Neil Osterweil

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

Photo from Flickr

BOSTON—Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, according to investigators.

In a single-center study, rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 and cut the rate of platelet wastage from expiration by more than half.

Adam L. Booth, MD, of the University of Texas in Galveston, and his colleagues described this study in a poster presentation at AABB 2018 (abstract INV4).

Platelets typically have a shelf life of 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted.

In March 2016, the U.S. Food and Drug Administration (FDA) published a draft guidance proposing a change in regulations to allow for an extended shelf life if platelets are collected in an FDA-approved, 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

Dr. Booth and his colleagues wanted to see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets.

The investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

The team looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and they excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, the annual wastage rate was 24%, or 332 of 1,371 platelet units purchased. Using a mean per-unit cost of $516.96, the annual cost was more than $171,000.

After the start of testing, the annualized rate of wastage dropped to 10%, or 117 of 1,168 platelet units. So the annualized cost was more than $60,000.

The difference in cost—minus the cost of rapid bacterial testing (roughly $22,500)—resulted in an annual savings for the institution of nearly $89,000.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

This study was internally funded. The authors reported having no conflicts of interest.

Photo from Flickr

BOSTON—Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, according to investigators.

In a single-center study, rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 and cut the rate of platelet wastage from expiration by more than half.

Adam L. Booth, MD, of the University of Texas in Galveston, and his colleagues described this study in a poster presentation at AABB 2018 (abstract INV4).

Platelets typically have a shelf life of 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted.

In March 2016, the U.S. Food and Drug Administration (FDA) published a draft guidance proposing a change in regulations to allow for an extended shelf life if platelets are collected in an FDA-approved, 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

Dr. Booth and his colleagues wanted to see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets.

The investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

The team looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and they excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, the annual wastage rate was 24%, or 332 of 1,371 platelet units purchased. Using a mean per-unit cost of $516.96, the annual cost was more than $171,000.

After the start of testing, the annualized rate of wastage dropped to 10%, or 117 of 1,168 platelet units. So the annualized cost was more than $60,000.

The difference in cost—minus the cost of rapid bacterial testing (roughly $22,500)—resulted in an annual savings for the institution of nearly $89,000.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

This study was internally funded. The authors reported having no conflicts of interest.

Photo from Flickr

BOSTON—Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, according to investigators.

In a single-center study, rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 and cut the rate of platelet wastage from expiration by more than half.

Adam L. Booth, MD, of the University of Texas in Galveston, and his colleagues described this study in a poster presentation at AABB 2018 (abstract INV4).

Platelets typically have a shelf life of 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted.

In March 2016, the U.S. Food and Drug Administration (FDA) published a draft guidance proposing a change in regulations to allow for an extended shelf life if platelets are collected in an FDA-approved, 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

Dr. Booth and his colleagues wanted to see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets.

The investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

The team looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and they excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, the annual wastage rate was 24%, or 332 of 1,371 platelet units purchased. Using a mean per-unit cost of $516.96, the annual cost was more than $171,000.

After the start of testing, the annualized rate of wastage dropped to 10%, or 117 of 1,168 platelet units. So the annualized cost was more than $60,000.

The difference in cost—minus the cost of rapid bacterial testing (roughly $22,500)—resulted in an annual savings for the institution of nearly $89,000.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

This study was internally funded. The authors reported having no conflicts of interest.

BOSTON – Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, investigators said.

ToyToy/Wikimedia Commons/Public Domain

Rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 per year and cut the rate of platelet wastage from expiration by more than half, reported Adam L. Booth, MD, chief resident in the department of pathology at the University of Texas, Galveston, and his colleagues.

“When a person takes all this time to come in and donate, they do it under the impression that they’re going to help somebody, or several people, and you hate to see those platelets wasted. You want them to be used,” he said in an interview at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.

Platelets typically have a shelf life of just 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted in a poster presentation.

A recently published Food and Drug Administration draft guidance for blood banks and transfusion services proposed changing regulations regarding bacterial control of blood products to allow for extended dating if the platelets are collected in an FDA-approved 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

To see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets, the investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

They looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, 332 units at a mean per-unit cost of $516.96 were wasted, for an annual cost of more than $171,000. After the start of testing, however, the annualized rate of waste dropped to 117 units, for an annualized cost of more than $60,000. The difference – minus the cost of rapid bacterial testing – resulted in an annual savings for the institution of nearly $89,000.

Prior to rapid testing, the annual wastage rate was 24%; after testing, it dropped to an annualized 10% rate, the investigators reported.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

“Our findings suggest that rapid bacterial testing can simultaneously enhance the safety of apheresis platelet transfusions and contribute to significant cost savings,” Dr. Booth and his colleagues wrote.

The study was internally funded. The authors reported having no conflicts of interest.

SOURCE: Booth AL et al. AABB18, Abstract INV4.

BOSTON – Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, investigators said.

ToyToy/Wikimedia Commons/Public Domain

Rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 per year and cut the rate of platelet wastage from expiration by more than half, reported Adam L. Booth, MD, chief resident in the department of pathology at the University of Texas, Galveston, and his colleagues.

“When a person takes all this time to come in and donate, they do it under the impression that they’re going to help somebody, or several people, and you hate to see those platelets wasted. You want them to be used,” he said in an interview at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.

Platelets typically have a shelf life of just 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted in a poster presentation.

A recently published Food and Drug Administration draft guidance for blood banks and transfusion services proposed changing regulations regarding bacterial control of blood products to allow for extended dating if the platelets are collected in an FDA-approved 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

To see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets, the investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

They looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, 332 units at a mean per-unit cost of $516.96 were wasted, for an annual cost of more than $171,000. After the start of testing, however, the annualized rate of waste dropped to 117 units, for an annualized cost of more than $60,000. The difference – minus the cost of rapid bacterial testing – resulted in an annual savings for the institution of nearly $89,000.

Prior to rapid testing, the annual wastage rate was 24%; after testing, it dropped to an annualized 10% rate, the investigators reported.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

“Our findings suggest that rapid bacterial testing can simultaneously enhance the safety of apheresis platelet transfusions and contribute to significant cost savings,” Dr. Booth and his colleagues wrote.

The study was internally funded. The authors reported having no conflicts of interest.

SOURCE: Booth AL et al. AABB18, Abstract INV4.

BOSTON – Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, investigators said.

ToyToy/Wikimedia Commons/Public Domain

Rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 per year and cut the rate of platelet wastage from expiration by more than half, reported Adam L. Booth, MD, chief resident in the department of pathology at the University of Texas, Galveston, and his colleagues.

“When a person takes all this time to come in and donate, they do it under the impression that they’re going to help somebody, or several people, and you hate to see those platelets wasted. You want them to be used,” he said in an interview at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.

Platelets typically have a shelf life of just 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted in a poster presentation.

A recently published Food and Drug Administration draft guidance for blood banks and transfusion services proposed changing regulations regarding bacterial control of blood products to allow for extended dating if the platelets are collected in an FDA-approved 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

To see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets, the investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

They looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, 332 units at a mean per-unit cost of $516.96 were wasted, for an annual cost of more than $171,000. After the start of testing, however, the annualized rate of waste dropped to 117 units, for an annualized cost of more than $60,000. The difference – minus the cost of rapid bacterial testing – resulted in an annual savings for the institution of nearly $89,000.

Prior to rapid testing, the annual wastage rate was 24%; after testing, it dropped to an annualized 10% rate, the investigators reported.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

“Our findings suggest that rapid bacterial testing can simultaneously enhance the safety of apheresis platelet transfusions and contribute to significant cost savings,” Dr. Booth and his colleagues wrote.

The study was internally funded. The authors reported having no conflicts of interest.

SOURCE: Booth AL et al. AABB18, Abstract INV4.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – A combination of the selective phosphoinositide 3-kinase inhibitor alpelisib and fulvestrant (Faslodex) was associated with significantly better progression-free survival than placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer with PIK3CA mutations, investigators in the SOLAR-1 trial reported.

Neil Osterweil/MDedge News

The addition of alpelisib, an inhibitor of the alpha isoform of the phosphoinositide 3-kinase (PI3K), to fulvestrant, a selective estrogen receptor modifier, was associated with a 35% improvement in progression-free survival (PFS), reported Fabrice André, MD, of Institut Gustave Roussy, Villejuif, France.

“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy, with or without a CDK 4/6 [cyclin-dependent kinases 4/6] inhibitor,” he said in a podium presentation at the European Society for Medical Oncology Congress.

Unlike other PI3K inhibitors which have activity spanning the alpha, beta, gamma, and delta isoforms of PI3K, alpelisib is specific for only the alpha isoform, giving it a safety profile that compares favorably with other agents in its class, Dr. André said.

Results of other studies combining PI3K inhibition with endocrine therapy have not borne especially sweet fruit. For example, the SANDPIPER trial, a study of the combination of fulvestrant and the PI3K inhibitor idelalisib (Zydelig) presented at the 2018 annual meeting of the American Society of Clinical Oncology, showed a benefit of 2 months more PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half of all patients treated with the combination.

In the SOLAR-1 trial, investigators randomized 572 postmenopausal women, or men (sex of patients not shown), with hormone receptor–positive, HER2-negative advanced breast cancer. Of the 572 patients, 341 were determined to have PIK3CA mutations.

To be eligible for the study, patients had to have good Eastern Cooperative Oncology Group performance status (1 or less) and have received one or more prior lines of endocrine therapy but no chemotherapy for advanced breast cancer.

Patients who had previously received fulvestrant, any PI3K inhibitor, Akt inhibitor, or mammalian target of rapamycin inhibitor were excluded.

The patients were randomly assigned to receive intramuscular fulvestrant 500 mg on days 1 and 15 of treatment cycle 1 and then every 28 days, plus either oral alpelisib (300 mg daily) or placebo.

Locally assessed PFS in patients with PIK3CA mutations, the primary endpoint, favored alpelisib. At a median follow-up of 20 months, the median PFS with alpelisib was 11 months, versus 5.7 months for placebo. The hazard ratio for progression with alpelisib was 0.65 (P = .00065).

A blinded independent review committee assessment of 50% of patients in the PIK3CA-mutant cohort supported the investigator-assessed findings, with a median PFS of 11.1 months with alpelisib, versus 3.7 months with placebo.

In contrast, a proof-of-concept analysis of the 231 patients without PIK3CA mutations could not show a benefit for alpelisib over placebo.

In the PIK3CA-mutant cohort, the overall response rates among patients with measurable disease were 35.7% with alpelisib versus 16.2% with placebo (P = .0002). Respective response rates among all patients were 26.6% and 12.8% (P = .0006).

Adverse events in the entire trial population included hyperglycemia leading to discontinuation of alpelisib in 6.3% of patients and rash leading to discontinuation of the drug in 3.2% of patients. There were no discontinuations for either hyperglycemia or rash in the placebo arm.

The hyperglycemia can be managed with metformin, Dr. André said.

At a briefing prior to presentation of the SOLAR-1 data in a symposium, briefing discussant Nadia Harbeck, MD, of the University of Munich Medical Center said that the trial represents a significant advance.

“We have numerous talks, also phase 3 trials, with PI3-kinase inhibitors where we saw marginal benefit, and the drugs weren’t usable in clinical practice because the tolerability was so bad. So this is now the first phase 3 data proving that if you have a targeted drug and the tumor has the target, you can actually almost double progression-free survival, and I think this will change the way we practice,” she said.

Neil Osterweil/MDedge News

Rebecca Dent, MD, a senior consultant at the National Cancer Centre Singapore, the invited discussant at the symposium, complimented the SOLAR-1 investigators for conducting a “clinically homogeneous, biomarker-driven clinical trial reflecting new pathways to registration.”

She suggested that the significant clinical toxicities seen with PI3K inhibitors might be ameliorated with different dosing schedules, pharmacodynamic endpoints such as hyperglycemia, or potential prophylaxis.

The trial demonstrated a clinically meaningful absolute PFS benefit, the best in class, but updated data, including overall survival data, are still needed, Dr. Dent said. “We also need to see the quality-of-life data; this is what’s important for our patients. Is this improving progression-free survival, is it improving quality of life, and is it improving overall survival? Only the future will tell.”

SOLAR-1 was sponsored by Novartis. Dr. André disclosed research grants from Novartis and others. Dr. Dent disclosed advisory board, honoraria, or travel support from Novartis and others. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others.

SOURCE: Andre F et al. ESMO 2018, Abstract LBA3_PR.

MUNICH – A combination of the selective phosphoinositide 3-kinase inhibitor alpelisib and fulvestrant (Faslodex) was associated with significantly better progression-free survival than placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer with PIK3CA mutations, investigators in the SOLAR-1 trial reported.

Neil Osterweil/MDedge News

The addition of alpelisib, an inhibitor of the alpha isoform of the phosphoinositide 3-kinase (PI3K), to fulvestrant, a selective estrogen receptor modifier, was associated with a 35% improvement in progression-free survival (PFS), reported Fabrice André, MD, of Institut Gustave Roussy, Villejuif, France.

“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy, with or without a CDK 4/6 [cyclin-dependent kinases 4/6] inhibitor,” he said in a podium presentation at the European Society for Medical Oncology Congress.

Unlike other PI3K inhibitors which have activity spanning the alpha, beta, gamma, and delta isoforms of PI3K, alpelisib is specific for only the alpha isoform, giving it a safety profile that compares favorably with other agents in its class, Dr. André said.

Results of other studies combining PI3K inhibition with endocrine therapy have not borne especially sweet fruit. For example, the SANDPIPER trial, a study of the combination of fulvestrant and the PI3K inhibitor idelalisib (Zydelig) presented at the 2018 annual meeting of the American Society of Clinical Oncology, showed a benefit of 2 months more PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half of all patients treated with the combination.

In the SOLAR-1 trial, investigators randomized 572 postmenopausal women, or men (sex of patients not shown), with hormone receptor–positive, HER2-negative advanced breast cancer. Of the 572 patients, 341 were determined to have PIK3CA mutations.

To be eligible for the study, patients had to have good Eastern Cooperative Oncology Group performance status (1 or less) and have received one or more prior lines of endocrine therapy but no chemotherapy for advanced breast cancer.

Patients who had previously received fulvestrant, any PI3K inhibitor, Akt inhibitor, or mammalian target of rapamycin inhibitor were excluded.

The patients were randomly assigned to receive intramuscular fulvestrant 500 mg on days 1 and 15 of treatment cycle 1 and then every 28 days, plus either oral alpelisib (300 mg daily) or placebo.

Locally assessed PFS in patients with PIK3CA mutations, the primary endpoint, favored alpelisib. At a median follow-up of 20 months, the median PFS with alpelisib was 11 months, versus 5.7 months for placebo. The hazard ratio for progression with alpelisib was 0.65 (P = .00065).

A blinded independent review committee assessment of 50% of patients in the PIK3CA-mutant cohort supported the investigator-assessed findings, with a median PFS of 11.1 months with alpelisib, versus 3.7 months with placebo.

In contrast, a proof-of-concept analysis of the 231 patients without PIK3CA mutations could not show a benefit for alpelisib over placebo.

In the PIK3CA-mutant cohort, the overall response rates among patients with measurable disease were 35.7% with alpelisib versus 16.2% with placebo (P = .0002). Respective response rates among all patients were 26.6% and 12.8% (P = .0006).

Adverse events in the entire trial population included hyperglycemia leading to discontinuation of alpelisib in 6.3% of patients and rash leading to discontinuation of the drug in 3.2% of patients. There were no discontinuations for either hyperglycemia or rash in the placebo arm.

The hyperglycemia can be managed with metformin, Dr. André said.

At a briefing prior to presentation of the SOLAR-1 data in a symposium, briefing discussant Nadia Harbeck, MD, of the University of Munich Medical Center said that the trial represents a significant advance.

“We have numerous talks, also phase 3 trials, with PI3-kinase inhibitors where we saw marginal benefit, and the drugs weren’t usable in clinical practice because the tolerability was so bad. So this is now the first phase 3 data proving that if you have a targeted drug and the tumor has the target, you can actually almost double progression-free survival, and I think this will change the way we practice,” she said.

Neil Osterweil/MDedge News

Rebecca Dent, MD, a senior consultant at the National Cancer Centre Singapore, the invited discussant at the symposium, complimented the SOLAR-1 investigators for conducting a “clinically homogeneous, biomarker-driven clinical trial reflecting new pathways to registration.”

She suggested that the significant clinical toxicities seen with PI3K inhibitors might be ameliorated with different dosing schedules, pharmacodynamic endpoints such as hyperglycemia, or potential prophylaxis.

The trial demonstrated a clinically meaningful absolute PFS benefit, the best in class, but updated data, including overall survival data, are still needed, Dr. Dent said. “We also need to see the quality-of-life data; this is what’s important for our patients. Is this improving progression-free survival, is it improving quality of life, and is it improving overall survival? Only the future will tell.”

SOLAR-1 was sponsored by Novartis. Dr. André disclosed research grants from Novartis and others. Dr. Dent disclosed advisory board, honoraria, or travel support from Novartis and others. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others.

SOURCE: Andre F et al. ESMO 2018, Abstract LBA3_PR.

MUNICH – A combination of the selective phosphoinositide 3-kinase inhibitor alpelisib and fulvestrant (Faslodex) was associated with significantly better progression-free survival than placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer with PIK3CA mutations, investigators in the SOLAR-1 trial reported.

Neil Osterweil/MDedge News

The addition of alpelisib, an inhibitor of the alpha isoform of the phosphoinositide 3-kinase (PI3K), to fulvestrant, a selective estrogen receptor modifier, was associated with a 35% improvement in progression-free survival (PFS), reported Fabrice André, MD, of Institut Gustave Roussy, Villejuif, France.

“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy, with or without a CDK 4/6 [cyclin-dependent kinases 4/6] inhibitor,” he said in a podium presentation at the European Society for Medical Oncology Congress.

Unlike other PI3K inhibitors which have activity spanning the alpha, beta, gamma, and delta isoforms of PI3K, alpelisib is specific for only the alpha isoform, giving it a safety profile that compares favorably with other agents in its class, Dr. André said.

Results of other studies combining PI3K inhibition with endocrine therapy have not borne especially sweet fruit. For example, the SANDPIPER trial, a study of the combination of fulvestrant and the PI3K inhibitor idelalisib (Zydelig) presented at the 2018 annual meeting of the American Society of Clinical Oncology, showed a benefit of 2 months more PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half of all patients treated with the combination.

In the SOLAR-1 trial, investigators randomized 572 postmenopausal women, or men (sex of patients not shown), with hormone receptor–positive, HER2-negative advanced breast cancer. Of the 572 patients, 341 were determined to have PIK3CA mutations.

To be eligible for the study, patients had to have good Eastern Cooperative Oncology Group performance status (1 or less) and have received one or more prior lines of endocrine therapy but no chemotherapy for advanced breast cancer.

Patients who had previously received fulvestrant, any PI3K inhibitor, Akt inhibitor, or mammalian target of rapamycin inhibitor were excluded.

The patients were randomly assigned to receive intramuscular fulvestrant 500 mg on days 1 and 15 of treatment cycle 1 and then every 28 days, plus either oral alpelisib (300 mg daily) or placebo.

Locally assessed PFS in patients with PIK3CA mutations, the primary endpoint, favored alpelisib. At a median follow-up of 20 months, the median PFS with alpelisib was 11 months, versus 5.7 months for placebo. The hazard ratio for progression with alpelisib was 0.65 (P = .00065).

A blinded independent review committee assessment of 50% of patients in the PIK3CA-mutant cohort supported the investigator-assessed findings, with a median PFS of 11.1 months with alpelisib, versus 3.7 months with placebo.

In contrast, a proof-of-concept analysis of the 231 patients without PIK3CA mutations could not show a benefit for alpelisib over placebo.

In the PIK3CA-mutant cohort, the overall response rates among patients with measurable disease were 35.7% with alpelisib versus 16.2% with placebo (P = .0002). Respective response rates among all patients were 26.6% and 12.8% (P = .0006).

Adverse events in the entire trial population included hyperglycemia leading to discontinuation of alpelisib in 6.3% of patients and rash leading to discontinuation of the drug in 3.2% of patients. There were no discontinuations for either hyperglycemia or rash in the placebo arm.

The hyperglycemia can be managed with metformin, Dr. André said.

At a briefing prior to presentation of the SOLAR-1 data in a symposium, briefing discussant Nadia Harbeck, MD, of the University of Munich Medical Center said that the trial represents a significant advance.

“We have numerous talks, also phase 3 trials, with PI3-kinase inhibitors where we saw marginal benefit, and the drugs weren’t usable in clinical practice because the tolerability was so bad. So this is now the first phase 3 data proving that if you have a targeted drug and the tumor has the target, you can actually almost double progression-free survival, and I think this will change the way we practice,” she said.

Neil Osterweil/MDedge News

Rebecca Dent, MD, a senior consultant at the National Cancer Centre Singapore, the invited discussant at the symposium, complimented the SOLAR-1 investigators for conducting a “clinically homogeneous, biomarker-driven clinical trial reflecting new pathways to registration.”

She suggested that the significant clinical toxicities seen with PI3K inhibitors might be ameliorated with different dosing schedules, pharmacodynamic endpoints such as hyperglycemia, or potential prophylaxis.

The trial demonstrated a clinically meaningful absolute PFS benefit, the best in class, but updated data, including overall survival data, are still needed, Dr. Dent said. “We also need to see the quality-of-life data; this is what’s important for our patients. Is this improving progression-free survival, is it improving quality of life, and is it improving overall survival? Only the future will tell.”

SOLAR-1 was sponsored by Novartis. Dr. André disclosed research grants from Novartis and others. Dr. Dent disclosed advisory board, honoraria, or travel support from Novartis and others. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others.

SOURCE: Andre F et al. ESMO 2018, Abstract LBA3_PR.

MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.

Neil Osterweil/MDedge News

Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.

“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.

The study was published online in the Lancet Oncology to coincide with the presentation.

Neil Osterweil/MDedge News

Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.

Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”

The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.

For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.

As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.

In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.

In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.

Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.

He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”

The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.

“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.

The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.

SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.

MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.

Neil Osterweil/MDedge News

Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.

“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.

The study was published online in the Lancet Oncology to coincide with the presentation.

Neil Osterweil/MDedge News

Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.

Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”

The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.

For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.

As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.

In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.

In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.

Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.

He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”

The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.

“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.

The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.

SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.

MUNICH – Radiotherapy of the primary tumor can improve overall survival in men with untreated metastatic adenocarcinoma of the prostate, a finding that suggests a possible life-extending role of radiotherapy in other metastatic tumor types, investigators in the STAMPEDE trial reported.

Neil Osterweil/MDedge News

Among 2,061 men from the United Kingdom and Switzerland with previously untreated metastatic prostate cancer, there was no survival advantage to adding local radiation to standard drug therapy in the overall study population. But among men with low disease burden (local invasion of bone or lymphatics) radiation to the prostate plus standard of care was associated with a 32% improvement in overall survival compared with standard therapy alone, said Chris Parker, MD, from the Royal Marsden NHS Foundation Trust.

“Prostate radiotherapy is a simple treatment, it’s very well tolerated, and it’s widely available in any cancer center throughout the world,” Dr. Parker said in a briefing prior to his presentation in a presidential symposium at the European Society for Medical Oncology Congress.

The study was published online in the Lancet Oncology to coincide with the presentation.

Neil Osterweil/MDedge News

Men who first present with metastatic prostate cancer account for about 10% of prostate cancer patients in the Western world, but may comprise as much as 60% of the prostate cancer population in some parts of Asia, noted briefing moderator and discussant Ignacio Duran, MD, from the Hospital Universitario Marques de Valdecilla, in Santander, Spain.

Prior to STAMPEDE, “we had never considered treating the local tumor in the context of wider-spread disease, and this is what the group of STAMPEDE really answered today with this study,” he said. “I think there is a substantial group of prostate cancer patients who might benefit from that. This opens the door to apply a new treatment that may have an impact in the life of these patients.”

The overarching goal of the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study is to assess novel approaches for men with hormone-naive prostate cancer.

For this aspect of the randomized, phase 3 trial, 2,061 men with newly diagnosed M1 prostate cancer were enrolled and randomly assigned to either androgen deprivation with or without docetaxel or to the same standard of care plus radiotherapy. Radiation was delivered in one of two schedules: 55 Gy delivered in 20 fractions over 4 weeks or 36 Gy in 6 fractions delivered over 6 weeks, started within 8 weeks of randomization or the start of docetaxel.

As noted before, death from any cause, the primary endpoint, was not significantly different between the study arms. But in a subgroup analysis by metastatic burden, the rate of 3-year overall survival in patients with low burden was 81% in the radiotherapy group, compared with 73% in the standard-of-care arm. The hazard ratio was 0.68 (P = .007) favoring radiation.

In contrast, the 3-year overall survival rate in the high metastatic burden arm (patients with four or more metastases to bone with at least one outside the axial skeleton and/or visceral metastases) was 53% with radiation, versus 54% without.

In all, 5% of patients in the radiotherapy arm had grade 3 or 4 adverse events during therapy, and 4% had postradiation adverse events.

Radiation was associated with small increases in the risk for bladder and bowel events, but these were generally “modest” in nature and were outweighed by the survival benefit, Dr. Parker said.

He noted that men with regional nodal invasion but not metastases were not included in the trial. “However, if prostate radiotherapy improves survival for men with distant metastases, we can be very confident that it would improve survival for men with regional nodal disease. There aren’t any trials addressing that question, and currently many of these men receive drug treatment alone. So going forward, prostate radiotherapy should be the standard treatment for these men as well.”

The concept of primary tumor irradiation may work for patients with other malignancies who have low burden (oligometastatic) disease, he added.

“Based on the findings of STAMPEDE, radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment,” commented R. Jeffrey Karnes, MD, from the Mayo Clinic in Rochester, Minnesota, and his colleagues, in an editorial accompanying the article in the Lancet Oncology.

The study is sponsored by the Medical Research Council of the United Kingdom. Dr. Parker disclosed research funding and personal fees from Bayer and personal fees from Advanced Accelerator Applications and Janssen Pharmaceuticals. Dr. Duran disclosed participation in compensated advisory boards for Roche and Bristol-Myers Squibb and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck.

SOURCE: Parker C et al. ESMO 2018, Abstract LBA5_PR.

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib (Ibrance) and fulvestrant (Faslodex) was associated with longer overall survival of women with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer in the PALOMA-3 trial.

Neil Osterweil/MDedge News

But the benefit seemed to be almost entirely limited to women with sensitivity to previous endocrine therapy; differences in overall survival among the entire cohort were not statistically significant, reported Massimo Cristofanilli, MD, of Northwestern University in Chicago, and his colleagues.

“These findings confirm that the use of palbociclib plus fulvestrant is a standard for care in patients with previously treated hormone receptor–positive, HER2-negative advanced breast cancer, he said in a briefing held prior to his presentation of the data at the European Society for Medical Oncology Congress.

The results were published simultaneously online in the New England Journal of Medicine.

Neil Osterweil/MDedge News

Briefing discussant Nadia Harbeck, MD, is a breast cancer specialist with the University of Munich Medical Center, who is a coinvestigator of PALOMA-3, noted that there are currently three marketed cyclin-dependent kinase (CDK) 4/6 inhibitors and that all three have been shown to be associated with prolonged progression-free survival (PFS).

Yet, “there’s still a lot of uncertainty out there in the community whether to give these drugs, when to give these drugs, and also from the payers’ perspective, because there’s no overall survival, and I think this is now going to change,” she said.

“Ten months overall survival benefit in a CDK 4/6 inhibitor study in the second-line setting I think is unprecedented, and I think will change people’s hearts who weren’t quite sure, and I think we can now confidently say to our patients that this is the drug to take,” she added.

Dr. Cristofanilli discussed results of a prespecified analysis of overall survival from the previously reported trial.

Investigators enrolled 521 patients with HR-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy, and randomly assigned them to fulvestrant plus palbociclib or placebo.

In addition to looking at overall survival, the analysis included evaluation of the effects of palbociclib in women both with and without sensitivity to endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status. In addition, the analysis looked at the efficacy of therapies after disease progression, and safety of the respective regimens.

The median overall survival at a median follow-up of 44.8 months was 34.9 months with palbociclib/fulvestrant vs. 28 months for placebo/fulvestrant, translating into a stratified hazard ratio (HR) for death in the palbociclib arm of 0.81, but this difference was not statistically significant (P = .09). The unstratified HR was 0.79 (P = .05; the prespecified significance threshold was a two-sided P value of .047).

When they looked at the 410 patients with documented sensitivity to previous endocrine therapy, however, the investigators found a median OS of 39.7 months with palbociclib vs. 29.7 months with placebo. The HR for death with palbociclib in this subgroup was 0.72, with a 95% confidence interval indicating statistical significance.

In contrast, among 111 patients with documented intrinsic endocrine resistance, the median OS with palbociclib was actually lower than in the placebo group, albeit not significantly, at 20.2 vs. 26.2 months, respectively (HR, 1.14; P = .012 for interaction).

The median time to starting chemotherapy was 17.6 months in the palbociclib/fulvestrant group vs. 8.8 months in the placebo/fulvestrant group (HR, 0.58; P less than .001).

The safety profile of the combination was similar to that seen in the primary analysis of PALOMA-3. Grade 3 or 4 neutropenia occurred in 70% of patients on palbociclib vs. none of the patients on placebo. Other grade 3 or 4 events included anemia in 4% vs. 2%, thrombocytopenia in 3% vs. none, and febrile neutropenia in 1% vs. none.

Other grade 3 or greater events occurring with palbociclib in more than 2% of patients were infections, fatigue, and elevated aspartate aminotransferase levels.

Neil Osterweil/MDedge News

Invited discussant Fatima Cardoso, MD, director of the breast unit of the Champalimaud Clinical Center in Lisbon, commented that PALOMA-3 was adequately powered for the primary endpoint of PFS, but not for a secondary overall survival endpoint.

She also raised questions that still need to be answered about the use of CDK 4/6 inhibitors with endocrine therapy in this population, including how to better identify which patients might benefit from the combination, whether the combination should be used in the first line or in subsequent lines of therapy, and whether it should be used in patients with or without prior endocrine therapy exposure.

Another unanswered question is whether disease progression accelerates after CDK 4/6 inhibitors are stopped.

“We need to confirm if this problem of post progression is true or not, and there may be a rationale to explore continuing beyond progression. This was a paradigm that changed in the HER2-positive population, and we now know that we need to continue to block the HER2 pathway, because if we don’t, the progression is faster. Will that apply here as well?,” she asked.

Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, commented that patients in PALOMA-3 were allowed to have had chemotherapy, and there is evidence to suggest that prior chemotherapy is a risk factor for resistance to other therapies as well.

“So looking at patients with hormone-sensitive disease who have done their chemotherapy, seeing a survival benefit in any subset of patients with hormone receptor–positive disease getting a targeted agent is already pretty exciting,” she said in an interview.

Dr. Rugo was not involved in PALOMA-3.

PALOMA-3 was supported by Pfizer. Dr. Cristofanilli disclosed personal fees from Pfizer, Novartis, and Merus. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others. Dr. Cardoso has disclosed consulting fees and institutional support from Pfizer and others. Dr. Rugo has received fees/honoraria and other support for activities for Pfizer and others.

SOURCE: Turner NC et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1810527.

MUNICH – The combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib (Ibrance) and fulvestrant (Faslodex) was associated with longer overall survival of women with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer in the PALOMA-3 trial.

Neil Osterweil/MDedge News

But the benefit seemed to be almost entirely limited to women with sensitivity to previous endocrine therapy; differences in overall survival among the entire cohort were not statistically significant, reported Massimo Cristofanilli, MD, of Northwestern University in Chicago, and his colleagues.

“These findings confirm that the use of palbociclib plus fulvestrant is a standard for care in patients with previously treated hormone receptor–positive, HER2-negative advanced breast cancer, he said in a briefing held prior to his presentation of the data at the European Society for Medical Oncology Congress.

The results were published simultaneously online in the New England Journal of Medicine.

Neil Osterweil/MDedge News

Briefing discussant Nadia Harbeck, MD, is a breast cancer specialist with the University of Munich Medical Center, who is a coinvestigator of PALOMA-3, noted that there are currently three marketed cyclin-dependent kinase (CDK) 4/6 inhibitors and that all three have been shown to be associated with prolonged progression-free survival (PFS).

Yet, “there’s still a lot of uncertainty out there in the community whether to give these drugs, when to give these drugs, and also from the payers’ perspective, because there’s no overall survival, and I think this is now going to change,” she said.

“Ten months overall survival benefit in a CDK 4/6 inhibitor study in the second-line setting I think is unprecedented, and I think will change people’s hearts who weren’t quite sure, and I think we can now confidently say to our patients that this is the drug to take,” she added.

Dr. Cristofanilli discussed results of a prespecified analysis of overall survival from the previously reported trial.

Investigators enrolled 521 patients with HR-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy, and randomly assigned them to fulvestrant plus palbociclib or placebo.

In addition to looking at overall survival, the analysis included evaluation of the effects of palbociclib in women both with and without sensitivity to endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status. In addition, the analysis looked at the efficacy of therapies after disease progression, and safety of the respective regimens.

The median overall survival at a median follow-up of 44.8 months was 34.9 months with palbociclib/fulvestrant vs. 28 months for placebo/fulvestrant, translating into a stratified hazard ratio (HR) for death in the palbociclib arm of 0.81, but this difference was not statistically significant (P = .09). The unstratified HR was 0.79 (P = .05; the prespecified significance threshold was a two-sided P value of .047).

When they looked at the 410 patients with documented sensitivity to previous endocrine therapy, however, the investigators found a median OS of 39.7 months with palbociclib vs. 29.7 months with placebo. The HR for death with palbociclib in this subgroup was 0.72, with a 95% confidence interval indicating statistical significance.

In contrast, among 111 patients with documented intrinsic endocrine resistance, the median OS with palbociclib was actually lower than in the placebo group, albeit not significantly, at 20.2 vs. 26.2 months, respectively (HR, 1.14; P = .012 for interaction).

The median time to starting chemotherapy was 17.6 months in the palbociclib/fulvestrant group vs. 8.8 months in the placebo/fulvestrant group (HR, 0.58; P less than .001).

The safety profile of the combination was similar to that seen in the primary analysis of PALOMA-3. Grade 3 or 4 neutropenia occurred in 70% of patients on palbociclib vs. none of the patients on placebo. Other grade 3 or 4 events included anemia in 4% vs. 2%, thrombocytopenia in 3% vs. none, and febrile neutropenia in 1% vs. none.

Other grade 3 or greater events occurring with palbociclib in more than 2% of patients were infections, fatigue, and elevated aspartate aminotransferase levels.

Neil Osterweil/MDedge News

Invited discussant Fatima Cardoso, MD, director of the breast unit of the Champalimaud Clinical Center in Lisbon, commented that PALOMA-3 was adequately powered for the primary endpoint of PFS, but not for a secondary overall survival endpoint.

She also raised questions that still need to be answered about the use of CDK 4/6 inhibitors with endocrine therapy in this population, including how to better identify which patients might benefit from the combination, whether the combination should be used in the first line or in subsequent lines of therapy, and whether it should be used in patients with or without prior endocrine therapy exposure.

Another unanswered question is whether disease progression accelerates after CDK 4/6 inhibitors are stopped.

“We need to confirm if this problem of post progression is true or not, and there may be a rationale to explore continuing beyond progression. This was a paradigm that changed in the HER2-positive population, and we now know that we need to continue to block the HER2 pathway, because if we don’t, the progression is faster. Will that apply here as well?,” she asked.

Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, commented that patients in PALOMA-3 were allowed to have had chemotherapy, and there is evidence to suggest that prior chemotherapy is a risk factor for resistance to other therapies as well.

“So looking at patients with hormone-sensitive disease who have done their chemotherapy, seeing a survival benefit in any subset of patients with hormone receptor–positive disease getting a targeted agent is already pretty exciting,” she said in an interview.

Dr. Rugo was not involved in PALOMA-3.

PALOMA-3 was supported by Pfizer. Dr. Cristofanilli disclosed personal fees from Pfizer, Novartis, and Merus. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others. Dr. Cardoso has disclosed consulting fees and institutional support from Pfizer and others. Dr. Rugo has received fees/honoraria and other support for activities for Pfizer and others.

SOURCE: Turner NC et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1810527.

MUNICH – The combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib (Ibrance) and fulvestrant (Faslodex) was associated with longer overall survival of women with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer in the PALOMA-3 trial.

Neil Osterweil/MDedge News

But the benefit seemed to be almost entirely limited to women with sensitivity to previous endocrine therapy; differences in overall survival among the entire cohort were not statistically significant, reported Massimo Cristofanilli, MD, of Northwestern University in Chicago, and his colleagues.

“These findings confirm that the use of palbociclib plus fulvestrant is a standard for care in patients with previously treated hormone receptor–positive, HER2-negative advanced breast cancer, he said in a briefing held prior to his presentation of the data at the European Society for Medical Oncology Congress.

The results were published simultaneously online in the New England Journal of Medicine.

Neil Osterweil/MDedge News

Briefing discussant Nadia Harbeck, MD, is a breast cancer specialist with the University of Munich Medical Center, who is a coinvestigator of PALOMA-3, noted that there are currently three marketed cyclin-dependent kinase (CDK) 4/6 inhibitors and that all three have been shown to be associated with prolonged progression-free survival (PFS).

Yet, “there’s still a lot of uncertainty out there in the community whether to give these drugs, when to give these drugs, and also from the payers’ perspective, because there’s no overall survival, and I think this is now going to change,” she said.

“Ten months overall survival benefit in a CDK 4/6 inhibitor study in the second-line setting I think is unprecedented, and I think will change people’s hearts who weren’t quite sure, and I think we can now confidently say to our patients that this is the drug to take,” she added.

Dr. Cristofanilli discussed results of a prespecified analysis of overall survival from the previously reported trial.

Investigators enrolled 521 patients with HR-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy, and randomly assigned them to fulvestrant plus palbociclib or placebo.

In addition to looking at overall survival, the analysis included evaluation of the effects of palbociclib in women both with and without sensitivity to endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status. In addition, the analysis looked at the efficacy of therapies after disease progression, and safety of the respective regimens.

The median overall survival at a median follow-up of 44.8 months was 34.9 months with palbociclib/fulvestrant vs. 28 months for placebo/fulvestrant, translating into a stratified hazard ratio (HR) for death in the palbociclib arm of 0.81, but this difference was not statistically significant (P = .09). The unstratified HR was 0.79 (P = .05; the prespecified significance threshold was a two-sided P value of .047).

When they looked at the 410 patients with documented sensitivity to previous endocrine therapy, however, the investigators found a median OS of 39.7 months with palbociclib vs. 29.7 months with placebo. The HR for death with palbociclib in this subgroup was 0.72, with a 95% confidence interval indicating statistical significance.

In contrast, among 111 patients with documented intrinsic endocrine resistance, the median OS with palbociclib was actually lower than in the placebo group, albeit not significantly, at 20.2 vs. 26.2 months, respectively (HR, 1.14; P = .012 for interaction).

The median time to starting chemotherapy was 17.6 months in the palbociclib/fulvestrant group vs. 8.8 months in the placebo/fulvestrant group (HR, 0.58; P less than .001).

The safety profile of the combination was similar to that seen in the primary analysis of PALOMA-3. Grade 3 or 4 neutropenia occurred in 70% of patients on palbociclib vs. none of the patients on placebo. Other grade 3 or 4 events included anemia in 4% vs. 2%, thrombocytopenia in 3% vs. none, and febrile neutropenia in 1% vs. none.

Other grade 3 or greater events occurring with palbociclib in more than 2% of patients were infections, fatigue, and elevated aspartate aminotransferase levels.

Neil Osterweil/MDedge News

Invited discussant Fatima Cardoso, MD, director of the breast unit of the Champalimaud Clinical Center in Lisbon, commented that PALOMA-3 was adequately powered for the primary endpoint of PFS, but not for a secondary overall survival endpoint.

She also raised questions that still need to be answered about the use of CDK 4/6 inhibitors with endocrine therapy in this population, including how to better identify which patients might benefit from the combination, whether the combination should be used in the first line or in subsequent lines of therapy, and whether it should be used in patients with or without prior endocrine therapy exposure.

Another unanswered question is whether disease progression accelerates after CDK 4/6 inhibitors are stopped.

“We need to confirm if this problem of post progression is true or not, and there may be a rationale to explore continuing beyond progression. This was a paradigm that changed in the HER2-positive population, and we now know that we need to continue to block the HER2 pathway, because if we don’t, the progression is faster. Will that apply here as well?,” she asked.

Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, commented that patients in PALOMA-3 were allowed to have had chemotherapy, and there is evidence to suggest that prior chemotherapy is a risk factor for resistance to other therapies as well.

“So looking at patients with hormone-sensitive disease who have done their chemotherapy, seeing a survival benefit in any subset of patients with hormone receptor–positive disease getting a targeted agent is already pretty exciting,” she said in an interview.

Dr. Rugo was not involved in PALOMA-3.

PALOMA-3 was supported by Pfizer. Dr. Cristofanilli disclosed personal fees from Pfizer, Novartis, and Merus. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others. Dr. Cardoso has disclosed consulting fees and institutional support from Pfizer and others. Dr. Rugo has received fees/honoraria and other support for activities for Pfizer and others.

SOURCE: Turner NC et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1810527.

MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Neil Osterweil/MDedge News

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

Neil Osterweil/MDedge News

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Neil Osterweil/MDedge News

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Neil Osterweil/MDedge News

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

Neil Osterweil/MDedge News

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Neil Osterweil/MDedge News

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Neil Osterweil/MDedge News

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

Neil Osterweil/MDedge News

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Neil Osterweil/MDedge News

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

MUNICH – Pretreatment genotyping of patients for a key metabolizing enzyme prior to therapy with a fluoropyrimidine agent can be performed in routine clinical practice and can significantly improve safety of the drugs, investigators reported.

Among 1,103 patients scheduled for fluoropyrimidine-based therapy with either fluorouracil (5-FU) or capecitabine alone or in combination with other therapies, toxicities were highest among patients with two common variant alleles of DPYD, the gene encoding for the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). The risk for toxicity was “markedly reduced” when doses were reduced by 50% in patients carrying the alleles, reported Linda Henricks, PharmD, from the Netherlands Cancer Institute, Amsterdam, and her colleagues.

“Our study was done in a daily clinical care setting in regional general hospitals and a few academic centers, showing the feasibility of implementation of upfront DPYD screening. To make DPYD-guided dosing feasible in all hospitals, the turnaround time for DPYD genotyping must be short to prevent a delay in the start of treatment,” they wrote in a study published in The Lancet Oncology prior to presentation of these data at the European Society of Medical Oncology Congress.

The laboratories participating in their study had turnaround times ranging from a few days up to 1 week, they noted.

Fluoropyrimidines are the backbones of therapy for several different malignancies, but up to 30% of patients treated with these drugs can experience severe toxicities because of reduced DPD activity, primarily caused by genetic variants in DPYD.

The investigators conducted a prospective multicenter study to see whether screening for the four most common variants could help clinicians tailor treatment programs to improve tolerability of fluoropyrimidine-based therapies.

They looked at the incidence of toxicities between patients carrying DPYD variant alleles and DPYD wild-type carriers in an intention-to-treat analysis, and compared relative risks for severe toxicities among patients with those of historical controls – patients with DPYD variant alleles who had been treated with a full-dose fluoropyrimidine in previous studies.

They enrolled 1,181 patients during May 2015–December 2017, of whom 1,103 were evaluable. Of this group, 92% (1,018 patients) had wild-type DPYD, and 8% (85) were heterozygous variant allele carriers.

The four variant alleles the investigators genotyped for were: DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A.

Patients who were heterozygous for c.2846A>T or c.1236G>A received doses reduced by 25%, and patients with DPYD*2A or c.1679T>G received doses reduced by 50%. Patients with DPYD wild-type were treated according to the current standard of care.

The incidence of severe fluoropyrimidine-related toxicity, the primary endpoint, was significantly higher among variant allele carriers compared with patients with wild-type DPYD (39% vs. 23%, respectively, P = .0013).

The relative risk for severe toxicity among patients with DPYD*2A treated in the current study with genotype-guided therapy was 1.31, compared with 2.87 for historical controls carrying the same variant.

Among c.1679T>G carriers, those treated with genotype-guided therapy had no severe toxicity, whereas the relative risk for historical controls was 4.30.

Respective relative risks for c.2846A>T carriers were 2.0 vs. 3.11, and for c.1236G>A carriers were 1.69 vs. 1.72.

“Although our study revealed that the applied approach of genotype-guided adaptive dosing significantly reduced severe fluoropyrimidine-induced toxicity and prevented treatment-related death, additional methods should be explored and prospectively tested to further reduce treatment-related toxicity, not only in DPYD variant allele carriers, but also in DPYD wild-type patients,” Dr. Henricks and her associates wrote.

The study was supported by the Dutch Cancer Society. Dr. Henricks and a coauthor report grants from the Society. One coauthor reported a prior unrestricted grant from Roche and one personal fee from Modra outside the submitted work.
 

SOURCE: Henricks LM et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30686-7.

MUNICH – Pretreatment genotyping of patients for a key metabolizing enzyme prior to therapy with a fluoropyrimidine agent can be performed in routine clinical practice and can significantly improve safety of the drugs, investigators reported.

Among 1,103 patients scheduled for fluoropyrimidine-based therapy with either fluorouracil (5-FU) or capecitabine alone or in combination with other therapies, toxicities were highest among patients with two common variant alleles of DPYD, the gene encoding for the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). The risk for toxicity was “markedly reduced” when doses were reduced by 50% in patients carrying the alleles, reported Linda Henricks, PharmD, from the Netherlands Cancer Institute, Amsterdam, and her colleagues.

“Our study was done in a daily clinical care setting in regional general hospitals and a few academic centers, showing the feasibility of implementation of upfront DPYD screening. To make DPYD-guided dosing feasible in all hospitals, the turnaround time for DPYD genotyping must be short to prevent a delay in the start of treatment,” they wrote in a study published in The Lancet Oncology prior to presentation of these data at the European Society of Medical Oncology Congress.

The laboratories participating in their study had turnaround times ranging from a few days up to 1 week, they noted.

Fluoropyrimidines are the backbones of therapy for several different malignancies, but up to 30% of patients treated with these drugs can experience severe toxicities because of reduced DPD activity, primarily caused by genetic variants in DPYD.

The investigators conducted a prospective multicenter study to see whether screening for the four most common variants could help clinicians tailor treatment programs to improve tolerability of fluoropyrimidine-based therapies.

They looked at the incidence of toxicities between patients carrying DPYD variant alleles and DPYD wild-type carriers in an intention-to-treat analysis, and compared relative risks for severe toxicities among patients with those of historical controls – patients with DPYD variant alleles who had been treated with a full-dose fluoropyrimidine in previous studies.

They enrolled 1,181 patients during May 2015–December 2017, of whom 1,103 were evaluable. Of this group, 92% (1,018 patients) had wild-type DPYD, and 8% (85) were heterozygous variant allele carriers.

The four variant alleles the investigators genotyped for were: DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A.

Patients who were heterozygous for c.2846A>T or c.1236G>A received doses reduced by 25%, and patients with DPYD*2A or c.1679T>G received doses reduced by 50%. Patients with DPYD wild-type were treated according to the current standard of care.

The incidence of severe fluoropyrimidine-related toxicity, the primary endpoint, was significantly higher among variant allele carriers compared with patients with wild-type DPYD (39% vs. 23%, respectively, P = .0013).

The relative risk for severe toxicity among patients with DPYD*2A treated in the current study with genotype-guided therapy was 1.31, compared with 2.87 for historical controls carrying the same variant.

Among c.1679T>G carriers, those treated with genotype-guided therapy had no severe toxicity, whereas the relative risk for historical controls was 4.30.

Respective relative risks for c.2846A>T carriers were 2.0 vs. 3.11, and for c.1236G>A carriers were 1.69 vs. 1.72.

“Although our study revealed that the applied approach of genotype-guided adaptive dosing significantly reduced severe fluoropyrimidine-induced toxicity and prevented treatment-related death, additional methods should be explored and prospectively tested to further reduce treatment-related toxicity, not only in DPYD variant allele carriers, but also in DPYD wild-type patients,” Dr. Henricks and her associates wrote.

The study was supported by the Dutch Cancer Society. Dr. Henricks and a coauthor report grants from the Society. One coauthor reported a prior unrestricted grant from Roche and one personal fee from Modra outside the submitted work.
 

SOURCE: Henricks LM et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30686-7.

MUNICH – Pretreatment genotyping of patients for a key metabolizing enzyme prior to therapy with a fluoropyrimidine agent can be performed in routine clinical practice and can significantly improve safety of the drugs, investigators reported.

Among 1,103 patients scheduled for fluoropyrimidine-based therapy with either fluorouracil (5-FU) or capecitabine alone or in combination with other therapies, toxicities were highest among patients with two common variant alleles of DPYD, the gene encoding for the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). The risk for toxicity was “markedly reduced” when doses were reduced by 50% in patients carrying the alleles, reported Linda Henricks, PharmD, from the Netherlands Cancer Institute, Amsterdam, and her colleagues.

“Our study was done in a daily clinical care setting in regional general hospitals and a few academic centers, showing the feasibility of implementation of upfront DPYD screening. To make DPYD-guided dosing feasible in all hospitals, the turnaround time for DPYD genotyping must be short to prevent a delay in the start of treatment,” they wrote in a study published in The Lancet Oncology prior to presentation of these data at the European Society of Medical Oncology Congress.

The laboratories participating in their study had turnaround times ranging from a few days up to 1 week, they noted.

Fluoropyrimidines are the backbones of therapy for several different malignancies, but up to 30% of patients treated with these drugs can experience severe toxicities because of reduced DPD activity, primarily caused by genetic variants in DPYD.

The investigators conducted a prospective multicenter study to see whether screening for the four most common variants could help clinicians tailor treatment programs to improve tolerability of fluoropyrimidine-based therapies.

They looked at the incidence of toxicities between patients carrying DPYD variant alleles and DPYD wild-type carriers in an intention-to-treat analysis, and compared relative risks for severe toxicities among patients with those of historical controls – patients with DPYD variant alleles who had been treated with a full-dose fluoropyrimidine in previous studies.

They enrolled 1,181 patients during May 2015–December 2017, of whom 1,103 were evaluable. Of this group, 92% (1,018 patients) had wild-type DPYD, and 8% (85) were heterozygous variant allele carriers.

The four variant alleles the investigators genotyped for were: DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A.

Patients who were heterozygous for c.2846A>T or c.1236G>A received doses reduced by 25%, and patients with DPYD*2A or c.1679T>G received doses reduced by 50%. Patients with DPYD wild-type were treated according to the current standard of care.

The incidence of severe fluoropyrimidine-related toxicity, the primary endpoint, was significantly higher among variant allele carriers compared with patients with wild-type DPYD (39% vs. 23%, respectively, P = .0013).

The relative risk for severe toxicity among patients with DPYD*2A treated in the current study with genotype-guided therapy was 1.31, compared with 2.87 for historical controls carrying the same variant.

Among c.1679T>G carriers, those treated with genotype-guided therapy had no severe toxicity, whereas the relative risk for historical controls was 4.30.

Respective relative risks for c.2846A>T carriers were 2.0 vs. 3.11, and for c.1236G>A carriers were 1.69 vs. 1.72.

“Although our study revealed that the applied approach of genotype-guided adaptive dosing significantly reduced severe fluoropyrimidine-induced toxicity and prevented treatment-related death, additional methods should be explored and prospectively tested to further reduce treatment-related toxicity, not only in DPYD variant allele carriers, but also in DPYD wild-type patients,” Dr. Henricks and her associates wrote.

The study was supported by the Dutch Cancer Society. Dr. Henricks and a coauthor report grants from the Society. One coauthor reported a prior unrestricted grant from Roche and one personal fee from Modra outside the submitted work.
 

SOURCE: Henricks LM et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30686-7.