Will Pass

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.

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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.

In patients with seropositive rheumatoid arthritis, seroconversion within the first year of treatment is not associated with long-term sustained drug-free remission (SDFR), according to results of a randomized, treat-to-target study of patients with early RA.

Suze777/Thinkstock

“The clinical significance of seroconversion in RA and especially its relationship with long-term SDFR, an approximation of disease ‘cure’ of RA, is a topic of major interest,” wrote Emma C. de Moel, of the department of rheumatology at Leiden (Netherlands) University Medical Center, and her coauthors.

“Previous studies found no association of seroconversion with remission or radiographic damage,” the investigators wrote in Annals of the Rheumatic Diseases. “We here investigated the association between seroconversion and ... SDFR and found no association.”

The study involved 381 patients with early RA (less than 2 years) from the IMPROVED trial who were treated with methotrexate and high-dose prednisone. At baseline and 12 months, 14 RA-associated autoantibodies were measured by ELISA, including anti-CCP2 and rheumatoid factor. Patients were monitored for long-term SDFR, defined as remission lasting longer than 1 year, beginning at any time, and persisting until the maximum follow-up of 5 years.

An association between seroconversion and SDFR was not found. At 12 months, 6 of 170 patients (3.5%) had seroconverted all autoantibodies to negative, and 2 of these 6 patients achieved SDFR, compared with 19 of 164 seropositive patients (11.6%) who achieved SDFR without seroconversion (P = .11). Additionally, neither the proportion of autoantibodies converted to negative nor relative decreases in autoantibody levels were associated with SDFR.

“It appears that seroconversion (as measured by current standards) does not identify a group of patients in ... true immunological remission, and is not superior to signals of low inflammatory load (e.g. by DAS 6) for predicting successful drug tapering,” the investigators concluded. “Future studies are needed to identify whether other immunological parameters such as the numbers or phenotype of circulating autoreactive B or T cells might be a better reflection of disease persistence and markers for immunological remission.”

The study was funded by ZonMw (the Netherlands Organization for Health Research and Development)-consortium Molecular Diagnostics in RA (MODIRA).

SOURCE: de Moel EC et al. Ann Rheum Dis. 2018 Jul 25. doi: 10.1136/annrheumdis-2018-213823.

In patients with seropositive rheumatoid arthritis, seroconversion within the first year of treatment is not associated with long-term sustained drug-free remission (SDFR), according to results of a randomized, treat-to-target study of patients with early RA.

Suze777/Thinkstock

“The clinical significance of seroconversion in RA and especially its relationship with long-term SDFR, an approximation of disease ‘cure’ of RA, is a topic of major interest,” wrote Emma C. de Moel, of the department of rheumatology at Leiden (Netherlands) University Medical Center, and her coauthors.

“Previous studies found no association of seroconversion with remission or radiographic damage,” the investigators wrote in Annals of the Rheumatic Diseases. “We here investigated the association between seroconversion and ... SDFR and found no association.”

The study involved 381 patients with early RA (less than 2 years) from the IMPROVED trial who were treated with methotrexate and high-dose prednisone. At baseline and 12 months, 14 RA-associated autoantibodies were measured by ELISA, including anti-CCP2 and rheumatoid factor. Patients were monitored for long-term SDFR, defined as remission lasting longer than 1 year, beginning at any time, and persisting until the maximum follow-up of 5 years.

An association between seroconversion and SDFR was not found. At 12 months, 6 of 170 patients (3.5%) had seroconverted all autoantibodies to negative, and 2 of these 6 patients achieved SDFR, compared with 19 of 164 seropositive patients (11.6%) who achieved SDFR without seroconversion (P = .11). Additionally, neither the proportion of autoantibodies converted to negative nor relative decreases in autoantibody levels were associated with SDFR.

“It appears that seroconversion (as measured by current standards) does not identify a group of patients in ... true immunological remission, and is not superior to signals of low inflammatory load (e.g. by DAS 6) for predicting successful drug tapering,” the investigators concluded. “Future studies are needed to identify whether other immunological parameters such as the numbers or phenotype of circulating autoreactive B or T cells might be a better reflection of disease persistence and markers for immunological remission.”

The study was funded by ZonMw (the Netherlands Organization for Health Research and Development)-consortium Molecular Diagnostics in RA (MODIRA).

SOURCE: de Moel EC et al. Ann Rheum Dis. 2018 Jul 25. doi: 10.1136/annrheumdis-2018-213823.

In patients with seropositive rheumatoid arthritis, seroconversion within the first year of treatment is not associated with long-term sustained drug-free remission (SDFR), according to results of a randomized, treat-to-target study of patients with early RA.

Suze777/Thinkstock

“The clinical significance of seroconversion in RA and especially its relationship with long-term SDFR, an approximation of disease ‘cure’ of RA, is a topic of major interest,” wrote Emma C. de Moel, of the department of rheumatology at Leiden (Netherlands) University Medical Center, and her coauthors.

“Previous studies found no association of seroconversion with remission or radiographic damage,” the investigators wrote in Annals of the Rheumatic Diseases. “We here investigated the association between seroconversion and ... SDFR and found no association.”

The study involved 381 patients with early RA (less than 2 years) from the IMPROVED trial who were treated with methotrexate and high-dose prednisone. At baseline and 12 months, 14 RA-associated autoantibodies were measured by ELISA, including anti-CCP2 and rheumatoid factor. Patients were monitored for long-term SDFR, defined as remission lasting longer than 1 year, beginning at any time, and persisting until the maximum follow-up of 5 years.

An association between seroconversion and SDFR was not found. At 12 months, 6 of 170 patients (3.5%) had seroconverted all autoantibodies to negative, and 2 of these 6 patients achieved SDFR, compared with 19 of 164 seropositive patients (11.6%) who achieved SDFR without seroconversion (P = .11). Additionally, neither the proportion of autoantibodies converted to negative nor relative decreases in autoantibody levels were associated with SDFR.

“It appears that seroconversion (as measured by current standards) does not identify a group of patients in ... true immunological remission, and is not superior to signals of low inflammatory load (e.g. by DAS 6) for predicting successful drug tapering,” the investigators concluded. “Future studies are needed to identify whether other immunological parameters such as the numbers or phenotype of circulating autoreactive B or T cells might be a better reflection of disease persistence and markers for immunological remission.”

The study was funded by ZonMw (the Netherlands Organization for Health Research and Development)-consortium Molecular Diagnostics in RA (MODIRA).

SOURCE: de Moel EC et al. Ann Rheum Dis. 2018 Jul 25. doi: 10.1136/annrheumdis-2018-213823.

In the third-line setting, avelumab is safer than chemotherapy for patients with metastatic gastric cancer, according to a recent study.

Although no primary or secondary endpoints were met, avelumab demonstrated similar antitumor activity compared with chemotherapy, reported Yung-Jue Bang, MD, PhD, of Seoul National University College of Medicine, South Korea, and his coauthors.

“There currently are no internationally recognized treatment guidelines for patients with advanced gastric cancer/gastroesophageal junction cancer [GC/GEJC] in whom two prior lines of therapy have failed,” the investigators wrote in Annals of Oncology.

The phase 3, randomized JAVELIN Gastric 300 trial compared avelumab, an anti–programmed death ligand 1 (PD-L1) monoclonal antibody, with physician’s choice of chemotherapy in 371 patients with metastatic GC/GEJC who had received two previous lines of systemic therapy. A total of 185 patients received avelumab and 186 patients received chemotherapy. Of those in the chemotherapy group, 120 (64.5%) were given irinotecan, 50 (29.0%) were given paclitaxel, and 3 (1.6%) received best supportive care only. The primary endpoint was overall survival, and secondary endpoints were objective response rate and progression-free survival. Safety and tolerability were also evaluated.

Neither primary nor secondary endpoints were met, and no significant difference in efficacy was found between treatment arms. However, tolerability was notably better in the avelumab treatment group. Treatment-related adverse events occurred in 90 patients (48.9%) in the avelumab group, compared with 131 patients (74.0%) in the chemotherapy group. Grade 3 or higher treatment-related adverse events were also less common in the avelumab group (9.2% vs. 31.6%). In the avelumab treatment arm, 4 patients (2.2%) had grade 3 or higher immune-related adverse events (autoimmune hypothyroidism, autoimmune hepatitis, elevated AST, and colitis).

“These results demonstrate that avelumab is better tolerated than chemotherapy in patients with heavily pretreated GC/GEJC, supporting the potential of avelumab for combination or maintenance therapy, even in later stages of disease,” the investigators wrote. “Nevertheless, the optimal strategy for incorporating checkpoint inhibitors into the continuum of care for patients with advanced GC/GEJC is still unknown, and studies of alternative anti–PD-1/PD-L1 treatment strategies in earlier lines of therapy are warranted.”

The study was funded by Merck and Pfizer. Authors reported compensation from AstraZeneca, Eli Lilly, Novartis, and others.

SOURCE: Bang YJ et al. Ann Oncol. 2018 Jul 24. doi:10.1093/annonc/mdy264.

In the third-line setting, avelumab is safer than chemotherapy for patients with metastatic gastric cancer, according to a recent study.

Although no primary or secondary endpoints were met, avelumab demonstrated similar antitumor activity compared with chemotherapy, reported Yung-Jue Bang, MD, PhD, of Seoul National University College of Medicine, South Korea, and his coauthors.

“There currently are no internationally recognized treatment guidelines for patients with advanced gastric cancer/gastroesophageal junction cancer [GC/GEJC] in whom two prior lines of therapy have failed,” the investigators wrote in Annals of Oncology.

The phase 3, randomized JAVELIN Gastric 300 trial compared avelumab, an anti–programmed death ligand 1 (PD-L1) monoclonal antibody, with physician’s choice of chemotherapy in 371 patients with metastatic GC/GEJC who had received two previous lines of systemic therapy. A total of 185 patients received avelumab and 186 patients received chemotherapy. Of those in the chemotherapy group, 120 (64.5%) were given irinotecan, 50 (29.0%) were given paclitaxel, and 3 (1.6%) received best supportive care only. The primary endpoint was overall survival, and secondary endpoints were objective response rate and progression-free survival. Safety and tolerability were also evaluated.

Neither primary nor secondary endpoints were met, and no significant difference in efficacy was found between treatment arms. However, tolerability was notably better in the avelumab treatment group. Treatment-related adverse events occurred in 90 patients (48.9%) in the avelumab group, compared with 131 patients (74.0%) in the chemotherapy group. Grade 3 or higher treatment-related adverse events were also less common in the avelumab group (9.2% vs. 31.6%). In the avelumab treatment arm, 4 patients (2.2%) had grade 3 or higher immune-related adverse events (autoimmune hypothyroidism, autoimmune hepatitis, elevated AST, and colitis).

“These results demonstrate that avelumab is better tolerated than chemotherapy in patients with heavily pretreated GC/GEJC, supporting the potential of avelumab for combination or maintenance therapy, even in later stages of disease,” the investigators wrote. “Nevertheless, the optimal strategy for incorporating checkpoint inhibitors into the continuum of care for patients with advanced GC/GEJC is still unknown, and studies of alternative anti–PD-1/PD-L1 treatment strategies in earlier lines of therapy are warranted.”

The study was funded by Merck and Pfizer. Authors reported compensation from AstraZeneca, Eli Lilly, Novartis, and others.

SOURCE: Bang YJ et al. Ann Oncol. 2018 Jul 24. doi:10.1093/annonc/mdy264.

In the third-line setting, avelumab is safer than chemotherapy for patients with metastatic gastric cancer, according to a recent study.

Although no primary or secondary endpoints were met, avelumab demonstrated similar antitumor activity compared with chemotherapy, reported Yung-Jue Bang, MD, PhD, of Seoul National University College of Medicine, South Korea, and his coauthors.

“There currently are no internationally recognized treatment guidelines for patients with advanced gastric cancer/gastroesophageal junction cancer [GC/GEJC] in whom two prior lines of therapy have failed,” the investigators wrote in Annals of Oncology.

The phase 3, randomized JAVELIN Gastric 300 trial compared avelumab, an anti–programmed death ligand 1 (PD-L1) monoclonal antibody, with physician’s choice of chemotherapy in 371 patients with metastatic GC/GEJC who had received two previous lines of systemic therapy. A total of 185 patients received avelumab and 186 patients received chemotherapy. Of those in the chemotherapy group, 120 (64.5%) were given irinotecan, 50 (29.0%) were given paclitaxel, and 3 (1.6%) received best supportive care only. The primary endpoint was overall survival, and secondary endpoints were objective response rate and progression-free survival. Safety and tolerability were also evaluated.

Neither primary nor secondary endpoints were met, and no significant difference in efficacy was found between treatment arms. However, tolerability was notably better in the avelumab treatment group. Treatment-related adverse events occurred in 90 patients (48.9%) in the avelumab group, compared with 131 patients (74.0%) in the chemotherapy group. Grade 3 or higher treatment-related adverse events were also less common in the avelumab group (9.2% vs. 31.6%). In the avelumab treatment arm, 4 patients (2.2%) had grade 3 or higher immune-related adverse events (autoimmune hypothyroidism, autoimmune hepatitis, elevated AST, and colitis).

“These results demonstrate that avelumab is better tolerated than chemotherapy in patients with heavily pretreated GC/GEJC, supporting the potential of avelumab for combination or maintenance therapy, even in later stages of disease,” the investigators wrote. “Nevertheless, the optimal strategy for incorporating checkpoint inhibitors into the continuum of care for patients with advanced GC/GEJC is still unknown, and studies of alternative anti–PD-1/PD-L1 treatment strategies in earlier lines of therapy are warranted.”

The study was funded by Merck and Pfizer. Authors reported compensation from AstraZeneca, Eli Lilly, Novartis, and others.

SOURCE: Bang YJ et al. Ann Oncol. 2018 Jul 24. doi:10.1093/annonc/mdy264.

For patients with non–small cell lung cancer (NSCLC), rapid EGFR-specific genotyping reduces time to initiation (TTI) of targeted therapy, compared with current next-generation sequencing (NGS) work flows, according to a recent study.

Rapid testing maintained concordance with NGS while cutting median turnaround time in half. In addition, an ultrarapid, next-day work flow allowed several highly symptomatic patients with NSCLC to start therapy within 1 week of biopsy, reported Ibiayi Dagogo-Jack, MD, of the Massachusetts General Hospital Waltham Cancer Center and her coauthors.

Molecular testing for patients with NSCLC is necessary to select appropriate therapies; however, “genotyping by NGS requires complex bioinformatics that can create treatment delays,” the investigators wrote in JCO Precision Oncology. “Some patients with NSCLC present with symptomatic disease that requires initiation of treatment before molecular testing results are available. To our knowledge, the impact of molecular testing turnaround time on clinical decision making has not been formally assessed in NSCLC.”

For rapid testing, biopsies were collected from 243 hospitalized patients with newly diagnosed, metastatic NSCLC and were then fixed in formalin. An EGFR-specific polymerase chain reaction assay was then used to identify exon 19 deletions and L858R mutations. The ultrarapid testing phase of the study involved eight highly symptomatic patients with newly diagnosed NSCLC. Biopsy samples in this group were frozen instead of fixed. Both the rapid and ultrarapid testing results were compared with 121 historical biopsies that had been genotyped by NGS.

The rapid testing’s work flow reduced TTI from 37 days to 22 days (P = .01) while maintaining high concordance with NGS (sensitivity, 98%; specificity, 100%). Median turnaround time dropped in half from 14 days to 7 days with rapid testing (P less than .001); ultrarapid testing had a turnaround time of approximately 1 day. The median TTI for the ultrarapid group was 9 days, and several patients were able to begin therapy within 1 week.

The investigators concluded that rapid and ultrarapid testing are a cost-effective, reliable means for decreasing turnaround time and TTI for patients with newly diagnosed, metastatic NSCLC. However, concurrent NGS genotyping should still be performed because NGS results may influence future therapy sequencing. With the ultrarapid work flow, additional sampling is recommended to offset the risk of tissue failure. The investigators noted that “the growing number of actionable targets substantiates the need for diagnostic strategies that expedite molecular analysis.”

The study was funded in part by the National Institutes of Health. Authors reported compensation from Merck, Boehringer Ingelheim, Takeda, and others.

SOURCE: Dagogo-Jack et al. JCO Precis Oncol. 2018 Jul 24. doi: 10.1200/PO.17.00299.

For patients with non–small cell lung cancer (NSCLC), rapid EGFR-specific genotyping reduces time to initiation (TTI) of targeted therapy, compared with current next-generation sequencing (NGS) work flows, according to a recent study.

Rapid testing maintained concordance with NGS while cutting median turnaround time in half. In addition, an ultrarapid, next-day work flow allowed several highly symptomatic patients with NSCLC to start therapy within 1 week of biopsy, reported Ibiayi Dagogo-Jack, MD, of the Massachusetts General Hospital Waltham Cancer Center and her coauthors.

Molecular testing for patients with NSCLC is necessary to select appropriate therapies; however, “genotyping by NGS requires complex bioinformatics that can create treatment delays,” the investigators wrote in JCO Precision Oncology. “Some patients with NSCLC present with symptomatic disease that requires initiation of treatment before molecular testing results are available. To our knowledge, the impact of molecular testing turnaround time on clinical decision making has not been formally assessed in NSCLC.”

For rapid testing, biopsies were collected from 243 hospitalized patients with newly diagnosed, metastatic NSCLC and were then fixed in formalin. An EGFR-specific polymerase chain reaction assay was then used to identify exon 19 deletions and L858R mutations. The ultrarapid testing phase of the study involved eight highly symptomatic patients with newly diagnosed NSCLC. Biopsy samples in this group were frozen instead of fixed. Both the rapid and ultrarapid testing results were compared with 121 historical biopsies that had been genotyped by NGS.

The rapid testing’s work flow reduced TTI from 37 days to 22 days (P = .01) while maintaining high concordance with NGS (sensitivity, 98%; specificity, 100%). Median turnaround time dropped in half from 14 days to 7 days with rapid testing (P less than .001); ultrarapid testing had a turnaround time of approximately 1 day. The median TTI for the ultrarapid group was 9 days, and several patients were able to begin therapy within 1 week.

The investigators concluded that rapid and ultrarapid testing are a cost-effective, reliable means for decreasing turnaround time and TTI for patients with newly diagnosed, metastatic NSCLC. However, concurrent NGS genotyping should still be performed because NGS results may influence future therapy sequencing. With the ultrarapid work flow, additional sampling is recommended to offset the risk of tissue failure. The investigators noted that “the growing number of actionable targets substantiates the need for diagnostic strategies that expedite molecular analysis.”

The study was funded in part by the National Institutes of Health. Authors reported compensation from Merck, Boehringer Ingelheim, Takeda, and others.

SOURCE: Dagogo-Jack et al. JCO Precis Oncol. 2018 Jul 24. doi: 10.1200/PO.17.00299.

For patients with non–small cell lung cancer (NSCLC), rapid EGFR-specific genotyping reduces time to initiation (TTI) of targeted therapy, compared with current next-generation sequencing (NGS) work flows, according to a recent study.

Rapid testing maintained concordance with NGS while cutting median turnaround time in half. In addition, an ultrarapid, next-day work flow allowed several highly symptomatic patients with NSCLC to start therapy within 1 week of biopsy, reported Ibiayi Dagogo-Jack, MD, of the Massachusetts General Hospital Waltham Cancer Center and her coauthors.

Molecular testing for patients with NSCLC is necessary to select appropriate therapies; however, “genotyping by NGS requires complex bioinformatics that can create treatment delays,” the investigators wrote in JCO Precision Oncology. “Some patients with NSCLC present with symptomatic disease that requires initiation of treatment before molecular testing results are available. To our knowledge, the impact of molecular testing turnaround time on clinical decision making has not been formally assessed in NSCLC.”

For rapid testing, biopsies were collected from 243 hospitalized patients with newly diagnosed, metastatic NSCLC and were then fixed in formalin. An EGFR-specific polymerase chain reaction assay was then used to identify exon 19 deletions and L858R mutations. The ultrarapid testing phase of the study involved eight highly symptomatic patients with newly diagnosed NSCLC. Biopsy samples in this group were frozen instead of fixed. Both the rapid and ultrarapid testing results were compared with 121 historical biopsies that had been genotyped by NGS.

The rapid testing’s work flow reduced TTI from 37 days to 22 days (P = .01) while maintaining high concordance with NGS (sensitivity, 98%; specificity, 100%). Median turnaround time dropped in half from 14 days to 7 days with rapid testing (P less than .001); ultrarapid testing had a turnaround time of approximately 1 day. The median TTI for the ultrarapid group was 9 days, and several patients were able to begin therapy within 1 week.

The investigators concluded that rapid and ultrarapid testing are a cost-effective, reliable means for decreasing turnaround time and TTI for patients with newly diagnosed, metastatic NSCLC. However, concurrent NGS genotyping should still be performed because NGS results may influence future therapy sequencing. With the ultrarapid work flow, additional sampling is recommended to offset the risk of tissue failure. The investigators noted that “the growing number of actionable targets substantiates the need for diagnostic strategies that expedite molecular analysis.”

The study was funded in part by the National Institutes of Health. Authors reported compensation from Merck, Boehringer Ingelheim, Takeda, and others.

SOURCE: Dagogo-Jack et al. JCO Precis Oncol. 2018 Jul 24. doi: 10.1200/PO.17.00299.

Prehospital administration of plasma to trauma patients at risk for hemorrhagic shock improves odds of survival, according to the Prehospital Air Medical Plasma (PAMPer) trial.

Patients who received plasma also had a decreased median prothrombin to time ratio, compared with those who received standard-care resuscitation alone.

Spotmatik/ThinkStock

Modern trauma patients benefit “from receiving less crystalloid-based therapy and early balanced blood component–based therapy once they arrive at a facility for definitive care,” Jason L. Sperry, MD, of the University of Pittsburgh and his coauthors wrote in the New England Journal of Medicine. These newer strategies aim to mitigate coagulopathy and its associated downstream complications.

Still, “a majority of deaths from traumatic hemorrhage continue to occur in the first hours after arrival at the trauma center, which underscores the importance of the prehospital environment for early interventions that provide benefit,” the investigators noted.

The PAMPer trial (NCT01818427) examined the efficacy and safety of prehospital plasma resuscitation, comparing it with standard-care resuscitation, in severely injured patients. The phase 3, randomized, superiority trial involved 501 trauma patients at risk for hemorrhagic shock who were transported from 27 air medical bases to nine trauma centers. In total, 230 patients received prehospital plasma and standard-care resuscitation, and 271 patients received standard-care alone. Standard-care included infusion of crystalloid fluids in a goal-directed manner. Air medical bases delivered each type of care in 1-month intervals.

Patients were eligible if they exhibited severe hypotension (systolic blood pressure less than 70 mm Hg) or both hypotension (systolic blood pressure less than 90 mm Hg) and tachycardia (greater than 108 beats per minute).

Eligible patients received two units of thawed plasma, which was completely delivered before administration of any other fluids. If infusion of plasma was not complete upon arrival at the trauma center, infusion was completed before any in-hospital fluids were administered. Following preexisting local protocols, 13 of 27 air transport teams carried 2U of red blood cells. If red blood cells were delivered, then this was performed after plasma administration if the patient was still hypotensive or obviously bleeding.

The 30-day mortality rate among all patients was 29.6%. Approximately one in three patients received a prehospital red blood cell transfusion, and nearly 60% underwent surgery within 24 hours of hospital admission.

A greater percentage of patients in the standard-care group were given red blood cell transfusions, compared with those in the plasma group. The standard-care patients also received greater volumes of crystalloid solution than did those receiving plasma.

The primary outcome, 30-day mortality, was 9.8% lower for patients who received plasma, compared with patients who received standard-care alone (23.2% vs. 33.0%; P = .03). Multivariate regression analysis revealed that plasma delivery accounted for a 39% lower risk of death within 30 days, compared with standard care (P = .02). Within 3 hours of randomization, Kaplan-Meier curves revealed a separation between the two treatment groups that persisted until 30 days.

Median prothrombin to time ratio, the only statistically significant secondary outcome, was lower in the plasma group than it was in the standard-care group (1.2 vs. 1.3; P less than .001).

Other measured parameters were similar between the two main treatment groups, including rates of nosocomial infections, allergic or transfusion-related reactions, acute lung injury/acute respiratory distress syndrome, and multiorgan failure.

“Although we cannot determine the independent or additive effects of prehospital administration of plasma and packed red cells, the survival benefits attributable to plasma administration persisted after adjustment for prehospital red-cell administration, and a subgroup analysis showed no heterogeneity of the treatment effect,” the investigators wrote.

The PAMPer trial was supported by a grant from the U.S. Army Medical Research and Materiel Command. One author reported funding from Janssen Pharmaceuticals, CSL Behring, Haemonetics, and Accriva Diagnostics, as well as having been named on a patent on TLR4 inhibitors for the treatment of inflammatory and infectious disorders.

SOURCE: Sperry JL et al. N Engl J Med. 2018 Jul 26;379(4):315-26.


 

Prehospital administration of plasma to trauma patients at risk for hemorrhagic shock improves odds of survival, according to the Prehospital Air Medical Plasma (PAMPer) trial.

Patients who received plasma also had a decreased median prothrombin to time ratio, compared with those who received standard-care resuscitation alone.

Spotmatik/ThinkStock

Modern trauma patients benefit “from receiving less crystalloid-based therapy and early balanced blood component–based therapy once they arrive at a facility for definitive care,” Jason L. Sperry, MD, of the University of Pittsburgh and his coauthors wrote in the New England Journal of Medicine. These newer strategies aim to mitigate coagulopathy and its associated downstream complications.

Still, “a majority of deaths from traumatic hemorrhage continue to occur in the first hours after arrival at the trauma center, which underscores the importance of the prehospital environment for early interventions that provide benefit,” the investigators noted.

The PAMPer trial (NCT01818427) examined the efficacy and safety of prehospital plasma resuscitation, comparing it with standard-care resuscitation, in severely injured patients. The phase 3, randomized, superiority trial involved 501 trauma patients at risk for hemorrhagic shock who were transported from 27 air medical bases to nine trauma centers. In total, 230 patients received prehospital plasma and standard-care resuscitation, and 271 patients received standard-care alone. Standard-care included infusion of crystalloid fluids in a goal-directed manner. Air medical bases delivered each type of care in 1-month intervals.

Patients were eligible if they exhibited severe hypotension (systolic blood pressure less than 70 mm Hg) or both hypotension (systolic blood pressure less than 90 mm Hg) and tachycardia (greater than 108 beats per minute).

Eligible patients received two units of thawed plasma, which was completely delivered before administration of any other fluids. If infusion of plasma was not complete upon arrival at the trauma center, infusion was completed before any in-hospital fluids were administered. Following preexisting local protocols, 13 of 27 air transport teams carried 2U of red blood cells. If red blood cells were delivered, then this was performed after plasma administration if the patient was still hypotensive or obviously bleeding.

The 30-day mortality rate among all patients was 29.6%. Approximately one in three patients received a prehospital red blood cell transfusion, and nearly 60% underwent surgery within 24 hours of hospital admission.

A greater percentage of patients in the standard-care group were given red blood cell transfusions, compared with those in the plasma group. The standard-care patients also received greater volumes of crystalloid solution than did those receiving plasma.

The primary outcome, 30-day mortality, was 9.8% lower for patients who received plasma, compared with patients who received standard-care alone (23.2% vs. 33.0%; P = .03). Multivariate regression analysis revealed that plasma delivery accounted for a 39% lower risk of death within 30 days, compared with standard care (P = .02). Within 3 hours of randomization, Kaplan-Meier curves revealed a separation between the two treatment groups that persisted until 30 days.

Median prothrombin to time ratio, the only statistically significant secondary outcome, was lower in the plasma group than it was in the standard-care group (1.2 vs. 1.3; P less than .001).

Other measured parameters were similar between the two main treatment groups, including rates of nosocomial infections, allergic or transfusion-related reactions, acute lung injury/acute respiratory distress syndrome, and multiorgan failure.

“Although we cannot determine the independent or additive effects of prehospital administration of plasma and packed red cells, the survival benefits attributable to plasma administration persisted after adjustment for prehospital red-cell administration, and a subgroup analysis showed no heterogeneity of the treatment effect,” the investigators wrote.

The PAMPer trial was supported by a grant from the U.S. Army Medical Research and Materiel Command. One author reported funding from Janssen Pharmaceuticals, CSL Behring, Haemonetics, and Accriva Diagnostics, as well as having been named on a patent on TLR4 inhibitors for the treatment of inflammatory and infectious disorders.

SOURCE: Sperry JL et al. N Engl J Med. 2018 Jul 26;379(4):315-26.


 

Prehospital administration of plasma to trauma patients at risk for hemorrhagic shock improves odds of survival, according to the Prehospital Air Medical Plasma (PAMPer) trial.

Patients who received plasma also had a decreased median prothrombin to time ratio, compared with those who received standard-care resuscitation alone.

Spotmatik/ThinkStock

Modern trauma patients benefit “from receiving less crystalloid-based therapy and early balanced blood component–based therapy once they arrive at a facility for definitive care,” Jason L. Sperry, MD, of the University of Pittsburgh and his coauthors wrote in the New England Journal of Medicine. These newer strategies aim to mitigate coagulopathy and its associated downstream complications.

Still, “a majority of deaths from traumatic hemorrhage continue to occur in the first hours after arrival at the trauma center, which underscores the importance of the prehospital environment for early interventions that provide benefit,” the investigators noted.

The PAMPer trial (NCT01818427) examined the efficacy and safety of prehospital plasma resuscitation, comparing it with standard-care resuscitation, in severely injured patients. The phase 3, randomized, superiority trial involved 501 trauma patients at risk for hemorrhagic shock who were transported from 27 air medical bases to nine trauma centers. In total, 230 patients received prehospital plasma and standard-care resuscitation, and 271 patients received standard-care alone. Standard-care included infusion of crystalloid fluids in a goal-directed manner. Air medical bases delivered each type of care in 1-month intervals.

Patients were eligible if they exhibited severe hypotension (systolic blood pressure less than 70 mm Hg) or both hypotension (systolic blood pressure less than 90 mm Hg) and tachycardia (greater than 108 beats per minute).

Eligible patients received two units of thawed plasma, which was completely delivered before administration of any other fluids. If infusion of plasma was not complete upon arrival at the trauma center, infusion was completed before any in-hospital fluids were administered. Following preexisting local protocols, 13 of 27 air transport teams carried 2U of red blood cells. If red blood cells were delivered, then this was performed after plasma administration if the patient was still hypotensive or obviously bleeding.

The 30-day mortality rate among all patients was 29.6%. Approximately one in three patients received a prehospital red blood cell transfusion, and nearly 60% underwent surgery within 24 hours of hospital admission.

A greater percentage of patients in the standard-care group were given red blood cell transfusions, compared with those in the plasma group. The standard-care patients also received greater volumes of crystalloid solution than did those receiving plasma.

The primary outcome, 30-day mortality, was 9.8% lower for patients who received plasma, compared with patients who received standard-care alone (23.2% vs. 33.0%; P = .03). Multivariate regression analysis revealed that plasma delivery accounted for a 39% lower risk of death within 30 days, compared with standard care (P = .02). Within 3 hours of randomization, Kaplan-Meier curves revealed a separation between the two treatment groups that persisted until 30 days.

Median prothrombin to time ratio, the only statistically significant secondary outcome, was lower in the plasma group than it was in the standard-care group (1.2 vs. 1.3; P less than .001).

Other measured parameters were similar between the two main treatment groups, including rates of nosocomial infections, allergic or transfusion-related reactions, acute lung injury/acute respiratory distress syndrome, and multiorgan failure.

“Although we cannot determine the independent or additive effects of prehospital administration of plasma and packed red cells, the survival benefits attributable to plasma administration persisted after adjustment for prehospital red-cell administration, and a subgroup analysis showed no heterogeneity of the treatment effect,” the investigators wrote.

The PAMPer trial was supported by a grant from the U.S. Army Medical Research and Materiel Command. One author reported funding from Janssen Pharmaceuticals, CSL Behring, Haemonetics, and Accriva Diagnostics, as well as having been named on a patent on TLR4 inhibitors for the treatment of inflammatory and infectious disorders.

SOURCE: Sperry JL et al. N Engl J Med. 2018 Jul 26;379(4):315-26.


 

For adult patients with HIV, earlier treatment results in faster and more likely virologic suppression along with greater linkage to care, according to the 2018 Recommendations of the International Antiviral Society-USA (IAS-USA).

The updated treatment and prevention guidelines also have outlined drug selection, including three-drug therapy (usually as a single-tablet combination) and two-drug switch therapy, as well as discouragement of cash incentives for treatment. The guidelines, written by Michael S. Saag, MD, of the University of Alabama at Birmingham and his coauthors, were published in JAMA.

Since the previous IAS-USA guidelines were published in 2016 (JAMA. 2016;316(2):191-210), multiple studies have investigated the importance of timely antiretroviral therapy (ART). In one study, patients with HIV began ART within 24 hours of diagnosis. These patients achieved virologic suppression (fewer than 200 HIV RNA copies/mL) quicker than patients treated according to previous guidelines (medians, 1.8 months vs. 4.3 months; P = .0001). Another study found that patients who began ART immediately were more likely to achieve viral suppression at 12 months (50% vs. 34%; P = .007) and become linked to care at 3 months (68% vs. 43%). As such, the updated guidelines recommended that ART should be started as soon as possible (even without supporting laboratory results). Exceptions were maintained for patients not ready to start therapy and those at risk for immune reconstitution syndrome.

With regard to initial treatment selection, three-drug therapy is recommended, incorporating an integrase single-strand transfer inhibitor (InSTI) with 2 nucleoside reverse transcriptase inhibitors.

Single-tablet formulations are effective, well tolerated, and promote medication adherence. Dolutegravir is not recommended in women who are pregnant or may become pregnant because it may increase the risk of neural tube defects. It is unclear whether other InSTIs pose similar risks. Although two-drug regimens are not recommended for initial therapy, they may be considered as switch therapy to reduce cost and complications.

The 2018 guidelines have discouraged cash incentives for ART adherence because such programs have proven ineffective. Conversely, noncash incentives are likely to be beneficial. Further recommendations to improve outcomes were wide ranging and included identification of patients subject to food scarcity or psychiatric disorders. For the latter, chronic depression has been associated with worse outcomes – including a two-fold mortality risk – and so appropriate treatment is recommended.

The researchers concluded with a brief review of future directions for HIV treatment and prevention. Long-acting injectable and oral antiretrovirals are under investigation, along with implantable and nanoparticle therapies.

“Clinicians who care for patients with HIV have a major role in advocating for programs and their patients at the local, national, and international levels,” the authors wrote. “Advocacy should go beyond access to ART and include access to mental health and substance abuse services, as well as efforts to end policies such as HIV criminalization that impede the ability to provide evidence-based care and prevention services.”

The authors reported support from Gilead, ViiV, Merck, and other sources. The current guidelines were funded by IAS-USA.

SOURCE: Saag MS et al. JAMA. 2018;320[4]:379-96.

For adult patients with HIV, earlier treatment results in faster and more likely virologic suppression along with greater linkage to care, according to the 2018 Recommendations of the International Antiviral Society-USA (IAS-USA).

The updated treatment and prevention guidelines also have outlined drug selection, including three-drug therapy (usually as a single-tablet combination) and two-drug switch therapy, as well as discouragement of cash incentives for treatment. The guidelines, written by Michael S. Saag, MD, of the University of Alabama at Birmingham and his coauthors, were published in JAMA.

Since the previous IAS-USA guidelines were published in 2016 (JAMA. 2016;316(2):191-210), multiple studies have investigated the importance of timely antiretroviral therapy (ART). In one study, patients with HIV began ART within 24 hours of diagnosis. These patients achieved virologic suppression (fewer than 200 HIV RNA copies/mL) quicker than patients treated according to previous guidelines (medians, 1.8 months vs. 4.3 months; P = .0001). Another study found that patients who began ART immediately were more likely to achieve viral suppression at 12 months (50% vs. 34%; P = .007) and become linked to care at 3 months (68% vs. 43%). As such, the updated guidelines recommended that ART should be started as soon as possible (even without supporting laboratory results). Exceptions were maintained for patients not ready to start therapy and those at risk for immune reconstitution syndrome.

With regard to initial treatment selection, three-drug therapy is recommended, incorporating an integrase single-strand transfer inhibitor (InSTI) with 2 nucleoside reverse transcriptase inhibitors.

Single-tablet formulations are effective, well tolerated, and promote medication adherence. Dolutegravir is not recommended in women who are pregnant or may become pregnant because it may increase the risk of neural tube defects. It is unclear whether other InSTIs pose similar risks. Although two-drug regimens are not recommended for initial therapy, they may be considered as switch therapy to reduce cost and complications.

The 2018 guidelines have discouraged cash incentives for ART adherence because such programs have proven ineffective. Conversely, noncash incentives are likely to be beneficial. Further recommendations to improve outcomes were wide ranging and included identification of patients subject to food scarcity or psychiatric disorders. For the latter, chronic depression has been associated with worse outcomes – including a two-fold mortality risk – and so appropriate treatment is recommended.

The researchers concluded with a brief review of future directions for HIV treatment and prevention. Long-acting injectable and oral antiretrovirals are under investigation, along with implantable and nanoparticle therapies.

“Clinicians who care for patients with HIV have a major role in advocating for programs and their patients at the local, national, and international levels,” the authors wrote. “Advocacy should go beyond access to ART and include access to mental health and substance abuse services, as well as efforts to end policies such as HIV criminalization that impede the ability to provide evidence-based care and prevention services.”

The authors reported support from Gilead, ViiV, Merck, and other sources. The current guidelines were funded by IAS-USA.

SOURCE: Saag MS et al. JAMA. 2018;320[4]:379-96.

For adult patients with HIV, earlier treatment results in faster and more likely virologic suppression along with greater linkage to care, according to the 2018 Recommendations of the International Antiviral Society-USA (IAS-USA).

The updated treatment and prevention guidelines also have outlined drug selection, including three-drug therapy (usually as a single-tablet combination) and two-drug switch therapy, as well as discouragement of cash incentives for treatment. The guidelines, written by Michael S. Saag, MD, of the University of Alabama at Birmingham and his coauthors, were published in JAMA.

Since the previous IAS-USA guidelines were published in 2016 (JAMA. 2016;316(2):191-210), multiple studies have investigated the importance of timely antiretroviral therapy (ART). In one study, patients with HIV began ART within 24 hours of diagnosis. These patients achieved virologic suppression (fewer than 200 HIV RNA copies/mL) quicker than patients treated according to previous guidelines (medians, 1.8 months vs. 4.3 months; P = .0001). Another study found that patients who began ART immediately were more likely to achieve viral suppression at 12 months (50% vs. 34%; P = .007) and become linked to care at 3 months (68% vs. 43%). As such, the updated guidelines recommended that ART should be started as soon as possible (even without supporting laboratory results). Exceptions were maintained for patients not ready to start therapy and those at risk for immune reconstitution syndrome.

With regard to initial treatment selection, three-drug therapy is recommended, incorporating an integrase single-strand transfer inhibitor (InSTI) with 2 nucleoside reverse transcriptase inhibitors.

Single-tablet formulations are effective, well tolerated, and promote medication adherence. Dolutegravir is not recommended in women who are pregnant or may become pregnant because it may increase the risk of neural tube defects. It is unclear whether other InSTIs pose similar risks. Although two-drug regimens are not recommended for initial therapy, they may be considered as switch therapy to reduce cost and complications.

The 2018 guidelines have discouraged cash incentives for ART adherence because such programs have proven ineffective. Conversely, noncash incentives are likely to be beneficial. Further recommendations to improve outcomes were wide ranging and included identification of patients subject to food scarcity or psychiatric disorders. For the latter, chronic depression has been associated with worse outcomes – including a two-fold mortality risk – and so appropriate treatment is recommended.

The researchers concluded with a brief review of future directions for HIV treatment and prevention. Long-acting injectable and oral antiretrovirals are under investigation, along with implantable and nanoparticle therapies.

“Clinicians who care for patients with HIV have a major role in advocating for programs and their patients at the local, national, and international levels,” the authors wrote. “Advocacy should go beyond access to ART and include access to mental health and substance abuse services, as well as efforts to end policies such as HIV criminalization that impede the ability to provide evidence-based care and prevention services.”

The authors reported support from Gilead, ViiV, Merck, and other sources. The current guidelines were funded by IAS-USA.

SOURCE: Saag MS et al. JAMA. 2018;320[4]:379-96.