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Peroral endoscopic myotomy (POEM) is safe and effective for several nonachalasia esophageal motility disorders, according to a retrospective study.

The procedure was clinically successful and relieved chest pain in most patients, reported Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Hospital in Baltimore.

POEM was introduced in 2008 as a less invasive alternative to laparoscopic Heller myotomy. During the procedure, submucosal tunneling is performed through the lower esophageal sphincter to the gastric cardia, thereby weakening the lower esophageal sphincter to allow passage of food.

POEM is clinically successful in 80%-90% of patients with achalasia. Although the procedure is regarded as safe and effective for achalasia, it has not been thoroughly researched for treatment of other esophageal motility disorders, including junction outflow obstruction (EGJOO), jackhammer esophagus (JE), or esophagogastric distal esophageal spasm (DES). EGJOO is similar to achalasia, but with peristalsis and a mean integrated relaxation pressure (IRP) greater than 15 mm Hg. Both JE and DES are spastic esophageal disorders. Patients with JE exhibit extreme esophageal hypercontractility, whereas patients with DES have a normal mean IRP and at least 20% premature contractions.

“The role POEM plays in management of these disorders is not clear, mainly due to scarcity of studies on this topic,” the authors wrote in Endoscopy International Open. “A previous multicenter study investigated the role of POEM in 73 patients with spastic esophageal disorders. However, the vast majority of patients (n = 54) in that study had type III (spastic) achalasia.” Since therapies such as botulinum toxin injections and calcium channel blockers are ineffective for many patients with nonachalasia esophageal motility disorders, “POEM is potentially an ideal treatment.”

The international, multicenter study involved 11 treatment centers and 50 patients. Patients with JE (n = 18), EGJOO (n = 15), and DES (n = 17) were included, each diagnosed according to the Chicago classification of esophageal motility disorders. Patients with type III achalasia were excluded.

Outcomes included technical success (completion of myotomy) and clinical success (Eckardt score at least 3 and symptom improvement). Prior to the procedure, the mean Eckardt score was 6.9 and chest pain was reported by almost three-quarters of the patients (72%).

Technical success was achieved in all patients. Myotomy thickness varied between cases; approximately half had a selective inner circular myotomy (48%), slightly less had a full-thickness myotomy (44%), and several were undefined (8%). Mean esophageal myotomy length was 12.5 cm and mean gastric myotomy length was 2.5 cm. Mean procedure time was approximately 90 minutes. Median duration of hospital stay was 2 days.

Nine adverse events (AEs) occurred in 8 patients, including submucosal hematoma, aspiration pneumonia, inadvertent mucosotomy, postprocedure pain, esophageal leak, bleed, and symptomatic capno-thorax/peritoneum.

“Although AEs occurred in 18% of patients,” the authors noted, “55.6% were rated as mild and 44.4% as moderate with no severe events. Most AEs can be managed intraprocedurally.”

Median follow-up time was approximately 8 months, during which 42 patients (87.5%) achieved clinical success, with many dramatically improved; over half of the patients (52%) had Eckardt scores of 0 or 1. From the group of patients who had chest pain prior to the procedure, 87% had resolution of chest pain. Although reflux developed in almost a quarter of the patients (22.2%), this was successfully managed with proton pump inhibitors in all instances. Most patients (82.9%) who underwent postoperative manometry had resolution of preoperative abnormalities.

Subgroup analysis was also performed. Clinical success was achieved in 94.1% of patients with DES, 93.3% of patients with EGJOO, and 75.0% with JE. Collectively, the spastic disorders (DES/JE) had a lower numerical response than EGJOO. However, the authors noted that “the difference was not statistically significant (P = .41), likely a type II error due to the relatively small number of included patients.” In all subgroups, postprocedural mean Eckardt scores decreased to less than 2. Patients with EGJOO were most likely to achieve Eckardt scores of 0 or 1. AEs were similar between subgroups.

“Remarkably, chest pain improved in more than 85% of patients,” the authors wrote. “Chest pain is frequently the major presenting symptom in these disorders and is difficult to treat.”

“It is important to mention that a long esophageal myotomy is essential to ensure that proximal esophageal spasms are effectively covered and treated,” the authors wrote. “Mean length of esophageal myotomy in patients with DES and JE in the current study was about 14 cm, which is more than twice the length of a typical endoscopic or surgical myotomy performed in achalasia patients.”

Even with the need for an extended myotomy, “results from the current study along with published data suggest POEM as an effective technique” for nonachalasia esophageal motility disorders, the authors concluded.

Since retrospective studies are inherently limited by design, the authors encouraged randomized trials to clarify the primary role of POEM in the management of nonachalasia esophageal motility disorders.

The authors reported compensation from Olympus, Boston Scientific, and Cook Medical.

SOURCE: Khashab MA et al. Endosc Int Open. 2018 Aug 10. doi: 10.1055/a-0625-6288.

Peroral endoscopic myotomy (POEM) is safe and effective for several nonachalasia esophageal motility disorders, according to a retrospective study.

The procedure was clinically successful and relieved chest pain in most patients, reported Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Hospital in Baltimore.

POEM was introduced in 2008 as a less invasive alternative to laparoscopic Heller myotomy. During the procedure, submucosal tunneling is performed through the lower esophageal sphincter to the gastric cardia, thereby weakening the lower esophageal sphincter to allow passage of food.

POEM is clinically successful in 80%-90% of patients with achalasia. Although the procedure is regarded as safe and effective for achalasia, it has not been thoroughly researched for treatment of other esophageal motility disorders, including junction outflow obstruction (EGJOO), jackhammer esophagus (JE), or esophagogastric distal esophageal spasm (DES). EGJOO is similar to achalasia, but with peristalsis and a mean integrated relaxation pressure (IRP) greater than 15 mm Hg. Both JE and DES are spastic esophageal disorders. Patients with JE exhibit extreme esophageal hypercontractility, whereas patients with DES have a normal mean IRP and at least 20% premature contractions.

“The role POEM plays in management of these disorders is not clear, mainly due to scarcity of studies on this topic,” the authors wrote in Endoscopy International Open. “A previous multicenter study investigated the role of POEM in 73 patients with spastic esophageal disorders. However, the vast majority of patients (n = 54) in that study had type III (spastic) achalasia.” Since therapies such as botulinum toxin injections and calcium channel blockers are ineffective for many patients with nonachalasia esophageal motility disorders, “POEM is potentially an ideal treatment.”

The international, multicenter study involved 11 treatment centers and 50 patients. Patients with JE (n = 18), EGJOO (n = 15), and DES (n = 17) were included, each diagnosed according to the Chicago classification of esophageal motility disorders. Patients with type III achalasia were excluded.

Outcomes included technical success (completion of myotomy) and clinical success (Eckardt score at least 3 and symptom improvement). Prior to the procedure, the mean Eckardt score was 6.9 and chest pain was reported by almost three-quarters of the patients (72%).

Technical success was achieved in all patients. Myotomy thickness varied between cases; approximately half had a selective inner circular myotomy (48%), slightly less had a full-thickness myotomy (44%), and several were undefined (8%). Mean esophageal myotomy length was 12.5 cm and mean gastric myotomy length was 2.5 cm. Mean procedure time was approximately 90 minutes. Median duration of hospital stay was 2 days.

Nine adverse events (AEs) occurred in 8 patients, including submucosal hematoma, aspiration pneumonia, inadvertent mucosotomy, postprocedure pain, esophageal leak, bleed, and symptomatic capno-thorax/peritoneum.

“Although AEs occurred in 18% of patients,” the authors noted, “55.6% were rated as mild and 44.4% as moderate with no severe events. Most AEs can be managed intraprocedurally.”

Median follow-up time was approximately 8 months, during which 42 patients (87.5%) achieved clinical success, with many dramatically improved; over half of the patients (52%) had Eckardt scores of 0 or 1. From the group of patients who had chest pain prior to the procedure, 87% had resolution of chest pain. Although reflux developed in almost a quarter of the patients (22.2%), this was successfully managed with proton pump inhibitors in all instances. Most patients (82.9%) who underwent postoperative manometry had resolution of preoperative abnormalities.

Subgroup analysis was also performed. Clinical success was achieved in 94.1% of patients with DES, 93.3% of patients with EGJOO, and 75.0% with JE. Collectively, the spastic disorders (DES/JE) had a lower numerical response than EGJOO. However, the authors noted that “the difference was not statistically significant (P = .41), likely a type II error due to the relatively small number of included patients.” In all subgroups, postprocedural mean Eckardt scores decreased to less than 2. Patients with EGJOO were most likely to achieve Eckardt scores of 0 or 1. AEs were similar between subgroups.

“Remarkably, chest pain improved in more than 85% of patients,” the authors wrote. “Chest pain is frequently the major presenting symptom in these disorders and is difficult to treat.”

“It is important to mention that a long esophageal myotomy is essential to ensure that proximal esophageal spasms are effectively covered and treated,” the authors wrote. “Mean length of esophageal myotomy in patients with DES and JE in the current study was about 14 cm, which is more than twice the length of a typical endoscopic or surgical myotomy performed in achalasia patients.”

Even with the need for an extended myotomy, “results from the current study along with published data suggest POEM as an effective technique” for nonachalasia esophageal motility disorders, the authors concluded.

Since retrospective studies are inherently limited by design, the authors encouraged randomized trials to clarify the primary role of POEM in the management of nonachalasia esophageal motility disorders.

The authors reported compensation from Olympus, Boston Scientific, and Cook Medical.

SOURCE: Khashab MA et al. Endosc Int Open. 2018 Aug 10. doi: 10.1055/a-0625-6288.

Peroral endoscopic myotomy (POEM) is safe and effective for several nonachalasia esophageal motility disorders, according to a retrospective study.

The procedure was clinically successful and relieved chest pain in most patients, reported Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Hospital in Baltimore.

POEM was introduced in 2008 as a less invasive alternative to laparoscopic Heller myotomy. During the procedure, submucosal tunneling is performed through the lower esophageal sphincter to the gastric cardia, thereby weakening the lower esophageal sphincter to allow passage of food.

POEM is clinically successful in 80%-90% of patients with achalasia. Although the procedure is regarded as safe and effective for achalasia, it has not been thoroughly researched for treatment of other esophageal motility disorders, including junction outflow obstruction (EGJOO), jackhammer esophagus (JE), or esophagogastric distal esophageal spasm (DES). EGJOO is similar to achalasia, but with peristalsis and a mean integrated relaxation pressure (IRP) greater than 15 mm Hg. Both JE and DES are spastic esophageal disorders. Patients with JE exhibit extreme esophageal hypercontractility, whereas patients with DES have a normal mean IRP and at least 20% premature contractions.

“The role POEM plays in management of these disorders is not clear, mainly due to scarcity of studies on this topic,” the authors wrote in Endoscopy International Open. “A previous multicenter study investigated the role of POEM in 73 patients with spastic esophageal disorders. However, the vast majority of patients (n = 54) in that study had type III (spastic) achalasia.” Since therapies such as botulinum toxin injections and calcium channel blockers are ineffective for many patients with nonachalasia esophageal motility disorders, “POEM is potentially an ideal treatment.”

The international, multicenter study involved 11 treatment centers and 50 patients. Patients with JE (n = 18), EGJOO (n = 15), and DES (n = 17) were included, each diagnosed according to the Chicago classification of esophageal motility disorders. Patients with type III achalasia were excluded.

Outcomes included technical success (completion of myotomy) and clinical success (Eckardt score at least 3 and symptom improvement). Prior to the procedure, the mean Eckardt score was 6.9 and chest pain was reported by almost three-quarters of the patients (72%).

Technical success was achieved in all patients. Myotomy thickness varied between cases; approximately half had a selective inner circular myotomy (48%), slightly less had a full-thickness myotomy (44%), and several were undefined (8%). Mean esophageal myotomy length was 12.5 cm and mean gastric myotomy length was 2.5 cm. Mean procedure time was approximately 90 minutes. Median duration of hospital stay was 2 days.

Nine adverse events (AEs) occurred in 8 patients, including submucosal hematoma, aspiration pneumonia, inadvertent mucosotomy, postprocedure pain, esophageal leak, bleed, and symptomatic capno-thorax/peritoneum.

“Although AEs occurred in 18% of patients,” the authors noted, “55.6% were rated as mild and 44.4% as moderate with no severe events. Most AEs can be managed intraprocedurally.”

Median follow-up time was approximately 8 months, during which 42 patients (87.5%) achieved clinical success, with many dramatically improved; over half of the patients (52%) had Eckardt scores of 0 or 1. From the group of patients who had chest pain prior to the procedure, 87% had resolution of chest pain. Although reflux developed in almost a quarter of the patients (22.2%), this was successfully managed with proton pump inhibitors in all instances. Most patients (82.9%) who underwent postoperative manometry had resolution of preoperative abnormalities.

Subgroup analysis was also performed. Clinical success was achieved in 94.1% of patients with DES, 93.3% of patients with EGJOO, and 75.0% with JE. Collectively, the spastic disorders (DES/JE) had a lower numerical response than EGJOO. However, the authors noted that “the difference was not statistically significant (P = .41), likely a type II error due to the relatively small number of included patients.” In all subgroups, postprocedural mean Eckardt scores decreased to less than 2. Patients with EGJOO were most likely to achieve Eckardt scores of 0 or 1. AEs were similar between subgroups.

“Remarkably, chest pain improved in more than 85% of patients,” the authors wrote. “Chest pain is frequently the major presenting symptom in these disorders and is difficult to treat.”

“It is important to mention that a long esophageal myotomy is essential to ensure that proximal esophageal spasms are effectively covered and treated,” the authors wrote. “Mean length of esophageal myotomy in patients with DES and JE in the current study was about 14 cm, which is more than twice the length of a typical endoscopic or surgical myotomy performed in achalasia patients.”

Even with the need for an extended myotomy, “results from the current study along with published data suggest POEM as an effective technique” for nonachalasia esophageal motility disorders, the authors concluded.

Since retrospective studies are inherently limited by design, the authors encouraged randomized trials to clarify the primary role of POEM in the management of nonachalasia esophageal motility disorders.

The authors reported compensation from Olympus, Boston Scientific, and Cook Medical.

SOURCE: Khashab MA et al. Endosc Int Open. 2018 Aug 10. doi: 10.1055/a-0625-6288.

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.

For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.

“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.

Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).

The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.

Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).

More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).

The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.

“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.

The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.

SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.

In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.

For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.

“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.

Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).

The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.

Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).

More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).

The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.

“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.

The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.

SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.

In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.

For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.

“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.

Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).

The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.

Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).

More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).

The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.

“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.

The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.

SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

MUNICH – For patients with heart disease, coronary artery disease, and normal sinus rhythm, giving rivaroxaban does not significantly reduce risks of death, myocardial infarction, or stroke, investigators in the COMMANDER trial said.

Rivaroxaban did not improve rehospitalization rates either, reported lead author Faiez Zannad, MD, PhD, from the University of Henri Poincaré in Nancy, France, and his co-investigators.

“After an episode of worsening chronic heart failure, rates of readmission to the hospital and of death are high, especially in the first few months,” they said in a presentation at the annual congress of the European Society of Cardiology. The report of the research was published simultaneously in the New England Journal of Medicine.

Findings from previous research have suggested that, for patients with coronary artery disease, a combination of antiplatelet agents and low-dose rivaroxaban (2.5 mg twice daily) reduced incidence of death, myocardial infarction, and stroke. The authors designed the COMMANDER trial to test a similar regimen in patients with chronic heart failure and coronary heart disease without an arrhythmia. Results were published simultaneously in the New England Journal of Medicine.

The COMMANDER trial involved 5,022 patients with coronary artery disease, reduced left ventricular ejection fraction (less than or equal to 40%), worsening chronic heart failure (index event within past 21 days), and normal splasma concentration of brain natriuretic peptide (BNP) of at least 200 ng per liter or N-terminal pro-brain natriuretic peptide (NT-proBNP) of at least 800 ng per liter.

Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily (n = 2,507) or placebo (n = 2,515). Treatment was given in addition to standard care for coronary disease or heart failure (single or dual antiplatelet therapy was allowed). Patients were assessed at week 4 and week 12, then every 12 weeks.

The primary efficacy outcome was a composite of stroke, myocardial infarction, or death from any cause. Secondary efficacy outcomes included death from cardiovascular disease, rehospitalization for heart failure, a composite of either, or rehospitalization for cardiovascular events. The principal safety outcome was a composite of bleeding into a critical space with potential for permanent disability or fatal bleeding.

Death, myocardial failure, or stroke occurred in 626 patients (25%) in the rivaroxaban group compared with 658 patients (26.2%) in the placebo group (P = .27). Secondary efficacy outcomes were also highly similar between groups, differing at most by 0.9%. The principal safety outcome (fatal bleeding or bleeding into a critical space) occurred in 18 patients (0.7%) in the rivaroxaban group and 23 patients (0.9%) in the placebo group (P = .25). Again, no significant difference was found between groups.

These results suggest that while low-dose rivaroxaban may be safe, it also offers no treatment benefit. “The most likely reason for the failure … is that thrombin-mediated events are not the major driver of heart failure-related events in patients with recent hospitalization for heart failure,” the authors wrote.

“Whether a higher dose of rivaroxaban could have led to a more favorable outcome remains unknown,” they concluded.

The COMMANDER trial was funded by Janssen Research and Development. Authors reported compensation from Bayer, Servier, Novartis, Impulse Dynamics, and others.

[email protected]

SOURCE: Zannad F et al. NEJM/ESC.

.

MUNICH – For patients with heart disease, coronary artery disease, and normal sinus rhythm, giving rivaroxaban does not significantly reduce risks of death, myocardial infarction, or stroke, investigators in the COMMANDER trial said.

Rivaroxaban did not improve rehospitalization rates either, reported lead author Faiez Zannad, MD, PhD, from the University of Henri Poincaré in Nancy, France, and his co-investigators.

“After an episode of worsening chronic heart failure, rates of readmission to the hospital and of death are high, especially in the first few months,” they said in a presentation at the annual congress of the European Society of Cardiology. The report of the research was published simultaneously in the New England Journal of Medicine.

Findings from previous research have suggested that, for patients with coronary artery disease, a combination of antiplatelet agents and low-dose rivaroxaban (2.5 mg twice daily) reduced incidence of death, myocardial infarction, and stroke. The authors designed the COMMANDER trial to test a similar regimen in patients with chronic heart failure and coronary heart disease without an arrhythmia. Results were published simultaneously in the New England Journal of Medicine.

The COMMANDER trial involved 5,022 patients with coronary artery disease, reduced left ventricular ejection fraction (less than or equal to 40%), worsening chronic heart failure (index event within past 21 days), and normal splasma concentration of brain natriuretic peptide (BNP) of at least 200 ng per liter or N-terminal pro-brain natriuretic peptide (NT-proBNP) of at least 800 ng per liter.

Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily (n = 2,507) or placebo (n = 2,515). Treatment was given in addition to standard care for coronary disease or heart failure (single or dual antiplatelet therapy was allowed). Patients were assessed at week 4 and week 12, then every 12 weeks.

The primary efficacy outcome was a composite of stroke, myocardial infarction, or death from any cause. Secondary efficacy outcomes included death from cardiovascular disease, rehospitalization for heart failure, a composite of either, or rehospitalization for cardiovascular events. The principal safety outcome was a composite of bleeding into a critical space with potential for permanent disability or fatal bleeding.

Death, myocardial failure, or stroke occurred in 626 patients (25%) in the rivaroxaban group compared with 658 patients (26.2%) in the placebo group (P = .27). Secondary efficacy outcomes were also highly similar between groups, differing at most by 0.9%. The principal safety outcome (fatal bleeding or bleeding into a critical space) occurred in 18 patients (0.7%) in the rivaroxaban group and 23 patients (0.9%) in the placebo group (P = .25). Again, no significant difference was found between groups.

These results suggest that while low-dose rivaroxaban may be safe, it also offers no treatment benefit. “The most likely reason for the failure … is that thrombin-mediated events are not the major driver of heart failure-related events in patients with recent hospitalization for heart failure,” the authors wrote.

“Whether a higher dose of rivaroxaban could have led to a more favorable outcome remains unknown,” they concluded.

The COMMANDER trial was funded by Janssen Research and Development. Authors reported compensation from Bayer, Servier, Novartis, Impulse Dynamics, and others.

[email protected]

SOURCE: Zannad F et al. NEJM/ESC.

.

MUNICH – For patients with heart disease, coronary artery disease, and normal sinus rhythm, giving rivaroxaban does not significantly reduce risks of death, myocardial infarction, or stroke, investigators in the COMMANDER trial said.

Rivaroxaban did not improve rehospitalization rates either, reported lead author Faiez Zannad, MD, PhD, from the University of Henri Poincaré in Nancy, France, and his co-investigators.

“After an episode of worsening chronic heart failure, rates of readmission to the hospital and of death are high, especially in the first few months,” they said in a presentation at the annual congress of the European Society of Cardiology. The report of the research was published simultaneously in the New England Journal of Medicine.

Findings from previous research have suggested that, for patients with coronary artery disease, a combination of antiplatelet agents and low-dose rivaroxaban (2.5 mg twice daily) reduced incidence of death, myocardial infarction, and stroke. The authors designed the COMMANDER trial to test a similar regimen in patients with chronic heart failure and coronary heart disease without an arrhythmia. Results were published simultaneously in the New England Journal of Medicine.

The COMMANDER trial involved 5,022 patients with coronary artery disease, reduced left ventricular ejection fraction (less than or equal to 40%), worsening chronic heart failure (index event within past 21 days), and normal splasma concentration of brain natriuretic peptide (BNP) of at least 200 ng per liter or N-terminal pro-brain natriuretic peptide (NT-proBNP) of at least 800 ng per liter.

Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily (n = 2,507) or placebo (n = 2,515). Treatment was given in addition to standard care for coronary disease or heart failure (single or dual antiplatelet therapy was allowed). Patients were assessed at week 4 and week 12, then every 12 weeks.

The primary efficacy outcome was a composite of stroke, myocardial infarction, or death from any cause. Secondary efficacy outcomes included death from cardiovascular disease, rehospitalization for heart failure, a composite of either, or rehospitalization for cardiovascular events. The principal safety outcome was a composite of bleeding into a critical space with potential for permanent disability or fatal bleeding.

Death, myocardial failure, or stroke occurred in 626 patients (25%) in the rivaroxaban group compared with 658 patients (26.2%) in the placebo group (P = .27). Secondary efficacy outcomes were also highly similar between groups, differing at most by 0.9%. The principal safety outcome (fatal bleeding or bleeding into a critical space) occurred in 18 patients (0.7%) in the rivaroxaban group and 23 patients (0.9%) in the placebo group (P = .25). Again, no significant difference was found between groups.

These results suggest that while low-dose rivaroxaban may be safe, it also offers no treatment benefit. “The most likely reason for the failure … is that thrombin-mediated events are not the major driver of heart failure-related events in patients with recent hospitalization for heart failure,” the authors wrote.

“Whether a higher dose of rivaroxaban could have led to a more favorable outcome remains unknown,” they concluded.

The COMMANDER trial was funded by Janssen Research and Development. Authors reported compensation from Bayer, Servier, Novartis, Impulse Dynamics, and others.

[email protected]

SOURCE: Zannad F et al. NEJM/ESC.

.

For patients hospitalized for medical illness, giving rivaroxaban after discharge does not significantly reduce the risk of venous thromboembolism, investigators reported.

Previous research suggested that the risk of major bleeding from rivaroxaban outweighed its benefits; however, major bleeding was uncommon in the MARINER trial, reported lead author Alex C. Spyropoulos, MD, of Hofstra University in Hempstead, N.Y., and his colleagues.

“Patients who are hospitalized for acute medical illnesses, such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases, are at increased risk for venous thromboembolism,” they wrote in the New England Journal of Medicine. The results were also presented at the annual congress of the European Society of Cardiology.

Although the increased risk of thromboembolism continues for at least 6 weeks after hospitalization, postdischarge anticoagulants, such as rivaroxaban, are controversial.

“Studies of extended thromboprophylaxis have shown either excess major bleeding or a benefit that is based mainly on reducing the risk of asymptomatic deep-vein thrombosis,” the investigators wrote.

The researchers aimed to clarify the benefits of rivaroxaban after hospitalization while modifying previous study regimens to limit major bleeding risk.

The double-blind MARINER study involved 12,019 patients who were hospitalized for medical illness and had an increased risk of venous thromboembolism. Hospitalization lasted 3-10 consecutive days. Sufficient risk of thromboembolism was defined by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (range, 0-10), or an IMPROVE score of 2 or 3 with a plasma D-dimer measurement more than double the upper normal limit.

Patients were randomized to receive either 10 mg of rivaroxaban daily (n = 6,007) or placebo (n = 6,012) for 45 days after discharge. Patients with renal impairment had a reduced dose of 7.5 mg rivaroxaban.

A composite of symptomatic or fatal venous thromboembolism was the primary efficacy outcome. Major bleeding was the safety benchmark.

Efficacy was similar in both groups. Symptomatic or fatal venous thromboembolism occurred in 50 patients (0.83%) in the rivaroxaban group, compared with 66 patients (1.10%) in the placebo group (P = .14). These findings suggest that rivaroxaban provides a minor and insignificant benefit.

Although major bleeding was slightly more common in patients receiving rivaroxaban, compared with patients receiving placebo (0.28% vs. 0.15%), the researchers suggested that, in large populations, the marginal benefit of rivaroxaban might outweigh the increased bleeding risk. Still, the authors noted that “the usefulness of extended thromboprophylaxis remains uncertain.”

“Future studies should more accurately identify deaths caused by thrombotic mechanisms and focus on the patients who are at highest risk and who may benefit from anticoagulant prophylaxis,” the researchers wrote.

Funding was provided by Janssen Research and Development. Most of the study authors reported fees or grants from Janssen during the study, and relationships with other companies outside of the submitted work.

SOURCE : Spyropoulos AC et al. N Engl J Med. 2018 Aug 26. doi: 10.1056/NEJMoa1805090.

For patients hospitalized for medical illness, giving rivaroxaban after discharge does not significantly reduce the risk of venous thromboembolism, investigators reported.

Previous research suggested that the risk of major bleeding from rivaroxaban outweighed its benefits; however, major bleeding was uncommon in the MARINER trial, reported lead author Alex C. Spyropoulos, MD, of Hofstra University in Hempstead, N.Y., and his colleagues.

“Patients who are hospitalized for acute medical illnesses, such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases, are at increased risk for venous thromboembolism,” they wrote in the New England Journal of Medicine. The results were also presented at the annual congress of the European Society of Cardiology.

Although the increased risk of thromboembolism continues for at least 6 weeks after hospitalization, postdischarge anticoagulants, such as rivaroxaban, are controversial.

“Studies of extended thromboprophylaxis have shown either excess major bleeding or a benefit that is based mainly on reducing the risk of asymptomatic deep-vein thrombosis,” the investigators wrote.

The researchers aimed to clarify the benefits of rivaroxaban after hospitalization while modifying previous study regimens to limit major bleeding risk.

The double-blind MARINER study involved 12,019 patients who were hospitalized for medical illness and had an increased risk of venous thromboembolism. Hospitalization lasted 3-10 consecutive days. Sufficient risk of thromboembolism was defined by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (range, 0-10), or an IMPROVE score of 2 or 3 with a plasma D-dimer measurement more than double the upper normal limit.

Patients were randomized to receive either 10 mg of rivaroxaban daily (n = 6,007) or placebo (n = 6,012) for 45 days after discharge. Patients with renal impairment had a reduced dose of 7.5 mg rivaroxaban.

A composite of symptomatic or fatal venous thromboembolism was the primary efficacy outcome. Major bleeding was the safety benchmark.

Efficacy was similar in both groups. Symptomatic or fatal venous thromboembolism occurred in 50 patients (0.83%) in the rivaroxaban group, compared with 66 patients (1.10%) in the placebo group (P = .14). These findings suggest that rivaroxaban provides a minor and insignificant benefit.

Although major bleeding was slightly more common in patients receiving rivaroxaban, compared with patients receiving placebo (0.28% vs. 0.15%), the researchers suggested that, in large populations, the marginal benefit of rivaroxaban might outweigh the increased bleeding risk. Still, the authors noted that “the usefulness of extended thromboprophylaxis remains uncertain.”

“Future studies should more accurately identify deaths caused by thrombotic mechanisms and focus on the patients who are at highest risk and who may benefit from anticoagulant prophylaxis,” the researchers wrote.

Funding was provided by Janssen Research and Development. Most of the study authors reported fees or grants from Janssen during the study, and relationships with other companies outside of the submitted work.

SOURCE : Spyropoulos AC et al. N Engl J Med. 2018 Aug 26. doi: 10.1056/NEJMoa1805090.

For patients hospitalized for medical illness, giving rivaroxaban after discharge does not significantly reduce the risk of venous thromboembolism, investigators reported.

Previous research suggested that the risk of major bleeding from rivaroxaban outweighed its benefits; however, major bleeding was uncommon in the MARINER trial, reported lead author Alex C. Spyropoulos, MD, of Hofstra University in Hempstead, N.Y., and his colleagues.

“Patients who are hospitalized for acute medical illnesses, such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases, are at increased risk for venous thromboembolism,” they wrote in the New England Journal of Medicine. The results were also presented at the annual congress of the European Society of Cardiology.

Although the increased risk of thromboembolism continues for at least 6 weeks after hospitalization, postdischarge anticoagulants, such as rivaroxaban, are controversial.

“Studies of extended thromboprophylaxis have shown either excess major bleeding or a benefit that is based mainly on reducing the risk of asymptomatic deep-vein thrombosis,” the investigators wrote.

The researchers aimed to clarify the benefits of rivaroxaban after hospitalization while modifying previous study regimens to limit major bleeding risk.

The double-blind MARINER study involved 12,019 patients who were hospitalized for medical illness and had an increased risk of venous thromboembolism. Hospitalization lasted 3-10 consecutive days. Sufficient risk of thromboembolism was defined by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (range, 0-10), or an IMPROVE score of 2 or 3 with a plasma D-dimer measurement more than double the upper normal limit.

Patients were randomized to receive either 10 mg of rivaroxaban daily (n = 6,007) or placebo (n = 6,012) for 45 days after discharge. Patients with renal impairment had a reduced dose of 7.5 mg rivaroxaban.

A composite of symptomatic or fatal venous thromboembolism was the primary efficacy outcome. Major bleeding was the safety benchmark.

Efficacy was similar in both groups. Symptomatic or fatal venous thromboembolism occurred in 50 patients (0.83%) in the rivaroxaban group, compared with 66 patients (1.10%) in the placebo group (P = .14). These findings suggest that rivaroxaban provides a minor and insignificant benefit.

Although major bleeding was slightly more common in patients receiving rivaroxaban, compared with patients receiving placebo (0.28% vs. 0.15%), the researchers suggested that, in large populations, the marginal benefit of rivaroxaban might outweigh the increased bleeding risk. Still, the authors noted that “the usefulness of extended thromboprophylaxis remains uncertain.”

“Future studies should more accurately identify deaths caused by thrombotic mechanisms and focus on the patients who are at highest risk and who may benefit from anticoagulant prophylaxis,” the researchers wrote.

Funding was provided by Janssen Research and Development. Most of the study authors reported fees or grants from Janssen during the study, and relationships with other companies outside of the submitted work.

SOURCE : Spyropoulos AC et al. N Engl J Med. 2018 Aug 26. doi: 10.1056/NEJMoa1805090.

Hypofractionated radiation therapy (RT) may be a more viable treatment option for oligometastatic renal cell carcinoma (RCC) than is generally recognized, a recent literature review has suggested.

Advances in stereotactic RT offer “new opportunities in RCC management” with limited toxicity, reported Francesca De Felice, PhD, of Sapienza University in Rome and her coauthor. The authors suggested that future studies investigate RT in combination with immunotherapy.

“Due to the assumption that RCC is a radioresistant tumor,” the authors wrote in Critical Reviews in Oncology/Hematology, “RT has long been considered a futile approach to manage primary disease” and is predominantly used for treatment of distant metastases with palliative intent. “This review provides highlights in current RCC strategies to potentially suggest a more tailored treatment approach in clinical daily practice.”

The investigators concluded that hypofractionated RT (greater than 3 Gy/fraction) deserves more serious consideration. “It has enormous advantages,” the authors wrote, “assuring ablative doses to the target meanwhile preserving surrounding normal tissues. Using stereotactic technique, surprising high local control rates have been achieved in several tumors (such as lung, liver, and bone), in both primary and oligometastatic setting[s].”

In five studies, single-dose RT (ranging from 8 to 24 Gy) was used to treat patients with RCC and extracranial metastases. Of the patients in these studies, 89% of them achieved local control, median overall survival (OS) ranged from 11.7 months to 21 months, and severe RT-related toxicity occurred 0%-4% of the time.

“Although [there is a] high level of data heterogeneity,” the authors wrote, “this systematic review suggested that stereotactic RT is associated with excellent local control rates and low toxicity incidence. Thus, if feasible, stereotactic RT represents an effective and safe approach to treat RCC metastasis.”

The authors cautioned that “the optimal high dose required for local tumor control has not yet been defined.”

The authors suggested that, in the future, immunotherapy in combination with RT may “produce synergistic effects, resulting in better response rate and duration, given the known immune-modulated abscopal effect of RT.” First, questions about treatment sequencing, dosing, and patient selection would need to be answered. “Further research should be aimed at these clinical needs in order to achieve the maximum benefit to RCC patient[s].”

This study did not receive specific funding.

SOURCE: Felice F et al. Crit Rev Oncol Hematol. 2018 Aug 1. doi: 10.1016/j.critrevonc.2018.06.002

Hypofractionated radiation therapy (RT) may be a more viable treatment option for oligometastatic renal cell carcinoma (RCC) than is generally recognized, a recent literature review has suggested.

Advances in stereotactic RT offer “new opportunities in RCC management” with limited toxicity, reported Francesca De Felice, PhD, of Sapienza University in Rome and her coauthor. The authors suggested that future studies investigate RT in combination with immunotherapy.

“Due to the assumption that RCC is a radioresistant tumor,” the authors wrote in Critical Reviews in Oncology/Hematology, “RT has long been considered a futile approach to manage primary disease” and is predominantly used for treatment of distant metastases with palliative intent. “This review provides highlights in current RCC strategies to potentially suggest a more tailored treatment approach in clinical daily practice.”

The investigators concluded that hypofractionated RT (greater than 3 Gy/fraction) deserves more serious consideration. “It has enormous advantages,” the authors wrote, “assuring ablative doses to the target meanwhile preserving surrounding normal tissues. Using stereotactic technique, surprising high local control rates have been achieved in several tumors (such as lung, liver, and bone), in both primary and oligometastatic setting[s].”

In five studies, single-dose RT (ranging from 8 to 24 Gy) was used to treat patients with RCC and extracranial metastases. Of the patients in these studies, 89% of them achieved local control, median overall survival (OS) ranged from 11.7 months to 21 months, and severe RT-related toxicity occurred 0%-4% of the time.

“Although [there is a] high level of data heterogeneity,” the authors wrote, “this systematic review suggested that stereotactic RT is associated with excellent local control rates and low toxicity incidence. Thus, if feasible, stereotactic RT represents an effective and safe approach to treat RCC metastasis.”

The authors cautioned that “the optimal high dose required for local tumor control has not yet been defined.”

The authors suggested that, in the future, immunotherapy in combination with RT may “produce synergistic effects, resulting in better response rate and duration, given the known immune-modulated abscopal effect of RT.” First, questions about treatment sequencing, dosing, and patient selection would need to be answered. “Further research should be aimed at these clinical needs in order to achieve the maximum benefit to RCC patient[s].”

This study did not receive specific funding.

SOURCE: Felice F et al. Crit Rev Oncol Hematol. 2018 Aug 1. doi: 10.1016/j.critrevonc.2018.06.002

Hypofractionated radiation therapy (RT) may be a more viable treatment option for oligometastatic renal cell carcinoma (RCC) than is generally recognized, a recent literature review has suggested.

Advances in stereotactic RT offer “new opportunities in RCC management” with limited toxicity, reported Francesca De Felice, PhD, of Sapienza University in Rome and her coauthor. The authors suggested that future studies investigate RT in combination with immunotherapy.

“Due to the assumption that RCC is a radioresistant tumor,” the authors wrote in Critical Reviews in Oncology/Hematology, “RT has long been considered a futile approach to manage primary disease” and is predominantly used for treatment of distant metastases with palliative intent. “This review provides highlights in current RCC strategies to potentially suggest a more tailored treatment approach in clinical daily practice.”

The investigators concluded that hypofractionated RT (greater than 3 Gy/fraction) deserves more serious consideration. “It has enormous advantages,” the authors wrote, “assuring ablative doses to the target meanwhile preserving surrounding normal tissues. Using stereotactic technique, surprising high local control rates have been achieved in several tumors (such as lung, liver, and bone), in both primary and oligometastatic setting[s].”

In five studies, single-dose RT (ranging from 8 to 24 Gy) was used to treat patients with RCC and extracranial metastases. Of the patients in these studies, 89% of them achieved local control, median overall survival (OS) ranged from 11.7 months to 21 months, and severe RT-related toxicity occurred 0%-4% of the time.

“Although [there is a] high level of data heterogeneity,” the authors wrote, “this systematic review suggested that stereotactic RT is associated with excellent local control rates and low toxicity incidence. Thus, if feasible, stereotactic RT represents an effective and safe approach to treat RCC metastasis.”

The authors cautioned that “the optimal high dose required for local tumor control has not yet been defined.”

The authors suggested that, in the future, immunotherapy in combination with RT may “produce synergistic effects, resulting in better response rate and duration, given the known immune-modulated abscopal effect of RT.” First, questions about treatment sequencing, dosing, and patient selection would need to be answered. “Further research should be aimed at these clinical needs in order to achieve the maximum benefit to RCC patient[s].”

This study did not receive specific funding.

SOURCE: Felice F et al. Crit Rev Oncol Hematol. 2018 Aug 1. doi: 10.1016/j.critrevonc.2018.06.002

The incidence of metastatic renal cell carcinoma (RCC) continues to rise, according to a recent study. In turn, skeletal-related events are also becoming more common.

Many patients with metastatic disease have skeletal involvement, so knowledge of skeletal-related events (SREs) is more important than ever, reported Masood Umer, MD, of Aga Khan University Hospital in Karachi, Pakistan, and his coauthors. SREs include nerve compression, hypercalcemia, impending fractures, and pathological fractures, any one of which may require medical or surgical intervention.

Beyond SREs, “bone metastases in RCC [have a] negative impact on progression-free survival and overall survival of patients treated with systemic therapies,” the authors wrote in Annals of Medicine and Surgery.

The authors conducted a literature review of skeletal metastasis in RCC, which included 947 patients, assessing incidence and discussing appropriate medical and surgical interventions.

A total of 26.7% of patients with RCC also had skeletal metastasis. The most common sites of metastasis were the proximal femur, pelvis, and spine. It was estimated that 85% of patients with metastatic RCC may experience SREs and related complications, with an average of more than two events per individual.

A multimodal approach is required, potentially involving surgical and medical interventions. For isolated bony metastases and fractures, surgery is often beneficial. Denosumab is the leading medical treatment; compared with zoledronic acid, denosumab prolongs time to first SRE by a median of approximately 8 months and reduces risk of first SRE by almost 20%. Risks of osteonecrosis are similar between agents.

The authors noted that research concerning the impact of targeted therapies on rates of bone metastasis and SREs is limited by patient exclusions in clinical trials. Granted, these agents have likely made for better outcomes.

“Advancement in targeted therapy in recent decades [has] made some improvement in treatment of SREs and has helped in improving patent’s quality of life, but still we are in need of further improvement in treatment modalities,” they concluded

This study did not receive specific funding.

SOURCE: Umer M et al. Ann Med Surg. 2018 Jan 21. doi: 10.1016/j.amsu.2018.01.002.

The incidence of metastatic renal cell carcinoma (RCC) continues to rise, according to a recent study. In turn, skeletal-related events are also becoming more common.

Many patients with metastatic disease have skeletal involvement, so knowledge of skeletal-related events (SREs) is more important than ever, reported Masood Umer, MD, of Aga Khan University Hospital in Karachi, Pakistan, and his coauthors. SREs include nerve compression, hypercalcemia, impending fractures, and pathological fractures, any one of which may require medical or surgical intervention.

Beyond SREs, “bone metastases in RCC [have a] negative impact on progression-free survival and overall survival of patients treated with systemic therapies,” the authors wrote in Annals of Medicine and Surgery.

The authors conducted a literature review of skeletal metastasis in RCC, which included 947 patients, assessing incidence and discussing appropriate medical and surgical interventions.

A total of 26.7% of patients with RCC also had skeletal metastasis. The most common sites of metastasis were the proximal femur, pelvis, and spine. It was estimated that 85% of patients with metastatic RCC may experience SREs and related complications, with an average of more than two events per individual.

A multimodal approach is required, potentially involving surgical and medical interventions. For isolated bony metastases and fractures, surgery is often beneficial. Denosumab is the leading medical treatment; compared with zoledronic acid, denosumab prolongs time to first SRE by a median of approximately 8 months and reduces risk of first SRE by almost 20%. Risks of osteonecrosis are similar between agents.

The authors noted that research concerning the impact of targeted therapies on rates of bone metastasis and SREs is limited by patient exclusions in clinical trials. Granted, these agents have likely made for better outcomes.

“Advancement in targeted therapy in recent decades [has] made some improvement in treatment of SREs and has helped in improving patent’s quality of life, but still we are in need of further improvement in treatment modalities,” they concluded

This study did not receive specific funding.

SOURCE: Umer M et al. Ann Med Surg. 2018 Jan 21. doi: 10.1016/j.amsu.2018.01.002.

The incidence of metastatic renal cell carcinoma (RCC) continues to rise, according to a recent study. In turn, skeletal-related events are also becoming more common.

Many patients with metastatic disease have skeletal involvement, so knowledge of skeletal-related events (SREs) is more important than ever, reported Masood Umer, MD, of Aga Khan University Hospital in Karachi, Pakistan, and his coauthors. SREs include nerve compression, hypercalcemia, impending fractures, and pathological fractures, any one of which may require medical or surgical intervention.

Beyond SREs, “bone metastases in RCC [have a] negative impact on progression-free survival and overall survival of patients treated with systemic therapies,” the authors wrote in Annals of Medicine and Surgery.

The authors conducted a literature review of skeletal metastasis in RCC, which included 947 patients, assessing incidence and discussing appropriate medical and surgical interventions.

A total of 26.7% of patients with RCC also had skeletal metastasis. The most common sites of metastasis were the proximal femur, pelvis, and spine. It was estimated that 85% of patients with metastatic RCC may experience SREs and related complications, with an average of more than two events per individual.

A multimodal approach is required, potentially involving surgical and medical interventions. For isolated bony metastases and fractures, surgery is often beneficial. Denosumab is the leading medical treatment; compared with zoledronic acid, denosumab prolongs time to first SRE by a median of approximately 8 months and reduces risk of first SRE by almost 20%. Risks of osteonecrosis are similar between agents.

The authors noted that research concerning the impact of targeted therapies on rates of bone metastasis and SREs is limited by patient exclusions in clinical trials. Granted, these agents have likely made for better outcomes.

“Advancement in targeted therapy in recent decades [has] made some improvement in treatment of SREs and has helped in improving patent’s quality of life, but still we are in need of further improvement in treatment modalities,” they concluded

This study did not receive specific funding.

SOURCE: Umer M et al. Ann Med Surg. 2018 Jan 21. doi: 10.1016/j.amsu.2018.01.002.

Nivolumab alone or in combination with ipilimumab met multiple endpoints against metastatic or locally advanced chemotherapy-refractory esophagogastric cancer in the recent phase 1/2 CheckMate-032 trial, thereby opening doors to a future phase 3 trial.

The agents demonstrated “clinically meaningful antitumor activity,” reported Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, New York, and her coauthors.

After the 2017 ATTRACTION-2 trial demonstrated improved survival rates, “nivolumab was approved in Japan for the treatment of patients with chemotherapy-refractory gastric and gastroesophageal junction [GEJ] cancers regardless of programmed death-ligand 1 [PD-L1] status,” the authors wrote in the Journal of Clinical Oncology.

Nivolumab is a checkpoint inhibitor, like pembrolizumab, which “was approved for the treatment of patients with chemotherapy-refractory PD-L1–positive gastric/GEJ cancer on the basis of the promising clinical activity observed in the KEYNOTE-059 trial,” the authors noted. Testing nivolumab in a Western population would therefore build on these previous trials. Combining nivolumab, a PD-l inhibitor, with ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, was based on “synergistic activity” reported in preclinical models, the authors wrote.

Results from the ongoing CheckMate-032 trial included 160 patients with metastatic or locally advanced chemotherapy-refractory esophageal, gastric, or gastroesophageal junction cancer treated at centers in Europe and the United States. Just under 80% of patients had received two or more prior therapies.

In the present trial, patients were given one of three treatment regimens: nivolumab 3 mg/kg every 2 weeks, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles (NIVO1 + IPI3), or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles (NIVO3 + IPI1). The primary endpoint was objective response rate (ORR). Secondary endpoints included 12-month progression-free survival and 12-month overall survival (OS).

Patients in the NIVO1 + IPI3 group achieved the best ORR (24%) and 12-month progression-free survival (17%) and also showed a promising 12-month OS (35%), second only to nivolumab monotherapy (39%). PD-L1 status was not predictive of treatment response.

Although NIVO1 + IPI3 was the most clinically effective, almost half (47%) of these patients also had grade 3 or higher adverse events, compared with more favorable rates of 17% and 27% for nivolumab monotherapy and NIVO3 + IPI1, respectively.

Still, the authors concluded, “on the basis of the numerically higher overall response and landmark OS rates in the NIVO1 + IPI3 arm, this combination was considered more likely to offer clinical benefit relative to currently available treatment regimens for first-line metastatic esophagogastric cancer and was selected for further evaluation in the phase 3 CheckMate-649 study (NCT02872116).” This trial, along with another to investigate nivolumab in the adjuvant setting (NCT02743494), are ongoing.

CheckMate-032 was supported by Bristol-Myers Squibb. The authors also reported funding from Merck, Incyte, Gilead Sciences, and others.

SOURCE: Janjigian YY et al. J Clin Oncol. 2018 Aug 15. doi: 10.1200/JCO.2017.76.6212.

Nivolumab alone or in combination with ipilimumab met multiple endpoints against metastatic or locally advanced chemotherapy-refractory esophagogastric cancer in the recent phase 1/2 CheckMate-032 trial, thereby opening doors to a future phase 3 trial.

The agents demonstrated “clinically meaningful antitumor activity,” reported Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, New York, and her coauthors.

After the 2017 ATTRACTION-2 trial demonstrated improved survival rates, “nivolumab was approved in Japan for the treatment of patients with chemotherapy-refractory gastric and gastroesophageal junction [GEJ] cancers regardless of programmed death-ligand 1 [PD-L1] status,” the authors wrote in the Journal of Clinical Oncology.

Nivolumab is a checkpoint inhibitor, like pembrolizumab, which “was approved for the treatment of patients with chemotherapy-refractory PD-L1–positive gastric/GEJ cancer on the basis of the promising clinical activity observed in the KEYNOTE-059 trial,” the authors noted. Testing nivolumab in a Western population would therefore build on these previous trials. Combining nivolumab, a PD-l inhibitor, with ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, was based on “synergistic activity” reported in preclinical models, the authors wrote.

Results from the ongoing CheckMate-032 trial included 160 patients with metastatic or locally advanced chemotherapy-refractory esophageal, gastric, or gastroesophageal junction cancer treated at centers in Europe and the United States. Just under 80% of patients had received two or more prior therapies.

In the present trial, patients were given one of three treatment regimens: nivolumab 3 mg/kg every 2 weeks, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles (NIVO1 + IPI3), or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles (NIVO3 + IPI1). The primary endpoint was objective response rate (ORR). Secondary endpoints included 12-month progression-free survival and 12-month overall survival (OS).

Patients in the NIVO1 + IPI3 group achieved the best ORR (24%) and 12-month progression-free survival (17%) and also showed a promising 12-month OS (35%), second only to nivolumab monotherapy (39%). PD-L1 status was not predictive of treatment response.

Although NIVO1 + IPI3 was the most clinically effective, almost half (47%) of these patients also had grade 3 or higher adverse events, compared with more favorable rates of 17% and 27% for nivolumab monotherapy and NIVO3 + IPI1, respectively.

Still, the authors concluded, “on the basis of the numerically higher overall response and landmark OS rates in the NIVO1 + IPI3 arm, this combination was considered more likely to offer clinical benefit relative to currently available treatment regimens for first-line metastatic esophagogastric cancer and was selected for further evaluation in the phase 3 CheckMate-649 study (NCT02872116).” This trial, along with another to investigate nivolumab in the adjuvant setting (NCT02743494), are ongoing.

CheckMate-032 was supported by Bristol-Myers Squibb. The authors also reported funding from Merck, Incyte, Gilead Sciences, and others.

SOURCE: Janjigian YY et al. J Clin Oncol. 2018 Aug 15. doi: 10.1200/JCO.2017.76.6212.

Nivolumab alone or in combination with ipilimumab met multiple endpoints against metastatic or locally advanced chemotherapy-refractory esophagogastric cancer in the recent phase 1/2 CheckMate-032 trial, thereby opening doors to a future phase 3 trial.

The agents demonstrated “clinically meaningful antitumor activity,” reported Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, New York, and her coauthors.

After the 2017 ATTRACTION-2 trial demonstrated improved survival rates, “nivolumab was approved in Japan for the treatment of patients with chemotherapy-refractory gastric and gastroesophageal junction [GEJ] cancers regardless of programmed death-ligand 1 [PD-L1] status,” the authors wrote in the Journal of Clinical Oncology.

Nivolumab is a checkpoint inhibitor, like pembrolizumab, which “was approved for the treatment of patients with chemotherapy-refractory PD-L1–positive gastric/GEJ cancer on the basis of the promising clinical activity observed in the KEYNOTE-059 trial,” the authors noted. Testing nivolumab in a Western population would therefore build on these previous trials. Combining nivolumab, a PD-l inhibitor, with ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, was based on “synergistic activity” reported in preclinical models, the authors wrote.

Results from the ongoing CheckMate-032 trial included 160 patients with metastatic or locally advanced chemotherapy-refractory esophageal, gastric, or gastroesophageal junction cancer treated at centers in Europe and the United States. Just under 80% of patients had received two or more prior therapies.

In the present trial, patients were given one of three treatment regimens: nivolumab 3 mg/kg every 2 weeks, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles (NIVO1 + IPI3), or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles (NIVO3 + IPI1). The primary endpoint was objective response rate (ORR). Secondary endpoints included 12-month progression-free survival and 12-month overall survival (OS).

Patients in the NIVO1 + IPI3 group achieved the best ORR (24%) and 12-month progression-free survival (17%) and also showed a promising 12-month OS (35%), second only to nivolumab monotherapy (39%). PD-L1 status was not predictive of treatment response.

Although NIVO1 + IPI3 was the most clinically effective, almost half (47%) of these patients also had grade 3 or higher adverse events, compared with more favorable rates of 17% and 27% for nivolumab monotherapy and NIVO3 + IPI1, respectively.

Still, the authors concluded, “on the basis of the numerically higher overall response and landmark OS rates in the NIVO1 + IPI3 arm, this combination was considered more likely to offer clinical benefit relative to currently available treatment regimens for first-line metastatic esophagogastric cancer and was selected for further evaluation in the phase 3 CheckMate-649 study (NCT02872116).” This trial, along with another to investigate nivolumab in the adjuvant setting (NCT02743494), are ongoing.

CheckMate-032 was supported by Bristol-Myers Squibb. The authors also reported funding from Merck, Incyte, Gilead Sciences, and others.

SOURCE: Janjigian YY et al. J Clin Oncol. 2018 Aug 15. doi: 10.1200/JCO.2017.76.6212.

For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

BluePlanetEarth/thinkstockphotos.com

More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m² subcutaneous IV for 7 days) or decitabine (20 mg/m² IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.

For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

BluePlanetEarth/thinkstockphotos.com

More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m² subcutaneous IV for 7 days) or decitabine (20 mg/m² IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.

For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

BluePlanetEarth/thinkstockphotos.com

More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m² subcutaneous IV for 7 days) or decitabine (20 mg/m² IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.