Neil Osterweil

A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.

In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.

BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.

“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
 

Lab-made nucleotide strings

Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.

In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.

However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.

In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.

The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.

“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.

Dr. Flood was not involved in the study.
 

Long half-life

BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).

In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.

The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.

The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.

At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.

But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).

“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.

They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
 

‘Super-exciting strategy’

“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.

“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.

The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.

A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.

In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.

BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.

“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
 

Lab-made nucleotide strings

Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.

In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.

However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.

In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.

The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.

“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.

Dr. Flood was not involved in the study.
 

Long half-life

BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).

In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.

The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.

The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.

At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.

But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).

“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.

They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
 

‘Super-exciting strategy’

“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.

“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.

The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.

A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.

In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.

BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.

“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
 

Lab-made nucleotide strings

Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.

In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.

However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.

In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.

The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.

“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.

Dr. Flood was not involved in the study.
 

Long half-life

BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).

In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.

The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.

The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.

At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.

But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).

“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.

They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
 

‘Super-exciting strategy’

“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.

“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.

The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Even the youngest patients with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) may be able to benefit from chimeric antigen reception T-cell (CAR T) therapy, investigators in an international consortium say.

Among 30 children aged under 2 years at the time of (B-ALL diagnosis, manufacturing of the CAR T product tisagenlecleucel (Kymriah) was feasible in 28 patients, and treatment resulted in high rates of minimal residual disease (MRD) negativity, complete responses, event-free survival, and overall survival, reported Sara Ghorashian, MD from the University College London Great Ormond Street Institute of Child Health, on behalf of the International BFM Resistant Disease Committee.

“The disease-related outcomes noted in this cohort of younger children predominantly with relapsed/refractory infant [mixed lineage leukemia]–rearranged ALL were at least as good as for the ELIANA study,” she said in an oral abstract presented during the European Hematology Association annual congress (Abstract S116).

The international, single-arm, open-label, ELIANA study was a phase 2 trial that included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T therapy.

“It’s fantastic data,” said Kevin J. Curran, MD, a pediatric hematologist/oncologist specializing in stem cell transplants and cellular therapy at Memorial Sloan Kettering Cancer Center, New York.

“Pediatric leukemia, while it’s the most common malignancy that happens in children, when you get down to this really small group, this under 3-year-old group, it’s hard to get a cohort, and for them to put together 30 patients, and show these great results is groundbreaking,” he said in an interview.

“Most importantly, it gives hope to parents who have young children who have really difficult to treat leukemia,” he said.

Dr. Curran was not involved in the study.
 

Scarce data on ALL in infants

“Children under 3 years of age were excluded from the ELIANA study, yet in terms of having often highly aggressive disease, with traditionally poor outcomes with conventional therapy, the need for novel forms of therapy for children with relapsed infant ALL is important,” Dr. Ghorashian said.

Because there is a paucity of data on outcomes in the youngest children, some health authorities will not support the use of tisagenlecleucel in this age group, and there are concerns about difficulties with performing leukapheresis in children weighing less than 10 kg, she noted.

To gain a better understanding of outcomes, members of the International BFM (Berlin-Frankfurt-Munster) Study Group conducted a retrospective analysis of data on all patients assessed for tisagenlecleucel for B-ALL who were aged under 3 years at screening at 1 of 15 centers in Europe and Israel.

A total of 30 patients were screened and had T cells harvested. Of this group, three patients did not receive CAR T infusions, two because of manufacturing failures, and one because of progressive disease.

Of the 27 patients who received CAR T infusions, 26 were evaluable for disease outcomes (1 had yet to reach the 30-day post infusion at the time of data cutoff).

The median age at diagnosis was 4.4 months, and the median age at infusion was 17.4 months; 19 of the 30 children in the entire cohort were boys. Mixed lineage leukemia rearrangements were found in 24 children, and 21 had undergone a stem cell transplant.

The children had a median of two prior lines of therapy, not including transplant. Seven of the children had received inotuzumab (Besponsa) and 11 had received blinotumumab (Blincyto).
 

High success rate

Of the 27 patients infused, 17 had sufficient cells harvested in a single day, and the remainder required 2-4 days. As noted, the CAR T product was successfully manufactured in 28 patients, with a median dose of 2.3 x 10⁶/kg of patient weight.

The treatment failed for 2 of the 26 efficacy-evaluable patients, resulting in an MRD-negative rate of 92%.

Event-free survival at 6 months was 67%, similar to that in ELIANA (73%), and the 12-month event-free survival was 58%, which was superior to that in ELIANA (50%).

The 6-month and 12-month overall survival rates among the younger children were identical at 88%, compared with 90% and 76%, respectively, in ELIANA.

The 6- and 12-month probability of ongoing B-cell depletion, indicating CAR T persistence, were 77% and 68%, respectively. In ELIANA, the 6-month probability of B-cell depletion was 83%.

A total of 10 of the 27 patients received further therapy, including 3 who were given maintenance therapy for poor CAR T persistence, 2 who underwent chemotherapy for relapse, and 5 who underwent allogeneic stem cell transplant.

Of six patients who experienced a relapse after having a complete response, two had CD19 relapse.
 

Low rate of serious CRS

At 30 days post infusion, grade 3 or greater cytokine release syndrome (CRS) had occurred in two patients, severe neurotoxicity occurred in one, and grade 3 or greater prolonged cytopenias occurred in eight patients.

The toxicity profile in this study was generally favorable in comparison with ELIANA, with shorter median duration of CRS, shorter median duration of CRS-related ICU stay, and a lower frequency of tocilizumab use. It should be noted, however, that the I-BFM investigators used American Society for Transplantation and Cellular Therapy CRS consenus criteria, whereas the ELIANA investigators used University of Pennsylvania criteria.

“If the longer-term follow-up data are encouraging, it might suggest that the outcomes from tisagenlecleucel therapy are comparable to that of stem cell transplantation in high-risk relapsed infant ALL, without the associated late effects, and possibly supports CAR T-cell therapy eventually replace stem cell transplantation in this setting,” Dr. Ghorashian said.

Dr. Curran, who leads the CAR T effort at MSK Kids, the children’s division of MSKCC, agreed that the goal is for CAR T to replace stem cell transplants.

“I hope I put my clinical practice out of business with my research practice,” he said, but added that “I think we need to do more research in figuring out how to best use CAR T cells, either earlier, or as some data suggest, by treating patients with lower disease burden we would get better durability.

“Because obviously in kids’ cancer one relapse is too much, and we want to be able to raise that bar and provide hope and a cure for all of our children,” he said.

The study was sponsored by the I-BFM Resistant Disease Committee and member institutions. Dr. Ghorashian disclosed advisory board activity for Novartis, maker of tisagenlecleucel, and patents and royalties from UCL Business. Dr. Curran research funding and consulting fees from Novartis.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

It may not be always necessary to approach the treatment of HER2-positive, hormone receptor–negative (HER2+/HR–) early breast cancer with added chemotherapy, survival results of a prospective multicenter randomized trial suggest.

In the ADAPT-HER2+/HR– trial, comparing a de-escalated 12-week neoadjuvant regimen consisting of dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel, the three-drug regimen was associated with high pathologic complete response(pCR) rates and excellent 5-year survival, irrespective of whether patients received additional chemotherapy, reported Nadia Harbeck, MD, PhD, of the University of Munich.

“Chemotherapy-free regimens are promising in highly sensitive tumors with early response, but future investigation of such chemotherapy-free regimens need to be focused on selected patients, like those with HER2 3+ tumors, non–basal-like tumors, those showing early response to the de-escalated therapy, and those with predictive RNA signatures such as immune signatures,” she said in an oral abstract session during the American Society of Clinical Oncology annual meeting (Abstract 503).
 

Under the WGS umbrella

The ADAPT HER2+/HR– trial (NCT01779206) is one of several conducted by the West German Study Group (WGS) on therapy for intrinsic breast cancer types.

In this study, 134 patients with HER2-positive, estrogen and progesterone receptor–negative tumors with no metastatic disease and good performance status were assigned on a 5:2 basis to neoadjuvant therapy with trastuzumab at a loading dose of 8 mg/kg for the first cycle followed by 6 mg/kg for subsequent cycles every 3 weeks x 4, plus pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks x 4 (92 patients), or to trastuzumab and pertuzumab at the same dose and schedule plus paclitaxel 80 mg/m² once weekly for 12 weeks.

Patients had surgery within 3 weeks of the end of study therapy unless they did not have a histologically confirmed pCR, in which case they went on to receive standard neoadjuvant therapy prior to surgery.

Adjuvant therapy was performed according to national guidelines, although patients with a pCR after 12 weeks of study therapy could be spared from adjuvant chemotherapy at the investigator’s discretion.

Patients underwent biopsy at 3 weeks for therapy for early response assessment, defined as either a Ki67 decrease of at least 30% from baseline, or low cellularity (less than 500 invasive tumor cells).
 

First survival results

The investigators previously reported the primary pCR endpoint from the trial, which showed a rate of 90% after 12 weeks in the three-drug arm, and a “substantial and clinically meaningful” pCR rate of 34% after the trastuzumab plus pertuzumab alone.

At ASCO 2021, Dr. Harbeck reported the first survival data from the trial.

After a median follow-up of 59.9 months, there were no statistically significant differences between trial arms in either overall survival, invasive disease-free survival (iDFS), or distant disease-free survival (dDFS).

The 5-year iDFS rate in the three-drug arm was 98%, compared with 87% for the dual HER2 blockade-only arm, a difference that was not statistically significant.

The 5-year dDFS rates were 98% and 92% respectively. There were only seven dDFS events during follow-up, Dr. Harbeck noted.

There were only six deaths during follow-up, with overall survival rates of 98% in the paclitaxel-containing arm, and 94% in the anti-HER2 antibodies–only arm, a difference of one overall survival event, Dr. Harbeck said.
 

pCR counts

However, patients who did not have pathologic complete responses at the end of first-line de-escalated therapy had worse outcomes, with a 5-year iDFS rate of 82%, compared with 98% for patients who had achieved a pCR. This translated into a hazard ratio for invasive disease in patients with pCRs of 0.14 (P = .011).

This difference occurred despite the study requirement that all patients who did not have pCR after 12 weeks of initial therapy would receive additional chemotherapy.

Looking at the tumor subtype among patients in the paclitaxel-free arm to see whether they could identify predictors of early response, the researchers found a pCR rate of 36.5% among 85 patients with nonbasal tumors, but 0% among 7 patients with basal tumors.

The investigators identified a population of patients whose tumors could be considered nonsensitive to dual HER2 blockade alone: Those with basal tumors, those tumors with low immunohistochemical HER2 expression, and those without an early response to therapy on biopsy 3 weeks into initial therapy. Among 31 of the 92 patients in the dual HER2 arm who met this description, 2 had pCRs, Dr. Harbeck noted.

The 5-year iDFS rate among patients in the dual blockade–only arm with nonsensitive tumors was 79%, compared with 93% for patients with treatment-responsive types, although there were only 13 invasive events total in this arm.

“If we look at the whole trial population, the negative prognostic impact of what we termed nonsensitive tumors was even significant regarding dDFS, with a hazard ratio of about 5,” she said.
 

‘A consistent theme’

Invited discussant Lisa A. Carey, MD, ScM, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the trial was underpowered for outcomes, but that results nonetheless suggest that patients with strongly HER2-driven tumors might get comparable benefits from less chemotherapy.

“This trial included only hormone receptor–negative, HER2-positive tumors, and these we know are likely to be HER2-enriched in terms of subtype, about three-quarters of them,”she said.

The previously reported pCR rate of 90% in the paclitaxel-containing arm, with 80% of patients requiring no further chemotherapy, resulted in the excellent 5-year iDFS and dDFS in this group, despite the relatively highly clinical stage, with about 60% of patients having clinical stage 2 or higher tumors, and more than 40% being node positive.

The idea that pCR itself can predict which patients could be spared from more intensive chemotherapy “is starting to look like a consistent theme,” she said.

Dr. Carey pointed out that in the KRISTINE trial comparing the combination of trastuzumab emtansine (T-DM1) and pertuzumab with standard chemotherapy in patients with HER2-positive stage I-III breast cancer, although the experimental combination was associated with lower pCR rates and worse event-free survival, rates of iDFS/dDFS were virtually identical for patients in both arms who achieved a pCR.

“So the question is can pCR mean that we can either eliminate additional therapy,” she said, noting that the question is currently being addressed prospectively in two clinical trials, COMPASS-pCR and DECRESCENDO.

ADAPT HER2+/HR- is sponsored by F. Hoffman-La Roche. Dr. Harbeck disclosed institutional research funding from Roche/Genentech, as well as honoraria and consulting/advising for multiple companies. Dr. Carey disclosed institutional research funding and other relationships with various companies.

It may not be always necessary to approach the treatment of HER2-positive, hormone receptor–negative (HER2+/HR–) early breast cancer with added chemotherapy, survival results of a prospective multicenter randomized trial suggest.

In the ADAPT-HER2+/HR– trial, comparing a de-escalated 12-week neoadjuvant regimen consisting of dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel, the three-drug regimen was associated with high pathologic complete response(pCR) rates and excellent 5-year survival, irrespective of whether patients received additional chemotherapy, reported Nadia Harbeck, MD, PhD, of the University of Munich.

“Chemotherapy-free regimens are promising in highly sensitive tumors with early response, but future investigation of such chemotherapy-free regimens need to be focused on selected patients, like those with HER2 3+ tumors, non–basal-like tumors, those showing early response to the de-escalated therapy, and those with predictive RNA signatures such as immune signatures,” she said in an oral abstract session during the American Society of Clinical Oncology annual meeting (Abstract 503).
 

Under the WGS umbrella

The ADAPT HER2+/HR– trial (NCT01779206) is one of several conducted by the West German Study Group (WGS) on therapy for intrinsic breast cancer types.

In this study, 134 patients with HER2-positive, estrogen and progesterone receptor–negative tumors with no metastatic disease and good performance status were assigned on a 5:2 basis to neoadjuvant therapy with trastuzumab at a loading dose of 8 mg/kg for the first cycle followed by 6 mg/kg for subsequent cycles every 3 weeks x 4, plus pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks x 4 (92 patients), or to trastuzumab and pertuzumab at the same dose and schedule plus paclitaxel 80 mg/m² once weekly for 12 weeks.

Patients had surgery within 3 weeks of the end of study therapy unless they did not have a histologically confirmed pCR, in which case they went on to receive standard neoadjuvant therapy prior to surgery.

Adjuvant therapy was performed according to national guidelines, although patients with a pCR after 12 weeks of study therapy could be spared from adjuvant chemotherapy at the investigator’s discretion.

Patients underwent biopsy at 3 weeks for therapy for early response assessment, defined as either a Ki67 decrease of at least 30% from baseline, or low cellularity (less than 500 invasive tumor cells).
 

First survival results

The investigators previously reported the primary pCR endpoint from the trial, which showed a rate of 90% after 12 weeks in the three-drug arm, and a “substantial and clinically meaningful” pCR rate of 34% after the trastuzumab plus pertuzumab alone.

At ASCO 2021, Dr. Harbeck reported the first survival data from the trial.

After a median follow-up of 59.9 months, there were no statistically significant differences between trial arms in either overall survival, invasive disease-free survival (iDFS), or distant disease-free survival (dDFS).

The 5-year iDFS rate in the three-drug arm was 98%, compared with 87% for the dual HER2 blockade-only arm, a difference that was not statistically significant.

The 5-year dDFS rates were 98% and 92% respectively. There were only seven dDFS events during follow-up, Dr. Harbeck noted.

There were only six deaths during follow-up, with overall survival rates of 98% in the paclitaxel-containing arm, and 94% in the anti-HER2 antibodies–only arm, a difference of one overall survival event, Dr. Harbeck said.
 

pCR counts

However, patients who did not have pathologic complete responses at the end of first-line de-escalated therapy had worse outcomes, with a 5-year iDFS rate of 82%, compared with 98% for patients who had achieved a pCR. This translated into a hazard ratio for invasive disease in patients with pCRs of 0.14 (P = .011).

This difference occurred despite the study requirement that all patients who did not have pCR after 12 weeks of initial therapy would receive additional chemotherapy.

Looking at the tumor subtype among patients in the paclitaxel-free arm to see whether they could identify predictors of early response, the researchers found a pCR rate of 36.5% among 85 patients with nonbasal tumors, but 0% among 7 patients with basal tumors.

The investigators identified a population of patients whose tumors could be considered nonsensitive to dual HER2 blockade alone: Those with basal tumors, those tumors with low immunohistochemical HER2 expression, and those without an early response to therapy on biopsy 3 weeks into initial therapy. Among 31 of the 92 patients in the dual HER2 arm who met this description, 2 had pCRs, Dr. Harbeck noted.

The 5-year iDFS rate among patients in the dual blockade–only arm with nonsensitive tumors was 79%, compared with 93% for patients with treatment-responsive types, although there were only 13 invasive events total in this arm.

“If we look at the whole trial population, the negative prognostic impact of what we termed nonsensitive tumors was even significant regarding dDFS, with a hazard ratio of about 5,” she said.
 

‘A consistent theme’

Invited discussant Lisa A. Carey, MD, ScM, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the trial was underpowered for outcomes, but that results nonetheless suggest that patients with strongly HER2-driven tumors might get comparable benefits from less chemotherapy.

“This trial included only hormone receptor–negative, HER2-positive tumors, and these we know are likely to be HER2-enriched in terms of subtype, about three-quarters of them,”she said.

The previously reported pCR rate of 90% in the paclitaxel-containing arm, with 80% of patients requiring no further chemotherapy, resulted in the excellent 5-year iDFS and dDFS in this group, despite the relatively highly clinical stage, with about 60% of patients having clinical stage 2 or higher tumors, and more than 40% being node positive.

The idea that pCR itself can predict which patients could be spared from more intensive chemotherapy “is starting to look like a consistent theme,” she said.

Dr. Carey pointed out that in the KRISTINE trial comparing the combination of trastuzumab emtansine (T-DM1) and pertuzumab with standard chemotherapy in patients with HER2-positive stage I-III breast cancer, although the experimental combination was associated with lower pCR rates and worse event-free survival, rates of iDFS/dDFS were virtually identical for patients in both arms who achieved a pCR.

“So the question is can pCR mean that we can either eliminate additional therapy,” she said, noting that the question is currently being addressed prospectively in two clinical trials, COMPASS-pCR and DECRESCENDO.

ADAPT HER2+/HR- is sponsored by F. Hoffman-La Roche. Dr. Harbeck disclosed institutional research funding from Roche/Genentech, as well as honoraria and consulting/advising for multiple companies. Dr. Carey disclosed institutional research funding and other relationships with various companies.

It may not be always necessary to approach the treatment of HER2-positive, hormone receptor–negative (HER2+/HR–) early breast cancer with added chemotherapy, survival results of a prospective multicenter randomized trial suggest.

In the ADAPT-HER2+/HR– trial, comparing a de-escalated 12-week neoadjuvant regimen consisting of dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel, the three-drug regimen was associated with high pathologic complete response(pCR) rates and excellent 5-year survival, irrespective of whether patients received additional chemotherapy, reported Nadia Harbeck, MD, PhD, of the University of Munich.

“Chemotherapy-free regimens are promising in highly sensitive tumors with early response, but future investigation of such chemotherapy-free regimens need to be focused on selected patients, like those with HER2 3+ tumors, non–basal-like tumors, those showing early response to the de-escalated therapy, and those with predictive RNA signatures such as immune signatures,” she said in an oral abstract session during the American Society of Clinical Oncology annual meeting (Abstract 503).
 

Under the WGS umbrella

The ADAPT HER2+/HR– trial (NCT01779206) is one of several conducted by the West German Study Group (WGS) on therapy for intrinsic breast cancer types.

In this study, 134 patients with HER2-positive, estrogen and progesterone receptor–negative tumors with no metastatic disease and good performance status were assigned on a 5:2 basis to neoadjuvant therapy with trastuzumab at a loading dose of 8 mg/kg for the first cycle followed by 6 mg/kg for subsequent cycles every 3 weeks x 4, plus pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks x 4 (92 patients), or to trastuzumab and pertuzumab at the same dose and schedule plus paclitaxel 80 mg/m² once weekly for 12 weeks.

Patients had surgery within 3 weeks of the end of study therapy unless they did not have a histologically confirmed pCR, in which case they went on to receive standard neoadjuvant therapy prior to surgery.

Adjuvant therapy was performed according to national guidelines, although patients with a pCR after 12 weeks of study therapy could be spared from adjuvant chemotherapy at the investigator’s discretion.

Patients underwent biopsy at 3 weeks for therapy for early response assessment, defined as either a Ki67 decrease of at least 30% from baseline, or low cellularity (less than 500 invasive tumor cells).
 

First survival results

The investigators previously reported the primary pCR endpoint from the trial, which showed a rate of 90% after 12 weeks in the three-drug arm, and a “substantial and clinically meaningful” pCR rate of 34% after the trastuzumab plus pertuzumab alone.

At ASCO 2021, Dr. Harbeck reported the first survival data from the trial.

After a median follow-up of 59.9 months, there were no statistically significant differences between trial arms in either overall survival, invasive disease-free survival (iDFS), or distant disease-free survival (dDFS).

The 5-year iDFS rate in the three-drug arm was 98%, compared with 87% for the dual HER2 blockade-only arm, a difference that was not statistically significant.

The 5-year dDFS rates were 98% and 92% respectively. There were only seven dDFS events during follow-up, Dr. Harbeck noted.

There were only six deaths during follow-up, with overall survival rates of 98% in the paclitaxel-containing arm, and 94% in the anti-HER2 antibodies–only arm, a difference of one overall survival event, Dr. Harbeck said.
 

pCR counts

However, patients who did not have pathologic complete responses at the end of first-line de-escalated therapy had worse outcomes, with a 5-year iDFS rate of 82%, compared with 98% for patients who had achieved a pCR. This translated into a hazard ratio for invasive disease in patients with pCRs of 0.14 (P = .011).

This difference occurred despite the study requirement that all patients who did not have pCR after 12 weeks of initial therapy would receive additional chemotherapy.

Looking at the tumor subtype among patients in the paclitaxel-free arm to see whether they could identify predictors of early response, the researchers found a pCR rate of 36.5% among 85 patients with nonbasal tumors, but 0% among 7 patients with basal tumors.

The investigators identified a population of patients whose tumors could be considered nonsensitive to dual HER2 blockade alone: Those with basal tumors, those tumors with low immunohistochemical HER2 expression, and those without an early response to therapy on biopsy 3 weeks into initial therapy. Among 31 of the 92 patients in the dual HER2 arm who met this description, 2 had pCRs, Dr. Harbeck noted.

The 5-year iDFS rate among patients in the dual blockade–only arm with nonsensitive tumors was 79%, compared with 93% for patients with treatment-responsive types, although there were only 13 invasive events total in this arm.

“If we look at the whole trial population, the negative prognostic impact of what we termed nonsensitive tumors was even significant regarding dDFS, with a hazard ratio of about 5,” she said.
 

‘A consistent theme’

Invited discussant Lisa A. Carey, MD, ScM, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the trial was underpowered for outcomes, but that results nonetheless suggest that patients with strongly HER2-driven tumors might get comparable benefits from less chemotherapy.

“This trial included only hormone receptor–negative, HER2-positive tumors, and these we know are likely to be HER2-enriched in terms of subtype, about three-quarters of them,”she said.

The previously reported pCR rate of 90% in the paclitaxel-containing arm, with 80% of patients requiring no further chemotherapy, resulted in the excellent 5-year iDFS and dDFS in this group, despite the relatively highly clinical stage, with about 60% of patients having clinical stage 2 or higher tumors, and more than 40% being node positive.

The idea that pCR itself can predict which patients could be spared from more intensive chemotherapy “is starting to look like a consistent theme,” she said.

Dr. Carey pointed out that in the KRISTINE trial comparing the combination of trastuzumab emtansine (T-DM1) and pertuzumab with standard chemotherapy in patients with HER2-positive stage I-III breast cancer, although the experimental combination was associated with lower pCR rates and worse event-free survival, rates of iDFS/dDFS were virtually identical for patients in both arms who achieved a pCR.

“So the question is can pCR mean that we can either eliminate additional therapy,” she said, noting that the question is currently being addressed prospectively in two clinical trials, COMPASS-pCR and DECRESCENDO.

ADAPT HER2+/HR- is sponsored by F. Hoffman-La Roche. Dr. Harbeck disclosed institutional research funding from Roche/Genentech, as well as honoraria and consulting/advising for multiple companies. Dr. Carey disclosed institutional research funding and other relationships with various companies.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

Build a better mousetrap, and the world will beat a path to your door. Find an accurate, completely noninvasive method for colorectal cancer screening and you’ll probably win the Nobel Prize for Medicine or Physiology.

But until then, we’ll have to make do with colonoscopy, fecal immunochemical testing (FIT), and other messy but necessary means for preventing full-blown CRC and reducing the risk of CRC morbidity and mortality. And start turning to them earlier in patients’ lives.

The U.S. Preventive Services Task Force (USPSTF) has issued an update of its 2016 recommendations for CRC screening, for the first time advising that screening for all average-risk adults begin at age 45. This new recommendation is in line with the guidelines issued by the American Cancer Society, which were updated in 2018, to reflect the inescapable truth that CRC is increasingly being diagnosed at a younger age.

Not to be left out, the U.S. Multi-Society Task Force (MSTF) – which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy – issued a statement supporting lowering the age of initial screening in normal-risk adults to 45, and promised that an update of the 2017 guidelines would include the new recommendation.
 

Recommendations influence reimbursement

Guidelines are often honored as much in the breach as in the observance, but those issued by the USPSTF have unique sway, according to Sonia S. Kupfer, MD, of the section of gastroenterology, hepatology, and nutrition at the University of Chicago, and colleagues.

“While other guidelines have recommended this younger age, the USPSTF guidelines directly inform insurance coverage and waiving of cost sharing as part of federal law,” they wrote in an editorial accompanying the USPSTF guideline statement in the Journal of the American Medical Association.

Although the USPSTF rated its recommendation on starting at age 45 a ‘B’ level – indicating a moderate certainty of moderate benefit – it’s an important step, Dr. Kupfer said in an interview.

“The big advantage here is that we may be able to make a dent in this early-onset colorectal cancer, which, having seen many of these patients, is very alarming, and they don’t always seem to have classic risk factors,” she said. “So, getting them when we can potentially prevent cancer by taking out polyps, or even getting them in an earlier stage, certainly will be beneficial.”

The MSTF also considered recommending 45 as the starting age for normal-risk patients in its 2017 guidelines, noted Douglas Rex, MD, who was chair of the committee that drew up those guidelines, as well as director of endoscopy at Indiana University Hospital in Indianapolis.

“Since that time there has been more evidence, and there’s also some empiric evidence, about the yield of screening in the 45- to 49-year-old age group,” he said in an interview.
 

The one that gets done

Although the various guidelines differ in specifics, all are in agreement on the general proposition that colonoscopy is the gold standard for screening and detecting the presence of polyps, adenomas, and CRC.

But as USPSTF member Martha Kubik, PhD, RN, director of the George Mason University School of Nursing in Fairfax, Va., said in a statement: “The right test is the one that gets done.”

Gastroenterologists acknowledge that despite its efficacy, colonoscopy is an invasive procedure involving meticulous and unpleasant and/or uncomfortable bowel prep, sedation, and significant time requirements. 

In the theory that something is better than nothing, with clinical evidence of varying degrees of quality, the USPSTF recommends the following procedures or tests for average-risk adults:

• Colonoscopy screening every 10 years.
•  every 10 years plus annual FIT.
• CT colonography every 5 years.
• High-sensitivity guaiac fecal occult blood test (gFOBT; Hemoccult II) or FIT every year.
• Stool DNA-FIT (Cologuard) every 1 to 3 years.

The Food and Drug Administration also recently approved an artificial intelligence device designed for use with an endoscope, which its manufacturer says can help clinicians detect gastrointestinal lesions they might otherwise miss. This is not a new screening method, but rather an enhancement of existing ones. It neither diagnoses lesions nor recommends treatments, and is not intended to take the place of laboratory sampling.

“I think artificial intelligence is poised to make colonoscopy more effective,” Dr. Rex said. “In the first five trials that we’ve seen, the average increase in the adenoma detection rate has been 11%, and for each 1% gain in the adenoma detection rate, patients have about a 3% decline in their risk of getting cancer after a colonoscopy and about a 5% decline in their risk for fatal cancer. Those are the largest gains that we’ve seen from a technology.”
 

Different evidence, varied outcomes

Despite the recommendations, a quick dive into the morass of evidence from multiple studies featured in the updated USPSTF guidelines shows that not all screening methods are created equal.

A single colonoscopy, for example, has been shown in large cohort studies to be associated with a 68% reduction in CRC mortality vs. no screening, compared with a 26% reduction with flexible sigmoidoscopy performed every 3-5 years, 22% reduction with Hemoccult II, and 10% with FIT every 2 years.

The USPSTF investigators did not find any studies evaluating the effectiveness of CT colonography, high-sensitivity gFOBT, stool DNA with or without FIT, or serum tests on CRC incidence, CRC mortality, or both.

The two visualization methods for which studies were available, colonoscopy and CT colonography, were generally comparable in sensitivity and specificity for detecting and correctly identifying adenomas 6 mm and larger, although colonography had higher sensitivity for CRC than colonoscopy.

When performed in two to nine annual or biennial rounds, gFOBT was associated with a reduction of CRC-specific mortality of 9% after 19.5 years and 22% at 30 years, compared with no screening.

In observational studies, screening colonoscopy and FIT were both associated with lower risk of CRC incidence or mortality, compared with no screening.
 

When to stop?

The major guidelines are all in agreement that once an individual reaches age 75, the decision about whether to continue screening should be made on a case-by-case basis, depending on the patient’s overall health, relative risks, and life expectancy.

But if a study published 2 days after the release of the USPSTF guidelines is any indication, just as 45 is the new 50 for starting screening, 85 may be the new 75 for stopping it.

As researchers from Mass General Cancer Center in Boston reported in JAMA Oncology, screening endoscopy for persons older than 75 in otherwise good health can reduce the risk for CRC incidence and CRC-related death by approximately 40%.

The researchers also found, however, that screening did not provide a significant survival benefit for individuals older than 75 with cardiovascular disease, diabetes, or three or more other health conditions.

“Until now, there really weren’t clear data to help us decide whether patients should be screened after age 75,” coinvestigator Andrew T. Chan. MD, MPH, a gastroenterologist and chief of the clinical and translational epidemiology unit at Mass General, said in a statement. “Current guidance was largely based on modeling and extrapolation of studies conducted in other age groups, and not on solid data to show whether screening was actually helpful in an older population.”

In an interview, Dr. Chan said that while the recommendation to screen older adults has to be tailored to individual risk factors, “it should help to provide more confidence for clinicians and patients.”

“I think this is particularly important, because we know that the population as a whole is aging, so more and more people are in this category of over the age of 75, and it’s not an infrequent issue in the clinic as to what to continue with respect to preventative interventions,” he said.

Dr. Kupfer said that the findings by Dr. Chan and colleagues are largely in keeping with guideline recommendations.

“We factor in a lot of different things, including comorbidities, in making the decision to continue screening up to age 85. Certainly, physiological age and chronological age aren’t always the same, so not every 75-year-old is going to be in the same boat,” she said.

“The risk goes up as people get older, but there starts to be competing mortality at some point, and if you have to do a colonoscopy there are obviously issues related to sedation that, as someone gets older, we have to take into consideration,” she added.

Patients frequently confuse screening with surveillance, Dr. Rex said, and he has had patients tell him: “I hear you don’t do these anymore on people over the age of 75.”

“But that’s not true,” Dr. Rex emphasized.

“Screening is generally considered appropriate even up to the age of 85, but between 75 and 85 it should be considered on an individual basis, and there are several considerations there,” Dr. Rex said. “One is whether a patient has ever been screened before. The second is how they were screened. Third is their life expectancy and how many comorbidities they have. And fourth is their personal feelings about it and interest in it.”

He pointed out that the false-positive rate of stool DNA-FIT tests increases with age, and that for older patients who were previously screened, a standard FIT test may be a more appropriate.
 

So doc, what should I do?

Multiple guidelines, levels of evidence, different screening methods with varying efficacy, individual risk factors – how can clinicians make sense of all these data at the practice level?

“Any modality can be used for screening. Colorectal cancer screening can be done in a number of different ways, and I think that sometimes gets lost in the shuffle, and the thought becomes that everybody has to get a colonoscopy at 45, but there are certainly other tests,” Dr. Kupfer said.

“This just reminds us that we should be thinking about ways we can be doing screening on a population basis, so that we make sure there is equity,” she said.

It’s also important to remember that patients with familial CRC syndromes should begin screening at an even earlier age than average-risk adults, she emphasized.

“To really make a dent in early-onset colorectal cancer, we have to continue to take an active case-finding approach,” she said.

Dr. Rex noted that despite minor differences, the major guidelines are all similar in their initial statements that screening works.

“We’ve still got 50,000 people a year dying from colorectal cancer, lots more than that of new cases,” he said. “If you look at a single factor contributing to that the most, it’s that a lot of the American public is not getting screened at all – it can be up to 40% of the population, depending on what state you’re in.”

Although there are a variety of screening methods available, there are few studies directly comparing them, leaving clinicians at the practice level with the task of presenting all or some of them to patients.

“What the Multi-Society Task Force says that is different, and I think that they get right, is that we don’t have any data [indicating] that offering five, six, or seven options increases the chance of screening – there’s really no evidence that going past two does,” Dr. Rex said.

“The list of options also includes things that nobody actually does,” he added. “For example, flexible sigmoidoscopy has dropped off the map, and FIT has largely replaced guaiac-based testing, even high-sensitivity guaiac. Nobody is really doing CT colonography. The three tests that are being used are colonoscopy, FIT, and [stool DNA-FIT].”

Dr. Rex said that he favors sequential offers, presenting colonoscopy first, emphasizing the benefits for higher-risk patients, and if the patients refuse, offering a fecal-based test.

“Minimizing the number of options makes the conversation feasible, and it’s still very responsible,” he said.

Dr. Kupfer has performed collaborative research with Myriad Genetic Laboratories. She is an editorial advisory board member for GI & Hepatology News from MDedge, part of the Medscape Professional Network. Dr. Rex serves or served as a consultant for Olympus Corporation; Boston Scientific; Medtronic; and Aries; and received research support from Endo-Aid; Olympus Corporation; and Medivators. He has ownership in ai4gi. He is an editorial board member for Medscape Gastroenterology. Dr. Chan has served as a consultant to Pfizer, Bayer AG, and Boehringer Ingelheim.
 

A version of this article first appeared on Medscape.com.

This article was updated June 8, 2021.

Build a better mousetrap, and the world will beat a path to your door. Find an accurate, completely noninvasive method for colorectal cancer screening and you’ll probably win the Nobel Prize for Medicine or Physiology.

But until then, we’ll have to make do with colonoscopy, fecal immunochemical testing (FIT), and other messy but necessary means for preventing full-blown CRC and reducing the risk of CRC morbidity and mortality. And start turning to them earlier in patients’ lives.

The U.S. Preventive Services Task Force (USPSTF) has issued an update of its 2016 recommendations for CRC screening, for the first time advising that screening for all average-risk adults begin at age 45. This new recommendation is in line with the guidelines issued by the American Cancer Society, which were updated in 2018, to reflect the inescapable truth that CRC is increasingly being diagnosed at a younger age.

Not to be left out, the U.S. Multi-Society Task Force (MSTF) – which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy – issued a statement supporting lowering the age of initial screening in normal-risk adults to 45, and promised that an update of the 2017 guidelines would include the new recommendation.
 

Recommendations influence reimbursement

Guidelines are often honored as much in the breach as in the observance, but those issued by the USPSTF have unique sway, according to Sonia S. Kupfer, MD, of the section of gastroenterology, hepatology, and nutrition at the University of Chicago, and colleagues.

“While other guidelines have recommended this younger age, the USPSTF guidelines directly inform insurance coverage and waiving of cost sharing as part of federal law,” they wrote in an editorial accompanying the USPSTF guideline statement in the Journal of the American Medical Association.

Although the USPSTF rated its recommendation on starting at age 45 a ‘B’ level – indicating a moderate certainty of moderate benefit – it’s an important step, Dr. Kupfer said in an interview.

“The big advantage here is that we may be able to make a dent in this early-onset colorectal cancer, which, having seen many of these patients, is very alarming, and they don’t always seem to have classic risk factors,” she said. “So, getting them when we can potentially prevent cancer by taking out polyps, or even getting them in an earlier stage, certainly will be beneficial.”

The MSTF also considered recommending 45 as the starting age for normal-risk patients in its 2017 guidelines, noted Douglas Rex, MD, who was chair of the committee that drew up those guidelines, as well as director of endoscopy at Indiana University Hospital in Indianapolis.

“Since that time there has been more evidence, and there’s also some empiric evidence, about the yield of screening in the 45- to 49-year-old age group,” he said in an interview.
 

The one that gets done

Although the various guidelines differ in specifics, all are in agreement on the general proposition that colonoscopy is the gold standard for screening and detecting the presence of polyps, adenomas, and CRC.

But as USPSTF member Martha Kubik, PhD, RN, director of the George Mason University School of Nursing in Fairfax, Va., said in a statement: “The right test is the one that gets done.”

Gastroenterologists acknowledge that despite its efficacy, colonoscopy is an invasive procedure involving meticulous and unpleasant and/or uncomfortable bowel prep, sedation, and significant time requirements. 

In the theory that something is better than nothing, with clinical evidence of varying degrees of quality, the USPSTF recommends the following procedures or tests for average-risk adults:

• Colonoscopy screening every 10 years.
•  every 10 years plus annual FIT.
• CT colonography every 5 years.
• High-sensitivity guaiac fecal occult blood test (gFOBT; Hemoccult II) or FIT every year.
• Stool DNA-FIT (Cologuard) every 1 to 3 years.

The Food and Drug Administration also recently approved an artificial intelligence device designed for use with an endoscope, which its manufacturer says can help clinicians detect gastrointestinal lesions they might otherwise miss. This is not a new screening method, but rather an enhancement of existing ones. It neither diagnoses lesions nor recommends treatments, and is not intended to take the place of laboratory sampling.

“I think artificial intelligence is poised to make colonoscopy more effective,” Dr. Rex said. “In the first five trials that we’ve seen, the average increase in the adenoma detection rate has been 11%, and for each 1% gain in the adenoma detection rate, patients have about a 3% decline in their risk of getting cancer after a colonoscopy and about a 5% decline in their risk for fatal cancer. Those are the largest gains that we’ve seen from a technology.”
 

Different evidence, varied outcomes

Despite the recommendations, a quick dive into the morass of evidence from multiple studies featured in the updated USPSTF guidelines shows that not all screening methods are created equal.

A single colonoscopy, for example, has been shown in large cohort studies to be associated with a 68% reduction in CRC mortality vs. no screening, compared with a 26% reduction with flexible sigmoidoscopy performed every 3-5 years, 22% reduction with Hemoccult II, and 10% with FIT every 2 years.

The USPSTF investigators did not find any studies evaluating the effectiveness of CT colonography, high-sensitivity gFOBT, stool DNA with or without FIT, or serum tests on CRC incidence, CRC mortality, or both.

The two visualization methods for which studies were available, colonoscopy and CT colonography, were generally comparable in sensitivity and specificity for detecting and correctly identifying adenomas 6 mm and larger, although colonography had higher sensitivity for CRC than colonoscopy.

When performed in two to nine annual or biennial rounds, gFOBT was associated with a reduction of CRC-specific mortality of 9% after 19.5 years and 22% at 30 years, compared with no screening.

In observational studies, screening colonoscopy and FIT were both associated with lower risk of CRC incidence or mortality, compared with no screening.
 

When to stop?

The major guidelines are all in agreement that once an individual reaches age 75, the decision about whether to continue screening should be made on a case-by-case basis, depending on the patient’s overall health, relative risks, and life expectancy.

But if a study published 2 days after the release of the USPSTF guidelines is any indication, just as 45 is the new 50 for starting screening, 85 may be the new 75 for stopping it.

As researchers from Mass General Cancer Center in Boston reported in JAMA Oncology, screening endoscopy for persons older than 75 in otherwise good health can reduce the risk for CRC incidence and CRC-related death by approximately 40%.

The researchers also found, however, that screening did not provide a significant survival benefit for individuals older than 75 with cardiovascular disease, diabetes, or three or more other health conditions.

“Until now, there really weren’t clear data to help us decide whether patients should be screened after age 75,” coinvestigator Andrew T. Chan. MD, MPH, a gastroenterologist and chief of the clinical and translational epidemiology unit at Mass General, said in a statement. “Current guidance was largely based on modeling and extrapolation of studies conducted in other age groups, and not on solid data to show whether screening was actually helpful in an older population.”

In an interview, Dr. Chan said that while the recommendation to screen older adults has to be tailored to individual risk factors, “it should help to provide more confidence for clinicians and patients.”

“I think this is particularly important, because we know that the population as a whole is aging, so more and more people are in this category of over the age of 75, and it’s not an infrequent issue in the clinic as to what to continue with respect to preventative interventions,” he said.

Dr. Kupfer said that the findings by Dr. Chan and colleagues are largely in keeping with guideline recommendations.

“We factor in a lot of different things, including comorbidities, in making the decision to continue screening up to age 85. Certainly, physiological age and chronological age aren’t always the same, so not every 75-year-old is going to be in the same boat,” she said.

“The risk goes up as people get older, but there starts to be competing mortality at some point, and if you have to do a colonoscopy there are obviously issues related to sedation that, as someone gets older, we have to take into consideration,” she added.

Patients frequently confuse screening with surveillance, Dr. Rex said, and he has had patients tell him: “I hear you don’t do these anymore on people over the age of 75.”

“But that’s not true,” Dr. Rex emphasized.

“Screening is generally considered appropriate even up to the age of 85, but between 75 and 85 it should be considered on an individual basis, and there are several considerations there,” Dr. Rex said. “One is whether a patient has ever been screened before. The second is how they were screened. Third is their life expectancy and how many comorbidities they have. And fourth is their personal feelings about it and interest in it.”

He pointed out that the false-positive rate of stool DNA-FIT tests increases with age, and that for older patients who were previously screened, a standard FIT test may be a more appropriate.
 

So doc, what should I do?

Multiple guidelines, levels of evidence, different screening methods with varying efficacy, individual risk factors – how can clinicians make sense of all these data at the practice level?

“Any modality can be used for screening. Colorectal cancer screening can be done in a number of different ways, and I think that sometimes gets lost in the shuffle, and the thought becomes that everybody has to get a colonoscopy at 45, but there are certainly other tests,” Dr. Kupfer said.

“This just reminds us that we should be thinking about ways we can be doing screening on a population basis, so that we make sure there is equity,” she said.

It’s also important to remember that patients with familial CRC syndromes should begin screening at an even earlier age than average-risk adults, she emphasized.

“To really make a dent in early-onset colorectal cancer, we have to continue to take an active case-finding approach,” she said.

Dr. Rex noted that despite minor differences, the major guidelines are all similar in their initial statements that screening works.

“We’ve still got 50,000 people a year dying from colorectal cancer, lots more than that of new cases,” he said. “If you look at a single factor contributing to that the most, it’s that a lot of the American public is not getting screened at all – it can be up to 40% of the population, depending on what state you’re in.”

Although there are a variety of screening methods available, there are few studies directly comparing them, leaving clinicians at the practice level with the task of presenting all or some of them to patients.

“What the Multi-Society Task Force says that is different, and I think that they get right, is that we don’t have any data [indicating] that offering five, six, or seven options increases the chance of screening – there’s really no evidence that going past two does,” Dr. Rex said.

“The list of options also includes things that nobody actually does,” he added. “For example, flexible sigmoidoscopy has dropped off the map, and FIT has largely replaced guaiac-based testing, even high-sensitivity guaiac. Nobody is really doing CT colonography. The three tests that are being used are colonoscopy, FIT, and [stool DNA-FIT].”

Dr. Rex said that he favors sequential offers, presenting colonoscopy first, emphasizing the benefits for higher-risk patients, and if the patients refuse, offering a fecal-based test.

“Minimizing the number of options makes the conversation feasible, and it’s still very responsible,” he said.

Dr. Kupfer has performed collaborative research with Myriad Genetic Laboratories. She is an editorial advisory board member for GI & Hepatology News from MDedge, part of the Medscape Professional Network. Dr. Rex serves or served as a consultant for Olympus Corporation; Boston Scientific; Medtronic; and Aries; and received research support from Endo-Aid; Olympus Corporation; and Medivators. He has ownership in ai4gi. He is an editorial board member for Medscape Gastroenterology. Dr. Chan has served as a consultant to Pfizer, Bayer AG, and Boehringer Ingelheim.
 

A version of this article first appeared on Medscape.com.

This article was updated June 8, 2021.

Build a better mousetrap, and the world will beat a path to your door. Find an accurate, completely noninvasive method for colorectal cancer screening and you’ll probably win the Nobel Prize for Medicine or Physiology.

But until then, we’ll have to make do with colonoscopy, fecal immunochemical testing (FIT), and other messy but necessary means for preventing full-blown CRC and reducing the risk of CRC morbidity and mortality. And start turning to them earlier in patients’ lives.

The U.S. Preventive Services Task Force (USPSTF) has issued an update of its 2016 recommendations for CRC screening, for the first time advising that screening for all average-risk adults begin at age 45. This new recommendation is in line with the guidelines issued by the American Cancer Society, which were updated in 2018, to reflect the inescapable truth that CRC is increasingly being diagnosed at a younger age.

Not to be left out, the U.S. Multi-Society Task Force (MSTF) – which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy – issued a statement supporting lowering the age of initial screening in normal-risk adults to 45, and promised that an update of the 2017 guidelines would include the new recommendation.
 

Recommendations influence reimbursement

Guidelines are often honored as much in the breach as in the observance, but those issued by the USPSTF have unique sway, according to Sonia S. Kupfer, MD, of the section of gastroenterology, hepatology, and nutrition at the University of Chicago, and colleagues.

“While other guidelines have recommended this younger age, the USPSTF guidelines directly inform insurance coverage and waiving of cost sharing as part of federal law,” they wrote in an editorial accompanying the USPSTF guideline statement in the Journal of the American Medical Association.

Although the USPSTF rated its recommendation on starting at age 45 a ‘B’ level – indicating a moderate certainty of moderate benefit – it’s an important step, Dr. Kupfer said in an interview.

“The big advantage here is that we may be able to make a dent in this early-onset colorectal cancer, which, having seen many of these patients, is very alarming, and they don’t always seem to have classic risk factors,” she said. “So, getting them when we can potentially prevent cancer by taking out polyps, or even getting them in an earlier stage, certainly will be beneficial.”

The MSTF also considered recommending 45 as the starting age for normal-risk patients in its 2017 guidelines, noted Douglas Rex, MD, who was chair of the committee that drew up those guidelines, as well as director of endoscopy at Indiana University Hospital in Indianapolis.

“Since that time there has been more evidence, and there’s also some empiric evidence, about the yield of screening in the 45- to 49-year-old age group,” he said in an interview.
 

The one that gets done

Although the various guidelines differ in specifics, all are in agreement on the general proposition that colonoscopy is the gold standard for screening and detecting the presence of polyps, adenomas, and CRC.

But as USPSTF member Martha Kubik, PhD, RN, director of the George Mason University School of Nursing in Fairfax, Va., said in a statement: “The right test is the one that gets done.”

Gastroenterologists acknowledge that despite its efficacy, colonoscopy is an invasive procedure involving meticulous and unpleasant and/or uncomfortable bowel prep, sedation, and significant time requirements. 

In the theory that something is better than nothing, with clinical evidence of varying degrees of quality, the USPSTF recommends the following procedures or tests for average-risk adults:

• Colonoscopy screening every 10 years.
•  every 10 years plus annual FIT.
• CT colonography every 5 years.
• High-sensitivity guaiac fecal occult blood test (gFOBT; Hemoccult II) or FIT every year.
• Stool DNA-FIT (Cologuard) every 1 to 3 years.

The Food and Drug Administration also recently approved an artificial intelligence device designed for use with an endoscope, which its manufacturer says can help clinicians detect gastrointestinal lesions they might otherwise miss. This is not a new screening method, but rather an enhancement of existing ones. It neither diagnoses lesions nor recommends treatments, and is not intended to take the place of laboratory sampling.

“I think artificial intelligence is poised to make colonoscopy more effective,” Dr. Rex said. “In the first five trials that we’ve seen, the average increase in the adenoma detection rate has been 11%, and for each 1% gain in the adenoma detection rate, patients have about a 3% decline in their risk of getting cancer after a colonoscopy and about a 5% decline in their risk for fatal cancer. Those are the largest gains that we’ve seen from a technology.”
 

Different evidence, varied outcomes

Despite the recommendations, a quick dive into the morass of evidence from multiple studies featured in the updated USPSTF guidelines shows that not all screening methods are created equal.

A single colonoscopy, for example, has been shown in large cohort studies to be associated with a 68% reduction in CRC mortality vs. no screening, compared with a 26% reduction with flexible sigmoidoscopy performed every 3-5 years, 22% reduction with Hemoccult II, and 10% with FIT every 2 years.

The USPSTF investigators did not find any studies evaluating the effectiveness of CT colonography, high-sensitivity gFOBT, stool DNA with or without FIT, or serum tests on CRC incidence, CRC mortality, or both.

The two visualization methods for which studies were available, colonoscopy and CT colonography, were generally comparable in sensitivity and specificity for detecting and correctly identifying adenomas 6 mm and larger, although colonography had higher sensitivity for CRC than colonoscopy.

When performed in two to nine annual or biennial rounds, gFOBT was associated with a reduction of CRC-specific mortality of 9% after 19.5 years and 22% at 30 years, compared with no screening.

In observational studies, screening colonoscopy and FIT were both associated with lower risk of CRC incidence or mortality, compared with no screening.
 

When to stop?

The major guidelines are all in agreement that once an individual reaches age 75, the decision about whether to continue screening should be made on a case-by-case basis, depending on the patient’s overall health, relative risks, and life expectancy.

But if a study published 2 days after the release of the USPSTF guidelines is any indication, just as 45 is the new 50 for starting screening, 85 may be the new 75 for stopping it.

As researchers from Mass General Cancer Center in Boston reported in JAMA Oncology, screening endoscopy for persons older than 75 in otherwise good health can reduce the risk for CRC incidence and CRC-related death by approximately 40%.

The researchers also found, however, that screening did not provide a significant survival benefit for individuals older than 75 with cardiovascular disease, diabetes, or three or more other health conditions.

“Until now, there really weren’t clear data to help us decide whether patients should be screened after age 75,” coinvestigator Andrew T. Chan. MD, MPH, a gastroenterologist and chief of the clinical and translational epidemiology unit at Mass General, said in a statement. “Current guidance was largely based on modeling and extrapolation of studies conducted in other age groups, and not on solid data to show whether screening was actually helpful in an older population.”

In an interview, Dr. Chan said that while the recommendation to screen older adults has to be tailored to individual risk factors, “it should help to provide more confidence for clinicians and patients.”

“I think this is particularly important, because we know that the population as a whole is aging, so more and more people are in this category of over the age of 75, and it’s not an infrequent issue in the clinic as to what to continue with respect to preventative interventions,” he said.

Dr. Kupfer said that the findings by Dr. Chan and colleagues are largely in keeping with guideline recommendations.

“We factor in a lot of different things, including comorbidities, in making the decision to continue screening up to age 85. Certainly, physiological age and chronological age aren’t always the same, so not every 75-year-old is going to be in the same boat,” she said.

“The risk goes up as people get older, but there starts to be competing mortality at some point, and if you have to do a colonoscopy there are obviously issues related to sedation that, as someone gets older, we have to take into consideration,” she added.

Patients frequently confuse screening with surveillance, Dr. Rex said, and he has had patients tell him: “I hear you don’t do these anymore on people over the age of 75.”

“But that’s not true,” Dr. Rex emphasized.

“Screening is generally considered appropriate even up to the age of 85, but between 75 and 85 it should be considered on an individual basis, and there are several considerations there,” Dr. Rex said. “One is whether a patient has ever been screened before. The second is how they were screened. Third is their life expectancy and how many comorbidities they have. And fourth is their personal feelings about it and interest in it.”

He pointed out that the false-positive rate of stool DNA-FIT tests increases with age, and that for older patients who were previously screened, a standard FIT test may be a more appropriate.
 

So doc, what should I do?

Multiple guidelines, levels of evidence, different screening methods with varying efficacy, individual risk factors – how can clinicians make sense of all these data at the practice level?

“Any modality can be used for screening. Colorectal cancer screening can be done in a number of different ways, and I think that sometimes gets lost in the shuffle, and the thought becomes that everybody has to get a colonoscopy at 45, but there are certainly other tests,” Dr. Kupfer said.

“This just reminds us that we should be thinking about ways we can be doing screening on a population basis, so that we make sure there is equity,” she said.

It’s also important to remember that patients with familial CRC syndromes should begin screening at an even earlier age than average-risk adults, she emphasized.

“To really make a dent in early-onset colorectal cancer, we have to continue to take an active case-finding approach,” she said.

Dr. Rex noted that despite minor differences, the major guidelines are all similar in their initial statements that screening works.

“We’ve still got 50,000 people a year dying from colorectal cancer, lots more than that of new cases,” he said. “If you look at a single factor contributing to that the most, it’s that a lot of the American public is not getting screened at all – it can be up to 40% of the population, depending on what state you’re in.”

Although there are a variety of screening methods available, there are few studies directly comparing them, leaving clinicians at the practice level with the task of presenting all or some of them to patients.

“What the Multi-Society Task Force says that is different, and I think that they get right, is that we don’t have any data [indicating] that offering five, six, or seven options increases the chance of screening – there’s really no evidence that going past two does,” Dr. Rex said.

“The list of options also includes things that nobody actually does,” he added. “For example, flexible sigmoidoscopy has dropped off the map, and FIT has largely replaced guaiac-based testing, even high-sensitivity guaiac. Nobody is really doing CT colonography. The three tests that are being used are colonoscopy, FIT, and [stool DNA-FIT].”

Dr. Rex said that he favors sequential offers, presenting colonoscopy first, emphasizing the benefits for higher-risk patients, and if the patients refuse, offering a fecal-based test.

“Minimizing the number of options makes the conversation feasible, and it’s still very responsible,” he said.

Dr. Kupfer has performed collaborative research with Myriad Genetic Laboratories. She is an editorial advisory board member for GI & Hepatology News from MDedge, part of the Medscape Professional Network. Dr. Rex serves or served as a consultant for Olympus Corporation; Boston Scientific; Medtronic; and Aries; and received research support from Endo-Aid; Olympus Corporation; and Medivators. He has ownership in ai4gi. He is an editorial board member for Medscape Gastroenterology. Dr. Chan has served as a consultant to Pfizer, Bayer AG, and Boehringer Ingelheim.
 

A version of this article first appeared on Medscape.com.

This article was updated June 8, 2021.

For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.

In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.

“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).

Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.

“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.

Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.

Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.

“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
 

Open-label trial

To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m² every 3 weeks, or paclitaxel 80 mg/m² weekly.

The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.

In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).

There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.

Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.

There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.

In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
 

Quality of life favors cabazitaxel

Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.

Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.

Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.

In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
 

Second-line may be better

ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.

“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.

However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.

Dr. Kok did not address quality of life differences between the regimens, however.

In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”

The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.

For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.

In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.

“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).

Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.

“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.

Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.

Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.

“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
 

Open-label trial

To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m² every 3 weeks, or paclitaxel 80 mg/m² weekly.

The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.

In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).

There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.

Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.

There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.

In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
 

Quality of life favors cabazitaxel

Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.

Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.

Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.

In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
 

Second-line may be better

ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.

“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.

However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.

Dr. Kok did not address quality of life differences between the regimens, however.

In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”

The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.

For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.

In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.

“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).

Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.

“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.

Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.

Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.

“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
 

Open-label trial

To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m² every 3 weeks, or paclitaxel 80 mg/m² weekly.

The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.

In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).

There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.

Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.

There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.

In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
 

Quality of life favors cabazitaxel

Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.

Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.

Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.

In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
 

Second-line may be better

ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.

“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.

However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.

Dr. Kok did not address quality of life differences between the regimens, however.

In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”

The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.

A novel 16-gene panel based on the biology of locoregional recurrence in early invasive breast cancer can both identify patients with a low risk of recurrence if they were to skip postsurgery radiation therapy, and predict which patients would be unlikely to benefit from adjuvant radiation, investigators reported.

Among 354 patients with stage I or II invasive estrogen receptor–positive (ER+), HER2-negative breast cancers who did not receive adjuvant systemic therapy, the genomic signature, dubbed POLAR (Profile for the Omission of Local Adjuvant Radiation) was prognostic for locoregional recurrence in patients who did not undergo radiation therapy, reported Martin Sjöström, MD, PhD, of the University of California, San Francisco, and colleagues.

They reported their findings in a poster presented during the American Society of Clinical Oncology (ASCO) annual meeting (Abstract 512).

“This is to our knowledge the first radiation-omission signature that is both prognostic and predictive: prognostic for outcomes in the absence of radiation, and predictive of benefits,” coauthor Corey Speers MD, PhD, of the University of Michigan, Ann Arbor, said in an interview.

The investigators conducted a retrospective analysis of data on patients enrolled in the SweBCG 91 RT trial, in which 1,187 patients with T1-2N0M0 breast cancer underwent a standardized radical sector resection and were then randomly assigned to either postoperative radiotherapy or no further treatment.

As the investigators reported in a long-term follow-up study presented in 2010 at the San Antonio Breast Cancer Symposium, the addition of postoperative radiation did not significantly affect overall survival, but was associated with a significant improvement in recurrence-free survival.

In the study presented at ASCO 2021, Dr. Sjöström and colleagues in Sweden, the United States, and Canada sought to determine whether they could identify a genomic signature that would identify women at very low risk for recurrence who could safely be spared from radiotherapy.

They focused on those patients in the study with ER+, HER2-negative tumors who did not receive adjuvant systemic therapy. The patients were divided into a training cohort of 243, and a validation cohort of 354 patients.

The investigators performed transcriptome-wide profiling of tumors, and identified both biological gene sets and individuals genes associated with locoregional recurrence among patients in the training set who did not receive radiotherapy.

The final POLAR genomic signature, containing 16 genes, was locked prior to testing in the validation cohort.

In a multivariable Cox model adjusting for age, grade, tumor size and luminal A vs. luminal B subtype, the POLAR gene set was prognostic for locoregional recurrence, with a hazard ratio (HR) of 1.7 (P < .001).

The 10-year locoregional recurrence rate for patients in the POLAR low-risk category who had not received radiation was 7%, and there was no significant benefit for POLAR low-risk patients who did receive radiation (HR 1.1, P = ns).

In contrast, patients classified as POLAR high risk who received radiotherapy had significantly lower risk for locoregional recurrence than high-risk patients who did not receive radiotherapy (HR 0.43, P = .0053).

Dr. Speers said that the POLAR signature appears to be unique in its ability to discriminate radiation-omission risk.

“At least looking in this cohort in the Swedish trial, none of other previously derived signatures – Mammaprint, ProSigna, Oncotype – were prognostic or predictive of locoregional recurrence events with radiation,” he said.

The investigators are currently exploring the POLAR signature in other clinical trials in which patients were randomized to receive radiation or no radiation.
 

­‘A true victory’

Invited discussant Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, pointed out that in randomized clinical trials, approximately 60% of patients treated for early breast cancer did not experience recurrence in the absence of radiation, and that radiation prevented recurrence in about 30%, while about 10% experienced recurrence despite receiving radiation.

He said that the study by Dr. Sjöström and colleagues asks the question “can we use molecular factors to help identify patients who will not recur with lumpectomy alone without radiation therapy?”

The 60% of patients who will not experience recurrence in the absence of radiation can be categorized into two subpopulations: those with no residual malignant clonogens – the population included in this study by Dr. Sjöström and colleagues – and those with residual clonogens in the breast or elsewhere in the body that are sensitive to adjuvant endocrine therapy.

He said that the 7% 10-year risk of recurrence among patients in the POLAR low-risk group, who had neither radiation nor endocrine therapy, “is an exceptional outcome, which should be applauded, and I would point out that this risk of local recurrence of only 7% is at least in the same ballpark as the risk of recurrence that we accept every day when we treat early stage breast cancer patients with mastectomy alone, so this is a true victory.

“When we reflect on these provocative results from Dr. Sjöström and colleagues, it prompts in mind the question, could there be a group of patients with early breast cancer for whom a true ‘one-and-done’ strategy could be effective and safe?” Dr. Smith said.

Getting there will require a multidisciplinary, multimodality approach, involving imaging features of the primary tumor, clinical and pathologic features, and molecular information such as that provided by the POLAR genomic signature, he said.

The study was supported by PFS Genomics. Dr. Sjöström reported institutional funding from PFS Genomics. Dr. Speers disclosed stock and other ownership interests in the company, and he has applied for a patent on methods and genomic classifiers for prognosis of breast cancer and predicting benefit from adjuvant radiotherapy. Dr. Smith reported an equity interest in Oncora Medical, and an uncompensated relationship with the American Society for Radiation Oncology.

A novel 16-gene panel based on the biology of locoregional recurrence in early invasive breast cancer can both identify patients with a low risk of recurrence if they were to skip postsurgery radiation therapy, and predict which patients would be unlikely to benefit from adjuvant radiation, investigators reported.

Among 354 patients with stage I or II invasive estrogen receptor–positive (ER+), HER2-negative breast cancers who did not receive adjuvant systemic therapy, the genomic signature, dubbed POLAR (Profile for the Omission of Local Adjuvant Radiation) was prognostic for locoregional recurrence in patients who did not undergo radiation therapy, reported Martin Sjöström, MD, PhD, of the University of California, San Francisco, and colleagues.

They reported their findings in a poster presented during the American Society of Clinical Oncology (ASCO) annual meeting (Abstract 512).

“This is to our knowledge the first radiation-omission signature that is both prognostic and predictive: prognostic for outcomes in the absence of radiation, and predictive of benefits,” coauthor Corey Speers MD, PhD, of the University of Michigan, Ann Arbor, said in an interview.

The investigators conducted a retrospective analysis of data on patients enrolled in the SweBCG 91 RT trial, in which 1,187 patients with T1-2N0M0 breast cancer underwent a standardized radical sector resection and were then randomly assigned to either postoperative radiotherapy or no further treatment.

As the investigators reported in a long-term follow-up study presented in 2010 at the San Antonio Breast Cancer Symposium, the addition of postoperative radiation did not significantly affect overall survival, but was associated with a significant improvement in recurrence-free survival.

In the study presented at ASCO 2021, Dr. Sjöström and colleagues in Sweden, the United States, and Canada sought to determine whether they could identify a genomic signature that would identify women at very low risk for recurrence who could safely be spared from radiotherapy.

They focused on those patients in the study with ER+, HER2-negative tumors who did not receive adjuvant systemic therapy. The patients were divided into a training cohort of 243, and a validation cohort of 354 patients.

The investigators performed transcriptome-wide profiling of tumors, and identified both biological gene sets and individuals genes associated with locoregional recurrence among patients in the training set who did not receive radiotherapy.

The final POLAR genomic signature, containing 16 genes, was locked prior to testing in the validation cohort.

In a multivariable Cox model adjusting for age, grade, tumor size and luminal A vs. luminal B subtype, the POLAR gene set was prognostic for locoregional recurrence, with a hazard ratio (HR) of 1.7 (P < .001).

The 10-year locoregional recurrence rate for patients in the POLAR low-risk category who had not received radiation was 7%, and there was no significant benefit for POLAR low-risk patients who did receive radiation (HR 1.1, P = ns).

In contrast, patients classified as POLAR high risk who received radiotherapy had significantly lower risk for locoregional recurrence than high-risk patients who did not receive radiotherapy (HR 0.43, P = .0053).

Dr. Speers said that the POLAR signature appears to be unique in its ability to discriminate radiation-omission risk.

“At least looking in this cohort in the Swedish trial, none of other previously derived signatures – Mammaprint, ProSigna, Oncotype – were prognostic or predictive of locoregional recurrence events with radiation,” he said.

The investigators are currently exploring the POLAR signature in other clinical trials in which patients were randomized to receive radiation or no radiation.
 

­‘A true victory’

Invited discussant Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, pointed out that in randomized clinical trials, approximately 60% of patients treated for early breast cancer did not experience recurrence in the absence of radiation, and that radiation prevented recurrence in about 30%, while about 10% experienced recurrence despite receiving radiation.

He said that the study by Dr. Sjöström and colleagues asks the question “can we use molecular factors to help identify patients who will not recur with lumpectomy alone without radiation therapy?”

The 60% of patients who will not experience recurrence in the absence of radiation can be categorized into two subpopulations: those with no residual malignant clonogens – the population included in this study by Dr. Sjöström and colleagues – and those with residual clonogens in the breast or elsewhere in the body that are sensitive to adjuvant endocrine therapy.

He said that the 7% 10-year risk of recurrence among patients in the POLAR low-risk group, who had neither radiation nor endocrine therapy, “is an exceptional outcome, which should be applauded, and I would point out that this risk of local recurrence of only 7% is at least in the same ballpark as the risk of recurrence that we accept every day when we treat early stage breast cancer patients with mastectomy alone, so this is a true victory.

“When we reflect on these provocative results from Dr. Sjöström and colleagues, it prompts in mind the question, could there be a group of patients with early breast cancer for whom a true ‘one-and-done’ strategy could be effective and safe?” Dr. Smith said.

Getting there will require a multidisciplinary, multimodality approach, involving imaging features of the primary tumor, clinical and pathologic features, and molecular information such as that provided by the POLAR genomic signature, he said.

The study was supported by PFS Genomics. Dr. Sjöström reported institutional funding from PFS Genomics. Dr. Speers disclosed stock and other ownership interests in the company, and he has applied for a patent on methods and genomic classifiers for prognosis of breast cancer and predicting benefit from adjuvant radiotherapy. Dr. Smith reported an equity interest in Oncora Medical, and an uncompensated relationship with the American Society for Radiation Oncology.

A novel 16-gene panel based on the biology of locoregional recurrence in early invasive breast cancer can both identify patients with a low risk of recurrence if they were to skip postsurgery radiation therapy, and predict which patients would be unlikely to benefit from adjuvant radiation, investigators reported.

Among 354 patients with stage I or II invasive estrogen receptor–positive (ER+), HER2-negative breast cancers who did not receive adjuvant systemic therapy, the genomic signature, dubbed POLAR (Profile for the Omission of Local Adjuvant Radiation) was prognostic for locoregional recurrence in patients who did not undergo radiation therapy, reported Martin Sjöström, MD, PhD, of the University of California, San Francisco, and colleagues.

They reported their findings in a poster presented during the American Society of Clinical Oncology (ASCO) annual meeting (Abstract 512).

“This is to our knowledge the first radiation-omission signature that is both prognostic and predictive: prognostic for outcomes in the absence of radiation, and predictive of benefits,” coauthor Corey Speers MD, PhD, of the University of Michigan, Ann Arbor, said in an interview.

The investigators conducted a retrospective analysis of data on patients enrolled in the SweBCG 91 RT trial, in which 1,187 patients with T1-2N0M0 breast cancer underwent a standardized radical sector resection and were then randomly assigned to either postoperative radiotherapy or no further treatment.

As the investigators reported in a long-term follow-up study presented in 2010 at the San Antonio Breast Cancer Symposium, the addition of postoperative radiation did not significantly affect overall survival, but was associated with a significant improvement in recurrence-free survival.

In the study presented at ASCO 2021, Dr. Sjöström and colleagues in Sweden, the United States, and Canada sought to determine whether they could identify a genomic signature that would identify women at very low risk for recurrence who could safely be spared from radiotherapy.

They focused on those patients in the study with ER+, HER2-negative tumors who did not receive adjuvant systemic therapy. The patients were divided into a training cohort of 243, and a validation cohort of 354 patients.

The investigators performed transcriptome-wide profiling of tumors, and identified both biological gene sets and individuals genes associated with locoregional recurrence among patients in the training set who did not receive radiotherapy.

The final POLAR genomic signature, containing 16 genes, was locked prior to testing in the validation cohort.

In a multivariable Cox model adjusting for age, grade, tumor size and luminal A vs. luminal B subtype, the POLAR gene set was prognostic for locoregional recurrence, with a hazard ratio (HR) of 1.7 (P < .001).

The 10-year locoregional recurrence rate for patients in the POLAR low-risk category who had not received radiation was 7%, and there was no significant benefit for POLAR low-risk patients who did receive radiation (HR 1.1, P = ns).

In contrast, patients classified as POLAR high risk who received radiotherapy had significantly lower risk for locoregional recurrence than high-risk patients who did not receive radiotherapy (HR 0.43, P = .0053).

Dr. Speers said that the POLAR signature appears to be unique in its ability to discriminate radiation-omission risk.

“At least looking in this cohort in the Swedish trial, none of other previously derived signatures – Mammaprint, ProSigna, Oncotype – were prognostic or predictive of locoregional recurrence events with radiation,” he said.

The investigators are currently exploring the POLAR signature in other clinical trials in which patients were randomized to receive radiation or no radiation.
 

­‘A true victory’

Invited discussant Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, pointed out that in randomized clinical trials, approximately 60% of patients treated for early breast cancer did not experience recurrence in the absence of radiation, and that radiation prevented recurrence in about 30%, while about 10% experienced recurrence despite receiving radiation.

He said that the study by Dr. Sjöström and colleagues asks the question “can we use molecular factors to help identify patients who will not recur with lumpectomy alone without radiation therapy?”

The 60% of patients who will not experience recurrence in the absence of radiation can be categorized into two subpopulations: those with no residual malignant clonogens – the population included in this study by Dr. Sjöström and colleagues – and those with residual clonogens in the breast or elsewhere in the body that are sensitive to adjuvant endocrine therapy.

He said that the 7% 10-year risk of recurrence among patients in the POLAR low-risk group, who had neither radiation nor endocrine therapy, “is an exceptional outcome, which should be applauded, and I would point out that this risk of local recurrence of only 7% is at least in the same ballpark as the risk of recurrence that we accept every day when we treat early stage breast cancer patients with mastectomy alone, so this is a true victory.

“When we reflect on these provocative results from Dr. Sjöström and colleagues, it prompts in mind the question, could there be a group of patients with early breast cancer for whom a true ‘one-and-done’ strategy could be effective and safe?” Dr. Smith said.

Getting there will require a multidisciplinary, multimodality approach, involving imaging features of the primary tumor, clinical and pathologic features, and molecular information such as that provided by the POLAR genomic signature, he said.

The study was supported by PFS Genomics. Dr. Sjöström reported institutional funding from PFS Genomics. Dr. Speers disclosed stock and other ownership interests in the company, and he has applied for a patent on methods and genomic classifiers for prognosis of breast cancer and predicting benefit from adjuvant radiotherapy. Dr. Smith reported an equity interest in Oncora Medical, and an uncompensated relationship with the American Society for Radiation Oncology.

For women with HER2-positive early breast cancer treated with an anthracycline-based regimen followed by trastuzumab (Herceptin), concurrent therapy with the angiotensin-converting enzyme (ACE) inhibitor lisinopril can help to prevent a decline in left-ventricular ejection fraction (LVEF) below 50%, investigators in a community-based study found.

Among 424 women with HER2-positive early-stage breast cancer, the rate of LVEF decline to below 50% was 21.4% among patients randomized to receive an anthracycline-based regimen, compared with 4.1% for patients who were treated with a non–anthracycline-based regimen.

Among patients in the anthracycline arm, treatment with lisinopril, but not carvedilol or placebo, was associated with significant protection against LVEF decline, reported Pamela N. Munster, MD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“The findings of this study suggested that the drop in left ventricular ejection fraction to below 50% or to below normal was much larger than previously reported in the anthracycline group,” she said in a video presentation during a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 509).

Although HER2 inhibition is a highly effective treatment strategy for patients with HER2-positive tumors, trastuzumab-associated decline in LVEF and clinical heart failure can result in treatment interruption or discontinuation of therapy, the authors noted.

They conducted the prospective randomized trial to see whether trastuzumab-associated cardiotoxicity could be mitigated by concurrent use of either an ACE inhibitor or beta-blocker.

They enrolled women with early HER2-positive breast cancer from 127 community-based oncology centers.

The patients were randomly assigned to receive either an anthracycline- or non–anthracycline-containing regimen, followed by a year of trastuzumab, and were then randomized again to receive either lisinopril, carvedilol, or placebo concurrently with trastuzumab.

The patients were assessed for cardiotoxicity every 12 weeks with a multiple-gated acquisition (MUGA) scan and echocardiogram. Cardiotoxicity was defined as an absolute decrease in LVEF of 10% or more, or at least 5% decrease in LVEF below 50% at baseline.
 

Small LVEF declines in all

The investigators observed that all patients in the study experienced a small but not clinically relevant decrease in LVEF during trastuzumab therapy, and that this decline was not significantly ameliorated by any of the interventions.

However, as noted before, among patients assigned to anthracycline-based regimens the rate of decline to LVEF below 50% was 21.4%, compared with 4.1 for patients assigned to non–anthracycline regimens.

LVEF declines of at least 10% occurred in 5.5% of patients who received anthracyclines, and in 14.4% of those who received a non-anthracycline regimen.

Among patients who received anthracycline, only 10.8% randomized to receive lisinopril prophylaxis experienced a decline in LVEF, compared with 30.5% assigned to placebo (P = .045).

“In contrast, while carvedilol showed a numerical prevention of LVEF below 50% to 22.8%, this was not statistically significant,” Dr. Munster said.

Decreases in LVEF of 10% or greater within the normal LVEF range were similar in both chemotherapy arms and were not affected by either lisinopril or carvedilol.

“Lisinopril was well tolerated in this group, even in patients without hypertension,” she said.

“In women treated in a community-based environment who could benefit from anthracyclines or where anthracyclines are indicated, one should anticipate the decrease in left ventricular ejection fraction to below normal to be larger than is reported by other groups. However, this could be prevented by lisinopril,” she concluded.
 

Low numbers overall

Invited discussant Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, noted that the overall number of cardiotoxicity events and the rate of important decreases in LVEF were comparatively low.

She also pointed out that the findings are in line with another recent analysis of the same cohort by the same authors, although in the earlier analysis the investigators found that the effect on cardiotoxicity-free survival was good with both agents compared with placebo, but slightly better with carvedilol (hazard ratio 0.49, P = .009) than with lisinopril (HR 0.53, P = .015).

“Lisinopril has the most important effect regarding preventing decrease of LVEF below 50%. When we look at the curves of LVEF drops above 10%, carvedilol seems to have a slightly bigger effect,” she said.

The trial was cosponsored by the SunCoast Community Clinical Oncology Programs Research Base at University of South Florida, Tampa, and by the National Cancer Institute. Dr. Munster disclosed leadership positions, stock ownership, and consulting or advisory roles with several companies. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

For women with HER2-positive early breast cancer treated with an anthracycline-based regimen followed by trastuzumab (Herceptin), concurrent therapy with the angiotensin-converting enzyme (ACE) inhibitor lisinopril can help to prevent a decline in left-ventricular ejection fraction (LVEF) below 50%, investigators in a community-based study found.

Among 424 women with HER2-positive early-stage breast cancer, the rate of LVEF decline to below 50% was 21.4% among patients randomized to receive an anthracycline-based regimen, compared with 4.1% for patients who were treated with a non–anthracycline-based regimen.

Among patients in the anthracycline arm, treatment with lisinopril, but not carvedilol or placebo, was associated with significant protection against LVEF decline, reported Pamela N. Munster, MD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“The findings of this study suggested that the drop in left ventricular ejection fraction to below 50% or to below normal was much larger than previously reported in the anthracycline group,” she said in a video presentation during a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 509).

Although HER2 inhibition is a highly effective treatment strategy for patients with HER2-positive tumors, trastuzumab-associated decline in LVEF and clinical heart failure can result in treatment interruption or discontinuation of therapy, the authors noted.

They conducted the prospective randomized trial to see whether trastuzumab-associated cardiotoxicity could be mitigated by concurrent use of either an ACE inhibitor or beta-blocker.

They enrolled women with early HER2-positive breast cancer from 127 community-based oncology centers.

The patients were randomly assigned to receive either an anthracycline- or non–anthracycline-containing regimen, followed by a year of trastuzumab, and were then randomized again to receive either lisinopril, carvedilol, or placebo concurrently with trastuzumab.

The patients were assessed for cardiotoxicity every 12 weeks with a multiple-gated acquisition (MUGA) scan and echocardiogram. Cardiotoxicity was defined as an absolute decrease in LVEF of 10% or more, or at least 5% decrease in LVEF below 50% at baseline.
 

Small LVEF declines in all

The investigators observed that all patients in the study experienced a small but not clinically relevant decrease in LVEF during trastuzumab therapy, and that this decline was not significantly ameliorated by any of the interventions.

However, as noted before, among patients assigned to anthracycline-based regimens the rate of decline to LVEF below 50% was 21.4%, compared with 4.1 for patients assigned to non–anthracycline regimens.

LVEF declines of at least 10% occurred in 5.5% of patients who received anthracyclines, and in 14.4% of those who received a non-anthracycline regimen.

Among patients who received anthracycline, only 10.8% randomized to receive lisinopril prophylaxis experienced a decline in LVEF, compared with 30.5% assigned to placebo (P = .045).

“In contrast, while carvedilol showed a numerical prevention of LVEF below 50% to 22.8%, this was not statistically significant,” Dr. Munster said.

Decreases in LVEF of 10% or greater within the normal LVEF range were similar in both chemotherapy arms and were not affected by either lisinopril or carvedilol.

“Lisinopril was well tolerated in this group, even in patients without hypertension,” she said.

“In women treated in a community-based environment who could benefit from anthracyclines or where anthracyclines are indicated, one should anticipate the decrease in left ventricular ejection fraction to below normal to be larger than is reported by other groups. However, this could be prevented by lisinopril,” she concluded.
 

Low numbers overall

Invited discussant Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, noted that the overall number of cardiotoxicity events and the rate of important decreases in LVEF were comparatively low.

She also pointed out that the findings are in line with another recent analysis of the same cohort by the same authors, although in the earlier analysis the investigators found that the effect on cardiotoxicity-free survival was good with both agents compared with placebo, but slightly better with carvedilol (hazard ratio 0.49, P = .009) than with lisinopril (HR 0.53, P = .015).

“Lisinopril has the most important effect regarding preventing decrease of LVEF below 50%. When we look at the curves of LVEF drops above 10%, carvedilol seems to have a slightly bigger effect,” she said.

The trial was cosponsored by the SunCoast Community Clinical Oncology Programs Research Base at University of South Florida, Tampa, and by the National Cancer Institute. Dr. Munster disclosed leadership positions, stock ownership, and consulting or advisory roles with several companies. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

For women with HER2-positive early breast cancer treated with an anthracycline-based regimen followed by trastuzumab (Herceptin), concurrent therapy with the angiotensin-converting enzyme (ACE) inhibitor lisinopril can help to prevent a decline in left-ventricular ejection fraction (LVEF) below 50%, investigators in a community-based study found.

Among 424 women with HER2-positive early-stage breast cancer, the rate of LVEF decline to below 50% was 21.4% among patients randomized to receive an anthracycline-based regimen, compared with 4.1% for patients who were treated with a non–anthracycline-based regimen.

Among patients in the anthracycline arm, treatment with lisinopril, but not carvedilol or placebo, was associated with significant protection against LVEF decline, reported Pamela N. Munster, MD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“The findings of this study suggested that the drop in left ventricular ejection fraction to below 50% or to below normal was much larger than previously reported in the anthracycline group,” she said in a video presentation during a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 509).

Although HER2 inhibition is a highly effective treatment strategy for patients with HER2-positive tumors, trastuzumab-associated decline in LVEF and clinical heart failure can result in treatment interruption or discontinuation of therapy, the authors noted.

They conducted the prospective randomized trial to see whether trastuzumab-associated cardiotoxicity could be mitigated by concurrent use of either an ACE inhibitor or beta-blocker.

They enrolled women with early HER2-positive breast cancer from 127 community-based oncology centers.

The patients were randomly assigned to receive either an anthracycline- or non–anthracycline-containing regimen, followed by a year of trastuzumab, and were then randomized again to receive either lisinopril, carvedilol, or placebo concurrently with trastuzumab.

The patients were assessed for cardiotoxicity every 12 weeks with a multiple-gated acquisition (MUGA) scan and echocardiogram. Cardiotoxicity was defined as an absolute decrease in LVEF of 10% or more, or at least 5% decrease in LVEF below 50% at baseline.
 

Small LVEF declines in all

The investigators observed that all patients in the study experienced a small but not clinically relevant decrease in LVEF during trastuzumab therapy, and that this decline was not significantly ameliorated by any of the interventions.

However, as noted before, among patients assigned to anthracycline-based regimens the rate of decline to LVEF below 50% was 21.4%, compared with 4.1 for patients assigned to non–anthracycline regimens.

LVEF declines of at least 10% occurred in 5.5% of patients who received anthracyclines, and in 14.4% of those who received a non-anthracycline regimen.

Among patients who received anthracycline, only 10.8% randomized to receive lisinopril prophylaxis experienced a decline in LVEF, compared with 30.5% assigned to placebo (P = .045).

“In contrast, while carvedilol showed a numerical prevention of LVEF below 50% to 22.8%, this was not statistically significant,” Dr. Munster said.

Decreases in LVEF of 10% or greater within the normal LVEF range were similar in both chemotherapy arms and were not affected by either lisinopril or carvedilol.

“Lisinopril was well tolerated in this group, even in patients without hypertension,” she said.

“In women treated in a community-based environment who could benefit from anthracyclines or where anthracyclines are indicated, one should anticipate the decrease in left ventricular ejection fraction to below normal to be larger than is reported by other groups. However, this could be prevented by lisinopril,” she concluded.
 

Low numbers overall

Invited discussant Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, noted that the overall number of cardiotoxicity events and the rate of important decreases in LVEF were comparatively low.

She also pointed out that the findings are in line with another recent analysis of the same cohort by the same authors, although in the earlier analysis the investigators found that the effect on cardiotoxicity-free survival was good with both agents compared with placebo, but slightly better with carvedilol (hazard ratio 0.49, P = .009) than with lisinopril (HR 0.53, P = .015).

“Lisinopril has the most important effect regarding preventing decrease of LVEF below 50%. When we look at the curves of LVEF drops above 10%, carvedilol seems to have a slightly bigger effect,” she said.

The trial was cosponsored by the SunCoast Community Clinical Oncology Programs Research Base at University of South Florida, Tampa, and by the National Cancer Institute. Dr. Munster disclosed leadership positions, stock ownership, and consulting or advisory roles with several companies. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

Reassuring news for women who receive a diagnosis of breast cancer during pregnancy: Pregnancy-induced alterations in the pharmacokinetics of chemotherapy do not appear to compromise outcomes for the mother.

That’s according to investigators who reviewed registry data on 662 pregnant women and 2,081 nonpregnant women with a diagnosis of breast cancer. After a median follow-up of 66 months, there were no significant differences in either disease-free survival (DFS) or overall survival (OS), and women who received more than 60% of their chemotherapy doses during pregnancy had survival comparable to that of nonpregnant women, reported Frédéric Amant, MD, PhD, of University Hospitals Leuven (Belgium).

“These results support initiation of chemotherapy for breast cancer during pregnancy where indicated for oncological reasons,” they reported in a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 515).

Although in general a diagnosis of breast cancer during pregnancy does not appear to affect the mother’s prognosis when standard therapy is used, “caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism, and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients,” the authors wrote.

To get a better picture of the prognosis for women diagnosed with breast cancer during pregnancy, the investigators created a cohort of patients from two multicenter registries: the International Network of Cancer, Infertility, and Pregnancy and the German Breast Group. Both registries collect data retrospectively and prospectively,

They used propensity scoring to smooth out differences in the baseline characteristics of pregnant women and nonpregnant controls.

The median age at diagnosis was 34 year for pregnant women, and 38 years for controls. Pregnant women were more likely than were controls to have stage II disease (60.1% vs. 56, 1%, P = .035), grade 3 tumors (74% vs. 62.2%, P < .001), hormone receptor–negative breast tumors (48.4% vs. 30%), and triple-negative breast cancer (38.9% vs. 26.9%, P < .001).

In Cox proportional hazard regression analysis controlling for age, stage, grade, hormone receptor status, HER2 status and histology, there were no significant differences between pregnant women and controls in either DFS (hazard ratio [HR] 1.02, P = .83) or OS (HR 1.08, P = .57).

As noted before, a subgroup analysis of 339 women who received more than 60% of their assigned chemotherapy doses during pregnancy also showed that survival was not significantly different from that of nonpregnant women (HR for DFS 0,71, P = .13; HR for OS 0.85, P = .39).
 

Termination does not benefit the mother

“Thanks to the important work of Dr. Amant in the INCIP [International Network on Cancer, Infertility, and Pregnancy] network and others around the world, we now have sufficient data to know that it’s safe to treat breast cancer during pregnancy, and that the prognosis of breast cancer during pregnancy is comparable to nonpregnant controls if we adjust for certain characteristics such as age and others,” said Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, the invited discussant.

­­“With this and other studies, we can come to the conclusion that pregnancy-induced alterations in the chemotherapy concentration due to altered pharmacokinetics does not seem to affect maternal prognosis, and therefore we should initiate treatment of breast cancer during wherever it’s indicated for oncological reasons, knowing that you can only use chemotherapy during the second or third trimester,” she said.

Dr. Cardoso emphasized that breast cancer during pregnancy is a rare situation requiring that treatment be given in a specialized center by an experienced multidisciplinary team, and that interrupting the pregnancy does not improve the mother’s prognosis.

“We have to spread the word to all health professionals who come across these women to stop advising them to immediately terminate pregnancy. For the children, the most important take-home message is avoid prematurely delivery,” she said.

Treatment for women with a diagnosis of breast cancer during pregnancy should be similar to that for nonpregnant women, with the exception of endocrine therapy and anti-HER2 agents, which should be withheld until after delivery, she added.

The study was supported by the European Research Council, Research Foundation Flanders, and Kom op tegen kanker (Stand Up to Cancer). Dr. Amant disclosed a consulting or advisory role for AstraZeneca and Clovis Oncology. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

Reassuring news for women who receive a diagnosis of breast cancer during pregnancy: Pregnancy-induced alterations in the pharmacokinetics of chemotherapy do not appear to compromise outcomes for the mother.

That’s according to investigators who reviewed registry data on 662 pregnant women and 2,081 nonpregnant women with a diagnosis of breast cancer. After a median follow-up of 66 months, there were no significant differences in either disease-free survival (DFS) or overall survival (OS), and women who received more than 60% of their chemotherapy doses during pregnancy had survival comparable to that of nonpregnant women, reported Frédéric Amant, MD, PhD, of University Hospitals Leuven (Belgium).

“These results support initiation of chemotherapy for breast cancer during pregnancy where indicated for oncological reasons,” they reported in a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 515).

Although in general a diagnosis of breast cancer during pregnancy does not appear to affect the mother’s prognosis when standard therapy is used, “caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism, and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients,” the authors wrote.

To get a better picture of the prognosis for women diagnosed with breast cancer during pregnancy, the investigators created a cohort of patients from two multicenter registries: the International Network of Cancer, Infertility, and Pregnancy and the German Breast Group. Both registries collect data retrospectively and prospectively,

They used propensity scoring to smooth out differences in the baseline characteristics of pregnant women and nonpregnant controls.

The median age at diagnosis was 34 year for pregnant women, and 38 years for controls. Pregnant women were more likely than were controls to have stage II disease (60.1% vs. 56, 1%, P = .035), grade 3 tumors (74% vs. 62.2%, P < .001), hormone receptor–negative breast tumors (48.4% vs. 30%), and triple-negative breast cancer (38.9% vs. 26.9%, P < .001).

In Cox proportional hazard regression analysis controlling for age, stage, grade, hormone receptor status, HER2 status and histology, there were no significant differences between pregnant women and controls in either DFS (hazard ratio [HR] 1.02, P = .83) or OS (HR 1.08, P = .57).

As noted before, a subgroup analysis of 339 women who received more than 60% of their assigned chemotherapy doses during pregnancy also showed that survival was not significantly different from that of nonpregnant women (HR for DFS 0,71, P = .13; HR for OS 0.85, P = .39).
 

Termination does not benefit the mother

“Thanks to the important work of Dr. Amant in the INCIP [International Network on Cancer, Infertility, and Pregnancy] network and others around the world, we now have sufficient data to know that it’s safe to treat breast cancer during pregnancy, and that the prognosis of breast cancer during pregnancy is comparable to nonpregnant controls if we adjust for certain characteristics such as age and others,” said Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, the invited discussant.

­­“With this and other studies, we can come to the conclusion that pregnancy-induced alterations in the chemotherapy concentration due to altered pharmacokinetics does not seem to affect maternal prognosis, and therefore we should initiate treatment of breast cancer during wherever it’s indicated for oncological reasons, knowing that you can only use chemotherapy during the second or third trimester,” she said.

Dr. Cardoso emphasized that breast cancer during pregnancy is a rare situation requiring that treatment be given in a specialized center by an experienced multidisciplinary team, and that interrupting the pregnancy does not improve the mother’s prognosis.

“We have to spread the word to all health professionals who come across these women to stop advising them to immediately terminate pregnancy. For the children, the most important take-home message is avoid prematurely delivery,” she said.

Treatment for women with a diagnosis of breast cancer during pregnancy should be similar to that for nonpregnant women, with the exception of endocrine therapy and anti-HER2 agents, which should be withheld until after delivery, she added.

The study was supported by the European Research Council, Research Foundation Flanders, and Kom op tegen kanker (Stand Up to Cancer). Dr. Amant disclosed a consulting or advisory role for AstraZeneca and Clovis Oncology. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

Reassuring news for women who receive a diagnosis of breast cancer during pregnancy: Pregnancy-induced alterations in the pharmacokinetics of chemotherapy do not appear to compromise outcomes for the mother.

That’s according to investigators who reviewed registry data on 662 pregnant women and 2,081 nonpregnant women with a diagnosis of breast cancer. After a median follow-up of 66 months, there were no significant differences in either disease-free survival (DFS) or overall survival (OS), and women who received more than 60% of their chemotherapy doses during pregnancy had survival comparable to that of nonpregnant women, reported Frédéric Amant, MD, PhD, of University Hospitals Leuven (Belgium).

“These results support initiation of chemotherapy for breast cancer during pregnancy where indicated for oncological reasons,” they reported in a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 515).

Although in general a diagnosis of breast cancer during pregnancy does not appear to affect the mother’s prognosis when standard therapy is used, “caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism, and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients,” the authors wrote.

To get a better picture of the prognosis for women diagnosed with breast cancer during pregnancy, the investigators created a cohort of patients from two multicenter registries: the International Network of Cancer, Infertility, and Pregnancy and the German Breast Group. Both registries collect data retrospectively and prospectively,

They used propensity scoring to smooth out differences in the baseline characteristics of pregnant women and nonpregnant controls.

The median age at diagnosis was 34 year for pregnant women, and 38 years for controls. Pregnant women were more likely than were controls to have stage II disease (60.1% vs. 56, 1%, P = .035), grade 3 tumors (74% vs. 62.2%, P < .001), hormone receptor–negative breast tumors (48.4% vs. 30%), and triple-negative breast cancer (38.9% vs. 26.9%, P < .001).

In Cox proportional hazard regression analysis controlling for age, stage, grade, hormone receptor status, HER2 status and histology, there were no significant differences between pregnant women and controls in either DFS (hazard ratio [HR] 1.02, P = .83) or OS (HR 1.08, P = .57).

As noted before, a subgroup analysis of 339 women who received more than 60% of their assigned chemotherapy doses during pregnancy also showed that survival was not significantly different from that of nonpregnant women (HR for DFS 0,71, P = .13; HR for OS 0.85, P = .39).
 

Termination does not benefit the mother

“Thanks to the important work of Dr. Amant in the INCIP [International Network on Cancer, Infertility, and Pregnancy] network and others around the world, we now have sufficient data to know that it’s safe to treat breast cancer during pregnancy, and that the prognosis of breast cancer during pregnancy is comparable to nonpregnant controls if we adjust for certain characteristics such as age and others,” said Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, the invited discussant.

­­“With this and other studies, we can come to the conclusion that pregnancy-induced alterations in the chemotherapy concentration due to altered pharmacokinetics does not seem to affect maternal prognosis, and therefore we should initiate treatment of breast cancer during wherever it’s indicated for oncological reasons, knowing that you can only use chemotherapy during the second or third trimester,” she said.

Dr. Cardoso emphasized that breast cancer during pregnancy is a rare situation requiring that treatment be given in a specialized center by an experienced multidisciplinary team, and that interrupting the pregnancy does not improve the mother’s prognosis.

“We have to spread the word to all health professionals who come across these women to stop advising them to immediately terminate pregnancy. For the children, the most important take-home message is avoid prematurely delivery,” she said.

Treatment for women with a diagnosis of breast cancer during pregnancy should be similar to that for nonpregnant women, with the exception of endocrine therapy and anti-HER2 agents, which should be withheld until after delivery, she added.

The study was supported by the European Research Council, Research Foundation Flanders, and Kom op tegen kanker (Stand Up to Cancer). Dr. Amant disclosed a consulting or advisory role for AstraZeneca and Clovis Oncology. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.