Type 2 diabetes mellitus remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, judging from the findings of an open-label, cluster-randomized trial.

Remission rates closely tracked weight loss, Michael E.J. Lean, MD, reported in the Dec. 5 online issue of the Lancet. Among those who lost 15 kg or more, 86% also normalized their hemoglobin A1c levels. Lesser weight losses were successful too, with diabetes remitting in 57% of those who lost 10-15 kg and 34% of those who lost 5-10 kg, reported Dr. Lean, who is chair of human nutrition at the University of Glasgow.

Weight loss conferred other benefits as well. Quality of life improved significantly, triglycerides declined, and about half of the subjects were able to discontinue both their antidiabetic and antihypertension prescriptions.

DiRECT (the Diabetes Remission Clinical Trial) didn’t include a strict exercise component – something that sets it apart from most dietary interventions, Dr. Lean noted in a press statement. Instead, the study’s “Counterweight-plus” diet intervention focused on very strict calorie control. Counterweight is a proprietary, subscription-based weight-loss program that costs about $570 for 1 year.

The paper offered few details about the intervention, which was supervised by a nurse and/or dietitian. For the first 3-5 months, patients consumed only Counterweight-branded soups and shakes, amounting to about 850 calories per day. After that, solid foods were reintroduced over 2-8 weeks. There was ongoing support for weight-loss maintenance, including cognitive-behavioral therapy, combined with strategies to increase physical activity. Activity strategies were confined to encouraging subjects to walk up to 15,000 steps per day in the second and third phase, but the investigators had little hope that this would actually occur.

“It was recognized that this target was unlikely to be achieved by many, and objectively measured physical activity showed no increase in physical activity in either group between baseline and 12 months, which underlines the difficulty this population has in maintaining increased activity,” they noted.

DiRECT enrolled 298 adults with type 2 diabetes recruited from 49 primary care practices across Scotland and England. They were about 54 years old, with a mean diabetes duration of about 3 years. Subjects were assigned to either the Counterweight-plus weight management program or best practice care under current guidelines. At baseline, subjects’ mean body mass index was 35 mg/m². Their mean HbA_1c was about 7.6%; about 75% were taking at least one antidiabetic medication, and 30% taking two or more. Hypertension was present in more than half.

In the active group, investigators withdrew all antidiabetic and antihypertensive medications when the diet commenced. Antihypertensives were restarted only if subjects experienced an increase in systolic blood pressure. Patients in the control group stayed on their medications.

At 12 months, the mean weight loss was significantly greater in the intervention group than the control group (10 kg vs. 1 kg). Weight loss of at least 15 kg occurred in 24% of the intervention group and none of the control group. It was most pronounced in the total diet replacement phase, falling by a mean of 14.5 kg; participants regained weigh during the food reintroduction phase (mean, 1 kg) and again during the maintenance phase (mean, 1.9 kg). Four subjects in the intervention group who experienced diabetes remission needed a “short rescue plan” on the total diet replacement phase because of weight regain within 60 days of the study’s end. The authors didn’t say how much weight these patients regained.

By the end of the study period, diabetes had remitted in 46% of the intervention group and 4% of the control group (odds ratio, 19.7) and was positively associated with the amount of weight loss.

At 12 months, 74% of the intervention group and 18% of the control group were off antidiabetic medications. HbA_1c was significantly better in the intervention group (mean 6.4% vs. 7.2%). Antihypertensive drugs also were less common among the intervention group (32% vs. 61%) at 12 months. Despite the reduction in medication, there were no significant changes in blood pressure from baseline.

Nine serious adverse events occurred among seven intervention subjects. Two (biliary colic and abdominal pain) occurred in the same subject and were considered related to the diet, but they did not withdraw promptly.

Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.

[email protected]

SOURCE: Lean M et al. Lancet 2017 Dec 5; doi: 10.1016/ S0140-6736(17)33102-1.

Type 2 diabetes mellitus remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, judging from the findings of an open-label, cluster-randomized trial.

Remission rates closely tracked weight loss, Michael E.J. Lean, MD, reported in the Dec. 5 online issue of the Lancet. Among those who lost 15 kg or more, 86% also normalized their hemoglobin A1c levels. Lesser weight losses were successful too, with diabetes remitting in 57% of those who lost 10-15 kg and 34% of those who lost 5-10 kg, reported Dr. Lean, who is chair of human nutrition at the University of Glasgow.

Weight loss conferred other benefits as well. Quality of life improved significantly, triglycerides declined, and about half of the subjects were able to discontinue both their antidiabetic and antihypertension prescriptions.

DiRECT (the Diabetes Remission Clinical Trial) didn’t include a strict exercise component – something that sets it apart from most dietary interventions, Dr. Lean noted in a press statement. Instead, the study’s “Counterweight-plus” diet intervention focused on very strict calorie control. Counterweight is a proprietary, subscription-based weight-loss program that costs about $570 for 1 year.

The paper offered few details about the intervention, which was supervised by a nurse and/or dietitian. For the first 3-5 months, patients consumed only Counterweight-branded soups and shakes, amounting to about 850 calories per day. After that, solid foods were reintroduced over 2-8 weeks. There was ongoing support for weight-loss maintenance, including cognitive-behavioral therapy, combined with strategies to increase physical activity. Activity strategies were confined to encouraging subjects to walk up to 15,000 steps per day in the second and third phase, but the investigators had little hope that this would actually occur.

“It was recognized that this target was unlikely to be achieved by many, and objectively measured physical activity showed no increase in physical activity in either group between baseline and 12 months, which underlines the difficulty this population has in maintaining increased activity,” they noted.

DiRECT enrolled 298 adults with type 2 diabetes recruited from 49 primary care practices across Scotland and England. They were about 54 years old, with a mean diabetes duration of about 3 years. Subjects were assigned to either the Counterweight-plus weight management program or best practice care under current guidelines. At baseline, subjects’ mean body mass index was 35 mg/m². Their mean HbA_1c was about 7.6%; about 75% were taking at least one antidiabetic medication, and 30% taking two or more. Hypertension was present in more than half.

In the active group, investigators withdrew all antidiabetic and antihypertensive medications when the diet commenced. Antihypertensives were restarted only if subjects experienced an increase in systolic blood pressure. Patients in the control group stayed on their medications.

At 12 months, the mean weight loss was significantly greater in the intervention group than the control group (10 kg vs. 1 kg). Weight loss of at least 15 kg occurred in 24% of the intervention group and none of the control group. It was most pronounced in the total diet replacement phase, falling by a mean of 14.5 kg; participants regained weigh during the food reintroduction phase (mean, 1 kg) and again during the maintenance phase (mean, 1.9 kg). Four subjects in the intervention group who experienced diabetes remission needed a “short rescue plan” on the total diet replacement phase because of weight regain within 60 days of the study’s end. The authors didn’t say how much weight these patients regained.

By the end of the study period, diabetes had remitted in 46% of the intervention group and 4% of the control group (odds ratio, 19.7) and was positively associated with the amount of weight loss.

At 12 months, 74% of the intervention group and 18% of the control group were off antidiabetic medications. HbA_1c was significantly better in the intervention group (mean 6.4% vs. 7.2%). Antihypertensive drugs also were less common among the intervention group (32% vs. 61%) at 12 months. Despite the reduction in medication, there were no significant changes in blood pressure from baseline.

Nine serious adverse events occurred among seven intervention subjects. Two (biliary colic and abdominal pain) occurred in the same subject and were considered related to the diet, but they did not withdraw promptly.

Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.

[email protected]

SOURCE: Lean M et al. Lancet 2017 Dec 5; doi: 10.1016/ S0140-6736(17)33102-1.

Type 2 diabetes mellitus remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, judging from the findings of an open-label, cluster-randomized trial.

Remission rates closely tracked weight loss, Michael E.J. Lean, MD, reported in the Dec. 5 online issue of the Lancet. Among those who lost 15 kg or more, 86% also normalized their hemoglobin A1c levels. Lesser weight losses were successful too, with diabetes remitting in 57% of those who lost 10-15 kg and 34% of those who lost 5-10 kg, reported Dr. Lean, who is chair of human nutrition at the University of Glasgow.

Weight loss conferred other benefits as well. Quality of life improved significantly, triglycerides declined, and about half of the subjects were able to discontinue both their antidiabetic and antihypertension prescriptions.

DiRECT (the Diabetes Remission Clinical Trial) didn’t include a strict exercise component – something that sets it apart from most dietary interventions, Dr. Lean noted in a press statement. Instead, the study’s “Counterweight-plus” diet intervention focused on very strict calorie control. Counterweight is a proprietary, subscription-based weight-loss program that costs about $570 for 1 year.

The paper offered few details about the intervention, which was supervised by a nurse and/or dietitian. For the first 3-5 months, patients consumed only Counterweight-branded soups and shakes, amounting to about 850 calories per day. After that, solid foods were reintroduced over 2-8 weeks. There was ongoing support for weight-loss maintenance, including cognitive-behavioral therapy, combined with strategies to increase physical activity. Activity strategies were confined to encouraging subjects to walk up to 15,000 steps per day in the second and third phase, but the investigators had little hope that this would actually occur.

“It was recognized that this target was unlikely to be achieved by many, and objectively measured physical activity showed no increase in physical activity in either group between baseline and 12 months, which underlines the difficulty this population has in maintaining increased activity,” they noted.

DiRECT enrolled 298 adults with type 2 diabetes recruited from 49 primary care practices across Scotland and England. They were about 54 years old, with a mean diabetes duration of about 3 years. Subjects were assigned to either the Counterweight-plus weight management program or best practice care under current guidelines. At baseline, subjects’ mean body mass index was 35 mg/m². Their mean HbA_1c was about 7.6%; about 75% were taking at least one antidiabetic medication, and 30% taking two or more. Hypertension was present in more than half.

In the active group, investigators withdrew all antidiabetic and antihypertensive medications when the diet commenced. Antihypertensives were restarted only if subjects experienced an increase in systolic blood pressure. Patients in the control group stayed on their medications.

At 12 months, the mean weight loss was significantly greater in the intervention group than the control group (10 kg vs. 1 kg). Weight loss of at least 15 kg occurred in 24% of the intervention group and none of the control group. It was most pronounced in the total diet replacement phase, falling by a mean of 14.5 kg; participants regained weigh during the food reintroduction phase (mean, 1 kg) and again during the maintenance phase (mean, 1.9 kg). Four subjects in the intervention group who experienced diabetes remission needed a “short rescue plan” on the total diet replacement phase because of weight regain within 60 days of the study’s end. The authors didn’t say how much weight these patients regained.

By the end of the study period, diabetes had remitted in 46% of the intervention group and 4% of the control group (odds ratio, 19.7) and was positively associated with the amount of weight loss.

At 12 months, 74% of the intervention group and 18% of the control group were off antidiabetic medications. HbA_1c was significantly better in the intervention group (mean 6.4% vs. 7.2%). Antihypertensive drugs also were less common among the intervention group (32% vs. 61%) at 12 months. Despite the reduction in medication, there were no significant changes in blood pressure from baseline.

Nine serious adverse events occurred among seven intervention subjects. Two (biliary colic and abdominal pain) occurred in the same subject and were considered related to the diet, but they did not withdraw promptly.

Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.

[email protected]

SOURCE: Lean M et al. Lancet 2017 Dec 5; doi: 10.1016/ S0140-6736(17)33102-1.

ATLANTA – In older patients with acute myeloid leukemia (AML) in complete remission after intensive chemotherapy, the addition of maintenance therapy with azacitidine significantly improved disease-free survival (DFS), according to results of a randomized, placebo-controlled phase 3 study.

Compared with observation, DFS was significantly improved in the maintenance azacitidine arm, according to results from the 116-patient HOVON97 trial presented at the annual meeting of the American Society of Hematology.

Overall survival was not significantly different between arms, possibly because of an excess of allogeneic transplant in the observation arm, according to Geert Huls, MD, PhD, of the department of hematology, University Medical Center Groningen, the Netherlands.

“When censored for allogeneic transplant, maintenance with azacitidine improves overall survival,” Dr. Huls said during an oral presentation on the findings.

The randomized maintenance therapy trial was designed to include 126 patients aged 60 years or older who had a confirmed diagnosis of AML and refractory anemia with excess of blasts (RAEB, RAEB-t) and who were in complete remission or in complete remission with incomplete blood count recovery after two cycles of therapy.

Investigators randomly assigned 116 patients to maintenance versus observation. Researchers intended to assign a total of 126 patients, but the trial was stopped early because of slow accrual, Dr. Huls said.

Maintenance treatment with azacitidine was given until relapse for no more than 12 cycles, according to the study protocol. Disease-free survival, the primary endpoint, was measured from the date of randomization to relapse or death from any cause.

Azacitidine maintenance therapy significantly improved DFS (P = .03), Dr. Huls said. After researchers adjusted for poor risk cytogenetic abnormalities at diagnosis and platelet count at study entry, the DFS difference remained significant (hazard ratio, 0.61; 95% confidence interval, 0.4-0.92; P = .019).

Overall survival, a secondary endpoint of the trial, was not significantly different between arms, even after adjustment for cytogenetic abnormalities and platelet counts, Dr. Huls said.

However, investigators found an excess of allogeneic transplant in the observation arm (11 patients, vs. 3 in the azacitidine arm). After they censored those 14 patients, they saw a difference in overall survival favoring azacitidine maintenance that approached significance (P = .07).

Dr. Huls speculated that the excess of transplant may have been related to “the psychology of the doctors.” In the maintenance arm, the physician’s thought process may have been that “ ‘this patient has now had two lines of treatment and has a relapse, and we are done,’ and in the [observation] arm he says, ‘well, the patient has had one arm of treatment, let’s go for another,’ ” Dr. Huls said.

Tolerability data showed that 14 adverse events were reported in the azacitidine maintenance arm, versus 4 for observation. One serious adverse event of grade 3 was reported in the azacitidine arm. The proportion of patients without platelet transfusions during the study was 86% for azacitidine and 93% for observation, and the proportion of patients without red blood cell transfusions was similarly 86% and 92% for the azacitidine and observation arms, respectively.

Dr. Huls reported financial relationships with Janssen and Celgene.

SOURCE: Huls G et al. ASH 2017 Abstract 463.

ATLANTA – In older patients with acute myeloid leukemia (AML) in complete remission after intensive chemotherapy, the addition of maintenance therapy with azacitidine significantly improved disease-free survival (DFS), according to results of a randomized, placebo-controlled phase 3 study.

Compared with observation, DFS was significantly improved in the maintenance azacitidine arm, according to results from the 116-patient HOVON97 trial presented at the annual meeting of the American Society of Hematology.

Overall survival was not significantly different between arms, possibly because of an excess of allogeneic transplant in the observation arm, according to Geert Huls, MD, PhD, of the department of hematology, University Medical Center Groningen, the Netherlands.

“When censored for allogeneic transplant, maintenance with azacitidine improves overall survival,” Dr. Huls said during an oral presentation on the findings.

The randomized maintenance therapy trial was designed to include 126 patients aged 60 years or older who had a confirmed diagnosis of AML and refractory anemia with excess of blasts (RAEB, RAEB-t) and who were in complete remission or in complete remission with incomplete blood count recovery after two cycles of therapy.

Investigators randomly assigned 116 patients to maintenance versus observation. Researchers intended to assign a total of 126 patients, but the trial was stopped early because of slow accrual, Dr. Huls said.

Maintenance treatment with azacitidine was given until relapse for no more than 12 cycles, according to the study protocol. Disease-free survival, the primary endpoint, was measured from the date of randomization to relapse or death from any cause.

Azacitidine maintenance therapy significantly improved DFS (P = .03), Dr. Huls said. After researchers adjusted for poor risk cytogenetic abnormalities at diagnosis and platelet count at study entry, the DFS difference remained significant (hazard ratio, 0.61; 95% confidence interval, 0.4-0.92; P = .019).

Overall survival, a secondary endpoint of the trial, was not significantly different between arms, even after adjustment for cytogenetic abnormalities and platelet counts, Dr. Huls said.

However, investigators found an excess of allogeneic transplant in the observation arm (11 patients, vs. 3 in the azacitidine arm). After they censored those 14 patients, they saw a difference in overall survival favoring azacitidine maintenance that approached significance (P = .07).

Dr. Huls speculated that the excess of transplant may have been related to “the psychology of the doctors.” In the maintenance arm, the physician’s thought process may have been that “ ‘this patient has now had two lines of treatment and has a relapse, and we are done,’ and in the [observation] arm he says, ‘well, the patient has had one arm of treatment, let’s go for another,’ ” Dr. Huls said.

Tolerability data showed that 14 adverse events were reported in the azacitidine maintenance arm, versus 4 for observation. One serious adverse event of grade 3 was reported in the azacitidine arm. The proportion of patients without platelet transfusions during the study was 86% for azacitidine and 93% for observation, and the proportion of patients without red blood cell transfusions was similarly 86% and 92% for the azacitidine and observation arms, respectively.

Dr. Huls reported financial relationships with Janssen and Celgene.

SOURCE: Huls G et al. ASH 2017 Abstract 463.

ATLANTA – In older patients with acute myeloid leukemia (AML) in complete remission after intensive chemotherapy, the addition of maintenance therapy with azacitidine significantly improved disease-free survival (DFS), according to results of a randomized, placebo-controlled phase 3 study.

Compared with observation, DFS was significantly improved in the maintenance azacitidine arm, according to results from the 116-patient HOVON97 trial presented at the annual meeting of the American Society of Hematology.

Overall survival was not significantly different between arms, possibly because of an excess of allogeneic transplant in the observation arm, according to Geert Huls, MD, PhD, of the department of hematology, University Medical Center Groningen, the Netherlands.

“When censored for allogeneic transplant, maintenance with azacitidine improves overall survival,” Dr. Huls said during an oral presentation on the findings.

The randomized maintenance therapy trial was designed to include 126 patients aged 60 years or older who had a confirmed diagnosis of AML and refractory anemia with excess of blasts (RAEB, RAEB-t) and who were in complete remission or in complete remission with incomplete blood count recovery after two cycles of therapy.

Investigators randomly assigned 116 patients to maintenance versus observation. Researchers intended to assign a total of 126 patients, but the trial was stopped early because of slow accrual, Dr. Huls said.

Maintenance treatment with azacitidine was given until relapse for no more than 12 cycles, according to the study protocol. Disease-free survival, the primary endpoint, was measured from the date of randomization to relapse or death from any cause.

Azacitidine maintenance therapy significantly improved DFS (P = .03), Dr. Huls said. After researchers adjusted for poor risk cytogenetic abnormalities at diagnosis and platelet count at study entry, the DFS difference remained significant (hazard ratio, 0.61; 95% confidence interval, 0.4-0.92; P = .019).

Overall survival, a secondary endpoint of the trial, was not significantly different between arms, even after adjustment for cytogenetic abnormalities and platelet counts, Dr. Huls said.

However, investigators found an excess of allogeneic transplant in the observation arm (11 patients, vs. 3 in the azacitidine arm). After they censored those 14 patients, they saw a difference in overall survival favoring azacitidine maintenance that approached significance (P = .07).

Dr. Huls speculated that the excess of transplant may have been related to “the psychology of the doctors.” In the maintenance arm, the physician’s thought process may have been that “ ‘this patient has now had two lines of treatment and has a relapse, and we are done,’ and in the [observation] arm he says, ‘well, the patient has had one arm of treatment, let’s go for another,’ ” Dr. Huls said.

Tolerability data showed that 14 adverse events were reported in the azacitidine maintenance arm, versus 4 for observation. One serious adverse event of grade 3 was reported in the azacitidine arm. The proportion of patients without platelet transfusions during the study was 86% for azacitidine and 93% for observation, and the proportion of patients without red blood cell transfusions was similarly 86% and 92% for the azacitidine and observation arms, respectively.

Dr. Huls reported financial relationships with Janssen and Celgene.

SOURCE: Huls G et al. ASH 2017 Abstract 463.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.

Susan London/Frontline Medical News

Predicting benefit

The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.

Study details

In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.

“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.

Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.

Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.

Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.

The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.

Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).

“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.

Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).

TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”

Improving efficacy

Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.

“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”

Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.

“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”

Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.

SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.

Susan London/Frontline Medical News

Predicting benefit

The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.

Study details

In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.

“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.

Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.

Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.

Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.

The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.

Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).

“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.

Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).

TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”

Improving efficacy

Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.

“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”

Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.

“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”

Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.

SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.

Susan London/Frontline Medical News

Predicting benefit

The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.

Study details

In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.

“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.

Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.

Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.

Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.

The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.

Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).

“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.

Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).

TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”

Improving efficacy

Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.

“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”

Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.

“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”

Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.

SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.

Receiving a trivalent inactivated influenza vaccine (TIV) did not protect children and adolescents with acute leukemia from developing the flu, said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.

Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.

luiscar/Thinkstock

Receiving a trivalent inactivated influenza vaccine (TIV) did not protect children and adolescents with acute leukemia from developing the flu, said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.

Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.

luiscar/Thinkstock

Receiving a trivalent inactivated influenza vaccine (TIV) did not protect children and adolescents with acute leukemia from developing the flu, said April Sykes of St. Jude Children’s Research Hospital in Carmel, Ind., and her associates.

Patients aged 1-21 years being treated for acute leukemia during three successive influenza seasons (2011-2012, 2012-2013, and 2013-2014) were identified by a retrospective review of EHRs; of those patients, 354 (71%) patients received TIV, and 98 (20%) received a booster dose of flu vaccine.

luiscar/Thinkstock

SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.

After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.

SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.

After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.

SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.

After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.

SAN ANTONIO – When it comes to adjuvant bisphosphonate therapy following adjuvant chemotherapy for high-risk early breast cancer, more is not better than less, phase 3 data from the randomized SUCCESS A study suggest.

Among 3,421 patients randomized to adjuvant bisphosphonate therapy following chemotherapy, there was barely a speck of difference in either disease-free survival (DFS) or overall survival (OS) between patients randomized to either 2 years or 5 years of adjuvant bisphosphonate therapy with zoledronate, reported Wolfgang Janni, MD, from University Hospital Ulm (Germany).

“We conclude 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density,” he said at the San Antonio Breast Cancer Symposium.

Adjuvant bisphosphonate therapy in patients with early breast cancer is associated with improved breast cancer–specific survival and reduced rates of breast cancer recurrence in bone, especially for postmenopausal patients, as shown in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, Dr. Janni noted.

German breast cancer guidelines state that postmenopausal women should be offered bisphosphonates as part of their adjuvant systemic therapy, but the optimal duration of therapy is uncertain, prompting the investigators to examine the issue in a randomized trial.

SUCCESS A was a multicenter, phase 3, randomized trial with a multifactorial 2 x 2 design, in patients with high-risk node-negative and node-positive disease. Patients were randomized to FEC100 chemotherapy followed by docetaxel with or without gemcitabine. Chemotherapy was followed by endocrine therapy with 2 years of tamoxifen followed by 3 years of anastrozole (Arimidex). At the start of endocrine therapy, patients were further randomized to receive either 2 or 5 years of adjuvant zoledronate, 4 mg intravenously every 3 months for 2 years, or the same schedule over 2 years, followed by 4 mg every 6 months for 3 years.

A total of 2,987 of the 3,421 patients randomized to a zoledronate schedule were available for inclusion in the analysis.

As noted, adapted DFS and OS, measured starting from 2 years after the start of zoledronate with a maximum observation time of 48 months, were virtually identical between the two treatment groups, with respective P values of .827 and .713. Similarly, in a multivariate regression analysis model adjusted for age, body mass index, menopausal status, tumor size, nodal stage, histological grade and type, hormone receptor status, HER2 status, surgery type, and chemotherapy regimen, the hazard ratio for 5 vs. 2 years was 0.97 for DFS and 0.98 for OS. Neither endpoint was significantly different between the groups.

Similarly, there was no significant differences in the number of bone recurrences as first distant recurrences or in premenopausal vs. postmenopausal women.

Adverse events of any grade were significantly higher with 5 years of bisphosphonate therapy (46.2% vs. 27.2%, P less than .001), including significantly higher grade 3 or greater adverse events (7.6% vs. 5.1%, P = .006).

Following presentation of the data in an oral session, moderator Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, questioned whether the follow-up was long enough to detect a clinically meaningful difference.

“The negative result of this study might be due to the small observation time,” Dr. Janni conceded.”We have a quite intensive drug regimen for the first 2 years, so this might also be a contributing factor [as to why] we did not see any difference.”

The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.

SOURCE: Janni et al. SABCS 2017 Abstract GS1-06

SAN ANTONIO – When it comes to adjuvant bisphosphonate therapy following adjuvant chemotherapy for high-risk early breast cancer, more is not better than less, phase 3 data from the randomized SUCCESS A study suggest.

Among 3,421 patients randomized to adjuvant bisphosphonate therapy following chemotherapy, there was barely a speck of difference in either disease-free survival (DFS) or overall survival (OS) between patients randomized to either 2 years or 5 years of adjuvant bisphosphonate therapy with zoledronate, reported Wolfgang Janni, MD, from University Hospital Ulm (Germany).

“We conclude 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density,” he said at the San Antonio Breast Cancer Symposium.

Adjuvant bisphosphonate therapy in patients with early breast cancer is associated with improved breast cancer–specific survival and reduced rates of breast cancer recurrence in bone, especially for postmenopausal patients, as shown in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, Dr. Janni noted.

German breast cancer guidelines state that postmenopausal women should be offered bisphosphonates as part of their adjuvant systemic therapy, but the optimal duration of therapy is uncertain, prompting the investigators to examine the issue in a randomized trial.

SUCCESS A was a multicenter, phase 3, randomized trial with a multifactorial 2 x 2 design, in patients with high-risk node-negative and node-positive disease. Patients were randomized to FEC100 chemotherapy followed by docetaxel with or without gemcitabine. Chemotherapy was followed by endocrine therapy with 2 years of tamoxifen followed by 3 years of anastrozole (Arimidex). At the start of endocrine therapy, patients were further randomized to receive either 2 or 5 years of adjuvant zoledronate, 4 mg intravenously every 3 months for 2 years, or the same schedule over 2 years, followed by 4 mg every 6 months for 3 years.

A total of 2,987 of the 3,421 patients randomized to a zoledronate schedule were available for inclusion in the analysis.

As noted, adapted DFS and OS, measured starting from 2 years after the start of zoledronate with a maximum observation time of 48 months, were virtually identical between the two treatment groups, with respective P values of .827 and .713. Similarly, in a multivariate regression analysis model adjusted for age, body mass index, menopausal status, tumor size, nodal stage, histological grade and type, hormone receptor status, HER2 status, surgery type, and chemotherapy regimen, the hazard ratio for 5 vs. 2 years was 0.97 for DFS and 0.98 for OS. Neither endpoint was significantly different between the groups.

Similarly, there was no significant differences in the number of bone recurrences as first distant recurrences or in premenopausal vs. postmenopausal women.

Adverse events of any grade were significantly higher with 5 years of bisphosphonate therapy (46.2% vs. 27.2%, P less than .001), including significantly higher grade 3 or greater adverse events (7.6% vs. 5.1%, P = .006).

Following presentation of the data in an oral session, moderator Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, questioned whether the follow-up was long enough to detect a clinically meaningful difference.

“The negative result of this study might be due to the small observation time,” Dr. Janni conceded.”We have a quite intensive drug regimen for the first 2 years, so this might also be a contributing factor [as to why] we did not see any difference.”

The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.

SOURCE: Janni et al. SABCS 2017 Abstract GS1-06

SAN ANTONIO – When it comes to adjuvant bisphosphonate therapy following adjuvant chemotherapy for high-risk early breast cancer, more is not better than less, phase 3 data from the randomized SUCCESS A study suggest.

Among 3,421 patients randomized to adjuvant bisphosphonate therapy following chemotherapy, there was barely a speck of difference in either disease-free survival (DFS) or overall survival (OS) between patients randomized to either 2 years or 5 years of adjuvant bisphosphonate therapy with zoledronate, reported Wolfgang Janni, MD, from University Hospital Ulm (Germany).

“We conclude 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density,” he said at the San Antonio Breast Cancer Symposium.

Adjuvant bisphosphonate therapy in patients with early breast cancer is associated with improved breast cancer–specific survival and reduced rates of breast cancer recurrence in bone, especially for postmenopausal patients, as shown in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, Dr. Janni noted.

German breast cancer guidelines state that postmenopausal women should be offered bisphosphonates as part of their adjuvant systemic therapy, but the optimal duration of therapy is uncertain, prompting the investigators to examine the issue in a randomized trial.

SUCCESS A was a multicenter, phase 3, randomized trial with a multifactorial 2 x 2 design, in patients with high-risk node-negative and node-positive disease. Patients were randomized to FEC100 chemotherapy followed by docetaxel with or without gemcitabine. Chemotherapy was followed by endocrine therapy with 2 years of tamoxifen followed by 3 years of anastrozole (Arimidex). At the start of endocrine therapy, patients were further randomized to receive either 2 or 5 years of adjuvant zoledronate, 4 mg intravenously every 3 months for 2 years, or the same schedule over 2 years, followed by 4 mg every 6 months for 3 years.

A total of 2,987 of the 3,421 patients randomized to a zoledronate schedule were available for inclusion in the analysis.

As noted, adapted DFS and OS, measured starting from 2 years after the start of zoledronate with a maximum observation time of 48 months, were virtually identical between the two treatment groups, with respective P values of .827 and .713. Similarly, in a multivariate regression analysis model adjusted for age, body mass index, menopausal status, tumor size, nodal stage, histological grade and type, hormone receptor status, HER2 status, surgery type, and chemotherapy regimen, the hazard ratio for 5 vs. 2 years was 0.97 for DFS and 0.98 for OS. Neither endpoint was significantly different between the groups.

Similarly, there was no significant differences in the number of bone recurrences as first distant recurrences or in premenopausal vs. postmenopausal women.

Adverse events of any grade were significantly higher with 5 years of bisphosphonate therapy (46.2% vs. 27.2%, P less than .001), including significantly higher grade 3 or greater adverse events (7.6% vs. 5.1%, P = .006).

Following presentation of the data in an oral session, moderator Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, questioned whether the follow-up was long enough to detect a clinically meaningful difference.

“The negative result of this study might be due to the small observation time,” Dr. Janni conceded.”We have a quite intensive drug regimen for the first 2 years, so this might also be a contributing factor [as to why] we did not see any difference.”

The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.

SOURCE: Janni et al. SABCS 2017 Abstract GS1-06

Cutaneous lupus erythematosus can be classified into acute, subacute, and chronic lesions. Chronic cutaneous lupus, or discoid lupus erythematosus (DLE), may occur independently of or in combination with systemic lupus erythematosus (SLE). They are one of the more common skin presentations seen in lupus. Young adults are typically affected, with a female-to-male ratio of 2:1. Progression from DLE to SLE is uncommon. However, patients with SLE will frequently develop discoid lesions.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

The differential diagnosis includes: subacute cutaneous lupus, lichen planus, seborrheic dermatitis, Jessner’s lymphocytic infiltrate, polymorphous light eruption, rosacea, granuloma faciale, and sarcoidosis. Histology of DLE may reveal hyperkeratosis, a thin epidermis with effacement of the rete ridges, a lichenoid and vacuolar interface dermatitis, and follicular plugging. Damaged keratinocytes called colloid bodies may be present. Increased mucin and thickening of the basement membrane are commonly seen. Active lesions will exhibit more of an inflammatory infiltrate. Direct immunofluorescence of lesional skin is positive in more than 75% of cases.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Cutaneous lupus erythematosus can be classified into acute, subacute, and chronic lesions. Chronic cutaneous lupus, or discoid lupus erythematosus (DLE), may occur independently of or in combination with systemic lupus erythematosus (SLE). They are one of the more common skin presentations seen in lupus. Young adults are typically affected, with a female-to-male ratio of 2:1. Progression from DLE to SLE is uncommon. However, patients with SLE will frequently develop discoid lesions.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

The differential diagnosis includes: subacute cutaneous lupus, lichen planus, seborrheic dermatitis, Jessner’s lymphocytic infiltrate, polymorphous light eruption, rosacea, granuloma faciale, and sarcoidosis. Histology of DLE may reveal hyperkeratosis, a thin epidermis with effacement of the rete ridges, a lichenoid and vacuolar interface dermatitis, and follicular plugging. Damaged keratinocytes called colloid bodies may be present. Increased mucin and thickening of the basement membrane are commonly seen. Active lesions will exhibit more of an inflammatory infiltrate. Direct immunofluorescence of lesional skin is positive in more than 75% of cases.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Cutaneous lupus erythematosus can be classified into acute, subacute, and chronic lesions. Chronic cutaneous lupus, or discoid lupus erythematosus (DLE), may occur independently of or in combination with systemic lupus erythematosus (SLE). They are one of the more common skin presentations seen in lupus. Young adults are typically affected, with a female-to-male ratio of 2:1. Progression from DLE to SLE is uncommon. However, patients with SLE will frequently develop discoid lesions.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

The differential diagnosis includes: subacute cutaneous lupus, lichen planus, seborrheic dermatitis, Jessner’s lymphocytic infiltrate, polymorphous light eruption, rosacea, granuloma faciale, and sarcoidosis. Histology of DLE may reveal hyperkeratosis, a thin epidermis with effacement of the rete ridges, a lichenoid and vacuolar interface dermatitis, and follicular plugging. Damaged keratinocytes called colloid bodies may be present. Increased mucin and thickening of the basement membrane are commonly seen. Active lesions will exhibit more of an inflammatory infiltrate. Direct immunofluorescence of lesional skin is positive in more than 75% of cases.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Six months of high-intensity treadmill walking largely preserved motor function in patients with recently diagnosed Parkinson’s disease, a phase 2 study has determined.

Patients randomized to the high-intensity exercise arm stayed very close to their baseline motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), while the scores of those randomized to a wait list increased a mean of 3 points over 24 weeks. The scores of patients randomized to an intermediate-intensity treadmill workout increased 2 points over the study, which was not significantly different than the increase seen in the control group, Margaret Schenkman, PhD, and her colleagues wrote Dec. 11 in JAMA Neurology.

Pavel Losevsky/iStockphoto

[email protected]

SOURCE: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517

Six months of high-intensity treadmill walking largely preserved motor function in patients with recently diagnosed Parkinson’s disease, a phase 2 study has determined.

Patients randomized to the high-intensity exercise arm stayed very close to their baseline motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), while the scores of those randomized to a wait list increased a mean of 3 points over 24 weeks. The scores of patients randomized to an intermediate-intensity treadmill workout increased 2 points over the study, which was not significantly different than the increase seen in the control group, Margaret Schenkman, PhD, and her colleagues wrote Dec. 11 in JAMA Neurology.

Pavel Losevsky/iStockphoto

[email protected]

SOURCE: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517

Six months of high-intensity treadmill walking largely preserved motor function in patients with recently diagnosed Parkinson’s disease, a phase 2 study has determined.

Patients randomized to the high-intensity exercise arm stayed very close to their baseline motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), while the scores of those randomized to a wait list increased a mean of 3 points over 24 weeks. The scores of patients randomized to an intermediate-intensity treadmill workout increased 2 points over the study, which was not significantly different than the increase seen in the control group, Margaret Schenkman, PhD, and her colleagues wrote Dec. 11 in JAMA Neurology.

Pavel Losevsky/iStockphoto

[email protected]

SOURCE: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517

GENEVA – The merits of addressing interleukin-23 as a novel therapeutic target in moderate to severe plaque psoriasis were abundantly displayed in 2-year outcomes data for two anti–IL-23 monoclonal antibodies – guselkumab and tildrakizumab – in studies presented back to back at the annual congress of the European Academy of Dermatology and Venereology.

These long-term, open-label extensions of previously reported phase 3, randomized, double-blind clinical trials provided evidence of multiple advantages for IL-23 inhibition. The story was similar for both agents: After 2 years of use in the extension studies, the two biologics demonstrated stellar treatment response rates that would have been unimaginable only a few years ago, maintenance of efficacy without drop-off over time, exceedingly low dropout rates, and a safety picture that remains reassuring as experience accumulates. Also, the subcutaneously administered IL-23 inhibitors are attractive from a patient convenience standpoint in that maintenance guselkumab is dosed at 100 mg once every 8 weeks, and tildrakizumab is given once every 12 weeks.

Still, there are differences between the two drugs, most notably in apparent effectiveness. While more than half of guselkumab-treated patients had a Psoriasis Area Severity Index (PASI) 100 response – that is, totally clear skin – at 2 years, that was the case for only one-quarter to one-third of patients on tildrakizumab.

Guselkumab (Tremfya) was approved by the Food and Drug Administration in July 2017 for treatment of adults with moderate to severe plaque psoriasis. Tildrakizumab remains investigational.
 

Guselkumab

The 2-year, open-label extension of the phase 3 VOYAGE 1 trial included 735 patients who were either on guselkumab continuously, crossed from adalimumab (Humira) to guselkumab after 48 weeks, or switched from placebo after 16 weeks.

Bruce Jancin/Frontline Medical News

Tildrakizumab

Two-year results from the ongoing 5-year extension of the phase 3 reSURFACE 1 and reSURFACE 2 trials were presented by Kim A. Papp, MD, PhD, president of Probity Medical Research, Waterloo, Ont. This presentation of 2-year outcomes for 1,237 study participants was a feat, considering that the 12-week results of the trials had been published less than 3 months earlier (Lancet. 2017 Jul 15;390[10091]:276-88).

Bruce Jancin/Frontline Medical News

Controversy over how to report long-term outcomes

A hot topic among clinical trialists in dermatology concerns how to report study results. The traditional method in studies funded by pharmaceutical companies is known as the “last observation carried forward” analysis. It casts the study drug results in the most favorable possible light because, when a subject drops out of a trial for any reason, their last measured value for response to treatment is carried forward as though the patient completed the study. Thus, psoriasis patients who drop out because they couldn’t tolerate a therapy or developed a serious side effect dictating discontinuation will be scored on the basis of their last PASI response, creating a bias in favor of active treatment.

A more conservative analytic method is known as the “nonresponder imputation” analysis. By this method, a patient who drops out of a trial is automatically categorized as a treatment failure, even if the reason was that the patient moved and could no longer make visits to the study center.

The prespecified guselkumab analysis presented by Dr. Blauvelt involved nonresponder imputation through year 1 and imputation based on the reason for discontinuation in the second year. In contrast, the 2-year tildrakizumab analysis presented by Dr. Papp used the far more common last observation carried forward method.

To help the audience appreciate the importance of looking at the analytic methods used in a studies and help them understand the clinical significance of the results, Dr. Blauvelt provided a reanalysis of the 2-year guselkumab data using the last observation carried forward method. Across the board, the numbers became more favorable. For example, the PASI 75 rate of 95.7% using the prespecified nonresponder imputation analysis crept up to 96.8% under the last observation carried forward method; for comparison, the PASI 75 rates were 81%-84% in the tildrakizumab analysis.

“If you wanted to compare apples to apples with some other drugs, you would use these numbers – the as-observed analysis numbers used by most other companies with other drugs. If you wanted to determine what the true-life numbers are, they’d probably be something between the nonresponder imputation and as-observed numbers,” said to Dr. Blauvelt.

Dr. Papp was untroubled by the use of the last observation carried forward method in the particular case of the tildrakizumab long-term extension study.

“There is reason to believe the as-observed analysis doesn’t affect the integrity of the data because the dropout rate is extraordinarily low,” he said.

The guselkumab analysis was sponsored by Janssen Pharmaceutica; the tildrakizumab analysis was sponsored by Merck and by Sun Pharma. Dr. Blauvelt and Dr. Papp were paid investigators in both studies and serve as scientific advisers to virtually all companies invested in the psoriasis therapy developmental pipeline.

[email protected]

GENEVA – The merits of addressing interleukin-23 as a novel therapeutic target in moderate to severe plaque psoriasis were abundantly displayed in 2-year outcomes data for two anti–IL-23 monoclonal antibodies – guselkumab and tildrakizumab – in studies presented back to back at the annual congress of the European Academy of Dermatology and Venereology.

These long-term, open-label extensions of previously reported phase 3, randomized, double-blind clinical trials provided evidence of multiple advantages for IL-23 inhibition. The story was similar for both agents: After 2 years of use in the extension studies, the two biologics demonstrated stellar treatment response rates that would have been unimaginable only a few years ago, maintenance of efficacy without drop-off over time, exceedingly low dropout rates, and a safety picture that remains reassuring as experience accumulates. Also, the subcutaneously administered IL-23 inhibitors are attractive from a patient convenience standpoint in that maintenance guselkumab is dosed at 100 mg once every 8 weeks, and tildrakizumab is given once every 12 weeks.

Still, there are differences between the two drugs, most notably in apparent effectiveness. While more than half of guselkumab-treated patients had a Psoriasis Area Severity Index (PASI) 100 response – that is, totally clear skin – at 2 years, that was the case for only one-quarter to one-third of patients on tildrakizumab.

Guselkumab (Tremfya) was approved by the Food and Drug Administration in July 2017 for treatment of adults with moderate to severe plaque psoriasis. Tildrakizumab remains investigational.
 

Guselkumab

The 2-year, open-label extension of the phase 3 VOYAGE 1 trial included 735 patients who were either on guselkumab continuously, crossed from adalimumab (Humira) to guselkumab after 48 weeks, or switched from placebo after 16 weeks.

Bruce Jancin/Frontline Medical News

Tildrakizumab

Two-year results from the ongoing 5-year extension of the phase 3 reSURFACE 1 and reSURFACE 2 trials were presented by Kim A. Papp, MD, PhD, president of Probity Medical Research, Waterloo, Ont. This presentation of 2-year outcomes for 1,237 study participants was a feat, considering that the 12-week results of the trials had been published less than 3 months earlier (Lancet. 2017 Jul 15;390[10091]:276-88).

Bruce Jancin/Frontline Medical News

Controversy over how to report long-term outcomes

A hot topic among clinical trialists in dermatology concerns how to report study results. The traditional method in studies funded by pharmaceutical companies is known as the “last observation carried forward” analysis. It casts the study drug results in the most favorable possible light because, when a subject drops out of a trial for any reason, their last measured value for response to treatment is carried forward as though the patient completed the study. Thus, psoriasis patients who drop out because they couldn’t tolerate a therapy or developed a serious side effect dictating discontinuation will be scored on the basis of their last PASI response, creating a bias in favor of active treatment.

A more conservative analytic method is known as the “nonresponder imputation” analysis. By this method, a patient who drops out of a trial is automatically categorized as a treatment failure, even if the reason was that the patient moved and could no longer make visits to the study center.

The prespecified guselkumab analysis presented by Dr. Blauvelt involved nonresponder imputation through year 1 and imputation based on the reason for discontinuation in the second year. In contrast, the 2-year tildrakizumab analysis presented by Dr. Papp used the far more common last observation carried forward method.

To help the audience appreciate the importance of looking at the analytic methods used in a studies and help them understand the clinical significance of the results, Dr. Blauvelt provided a reanalysis of the 2-year guselkumab data using the last observation carried forward method. Across the board, the numbers became more favorable. For example, the PASI 75 rate of 95.7% using the prespecified nonresponder imputation analysis crept up to 96.8% under the last observation carried forward method; for comparison, the PASI 75 rates were 81%-84% in the tildrakizumab analysis.

“If you wanted to compare apples to apples with some other drugs, you would use these numbers – the as-observed analysis numbers used by most other companies with other drugs. If you wanted to determine what the true-life numbers are, they’d probably be something between the nonresponder imputation and as-observed numbers,” said to Dr. Blauvelt.

Dr. Papp was untroubled by the use of the last observation carried forward method in the particular case of the tildrakizumab long-term extension study.

“There is reason to believe the as-observed analysis doesn’t affect the integrity of the data because the dropout rate is extraordinarily low,” he said.

The guselkumab analysis was sponsored by Janssen Pharmaceutica; the tildrakizumab analysis was sponsored by Merck and by Sun Pharma. Dr. Blauvelt and Dr. Papp were paid investigators in both studies and serve as scientific advisers to virtually all companies invested in the psoriasis therapy developmental pipeline.

[email protected]

GENEVA – The merits of addressing interleukin-23 as a novel therapeutic target in moderate to severe plaque psoriasis were abundantly displayed in 2-year outcomes data for two anti–IL-23 monoclonal antibodies – guselkumab and tildrakizumab – in studies presented back to back at the annual congress of the European Academy of Dermatology and Venereology.

These long-term, open-label extensions of previously reported phase 3, randomized, double-blind clinical trials provided evidence of multiple advantages for IL-23 inhibition. The story was similar for both agents: After 2 years of use in the extension studies, the two biologics demonstrated stellar treatment response rates that would have been unimaginable only a few years ago, maintenance of efficacy without drop-off over time, exceedingly low dropout rates, and a safety picture that remains reassuring as experience accumulates. Also, the subcutaneously administered IL-23 inhibitors are attractive from a patient convenience standpoint in that maintenance guselkumab is dosed at 100 mg once every 8 weeks, and tildrakizumab is given once every 12 weeks.

Still, there are differences between the two drugs, most notably in apparent effectiveness. While more than half of guselkumab-treated patients had a Psoriasis Area Severity Index (PASI) 100 response – that is, totally clear skin – at 2 years, that was the case for only one-quarter to one-third of patients on tildrakizumab.

Guselkumab (Tremfya) was approved by the Food and Drug Administration in July 2017 for treatment of adults with moderate to severe plaque psoriasis. Tildrakizumab remains investigational.
 

Guselkumab

The 2-year, open-label extension of the phase 3 VOYAGE 1 trial included 735 patients who were either on guselkumab continuously, crossed from adalimumab (Humira) to guselkumab after 48 weeks, or switched from placebo after 16 weeks.

Bruce Jancin/Frontline Medical News

Tildrakizumab

Two-year results from the ongoing 5-year extension of the phase 3 reSURFACE 1 and reSURFACE 2 trials were presented by Kim A. Papp, MD, PhD, president of Probity Medical Research, Waterloo, Ont. This presentation of 2-year outcomes for 1,237 study participants was a feat, considering that the 12-week results of the trials had been published less than 3 months earlier (Lancet. 2017 Jul 15;390[10091]:276-88).

Bruce Jancin/Frontline Medical News

Controversy over how to report long-term outcomes

A hot topic among clinical trialists in dermatology concerns how to report study results. The traditional method in studies funded by pharmaceutical companies is known as the “last observation carried forward” analysis. It casts the study drug results in the most favorable possible light because, when a subject drops out of a trial for any reason, their last measured value for response to treatment is carried forward as though the patient completed the study. Thus, psoriasis patients who drop out because they couldn’t tolerate a therapy or developed a serious side effect dictating discontinuation will be scored on the basis of their last PASI response, creating a bias in favor of active treatment.

A more conservative analytic method is known as the “nonresponder imputation” analysis. By this method, a patient who drops out of a trial is automatically categorized as a treatment failure, even if the reason was that the patient moved and could no longer make visits to the study center.

The prespecified guselkumab analysis presented by Dr. Blauvelt involved nonresponder imputation through year 1 and imputation based on the reason for discontinuation in the second year. In contrast, the 2-year tildrakizumab analysis presented by Dr. Papp used the far more common last observation carried forward method.

To help the audience appreciate the importance of looking at the analytic methods used in a studies and help them understand the clinical significance of the results, Dr. Blauvelt provided a reanalysis of the 2-year guselkumab data using the last observation carried forward method. Across the board, the numbers became more favorable. For example, the PASI 75 rate of 95.7% using the prespecified nonresponder imputation analysis crept up to 96.8% under the last observation carried forward method; for comparison, the PASI 75 rates were 81%-84% in the tildrakizumab analysis.

“If you wanted to compare apples to apples with some other drugs, you would use these numbers – the as-observed analysis numbers used by most other companies with other drugs. If you wanted to determine what the true-life numbers are, they’d probably be something between the nonresponder imputation and as-observed numbers,” said to Dr. Blauvelt.

Dr. Papp was untroubled by the use of the last observation carried forward method in the particular case of the tildrakizumab long-term extension study.

“There is reason to believe the as-observed analysis doesn’t affect the integrity of the data because the dropout rate is extraordinarily low,” he said.

The guselkumab analysis was sponsored by Janssen Pharmaceutica; the tildrakizumab analysis was sponsored by Merck and by Sun Pharma. Dr. Blauvelt and Dr. Papp were paid investigators in both studies and serve as scientific advisers to virtually all companies invested in the psoriasis therapy developmental pipeline.

[email protected]

ATLANTA – In the ZUMA-1 trial, more than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.

Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.

In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.

ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.

ATLANTA – In the ZUMA-1 trial, more than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.

Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.

In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.

ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.

ATLANTA – In the ZUMA-1 trial, more than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.

Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.

In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.

ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.