studied the effectiveness of behavioral treatment alone following withdrawal,” Dr. Grazzi commented. “In particular, mindfulness is an emerging technique that has been recognized as a useful treatment for pain, but up until now, no application has been made for migraine and chronic migraine in particular.”

On average, the 44 patients enrolled in the trial had migraine on about 20 days of each month and used medication on most of those days.

All patients underwent a 5-day medication withdrawal in a day hospital treatment program. They were then split evenly into two groups: tailored pharmacologic prophylaxis and mindfulness training.

The mindfulness training entailed six 45-minute weekly sessions of guided meditation practice, with instructions to practice at home at least 7 minutes daily. In addition, patients were encouraged to get regular aerobic exercise and advised about lifestyle modifications as indicated.

Six months later, the pharmacotherapy group and mindfulness group had significant and statistically indistinguishable reductions in the number of migraine days per month (41.8% vs. 45.2%) and the number of medication uses per month (38.3% vs. 51.7%).

Both groups had a slight rebound in these measures between 3 and 6 months, but the increase in days of medication use was less marked in the mindfulness group. “Our explanation for that is that this group of patients can manage better their pain, and so they can reduce the use of medication when they suffer from pain,” Dr. Grazzi commented.

The pharmacotherapy and mindfulness groups also had comparable improvements in scores on the Migraine Disability Assessment (MIDAS) questionnaire (52.1% vs. 36.3%), the Beck Depression Inventory (41.9% vs. 33.8%), and the 6-item Headache Impact Test (HIT-6) (6.7% vs. 8.5%). State anxiety and trait anxiety improved in both groups as well.

“Data collection is now ongoing to determine if, with longer follow-up, we have significant results,” commented Dr. Grazzi. “It’s very common that patients after withdrawal tend to get better immediately, but then they relapse fairly easily. So we have to control and follow patients for 1 year to be sure about our encouraging results.”

Dr. Grazzi disclosed that she is a consultant/advisor for Allergan and ElectroCore Medical.

VANCOUVER – Mindfulness works as well as pharmacotherapy for prevention in patients who have chronic migraine with medication overuse, suggest initial findings of a trial reported at the annual meeting of the American Academy of Neurology.

Results at 6 months showed that both pharmacotherapy and a 6-week mindfulness training program netted 40% to 50% reductions in migraine days and medication uses per month, with no significant differences between these approaches.

Susan London/Frontline Medical News

“The effects of mindfulness alone seemed to be comparable to those obtained for medication alone in this particular group of patients,” commented lead author Dr. Licia Grazzi, a neurologist with the Headache Center, Carlo Besta Neurological Institute and Foundation, in Milan.

“We didn’t assess it specifically, but patients commented that mindfulness [produced no] side effects. Patients adhered very well to the treatment; they came to the sessions, so they could follow the treatment in an adequate way,” she added.

Giving some background, Dr. Grazzi noted that chronic migraine is especially disabling and hard to treatment in the context of medication overuse. Conventional management entails a period of medication weaning, followed by reintroduction of medication at appropriate levels plus adjunctive therapies as needed.

“Researchers have not studied the effectiveness of behavioral treatment alone following withdrawal,” Dr. Grazzi commented. “In particular, mindfulness is an emerging technique that has been recognized as a useful treatment for pain, but up until now, no application has been made for migraine and chronic migraine in particular.”

On average, the 44 patients enrolled in the trial had migraine on about 20 days of each month and used medication on most of those days.

All patients underwent a 5-day medication withdrawal in a day hospital treatment program. They were then split evenly into two groups: tailored pharmacologic prophylaxis and mindfulness training.

The mindfulness training entailed six 45-minute weekly sessions of guided meditation practice, with instructions to practice at home at least 7 minutes daily. In addition, patients were encouraged to get regular aerobic exercise and advised about lifestyle modifications as indicated.

Six months later, the pharmacotherapy group and mindfulness group had significant and statistically indistinguishable reductions in the number of migraine days per month (41.8% vs. 45.2%) and the number of medication uses per month (38.3% vs. 51.7%).

Both groups had a slight rebound in these measures between 3 and 6 months, but the increase in days of medication use was less marked in the mindfulness group. “Our explanation for that is that this group of patients can manage better their pain, and so they can reduce the use of medication when they suffer from pain,” Dr. Grazzi commented.

The pharmacotherapy and mindfulness groups also had comparable improvements in scores on the Migraine Disability Assessment (MIDAS) questionnaire (52.1% vs. 36.3%), the Beck Depression Inventory (41.9% vs. 33.8%), and the 6-item Headache Impact Test (HIT-6) (6.7% vs. 8.5%). State anxiety and trait anxiety improved in both groups as well.

“Data collection is now ongoing to determine if, with longer follow-up, we have significant results,” commented Dr. Grazzi. “It’s very common that patients after withdrawal tend to get better immediately, but then they relapse fairly easily. So we have to control and follow patients for 1 year to be sure about our encouraging results.”

Dr. Grazzi disclosed that she is a consultant/advisor for Allergan and ElectroCore Medical.

VANCOUVER – Mindfulness works as well as pharmacotherapy for prevention in patients who have chronic migraine with medication overuse, suggest initial findings of a trial reported at the annual meeting of the American Academy of Neurology.

Results at 6 months showed that both pharmacotherapy and a 6-week mindfulness training program netted 40% to 50% reductions in migraine days and medication uses per month, with no significant differences between these approaches.

Susan London/Frontline Medical News

“The effects of mindfulness alone seemed to be comparable to those obtained for medication alone in this particular group of patients,” commented lead author Dr. Licia Grazzi, a neurologist with the Headache Center, Carlo Besta Neurological Institute and Foundation, in Milan.

“We didn’t assess it specifically, but patients commented that mindfulness [produced no] side effects. Patients adhered very well to the treatment; they came to the sessions, so they could follow the treatment in an adequate way,” she added.

Giving some background, Dr. Grazzi noted that chronic migraine is especially disabling and hard to treatment in the context of medication overuse. Conventional management entails a period of medication weaning, followed by reintroduction of medication at appropriate levels plus adjunctive therapies as needed.

“Researchers have not studied the effectiveness of behavioral treatment alone following withdrawal,” Dr. Grazzi commented. “In particular, mindfulness is an emerging technique that has been recognized as a useful treatment for pain, but up until now, no application has been made for migraine and chronic migraine in particular.”

On average, the 44 patients enrolled in the trial had migraine on about 20 days of each month and used medication on most of those days.

All patients underwent a 5-day medication withdrawal in a day hospital treatment program. They were then split evenly into two groups: tailored pharmacologic prophylaxis and mindfulness training.

The mindfulness training entailed six 45-minute weekly sessions of guided meditation practice, with instructions to practice at home at least 7 minutes daily. In addition, patients were encouraged to get regular aerobic exercise and advised about lifestyle modifications as indicated.

Six months later, the pharmacotherapy group and mindfulness group had significant and statistically indistinguishable reductions in the number of migraine days per month (41.8% vs. 45.2%) and the number of medication uses per month (38.3% vs. 51.7%).

Both groups had a slight rebound in these measures between 3 and 6 months, but the increase in days of medication use was less marked in the mindfulness group. “Our explanation for that is that this group of patients can manage better their pain, and so they can reduce the use of medication when they suffer from pain,” Dr. Grazzi commented.

The pharmacotherapy and mindfulness groups also had comparable improvements in scores on the Migraine Disability Assessment (MIDAS) questionnaire (52.1% vs. 36.3%), the Beck Depression Inventory (41.9% vs. 33.8%), and the 6-item Headache Impact Test (HIT-6) (6.7% vs. 8.5%). State anxiety and trait anxiety improved in both groups as well.

“Data collection is now ongoing to determine if, with longer follow-up, we have significant results,” commented Dr. Grazzi. “It’s very common that patients after withdrawal tend to get better immediately, but then they relapse fairly easily. So we have to control and follow patients for 1 year to be sure about our encouraging results.”

Dr. Grazzi disclosed that she is a consultant/advisor for Allergan and ElectroCore Medical.