Pharmacology

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

VANCOUVER – In patients undergoing hysterectomy, preoperative depression is associated with an increased risk of first-time persistent opioid use after surgery.

Liderina/Thinkstock

Women with depression had an 8% increased risk of perioperative opioid use but a 43% increased risk of persistent use, defined as at least one perioperative prescription followed by at least one prescription 90 days or longer after surgery.

Opioid prescriptions after surgery have been on the rise in recent years, and this has led to a focus on how chronic pain disorders are managed. But studies have shown that patients undergoing general surgery, both minor and major, are at increased risk of persistent opioid use, even after a single surgery, according to Erin Carey, MD, director of the division of minimally invasive gynecologic surgery at the University of North Carolina at Chapel Hill, who presented the research at the meeting sponsored by AAGL.

“We also know that preoperative depression has been linked to adverse outcomes after hysterectomy, both acute postoperative pain in the first 2 days after surgery, and increasing the risk of chronic postoperative pain,” Dr. Carey said.

That prompted her and her team to look at whether preoperative depression might influence the risk of new persistent opioid use after hysterectomy. They analyzed data from the IBM Watson/Truven Health Analytics MarketScan database of claims-based data, which collects information from a variety of sources, including electronic medical records and workplace records such as absences, disability, and long-term disability.

“So it does allow for long-term tracking, which makes it optimal for this type of study,” said Dr. Carey.

The study included 382,078 hysterectomies performed between 2001 and 2015 on women who had continuous prescription plans 180 days before to 180 days after the procedure, excluding anyone who had an opioid prescription in the previous 180 days; 60% of the procedures were minimally invasive. About 20% of women were considered to have depression before the procedure, based on a diagnosis (55%), an antidepressant prescription (22%), or both (23%).

There were some differences at baseline between the two populations: Women with preoperative depression were more likely to have a comorbid pain disorder, compared with patients without depression (20% vs. 14%), another psychiatric disorder (2% vs. less than 1%), and a Charlson comorbidity (12% vs. 9%). They also were less likely to undergo a minimally invasive procedure than women without depression (66% vs. 79%). There was an increase in the prevalence of depression over time, from 16% to 23%.

Overall, 74% of women were prescribed an opioid during the perioperative period; 17% were filled before the hysterectomy was performed. Preoperative fills also increased over time, from 4% in 2001 to 21% in 2015.

Women with preoperative depression were at a slightly greater risk for perioperative opioid use (risk ratio, 1.08), but a greater risk for persistent postoperative opioid use (11% vs. 8%; RR, 1.43). The heightened risk for opioid use was similar whether the surgery was performed on an outpatient or inpatient basis.

The presence of other comorbidities in women with diagnosed depression or prescribed antidepressants complicates the findings, according to Dr. Carey. “There may be additional chronic pain factors that are confounding this data, but it is consistent with other data that de novo postoperative opioid dependence may be a higher risk for these patients, so it’s important for us to look at that critically.”

Dr. Carey has been a consultant for Teleflex Medical and a speaker for Med-IQ.

VANCOUVER – In patients undergoing hysterectomy, preoperative depression is associated with an increased risk of first-time persistent opioid use after surgery.

Liderina/Thinkstock

Women with depression had an 8% increased risk of perioperative opioid use but a 43% increased risk of persistent use, defined as at least one perioperative prescription followed by at least one prescription 90 days or longer after surgery.

Opioid prescriptions after surgery have been on the rise in recent years, and this has led to a focus on how chronic pain disorders are managed. But studies have shown that patients undergoing general surgery, both minor and major, are at increased risk of persistent opioid use, even after a single surgery, according to Erin Carey, MD, director of the division of minimally invasive gynecologic surgery at the University of North Carolina at Chapel Hill, who presented the research at the meeting sponsored by AAGL.

“We also know that preoperative depression has been linked to adverse outcomes after hysterectomy, both acute postoperative pain in the first 2 days after surgery, and increasing the risk of chronic postoperative pain,” Dr. Carey said.

That prompted her and her team to look at whether preoperative depression might influence the risk of new persistent opioid use after hysterectomy. They analyzed data from the IBM Watson/Truven Health Analytics MarketScan database of claims-based data, which collects information from a variety of sources, including electronic medical records and workplace records such as absences, disability, and long-term disability.

“So it does allow for long-term tracking, which makes it optimal for this type of study,” said Dr. Carey.

The study included 382,078 hysterectomies performed between 2001 and 2015 on women who had continuous prescription plans 180 days before to 180 days after the procedure, excluding anyone who had an opioid prescription in the previous 180 days; 60% of the procedures were minimally invasive. About 20% of women were considered to have depression before the procedure, based on a diagnosis (55%), an antidepressant prescription (22%), or both (23%).

There were some differences at baseline between the two populations: Women with preoperative depression were more likely to have a comorbid pain disorder, compared with patients without depression (20% vs. 14%), another psychiatric disorder (2% vs. less than 1%), and a Charlson comorbidity (12% vs. 9%). They also were less likely to undergo a minimally invasive procedure than women without depression (66% vs. 79%). There was an increase in the prevalence of depression over time, from 16% to 23%.

Overall, 74% of women were prescribed an opioid during the perioperative period; 17% were filled before the hysterectomy was performed. Preoperative fills also increased over time, from 4% in 2001 to 21% in 2015.

Women with preoperative depression were at a slightly greater risk for perioperative opioid use (risk ratio, 1.08), but a greater risk for persistent postoperative opioid use (11% vs. 8%; RR, 1.43). The heightened risk for opioid use was similar whether the surgery was performed on an outpatient or inpatient basis.

The presence of other comorbidities in women with diagnosed depression or prescribed antidepressants complicates the findings, according to Dr. Carey. “There may be additional chronic pain factors that are confounding this data, but it is consistent with other data that de novo postoperative opioid dependence may be a higher risk for these patients, so it’s important for us to look at that critically.”

Dr. Carey has been a consultant for Teleflex Medical and a speaker for Med-IQ.

VANCOUVER – In patients undergoing hysterectomy, preoperative depression is associated with an increased risk of first-time persistent opioid use after surgery.

Liderina/Thinkstock

Women with depression had an 8% increased risk of perioperative opioid use but a 43% increased risk of persistent use, defined as at least one perioperative prescription followed by at least one prescription 90 days or longer after surgery.

Opioid prescriptions after surgery have been on the rise in recent years, and this has led to a focus on how chronic pain disorders are managed. But studies have shown that patients undergoing general surgery, both minor and major, are at increased risk of persistent opioid use, even after a single surgery, according to Erin Carey, MD, director of the division of minimally invasive gynecologic surgery at the University of North Carolina at Chapel Hill, who presented the research at the meeting sponsored by AAGL.

“We also know that preoperative depression has been linked to adverse outcomes after hysterectomy, both acute postoperative pain in the first 2 days after surgery, and increasing the risk of chronic postoperative pain,” Dr. Carey said.

That prompted her and her team to look at whether preoperative depression might influence the risk of new persistent opioid use after hysterectomy. They analyzed data from the IBM Watson/Truven Health Analytics MarketScan database of claims-based data, which collects information from a variety of sources, including electronic medical records and workplace records such as absences, disability, and long-term disability.

“So it does allow for long-term tracking, which makes it optimal for this type of study,” said Dr. Carey.

The study included 382,078 hysterectomies performed between 2001 and 2015 on women who had continuous prescription plans 180 days before to 180 days after the procedure, excluding anyone who had an opioid prescription in the previous 180 days; 60% of the procedures were minimally invasive. About 20% of women were considered to have depression before the procedure, based on a diagnosis (55%), an antidepressant prescription (22%), or both (23%).

There were some differences at baseline between the two populations: Women with preoperative depression were more likely to have a comorbid pain disorder, compared with patients without depression (20% vs. 14%), another psychiatric disorder (2% vs. less than 1%), and a Charlson comorbidity (12% vs. 9%). They also were less likely to undergo a minimally invasive procedure than women without depression (66% vs. 79%). There was an increase in the prevalence of depression over time, from 16% to 23%.

Overall, 74% of women were prescribed an opioid during the perioperative period; 17% were filled before the hysterectomy was performed. Preoperative fills also increased over time, from 4% in 2001 to 21% in 2015.

Women with preoperative depression were at a slightly greater risk for perioperative opioid use (risk ratio, 1.08), but a greater risk for persistent postoperative opioid use (11% vs. 8%; RR, 1.43). The heightened risk for opioid use was similar whether the surgery was performed on an outpatient or inpatient basis.

The presence of other comorbidities in women with diagnosed depression or prescribed antidepressants complicates the findings, according to Dr. Carey. “There may be additional chronic pain factors that are confounding this data, but it is consistent with other data that de novo postoperative opioid dependence may be a higher risk for these patients, so it’s important for us to look at that critically.”

Dr. Carey has been a consultant for Teleflex Medical and a speaker for Med-IQ.

Ibrutinib monotherapy was associated with lower total health care costs compared with chemoimmunotherapy in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to a retrospective study.

©Mathier/thinkstockphotos.com

“This study compared time to next treatment, health care resource utilization, and total direct costs among patients with CLL initiating front-line ibrutinib single agent or chemoimmunotherapy,” wrote Bruno Emond, of Analysis Group, Montreal, and colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.

The researchers retrospectively analyzed data from 1,161 patients with CLL who were started on ibrutinib monotherapy or chemoimmunotherapy from 2014 to 2017. Data were collected from the Optum Clinformatics Extended DataMart De-Identified Databases.

Between the two groups, differences in baseline characteristics were controlled for by way of inverse probability of treatment weighting. Two treatment periods were included in the study: the initial 6 months of treatment and entire duration of frontline therapy.

The team also conducted a subgroup analysis of patients treated with bendamustine and rituximab. This cohort was analyzed independently since the regimen is commonly used in clinical practice.

After analysis, the researchers found that ibrutinib monotherapy was associated with net monthly cost savings of $3,766 (P less than .0001), compared with chemoimmunotherapy and bendamustine/rituximab over the frontline therapy period.

Ibrutinib patients had fewer monthly days with outpatient services (rate ratio, 0.75; 95% confidence interval, 0.60-0.94; P = .0200), compared with those on chemoimmunotherapy; and were less likely to initiate a next line of treatment, compared with chemoimmunotherapy patients (hazard ratio, 0.54; 95% CI, 0.33-0.90; P = .0163).

“Cost savings and reductions in health care resource utilization were even more pronounced when considering only the first 6 months of front-line treatment,” the researchers wrote.

The researchers acknowledged that two key limitations of the study were the potential influence of unobserved confounding factors and the use of claims data, which could include errors and omissions.

“These results suggest that ibrutinib single-agent is associated with lower total costs driven by lower medical costs, despite higher pharmacy costs, compared with chemoimmunotherapy and bendamustine/rituximab,” they concluded.

The authors reported financial affiliations with Janssen Scientific Affairs, which funded the study, and other companies.

SOURCE: Emond B et al. Clin Lymphoma Myeloma Leuk. 2019 Aug 26. doi: 10.1016/j.clml.2019.08.004.

Ibrutinib monotherapy was associated with lower total health care costs compared with chemoimmunotherapy in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to a retrospective study.

©Mathier/thinkstockphotos.com

“This study compared time to next treatment, health care resource utilization, and total direct costs among patients with CLL initiating front-line ibrutinib single agent or chemoimmunotherapy,” wrote Bruno Emond, of Analysis Group, Montreal, and colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.

The researchers retrospectively analyzed data from 1,161 patients with CLL who were started on ibrutinib monotherapy or chemoimmunotherapy from 2014 to 2017. Data were collected from the Optum Clinformatics Extended DataMart De-Identified Databases.

Between the two groups, differences in baseline characteristics were controlled for by way of inverse probability of treatment weighting. Two treatment periods were included in the study: the initial 6 months of treatment and entire duration of frontline therapy.

The team also conducted a subgroup analysis of patients treated with bendamustine and rituximab. This cohort was analyzed independently since the regimen is commonly used in clinical practice.

After analysis, the researchers found that ibrutinib monotherapy was associated with net monthly cost savings of $3,766 (P less than .0001), compared with chemoimmunotherapy and bendamustine/rituximab over the frontline therapy period.

Ibrutinib patients had fewer monthly days with outpatient services (rate ratio, 0.75; 95% confidence interval, 0.60-0.94; P = .0200), compared with those on chemoimmunotherapy; and were less likely to initiate a next line of treatment, compared with chemoimmunotherapy patients (hazard ratio, 0.54; 95% CI, 0.33-0.90; P = .0163).

“Cost savings and reductions in health care resource utilization were even more pronounced when considering only the first 6 months of front-line treatment,” the researchers wrote.

The researchers acknowledged that two key limitations of the study were the potential influence of unobserved confounding factors and the use of claims data, which could include errors and omissions.

“These results suggest that ibrutinib single-agent is associated with lower total costs driven by lower medical costs, despite higher pharmacy costs, compared with chemoimmunotherapy and bendamustine/rituximab,” they concluded.

The authors reported financial affiliations with Janssen Scientific Affairs, which funded the study, and other companies.

SOURCE: Emond B et al. Clin Lymphoma Myeloma Leuk. 2019 Aug 26. doi: 10.1016/j.clml.2019.08.004.

Ibrutinib monotherapy was associated with lower total health care costs compared with chemoimmunotherapy in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to a retrospective study.

©Mathier/thinkstockphotos.com

“This study compared time to next treatment, health care resource utilization, and total direct costs among patients with CLL initiating front-line ibrutinib single agent or chemoimmunotherapy,” wrote Bruno Emond, of Analysis Group, Montreal, and colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.

The researchers retrospectively analyzed data from 1,161 patients with CLL who were started on ibrutinib monotherapy or chemoimmunotherapy from 2014 to 2017. Data were collected from the Optum Clinformatics Extended DataMart De-Identified Databases.

Between the two groups, differences in baseline characteristics were controlled for by way of inverse probability of treatment weighting. Two treatment periods were included in the study: the initial 6 months of treatment and entire duration of frontline therapy.

The team also conducted a subgroup analysis of patients treated with bendamustine and rituximab. This cohort was analyzed independently since the regimen is commonly used in clinical practice.

After analysis, the researchers found that ibrutinib monotherapy was associated with net monthly cost savings of $3,766 (P less than .0001), compared with chemoimmunotherapy and bendamustine/rituximab over the frontline therapy period.

Ibrutinib patients had fewer monthly days with outpatient services (rate ratio, 0.75; 95% confidence interval, 0.60-0.94; P = .0200), compared with those on chemoimmunotherapy; and were less likely to initiate a next line of treatment, compared with chemoimmunotherapy patients (hazard ratio, 0.54; 95% CI, 0.33-0.90; P = .0163).

“Cost savings and reductions in health care resource utilization were even more pronounced when considering only the first 6 months of front-line treatment,” the researchers wrote.

The researchers acknowledged that two key limitations of the study were the potential influence of unobserved confounding factors and the use of claims data, which could include errors and omissions.

“These results suggest that ibrutinib single-agent is associated with lower total costs driven by lower medical costs, despite higher pharmacy costs, compared with chemoimmunotherapy and bendamustine/rituximab,” they concluded.

The authors reported financial affiliations with Janssen Scientific Affairs, which funded the study, and other companies.

SOURCE: Emond B et al. Clin Lymphoma Myeloma Leuk. 2019 Aug 26. doi: 10.1016/j.clml.2019.08.004.

Early treatment with lenalidomide may delay disease progression and prevent end-organ damage in patients with high-risk smoldering multiple myeloma (SMM), according to findings from a phase 3 trial.

While observation is the current standard of care in SMM, early therapy may represent a new standard for patients with high-risk disease, explained Sagar Lonial, MD, of Winship Cancer Institute, Emory University, Atlanta, and colleagues. Their findings were published in the Journal of Clinical Oncology.

The randomized, open-label, phase 3 study included 182 patients with intermediate- or high-risk SMM. Study patients were randomly allocated to receive either oral lenalidomide at 25 mg daily on days 1-21 of a 28-day cycle or observation.

Study subjects were stratified based on time since SMM diagnosis – 1 year or less vs. more than 1 year, and all patients in the lenalidomide arm received aspirin at 325 mg on days 1-28. Both interventions were maintained until unacceptable toxicity, disease progression, or withdrawal for other reasons.

The primary outcome was progression-free survival (PFS), measured from baseline to the development of symptomatic multiple myeloma (MM). The criteria for progression included evidence of end-organ damage in relation to MM and biochemical disease progression.

The researchers found that at 1 year PFS was 98% in the lenalidomide group and 89% in the observation group. At 2 years, PFS was 93% in the lenalidomide group and 76% in the observation group. PFS was 91% in the lenalidomide group and 66% in the observation group at 3 years (hazard ratio, 0.28; P = .002).

Among lenalidomide-treated patients, grade 3 or 4 hematologic and nonhematologic adverse events occurred in 36 patients (41%). Nonhematologic adverse events occurred in 25 patients (28%).

Frequent AEs among lenalidomide-treated patients included grade 4 decreased neutrophil count (4.5%), as well as grade 3 infections (20.5%), hypertension (9.1%), fatigue (6.8%), skin problems (5.7%), dyspnea (5.7%), and hypokalemia (3.4%). “In most cases, [adverse events] could be managed with dose modifications,” they wrote.

To reduce long-term toxicity, the researchers recommended a 2-year duration of therapy for patients at highest risk.

“Our results support the use of early intervention in patients with high-risk SMM – as defined by the 20/2/20 criteria where our magnitude of benefit was the greatest – rather than continued observation,” the researchers wrote.

The trial was funded by the National Cancer Institute. The authors reported financial affiliations with AbbVie, Aduro Biotech, Amgen, Bristol-Myers Squibb, Celgene, Juno Therapeutics, Kite Pharma, Sanofi, Takeda, and several other companies.

SOURCE: Lonial S et al. J Clin Oncol. 2019 Oct 25. doi: 10.1200/JCO.19.01740.

Early treatment with lenalidomide may delay disease progression and prevent end-organ damage in patients with high-risk smoldering multiple myeloma (SMM), according to findings from a phase 3 trial.

While observation is the current standard of care in SMM, early therapy may represent a new standard for patients with high-risk disease, explained Sagar Lonial, MD, of Winship Cancer Institute, Emory University, Atlanta, and colleagues. Their findings were published in the Journal of Clinical Oncology.

The randomized, open-label, phase 3 study included 182 patients with intermediate- or high-risk SMM. Study patients were randomly allocated to receive either oral lenalidomide at 25 mg daily on days 1-21 of a 28-day cycle or observation.

Study subjects were stratified based on time since SMM diagnosis – 1 year or less vs. more than 1 year, and all patients in the lenalidomide arm received aspirin at 325 mg on days 1-28. Both interventions were maintained until unacceptable toxicity, disease progression, or withdrawal for other reasons.

The primary outcome was progression-free survival (PFS), measured from baseline to the development of symptomatic multiple myeloma (MM). The criteria for progression included evidence of end-organ damage in relation to MM and biochemical disease progression.

The researchers found that at 1 year PFS was 98% in the lenalidomide group and 89% in the observation group. At 2 years, PFS was 93% in the lenalidomide group and 76% in the observation group. PFS was 91% in the lenalidomide group and 66% in the observation group at 3 years (hazard ratio, 0.28; P = .002).

Among lenalidomide-treated patients, grade 3 or 4 hematologic and nonhematologic adverse events occurred in 36 patients (41%). Nonhematologic adverse events occurred in 25 patients (28%).

Frequent AEs among lenalidomide-treated patients included grade 4 decreased neutrophil count (4.5%), as well as grade 3 infections (20.5%), hypertension (9.1%), fatigue (6.8%), skin problems (5.7%), dyspnea (5.7%), and hypokalemia (3.4%). “In most cases, [adverse events] could be managed with dose modifications,” they wrote.

To reduce long-term toxicity, the researchers recommended a 2-year duration of therapy for patients at highest risk.

“Our results support the use of early intervention in patients with high-risk SMM – as defined by the 20/2/20 criteria where our magnitude of benefit was the greatest – rather than continued observation,” the researchers wrote.

The trial was funded by the National Cancer Institute. The authors reported financial affiliations with AbbVie, Aduro Biotech, Amgen, Bristol-Myers Squibb, Celgene, Juno Therapeutics, Kite Pharma, Sanofi, Takeda, and several other companies.

SOURCE: Lonial S et al. J Clin Oncol. 2019 Oct 25. doi: 10.1200/JCO.19.01740.

Early treatment with lenalidomide may delay disease progression and prevent end-organ damage in patients with high-risk smoldering multiple myeloma (SMM), according to findings from a phase 3 trial.

While observation is the current standard of care in SMM, early therapy may represent a new standard for patients with high-risk disease, explained Sagar Lonial, MD, of Winship Cancer Institute, Emory University, Atlanta, and colleagues. Their findings were published in the Journal of Clinical Oncology.

The randomized, open-label, phase 3 study included 182 patients with intermediate- or high-risk SMM. Study patients were randomly allocated to receive either oral lenalidomide at 25 mg daily on days 1-21 of a 28-day cycle or observation.

Study subjects were stratified based on time since SMM diagnosis – 1 year or less vs. more than 1 year, and all patients in the lenalidomide arm received aspirin at 325 mg on days 1-28. Both interventions were maintained until unacceptable toxicity, disease progression, or withdrawal for other reasons.

The primary outcome was progression-free survival (PFS), measured from baseline to the development of symptomatic multiple myeloma (MM). The criteria for progression included evidence of end-organ damage in relation to MM and biochemical disease progression.

The researchers found that at 1 year PFS was 98% in the lenalidomide group and 89% in the observation group. At 2 years, PFS was 93% in the lenalidomide group and 76% in the observation group. PFS was 91% in the lenalidomide group and 66% in the observation group at 3 years (hazard ratio, 0.28; P = .002).

Among lenalidomide-treated patients, grade 3 or 4 hematologic and nonhematologic adverse events occurred in 36 patients (41%). Nonhematologic adverse events occurred in 25 patients (28%).

Frequent AEs among lenalidomide-treated patients included grade 4 decreased neutrophil count (4.5%), as well as grade 3 infections (20.5%), hypertension (9.1%), fatigue (6.8%), skin problems (5.7%), dyspnea (5.7%), and hypokalemia (3.4%). “In most cases, [adverse events] could be managed with dose modifications,” they wrote.

To reduce long-term toxicity, the researchers recommended a 2-year duration of therapy for patients at highest risk.

“Our results support the use of early intervention in patients with high-risk SMM – as defined by the 20/2/20 criteria where our magnitude of benefit was the greatest – rather than continued observation,” the researchers wrote.

The trial was funded by the National Cancer Institute. The authors reported financial affiliations with AbbVie, Aduro Biotech, Amgen, Bristol-Myers Squibb, Celgene, Juno Therapeutics, Kite Pharma, Sanofi, Takeda, and several other companies.

SOURCE: Lonial S et al. J Clin Oncol. 2019 Oct 25. doi: 10.1200/JCO.19.01740.

NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).

Jennifer Smith/MDedge News

Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.

These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.

Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.

He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*

With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.

Discovery cohort

The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.

The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.

The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).

The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).

Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).

Validation cohort and bone marrow samples

The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.

Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).

Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.

Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.

The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.

Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.

“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.

“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”

Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.

jensmith@mdedge.com

SOURCE: Rutella S et al. SITC 2019. Abstract O3.

*This article was updated on 11/19/2019.

NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).

Jennifer Smith/MDedge News

Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.

These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.

Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.

He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*

With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.

Discovery cohort

The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.

The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.

The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).

The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).

Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).

Validation cohort and bone marrow samples

The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.

Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).

Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.

Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.

The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.

Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.

“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.

“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”

Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.

jensmith@mdedge.com

SOURCE: Rutella S et al. SITC 2019. Abstract O3.

*This article was updated on 11/19/2019.

NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).

Jennifer Smith/MDedge News

Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.

These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.

Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.

He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*

With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.

Discovery cohort

The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.

The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.

The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).

The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).

Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).

Validation cohort and bone marrow samples

The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.

Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).

Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.

Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.

The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.

Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.

“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.

“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”

Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.

jensmith@mdedge.com

SOURCE: Rutella S et al. SITC 2019. Abstract O3.

*This article was updated on 11/19/2019.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

PHILADELPHIA – The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A^1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A_1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A_1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

mzoler@mdedge.com

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

PHILADELPHIA – The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A^1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A_1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A_1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

mzoler@mdedge.com

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

PHILADELPHIA – The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A^1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A_1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A_1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

mzoler@mdedge.com

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

The Food and Drug Administration announced that it has approved cefiderocol (Fetroja), an IV antibacterial drug to treat complicated urinary tract infections (cUTIs), including kidney infections, caused by multidrug-resistant gram-negative microorganisms in patients 18 years of age or older.

The safety and effectiveness of cefiderocol was demonstrated in a pivotal study of 448 patients with cUTIs. Published results indicated that 73% of patients had resolution of symptoms and eradication of the bacteria approximately 7 days after completing treatment, compared with 55% in patients who received an alternative antibiotic.

The approval is for patients who have limited or no alternative treatment options and includes a label warning regarding cefiderocol’s higher all-cause mortality observed in comparison to patients treated with other antibiotics in a trial of critically ill patients having multidrug-resistant gram-negative bacterial infections (clinical trials. gov NCT02714595).

The cause of the increase in mortality has not been determined, according to the FDA. Some of the deaths in the study were attributable to worsening or complications of infection, or underlying comorbidities, in patients treated for hospital-acquired/ventilator-associated pneumonia (i.e., nosocomial pneumonia), bloodstream infections, or sepsis. Thus, safety and efficacy of cefiderocol has not been established for the treating these types of infections, according to the announcement.

Adverse reactions observed in patients treated with cefiderocol included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion-site reactions, and candidiasis. The FDA added that cefiderocol should not be used in persons known to have a severe hypersensitivity to beta-lactam antibacterial drugs.

“A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections, like cUTIs. This approval represents another step forward in the FDA’s overall efforts to ensure safe and effective antimicrobial drugs are available to patients for treating infections,” John Farley, MD, acting director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research said in the FDA press statement.

Fetroja is a product of Shionogi.

mlesney@mdedge.com

The Food and Drug Administration announced that it has approved cefiderocol (Fetroja), an IV antibacterial drug to treat complicated urinary tract infections (cUTIs), including kidney infections, caused by multidrug-resistant gram-negative microorganisms in patients 18 years of age or older.

The safety and effectiveness of cefiderocol was demonstrated in a pivotal study of 448 patients with cUTIs. Published results indicated that 73% of patients had resolution of symptoms and eradication of the bacteria approximately 7 days after completing treatment, compared with 55% in patients who received an alternative antibiotic.

The approval is for patients who have limited or no alternative treatment options and includes a label warning regarding cefiderocol’s higher all-cause mortality observed in comparison to patients treated with other antibiotics in a trial of critically ill patients having multidrug-resistant gram-negative bacterial infections (clinical trials. gov NCT02714595).

The cause of the increase in mortality has not been determined, according to the FDA. Some of the deaths in the study were attributable to worsening or complications of infection, or underlying comorbidities, in patients treated for hospital-acquired/ventilator-associated pneumonia (i.e., nosocomial pneumonia), bloodstream infections, or sepsis. Thus, safety and efficacy of cefiderocol has not been established for the treating these types of infections, according to the announcement.

Adverse reactions observed in patients treated with cefiderocol included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion-site reactions, and candidiasis. The FDA added that cefiderocol should not be used in persons known to have a severe hypersensitivity to beta-lactam antibacterial drugs.

“A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections, like cUTIs. This approval represents another step forward in the FDA’s overall efforts to ensure safe and effective antimicrobial drugs are available to patients for treating infections,” John Farley, MD, acting director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research said in the FDA press statement.

Fetroja is a product of Shionogi.

mlesney@mdedge.com

The Food and Drug Administration announced that it has approved cefiderocol (Fetroja), an IV antibacterial drug to treat complicated urinary tract infections (cUTIs), including kidney infections, caused by multidrug-resistant gram-negative microorganisms in patients 18 years of age or older.

The safety and effectiveness of cefiderocol was demonstrated in a pivotal study of 448 patients with cUTIs. Published results indicated that 73% of patients had resolution of symptoms and eradication of the bacteria approximately 7 days after completing treatment, compared with 55% in patients who received an alternative antibiotic.

The approval is for patients who have limited or no alternative treatment options and includes a label warning regarding cefiderocol’s higher all-cause mortality observed in comparison to patients treated with other antibiotics in a trial of critically ill patients having multidrug-resistant gram-negative bacterial infections (clinical trials. gov NCT02714595).

The cause of the increase in mortality has not been determined, according to the FDA. Some of the deaths in the study were attributable to worsening or complications of infection, or underlying comorbidities, in patients treated for hospital-acquired/ventilator-associated pneumonia (i.e., nosocomial pneumonia), bloodstream infections, or sepsis. Thus, safety and efficacy of cefiderocol has not been established for the treating these types of infections, according to the announcement.

Adverse reactions observed in patients treated with cefiderocol included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion-site reactions, and candidiasis. The FDA added that cefiderocol should not be used in persons known to have a severe hypersensitivity to beta-lactam antibacterial drugs.

“A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections, like cUTIs. This approval represents another step forward in the FDA’s overall efforts to ensure safe and effective antimicrobial drugs are available to patients for treating infections,” John Farley, MD, acting director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research said in the FDA press statement.

Fetroja is a product of Shionogi.

mlesney@mdedge.com

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.