Article

Key clinical point: Prusogliptin as an add-on therapy to metformin was superior to metformin monotherapy in improving glycemic control and was safe and well tolerated in patients with type 2 diabetes mellitus (T2D) inadequately controlled with metformin.

Major finding: At week 24, prusogliptin + metformin vs metformin + placebo led to significantly higher reductions in glycated hemoglobin (least squares mean change [LSM] −0.70% vs −0.07%; P < .001), fasting plasma glucose (LSM −0.63 vs 0.07 mmol/L; P  =  .025), and 2-hour postprandial plasma glucose (LSM −2.43 vs −0.70 mmol/L; P < .001) levels, with the incidence of adverse events being similar between the treatment groups.

Study details: Findings are from a 24-week, superiority, phase 3 trial including 206 patients with T2D with blood glucose levels inadequately controlled on metformin who were randomly assigned to receive prusogliptin + metformin (n = 138) or placebo + metformin (n = 68).

Disclosures: This study was funded by the CSPC Zhongqi Pharmaceutical Technology Co., Ltd. Some authors are employees of CSPC Zhongqi Pharmaceutical Technology.

Source: Xu J et al. Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes mellitus: A 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial. Diabetes Obes Metab. 2022 (Jul 6). Doi: 10.1111/dom.14810

Key clinical point: Prusogliptin as an add-on therapy to metformin was superior to metformin monotherapy in improving glycemic control and was safe and well tolerated in patients with type 2 diabetes mellitus (T2D) inadequately controlled with metformin.

Major finding: At week 24, prusogliptin + metformin vs metformin + placebo led to significantly higher reductions in glycated hemoglobin (least squares mean change [LSM] −0.70% vs −0.07%; P < .001), fasting plasma glucose (LSM −0.63 vs 0.07 mmol/L; P  =  .025), and 2-hour postprandial plasma glucose (LSM −2.43 vs −0.70 mmol/L; P < .001) levels, with the incidence of adverse events being similar between the treatment groups.

Study details: Findings are from a 24-week, superiority, phase 3 trial including 206 patients with T2D with blood glucose levels inadequately controlled on metformin who were randomly assigned to receive prusogliptin + metformin (n = 138) or placebo + metformin (n = 68).

Disclosures: This study was funded by the CSPC Zhongqi Pharmaceutical Technology Co., Ltd. Some authors are employees of CSPC Zhongqi Pharmaceutical Technology.

Source: Xu J et al. Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes mellitus: A 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial. Diabetes Obes Metab. 2022 (Jul 6). Doi: 10.1111/dom.14810

Key clinical point: Prusogliptin as an add-on therapy to metformin was superior to metformin monotherapy in improving glycemic control and was safe and well tolerated in patients with type 2 diabetes mellitus (T2D) inadequately controlled with metformin.

Major finding: At week 24, prusogliptin + metformin vs metformin + placebo led to significantly higher reductions in glycated hemoglobin (least squares mean change [LSM] −0.70% vs −0.07%; P < .001), fasting plasma glucose (LSM −0.63 vs 0.07 mmol/L; P  =  .025), and 2-hour postprandial plasma glucose (LSM −2.43 vs −0.70 mmol/L; P < .001) levels, with the incidence of adverse events being similar between the treatment groups.

Study details: Findings are from a 24-week, superiority, phase 3 trial including 206 patients with T2D with blood glucose levels inadequately controlled on metformin who were randomly assigned to receive prusogliptin + metformin (n = 138) or placebo + metformin (n = 68).

Disclosures: This study was funded by the CSPC Zhongqi Pharmaceutical Technology Co., Ltd. Some authors are employees of CSPC Zhongqi Pharmaceutical Technology.

Source: Xu J et al. Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes mellitus: A 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial. Diabetes Obes Metab. 2022 (Jul 6). Doi: 10.1111/dom.14810

Key clinical point: Initiation of semaglutide in patients with type 2 diabetes mellitus (T2D) on high daily doses of insulin at baseline led to a significant improvement in glycemic control, body weight, and reduction in total daily dose (TDD) of insulin.

Major finding: From baseline to 6 months, the TDD of insulin (183 ± 98 to 143 ± 99 units, respectively), glycated hemoglobin level (8.9% ± 1.3% to 7.6% ± 1.5%, respectively), and body weight (123.9 ± 23.5 to 118.9 ± 22.9 kg, respectively; all P < .001) reduced significantly in patients on high daily doses of insulin who received semaglutide.

Study details: Findings are from a retrospective analysis including 72 patients with T2D on high TDD of insulin (≥100 units) who were prescribed semaglutide.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Meyer J et al. The effects of adding semaglutide to high daily dose insulin regimens in patients with type 2 diabetes. Ann Pharmacother. 2022 (Jul 1). Doi: 10.1177/10600280221107381

Key clinical point: Initiation of semaglutide in patients with type 2 diabetes mellitus (T2D) on high daily doses of insulin at baseline led to a significant improvement in glycemic control, body weight, and reduction in total daily dose (TDD) of insulin.

Major finding: From baseline to 6 months, the TDD of insulin (183 ± 98 to 143 ± 99 units, respectively), glycated hemoglobin level (8.9% ± 1.3% to 7.6% ± 1.5%, respectively), and body weight (123.9 ± 23.5 to 118.9 ± 22.9 kg, respectively; all P < .001) reduced significantly in patients on high daily doses of insulin who received semaglutide.

Study details: Findings are from a retrospective analysis including 72 patients with T2D on high TDD of insulin (≥100 units) who were prescribed semaglutide.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Meyer J et al. The effects of adding semaglutide to high daily dose insulin regimens in patients with type 2 diabetes. Ann Pharmacother. 2022 (Jul 1). Doi: 10.1177/10600280221107381

Key clinical point: Initiation of semaglutide in patients with type 2 diabetes mellitus (T2D) on high daily doses of insulin at baseline led to a significant improvement in glycemic control, body weight, and reduction in total daily dose (TDD) of insulin.

Major finding: From baseline to 6 months, the TDD of insulin (183 ± 98 to 143 ± 99 units, respectively), glycated hemoglobin level (8.9% ± 1.3% to 7.6% ± 1.5%, respectively), and body weight (123.9 ± 23.5 to 118.9 ± 22.9 kg, respectively; all P < .001) reduced significantly in patients on high daily doses of insulin who received semaglutide.

Study details: Findings are from a retrospective analysis including 72 patients with T2D on high TDD of insulin (≥100 units) who were prescribed semaglutide.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Meyer J et al. The effects of adding semaglutide to high daily dose insulin regimens in patients with type 2 diabetes. Ann Pharmacother. 2022 (Jul 1). Doi: 10.1177/10600280221107381

Key clinical point: Dipeptidyl peptidase-4 (DPP4) inhibitors significantly increased the risk for the composite of gallbladder or biliary diseases and cholecystitis but not for cholelithiasis and biliary diseases in patients with type 2 diabetes (T2D), especially those with a longer treatment duration.

Major finding: Compared with placebo or non-incretin drugs, DPP4 inhibitors were associated with a significantly higher risk for composite of gallbladder or biliary diseases (odds ratio [OR] 1.22; 95% CI 1.04-1.43) and cholecystitis (OR 1.43; 95% CI 1.14-1.79), but not for cholelithiasis (OR 1.08; 95% CI 0.83-1.39) and biliary diseases (OR 1.00; 95% CI 0.68-1.47), and the association remained significant with the long-term (≥26 weeks) use of DPP4 inhibitors.

Study details: The data come from a systematic review and pairwise meta-analysis of 82 randomized trials including 104,833 patients with T2D.

Disclosures: This study was partially supported by Beijing Natural Science Foundation, National Natural Science Foundation of China, and others. The authors declared receiving support from the funding institutions.

Source: He L et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials BMJ. 2022;377:e068882 (Jun 28). Doi: 10.1136/bmj-2021-068882

Key clinical point: Dipeptidyl peptidase-4 (DPP4) inhibitors significantly increased the risk for the composite of gallbladder or biliary diseases and cholecystitis but not for cholelithiasis and biliary diseases in patients with type 2 diabetes (T2D), especially those with a longer treatment duration.

Major finding: Compared with placebo or non-incretin drugs, DPP4 inhibitors were associated with a significantly higher risk for composite of gallbladder or biliary diseases (odds ratio [OR] 1.22; 95% CI 1.04-1.43) and cholecystitis (OR 1.43; 95% CI 1.14-1.79), but not for cholelithiasis (OR 1.08; 95% CI 0.83-1.39) and biliary diseases (OR 1.00; 95% CI 0.68-1.47), and the association remained significant with the long-term (≥26 weeks) use of DPP4 inhibitors.

Study details: The data come from a systematic review and pairwise meta-analysis of 82 randomized trials including 104,833 patients with T2D.

Disclosures: This study was partially supported by Beijing Natural Science Foundation, National Natural Science Foundation of China, and others. The authors declared receiving support from the funding institutions.

Source: He L et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials BMJ. 2022;377:e068882 (Jun 28). Doi: 10.1136/bmj-2021-068882

Key clinical point: Dipeptidyl peptidase-4 (DPP4) inhibitors significantly increased the risk for the composite of gallbladder or biliary diseases and cholecystitis but not for cholelithiasis and biliary diseases in patients with type 2 diabetes (T2D), especially those with a longer treatment duration.

Major finding: Compared with placebo or non-incretin drugs, DPP4 inhibitors were associated with a significantly higher risk for composite of gallbladder or biliary diseases (odds ratio [OR] 1.22; 95% CI 1.04-1.43) and cholecystitis (OR 1.43; 95% CI 1.14-1.79), but not for cholelithiasis (OR 1.08; 95% CI 0.83-1.39) and biliary diseases (OR 1.00; 95% CI 0.68-1.47), and the association remained significant with the long-term (≥26 weeks) use of DPP4 inhibitors.

Study details: The data come from a systematic review and pairwise meta-analysis of 82 randomized trials including 104,833 patients with T2D.

Disclosures: This study was partially supported by Beijing Natural Science Foundation, National Natural Science Foundation of China, and others. The authors declared receiving support from the funding institutions.

Source: He L et al. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials BMJ. 2022;377:e068882 (Jun 28). Doi: 10.1136/bmj-2021-068882

Key clinical point: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) use was associated with a lower risk for new-onset atrial fibrillation (AF) in patients with type 2 diabetes (T2D) compared with the use of either glucagon-like peptide-1 receptor agonists (GLP-1RA) or dipeptidyl peptidase-4 inhibitors (DPP4i).

Major finding: Use of SGLT2i was associated with a lower risk for new-onset AF compared with the use of DPP4i (hazard ratio [HR] 0.90; P  =  .0028) or GLP-1RA (HR 0.74; P  =  .0007), with no significant difference being observed between the risk associated with GLP-1RA and DPP4i (HR 1.01; P  =  .8980).

Study details: This was a retrospective cohort study that included 344,893, 44,370, and 393,100 patients with T2D and without preexisting AF who were treated with SGLT2i, GLP-1RA, and DPP4i, respectively.

Disclosures: This study was supported by grants from the Ministry of Science and Technology and Chang Gung Memorial Hospital, Linkou, Taiwan. The authors declared no competing interests.

Source: Chan YH et al. The risk of incident atrial fibrillation in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors: A nationwide cohort study. Cardiovasc Diabetol. 2022;21:118 (Jun 28). Doi: 10.1186/s12933-022-01549-x

Key clinical point: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) use was associated with a lower risk for new-onset atrial fibrillation (AF) in patients with type 2 diabetes (T2D) compared with the use of either glucagon-like peptide-1 receptor agonists (GLP-1RA) or dipeptidyl peptidase-4 inhibitors (DPP4i).

Major finding: Use of SGLT2i was associated with a lower risk for new-onset AF compared with the use of DPP4i (hazard ratio [HR] 0.90; P  =  .0028) or GLP-1RA (HR 0.74; P  =  .0007), with no significant difference being observed between the risk associated with GLP-1RA and DPP4i (HR 1.01; P  =  .8980).

Study details: This was a retrospective cohort study that included 344,893, 44,370, and 393,100 patients with T2D and without preexisting AF who were treated with SGLT2i, GLP-1RA, and DPP4i, respectively.

Disclosures: This study was supported by grants from the Ministry of Science and Technology and Chang Gung Memorial Hospital, Linkou, Taiwan. The authors declared no competing interests.

Source: Chan YH et al. The risk of incident atrial fibrillation in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors: A nationwide cohort study. Cardiovasc Diabetol. 2022;21:118 (Jun 28). Doi: 10.1186/s12933-022-01549-x

Key clinical point: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) use was associated with a lower risk for new-onset atrial fibrillation (AF) in patients with type 2 diabetes (T2D) compared with the use of either glucagon-like peptide-1 receptor agonists (GLP-1RA) or dipeptidyl peptidase-4 inhibitors (DPP4i).

Major finding: Use of SGLT2i was associated with a lower risk for new-onset AF compared with the use of DPP4i (hazard ratio [HR] 0.90; P  =  .0028) or GLP-1RA (HR 0.74; P  =  .0007), with no significant difference being observed between the risk associated with GLP-1RA and DPP4i (HR 1.01; P  =  .8980).

Study details: This was a retrospective cohort study that included 344,893, 44,370, and 393,100 patients with T2D and without preexisting AF who were treated with SGLT2i, GLP-1RA, and DPP4i, respectively.

Disclosures: This study was supported by grants from the Ministry of Science and Technology and Chang Gung Memorial Hospital, Linkou, Taiwan. The authors declared no competing interests.

Source: Chan YH et al. The risk of incident atrial fibrillation in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors: A nationwide cohort study. Cardiovasc Diabetol. 2022;21:118 (Jun 28). Doi: 10.1186/s12933-022-01549-x

Key clinical point: Once-weekly semaglutide plus lifestyle intervention significantly improved glucose parameters with a greater likelihood of achieving normoglycemia compared with placebo in patients with baseline prediabetes.

Major finding: Semaglutide vs placebo led to a significant reduction in the glycated hemoglobin level, fasting plasma glucose level, and homeostasis model assessment of insulin resistance (all P < .01), in addition to a significant increase in the proportion of patients experiencing normoglycemia (STEP 1: 84.1% vs 47.8%; STEP 3: 89.5% vs 55.0%; STEP 4: 89.8% vs 70.4%; P < .0001).

Study details: This was a post hoc analysis data of the STEP 1, 3, and 4 trials including 1536 patients with prediabetes who were randomly assigned to received semaglutide or placebo.

Disclosures: The STEP trials were funded by Novo Nordisk. Some authors declared receiving personal fees, speaker fees, advisory or consulting fees, and research funding or other support from various organizations. Three authors are employees and shareholders of Novo Nordisk.

Source: Perreault L et al. Changes in glucose metabolism and glycemic status with once-weekly subcutaneous semaglutide 2.4 mg among participants with prediabetes in the STEP program. Diabetes Care. 2022 (Jul 5). Doi: 10.2337/dc21-1785

Key clinical point: Once-weekly semaglutide plus lifestyle intervention significantly improved glucose parameters with a greater likelihood of achieving normoglycemia compared with placebo in patients with baseline prediabetes.

Major finding: Semaglutide vs placebo led to a significant reduction in the glycated hemoglobin level, fasting plasma glucose level, and homeostasis model assessment of insulin resistance (all P < .01), in addition to a significant increase in the proportion of patients experiencing normoglycemia (STEP 1: 84.1% vs 47.8%; STEP 3: 89.5% vs 55.0%; STEP 4: 89.8% vs 70.4%; P < .0001).

Study details: This was a post hoc analysis data of the STEP 1, 3, and 4 trials including 1536 patients with prediabetes who were randomly assigned to received semaglutide or placebo.

Disclosures: The STEP trials were funded by Novo Nordisk. Some authors declared receiving personal fees, speaker fees, advisory or consulting fees, and research funding or other support from various organizations. Three authors are employees and shareholders of Novo Nordisk.

Source: Perreault L et al. Changes in glucose metabolism and glycemic status with once-weekly subcutaneous semaglutide 2.4 mg among participants with prediabetes in the STEP program. Diabetes Care. 2022 (Jul 5). Doi: 10.2337/dc21-1785

Key clinical point: Once-weekly semaglutide plus lifestyle intervention significantly improved glucose parameters with a greater likelihood of achieving normoglycemia compared with placebo in patients with baseline prediabetes.

Major finding: Semaglutide vs placebo led to a significant reduction in the glycated hemoglobin level, fasting plasma glucose level, and homeostasis model assessment of insulin resistance (all P < .01), in addition to a significant increase in the proportion of patients experiencing normoglycemia (STEP 1: 84.1% vs 47.8%; STEP 3: 89.5% vs 55.0%; STEP 4: 89.8% vs 70.4%; P < .0001).

Study details: This was a post hoc analysis data of the STEP 1, 3, and 4 trials including 1536 patients with prediabetes who were randomly assigned to received semaglutide or placebo.

Disclosures: The STEP trials were funded by Novo Nordisk. Some authors declared receiving personal fees, speaker fees, advisory or consulting fees, and research funding or other support from various organizations. Three authors are employees and shareholders of Novo Nordisk.

Source: Perreault L et al. Changes in glucose metabolism and glycemic status with once-weekly subcutaneous semaglutide 2.4 mg among participants with prediabetes in the STEP program. Diabetes Care. 2022 (Jul 5). Doi: 10.2337/dc21-1785

Key clinical point: Once-weekly efpeglenatide vs placebo led to significant improvements in glycemic control and body weight in patients with type 2 diabetes (T2D), with a safety profile similar to that of glucagon-like peptide 1 receptor agonist.

Major finding: At 30 weeks, 2 mg efpeglenatide (least squares mean difference [LSM] 0.5%; P  =  .0054), 4 mg (LSM 0.8%; P < .0001), and 6 mg (LSM 1.0%; P < .0001) vs placebo led to a significantly greater reduction in glycated hemoglobin levels, with a significant reduction in body weight with 4 and 6 mg efpeglenatide (both P < .05).

Study details: The data come from the AMPLITUDE-M trial including 406 patients with T2D inadequately controlled with diet and exercise alone who were randomly assigned to receive efpeglenatide (n = 304) or placebo (n = 102).

Disclosures: This study was initially sponsored by Sanofi and thereafter, the sponsorship was transferred to Hanmi Pharmaceutical Co., Ltd. Some authors reported serving as advisory board members or speakers and receiving research support from various organizations, including Sanofi. The other authors are employees of and hold stocks in  Sanofi or Hanmi Pharmaceutical Co.

Source: Frias JP et al. Efficacy and safety of once-weekly efpeglenatide monotherapy versus placebo in type 2 diabetes: The AMPLITUDE-M randomized controlled trial. Diabetes Care. 2022;45(7):1592-1600 (Jul 6). Doi:  10.2337/dc21-2656

Key clinical point: Once-weekly efpeglenatide vs placebo led to significant improvements in glycemic control and body weight in patients with type 2 diabetes (T2D), with a safety profile similar to that of glucagon-like peptide 1 receptor agonist.

Major finding: At 30 weeks, 2 mg efpeglenatide (least squares mean difference [LSM] 0.5%; P  =  .0054), 4 mg (LSM 0.8%; P < .0001), and 6 mg (LSM 1.0%; P < .0001) vs placebo led to a significantly greater reduction in glycated hemoglobin levels, with a significant reduction in body weight with 4 and 6 mg efpeglenatide (both P < .05).

Study details: The data come from the AMPLITUDE-M trial including 406 patients with T2D inadequately controlled with diet and exercise alone who were randomly assigned to receive efpeglenatide (n = 304) or placebo (n = 102).

Disclosures: This study was initially sponsored by Sanofi and thereafter, the sponsorship was transferred to Hanmi Pharmaceutical Co., Ltd. Some authors reported serving as advisory board members or speakers and receiving research support from various organizations, including Sanofi. The other authors are employees of and hold stocks in  Sanofi or Hanmi Pharmaceutical Co.

Source: Frias JP et al. Efficacy and safety of once-weekly efpeglenatide monotherapy versus placebo in type 2 diabetes: The AMPLITUDE-M randomized controlled trial. Diabetes Care. 2022;45(7):1592-1600 (Jul 6). Doi:  10.2337/dc21-2656

Key clinical point: Once-weekly efpeglenatide vs placebo led to significant improvements in glycemic control and body weight in patients with type 2 diabetes (T2D), with a safety profile similar to that of glucagon-like peptide 1 receptor agonist.

Major finding: At 30 weeks, 2 mg efpeglenatide (least squares mean difference [LSM] 0.5%; P  =  .0054), 4 mg (LSM 0.8%; P < .0001), and 6 mg (LSM 1.0%; P < .0001) vs placebo led to a significantly greater reduction in glycated hemoglobin levels, with a significant reduction in body weight with 4 and 6 mg efpeglenatide (both P < .05).

Study details: The data come from the AMPLITUDE-M trial including 406 patients with T2D inadequately controlled with diet and exercise alone who were randomly assigned to receive efpeglenatide (n = 304) or placebo (n = 102).

Disclosures: This study was initially sponsored by Sanofi and thereafter, the sponsorship was transferred to Hanmi Pharmaceutical Co., Ltd. Some authors reported serving as advisory board members or speakers and receiving research support from various organizations, including Sanofi. The other authors are employees of and hold stocks in  Sanofi or Hanmi Pharmaceutical Co.

Source: Frias JP et al. Efficacy and safety of once-weekly efpeglenatide monotherapy versus placebo in type 2 diabetes: The AMPLITUDE-M randomized controlled trial. Diabetes Care. 2022;45(7):1592-1600 (Jul 6). Doi:  10.2337/dc21-2656

The study by Huang and colleagues investigates the long-term effects and potential mechanisms of action of transcutaneous electrical acustimulation (TEA) in patients with IBS with constipation (IBS-C) experiencing colonic transit issues and visceral hypersensitivity. Patients with IBS-C receiving TEA had increased frequency of spontaneous bowel movements and significant improvements in analog pain score compared with the placebo group. This supports the benefit of TEA for improving constipation and the concomitant symptoms by accelerating colonic transit and reducing rectal sensation. It can be inferred that the improvement of these symptoms will lead to enhanced quality of life in patients with IBS-C.

The study by Melchior and colleagues¹ emphasizes the effect that IBS can have on a patient's life. Patients with IBS report reduced disease-specific quality of life. The cumulative impact of the demographic factors and the severity of psychological symptoms, somatic symptoms, and gastrointestinal symptoms are associated with decreased quality of life. The severity of this impact is determined by the combination of these factors and the level of severity at which they occur. This decrease in quality of life can lead to increased anxiety related to gastrointestinal function. It is important for providers to acknowledge the effect that gastrointestinal function has on the patient's life in a broader sense. The appreciation and understanding of the patient experience enhances the therapeutic relationship and shared decision-making between the patient and the healthcare provider.

Additional References

1. Melchior C, Colomier E, Trindade IA, et al. Irritable bowel syndrome: Factors of importance for disease-specific quality of life. United European Gastroenterol J. 2022 Jul 13. Doi: 10.1002/ueg2.12277  

The study by Huang and colleagues investigates the long-term effects and potential mechanisms of action of transcutaneous electrical acustimulation (TEA) in patients with IBS with constipation (IBS-C) experiencing colonic transit issues and visceral hypersensitivity. Patients with IBS-C receiving TEA had increased frequency of spontaneous bowel movements and significant improvements in analog pain score compared with the placebo group. This supports the benefit of TEA for improving constipation and the concomitant symptoms by accelerating colonic transit and reducing rectal sensation. It can be inferred that the improvement of these symptoms will lead to enhanced quality of life in patients with IBS-C.

The study by Melchior and colleagues¹ emphasizes the effect that IBS can have on a patient's life. Patients with IBS report reduced disease-specific quality of life. The cumulative impact of the demographic factors and the severity of psychological symptoms, somatic symptoms, and gastrointestinal symptoms are associated with decreased quality of life. The severity of this impact is determined by the combination of these factors and the level of severity at which they occur. This decrease in quality of life can lead to increased anxiety related to gastrointestinal function. It is important for providers to acknowledge the effect that gastrointestinal function has on the patient's life in a broader sense. The appreciation and understanding of the patient experience enhances the therapeutic relationship and shared decision-making between the patient and the healthcare provider.

Additional References

1. Melchior C, Colomier E, Trindade IA, et al. Irritable bowel syndrome: Factors of importance for disease-specific quality of life. United European Gastroenterol J. 2022 Jul 13. Doi: 10.1002/ueg2.12277  

The study by Huang and colleagues investigates the long-term effects and potential mechanisms of action of transcutaneous electrical acustimulation (TEA) in patients with IBS with constipation (IBS-C) experiencing colonic transit issues and visceral hypersensitivity. Patients with IBS-C receiving TEA had increased frequency of spontaneous bowel movements and significant improvements in analog pain score compared with the placebo group. This supports the benefit of TEA for improving constipation and the concomitant symptoms by accelerating colonic transit and reducing rectal sensation. It can be inferred that the improvement of these symptoms will lead to enhanced quality of life in patients with IBS-C.

The study by Melchior and colleagues¹ emphasizes the effect that IBS can have on a patient's life. Patients with IBS report reduced disease-specific quality of life. The cumulative impact of the demographic factors and the severity of psychological symptoms, somatic symptoms, and gastrointestinal symptoms are associated with decreased quality of life. The severity of this impact is determined by the combination of these factors and the level of severity at which they occur. This decrease in quality of life can lead to increased anxiety related to gastrointestinal function. It is important for providers to acknowledge the effect that gastrointestinal function has on the patient's life in a broader sense. The appreciation and understanding of the patient experience enhances the therapeutic relationship and shared decision-making between the patient and the healthcare provider.

Additional References

1. Melchior C, Colomier E, Trindade IA, et al. Irritable bowel syndrome: Factors of importance for disease-specific quality of life. United European Gastroenterol J. 2022 Jul 13. Doi: 10.1002/ueg2.12277  

DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003). The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd. These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.

Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues, this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.

Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues, 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).

In summary, the phase 3 IMpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting.

DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003). The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd. These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.

Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues, this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.

Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues, 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).

In summary, the phase 3 IMpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting.

DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003). The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd. These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.

Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues, this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.

Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues, 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).

In summary, the phase 3 IMpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.