Roxanne Nelson

Investigational agent fruquintinib holds promise as a third- or fourth-line treatment option for patients with advanced non–small-cell lung cancer (NSCLC), according to new findings published in the Journal of Clinical Oncology.

The median progression free survival (PFS) as evaluated by a blinded image central review committee and the study’s primary endpoint, was more than threefold higher than observed with placebo; 3.8 months (95% confidence interval, 2.8 to 4.6 months) with fruquintinib versus 1.1 months (95% CI, 1.0 to 1.9 months) with placebo (stratified HR was 0.34 (95% CI,0.20 to 0.57; P less than .001). PFS assessed by investigators was nearly identical.

Median overall survival, however, was numerically longer for patients in the placebo arm versus the fruquintinib arm (7.7 and 9.7 months in the fruquintinib and placebo groups; stratified HR, 0.70; 95% CI, 0.43 to 1.15; P = .152). The authors point out that overall survival is a secondary endpoint and the study was insufficiently powered to assess differences in overall survival.

“In patients with NSCLC who experienced treatment failure with two standard chemotherapies, fruquintinib may provide a clinically meaningful benefit, and further evidence of a statistically significant OS benefit of fruquintinib is expected from a phase 3 randomized study in this target population,” wrote Dr. Shun Lu of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Jiao Tong University, Shanghai, China, and colleagues.

Fruquintinib is a highly selective inhibitor of VEGFR-1, -2 and -3 kinases, and showed promising activity against solid tumors, including NSCLC, in a phase 1 trial. The current phase 2 trial evaluated the efficacy and safety of single-agent fruquintinib in 91 patients with advanced nonsquamous NSCLC. All patients had experienced disease progression after two lines of standard chemotherapy, and were randomly assigned to be treated with either fruquintinib (n = 61) or placebo (n = 30).

At data cutoff for PFS analysis, a total of 46 patients (75.4%) in the fruquintinib group and 25 (83.3%) in the placebo group had experienced a PFS event. The median follow-up for survival was 28.0 months for fruquintinib and 25.4 months for the placebo group.

Both the 3- and 6-month survival rates were numerically higher for patients receiving fruquintinib group versus placebo (90.2% vs. 73.3% for 3-month survival and 67.2% vs. 58.8% for 6-month survival).

The results for other secondary endpoints showed a more favorable overall response rate for fruquintinib vs placebo (13.1% vs 0%; P = .041), as was the disease control rate (60.7% vs 13.3%; P less than .001).

Subgroup analyses favored PFS with fruquintinib, as it was significantly longer vs. placebo for all patient subsets except for those with brain metastases. The median overall survival also was numerically greater with fruquintinib among patients positive for EGFR mutations (8.4 vs. 5.5 months; HR, 0.58; 95% CI, 0.30-1.141 P =.11).

Treatment emergent adverse events were higher in the fruquintinib arm (100% vs. 90%), but most of these were grade 1/2 in both groups. The most common grade 3 and higher events observed with fruquintinib were hypertension (8.2%), hand-foot syndrome (4.9%), and proteinuria (4.9%).

SOURCE: Lu S. et al. J Clin Oncol. 2018 Mar. 12 doi: 10.1200/JCO.2017.76.7145.

Investigational agent fruquintinib holds promise as a third- or fourth-line treatment option for patients with advanced non–small-cell lung cancer (NSCLC), according to new findings published in the Journal of Clinical Oncology.

The median progression free survival (PFS) as evaluated by a blinded image central review committee and the study’s primary endpoint, was more than threefold higher than observed with placebo; 3.8 months (95% confidence interval, 2.8 to 4.6 months) with fruquintinib versus 1.1 months (95% CI, 1.0 to 1.9 months) with placebo (stratified HR was 0.34 (95% CI,0.20 to 0.57; P less than .001). PFS assessed by investigators was nearly identical.

Median overall survival, however, was numerically longer for patients in the placebo arm versus the fruquintinib arm (7.7 and 9.7 months in the fruquintinib and placebo groups; stratified HR, 0.70; 95% CI, 0.43 to 1.15; P = .152). The authors point out that overall survival is a secondary endpoint and the study was insufficiently powered to assess differences in overall survival.

“In patients with NSCLC who experienced treatment failure with two standard chemotherapies, fruquintinib may provide a clinically meaningful benefit, and further evidence of a statistically significant OS benefit of fruquintinib is expected from a phase 3 randomized study in this target population,” wrote Dr. Shun Lu of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Jiao Tong University, Shanghai, China, and colleagues.

Fruquintinib is a highly selective inhibitor of VEGFR-1, -2 and -3 kinases, and showed promising activity against solid tumors, including NSCLC, in a phase 1 trial. The current phase 2 trial evaluated the efficacy and safety of single-agent fruquintinib in 91 patients with advanced nonsquamous NSCLC. All patients had experienced disease progression after two lines of standard chemotherapy, and were randomly assigned to be treated with either fruquintinib (n = 61) or placebo (n = 30).

At data cutoff for PFS analysis, a total of 46 patients (75.4%) in the fruquintinib group and 25 (83.3%) in the placebo group had experienced a PFS event. The median follow-up for survival was 28.0 months for fruquintinib and 25.4 months for the placebo group.

Both the 3- and 6-month survival rates were numerically higher for patients receiving fruquintinib group versus placebo (90.2% vs. 73.3% for 3-month survival and 67.2% vs. 58.8% for 6-month survival).

The results for other secondary endpoints showed a more favorable overall response rate for fruquintinib vs placebo (13.1% vs 0%; P = .041), as was the disease control rate (60.7% vs 13.3%; P less than .001).

Subgroup analyses favored PFS with fruquintinib, as it was significantly longer vs. placebo for all patient subsets except for those with brain metastases. The median overall survival also was numerically greater with fruquintinib among patients positive for EGFR mutations (8.4 vs. 5.5 months; HR, 0.58; 95% CI, 0.30-1.141 P =.11).

Treatment emergent adverse events were higher in the fruquintinib arm (100% vs. 90%), but most of these were grade 1/2 in both groups. The most common grade 3 and higher events observed with fruquintinib were hypertension (8.2%), hand-foot syndrome (4.9%), and proteinuria (4.9%).

SOURCE: Lu S. et al. J Clin Oncol. 2018 Mar. 12 doi: 10.1200/JCO.2017.76.7145.

Investigational agent fruquintinib holds promise as a third- or fourth-line treatment option for patients with advanced non–small-cell lung cancer (NSCLC), according to new findings published in the Journal of Clinical Oncology.

The median progression free survival (PFS) as evaluated by a blinded image central review committee and the study’s primary endpoint, was more than threefold higher than observed with placebo; 3.8 months (95% confidence interval, 2.8 to 4.6 months) with fruquintinib versus 1.1 months (95% CI, 1.0 to 1.9 months) with placebo (stratified HR was 0.34 (95% CI,0.20 to 0.57; P less than .001). PFS assessed by investigators was nearly identical.

Median overall survival, however, was numerically longer for patients in the placebo arm versus the fruquintinib arm (7.7 and 9.7 months in the fruquintinib and placebo groups; stratified HR, 0.70; 95% CI, 0.43 to 1.15; P = .152). The authors point out that overall survival is a secondary endpoint and the study was insufficiently powered to assess differences in overall survival.

“In patients with NSCLC who experienced treatment failure with two standard chemotherapies, fruquintinib may provide a clinically meaningful benefit, and further evidence of a statistically significant OS benefit of fruquintinib is expected from a phase 3 randomized study in this target population,” wrote Dr. Shun Lu of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Jiao Tong University, Shanghai, China, and colleagues.

Fruquintinib is a highly selective inhibitor of VEGFR-1, -2 and -3 kinases, and showed promising activity against solid tumors, including NSCLC, in a phase 1 trial. The current phase 2 trial evaluated the efficacy and safety of single-agent fruquintinib in 91 patients with advanced nonsquamous NSCLC. All patients had experienced disease progression after two lines of standard chemotherapy, and were randomly assigned to be treated with either fruquintinib (n = 61) or placebo (n = 30).

At data cutoff for PFS analysis, a total of 46 patients (75.4%) in the fruquintinib group and 25 (83.3%) in the placebo group had experienced a PFS event. The median follow-up for survival was 28.0 months for fruquintinib and 25.4 months for the placebo group.

Both the 3- and 6-month survival rates were numerically higher for patients receiving fruquintinib group versus placebo (90.2% vs. 73.3% for 3-month survival and 67.2% vs. 58.8% for 6-month survival).

The results for other secondary endpoints showed a more favorable overall response rate for fruquintinib vs placebo (13.1% vs 0%; P = .041), as was the disease control rate (60.7% vs 13.3%; P less than .001).

Subgroup analyses favored PFS with fruquintinib, as it was significantly longer vs. placebo for all patient subsets except for those with brain metastases. The median overall survival also was numerically greater with fruquintinib among patients positive for EGFR mutations (8.4 vs. 5.5 months; HR, 0.58; 95% CI, 0.30-1.141 P =.11).

Treatment emergent adverse events were higher in the fruquintinib arm (100% vs. 90%), but most of these were grade 1/2 in both groups. The most common grade 3 and higher events observed with fruquintinib were hypertension (8.2%), hand-foot syndrome (4.9%), and proteinuria (4.9%).

SOURCE: Lu S. et al. J Clin Oncol. 2018 Mar. 12 doi: 10.1200/JCO.2017.76.7145.

When a standardized radiologic threshold of greater than 50% is used, patients with unifocal cystic renal cell carcinoma (cRCC) have an excellent prognosis with active surveillance and following surgical resection, findings from a new study show.

At a median follow-up of 5.4 years (IQR 2.8-7.8), none of the 138 patients in the cohort experienced a tumor recurrence or metastasis from cRCC, and 7 (5.1%) died from non–renal-related causes. When comparing patients who initially underwent surgery to those who were initially managed with active surveillance, the researchers found that there was no significant difference in overall survival (P = .07). There were no deaths due to kidney cancer in the entire cohort.

The terminology of cRCC has historically been used to describe an indolent version of RCC that consists primarily of cysts, and the threshold of cystic involvement has traditionally been greater than 75% cystic on pathologic examination.

However, this classification does not contribute to the preoperative decision-making process, the study authors noted in Journal of Urology.

“Cross-sectional imaging provides the benefit of assessing tumor morphology without surgical manipulation, allowing for an accurate assessment of the solid and cystic components and classification of cRCC ,” write Ari Hakimi, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.

Studies evaluating radiologic criteria for cRCC diagnosis have suggested that cystic changes in 5%-45% of the total mass observed on imaging are associated with favorable survival. Thus, the authors sought to improve the preoperative assessment of cystic renal masses by evaluating cRCC as an enhancing renal lesion that is greater than 50% cystic on cross-sectional imaging. The goal of the current study was then to compare the long-term outcomes of patients with cRCC who underwent surgery and active surveillance using this hypothesized threshold.

The cohort included 138 patients who underwent surgery at Memorial Sloan Kettering Cancer Center for a renal mass from January 2000 to December 2015, and of this group, 102 (73.9%) had renal cell carcinoma and 36 (26.1%) had benign masses. Most of the tumors were Fuhrman grade 1-2 (77.5%), ≤pT2 stage (83.4%) and clear cell histology (65.9%), while the majority of cRCC lesions were Bosniak 3 and 4 (93.5%) and had a solid component of less than 25% (83.3%). On multivariate analysis, men (P = .007) were more likely to have malignant lesions and Bosniak 3 lesions were more likely to be malignant (P = .01).

In the subgroup of 38 active surveillance patients, 27 (71.1%) remained on active surveillance while 11 (28.9%) subsequently had surgery, of which all underwent partial nephrectomy. The median overall growth rate for lesions was 1.0 mm/year (IQR 0-2.8) over 25.3 months (IQR 16.3-44.8), and no evidence of recurrence or metastasis was reported in any of these patients at a median follow-up of 4.3 years (IQR 2.1-5.7) from first imaging diagnosis or 6.9 years (IQR 4.9-8.5) after surgery.

“We believe that our radiologic definition allows for more inclusive criteria of cRCC and would encourage kidney sparing approaches or implementation of AS protocols when feasible,” the authors concluded.

SOURCE: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087

When a standardized radiologic threshold of greater than 50% is used, patients with unifocal cystic renal cell carcinoma (cRCC) have an excellent prognosis with active surveillance and following surgical resection, findings from a new study show.

At a median follow-up of 5.4 years (IQR 2.8-7.8), none of the 138 patients in the cohort experienced a tumor recurrence or metastasis from cRCC, and 7 (5.1%) died from non–renal-related causes. When comparing patients who initially underwent surgery to those who were initially managed with active surveillance, the researchers found that there was no significant difference in overall survival (P = .07). There were no deaths due to kidney cancer in the entire cohort.

The terminology of cRCC has historically been used to describe an indolent version of RCC that consists primarily of cysts, and the threshold of cystic involvement has traditionally been greater than 75% cystic on pathologic examination.

However, this classification does not contribute to the preoperative decision-making process, the study authors noted in Journal of Urology.

“Cross-sectional imaging provides the benefit of assessing tumor morphology without surgical manipulation, allowing for an accurate assessment of the solid and cystic components and classification of cRCC ,” write Ari Hakimi, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.

Studies evaluating radiologic criteria for cRCC diagnosis have suggested that cystic changes in 5%-45% of the total mass observed on imaging are associated with favorable survival. Thus, the authors sought to improve the preoperative assessment of cystic renal masses by evaluating cRCC as an enhancing renal lesion that is greater than 50% cystic on cross-sectional imaging. The goal of the current study was then to compare the long-term outcomes of patients with cRCC who underwent surgery and active surveillance using this hypothesized threshold.

The cohort included 138 patients who underwent surgery at Memorial Sloan Kettering Cancer Center for a renal mass from January 2000 to December 2015, and of this group, 102 (73.9%) had renal cell carcinoma and 36 (26.1%) had benign masses. Most of the tumors were Fuhrman grade 1-2 (77.5%), ≤pT2 stage (83.4%) and clear cell histology (65.9%), while the majority of cRCC lesions were Bosniak 3 and 4 (93.5%) and had a solid component of less than 25% (83.3%). On multivariate analysis, men (P = .007) were more likely to have malignant lesions and Bosniak 3 lesions were more likely to be malignant (P = .01).

In the subgroup of 38 active surveillance patients, 27 (71.1%) remained on active surveillance while 11 (28.9%) subsequently had surgery, of which all underwent partial nephrectomy. The median overall growth rate for lesions was 1.0 mm/year (IQR 0-2.8) over 25.3 months (IQR 16.3-44.8), and no evidence of recurrence or metastasis was reported in any of these patients at a median follow-up of 4.3 years (IQR 2.1-5.7) from first imaging diagnosis or 6.9 years (IQR 4.9-8.5) after surgery.

“We believe that our radiologic definition allows for more inclusive criteria of cRCC and would encourage kidney sparing approaches or implementation of AS protocols when feasible,” the authors concluded.

SOURCE: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087

When a standardized radiologic threshold of greater than 50% is used, patients with unifocal cystic renal cell carcinoma (cRCC) have an excellent prognosis with active surveillance and following surgical resection, findings from a new study show.

At a median follow-up of 5.4 years (IQR 2.8-7.8), none of the 138 patients in the cohort experienced a tumor recurrence or metastasis from cRCC, and 7 (5.1%) died from non–renal-related causes. When comparing patients who initially underwent surgery to those who were initially managed with active surveillance, the researchers found that there was no significant difference in overall survival (P = .07). There were no deaths due to kidney cancer in the entire cohort.

The terminology of cRCC has historically been used to describe an indolent version of RCC that consists primarily of cysts, and the threshold of cystic involvement has traditionally been greater than 75% cystic on pathologic examination.

However, this classification does not contribute to the preoperative decision-making process, the study authors noted in Journal of Urology.

“Cross-sectional imaging provides the benefit of assessing tumor morphology without surgical manipulation, allowing for an accurate assessment of the solid and cystic components and classification of cRCC ,” write Ari Hakimi, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.

Studies evaluating radiologic criteria for cRCC diagnosis have suggested that cystic changes in 5%-45% of the total mass observed on imaging are associated with favorable survival. Thus, the authors sought to improve the preoperative assessment of cystic renal masses by evaluating cRCC as an enhancing renal lesion that is greater than 50% cystic on cross-sectional imaging. The goal of the current study was then to compare the long-term outcomes of patients with cRCC who underwent surgery and active surveillance using this hypothesized threshold.

The cohort included 138 patients who underwent surgery at Memorial Sloan Kettering Cancer Center for a renal mass from January 2000 to December 2015, and of this group, 102 (73.9%) had renal cell carcinoma and 36 (26.1%) had benign masses. Most of the tumors were Fuhrman grade 1-2 (77.5%), ≤pT2 stage (83.4%) and clear cell histology (65.9%), while the majority of cRCC lesions were Bosniak 3 and 4 (93.5%) and had a solid component of less than 25% (83.3%). On multivariate analysis, men (P = .007) were more likely to have malignant lesions and Bosniak 3 lesions were more likely to be malignant (P = .01).

In the subgroup of 38 active surveillance patients, 27 (71.1%) remained on active surveillance while 11 (28.9%) subsequently had surgery, of which all underwent partial nephrectomy. The median overall growth rate for lesions was 1.0 mm/year (IQR 0-2.8) over 25.3 months (IQR 16.3-44.8), and no evidence of recurrence or metastasis was reported in any of these patients at a median follow-up of 4.3 years (IQR 2.1-5.7) from first imaging diagnosis or 6.9 years (IQR 4.9-8.5) after surgery.

“We believe that our radiologic definition allows for more inclusive criteria of cRCC and would encourage kidney sparing approaches or implementation of AS protocols when feasible,” the authors concluded.

SOURCE: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087

SAN DIEGO – Spray-dried plasma compared well with fresh frozen plasma in two in vitro studies, but clinical studies are needed to confirm the findings, researchers reported at the annual meeting of the American Association of Blood Banks.

The product’s logistical benefits include ease of transport, stability at room temperature, and the ability to be rapidly reconstituted – attributes that make it particularly useful in combat situations and prehospital settings where it is impractical to administer fresh frozen plasma (FFP).

The advantages of reconstituted blood products in combat settings have prompted recent efforts to speed their availability. The Food and Drug Administration and the Department of Defense recently announced a joint program to expedite the FDA’s review of products that could diagnose, treat, or prevent life-threatening conditions facing U.S. military personnel. It would be a fast-track process similar to how the FDA handles the breakthrough designation program.

In the first study, the investigators compared spray-dried plasma (SpDP) and FFP in reconstituted whole blood to test their hypothesis that SpDP is not inferior to FFP in facilitating platelet adhesion and thrombus formation, as evaluated by using a microfusion assay.

“Trauma is frequently associated with the use of plasma,” said Rachel S. Bercovitz, MD, MS, of the BloodCenter of Wisconsin and associate professor of pediatrics (hematology, oncology, and stem cell transplantation) at Northwestern University, Chicago.

Compared with FFP, SpDP can be reconstituted in 5 minutes and has more than 80% of the procoagulation and anticoagulation proteins, she explained. “Factor 8 levels were lower in the spray-dried plasma and were about at the 70% level of FFP. The other factor that was reduced, as compared to the FFP, was the von Willebrand factor (vWF), which was about 60% in SpDP compared to FFP.”

Whole blood was obtained from healthy volunteers and red blood cells (RBCs) were separated from platelet-rich plasma, and following standard procedures, resuspended in either SpDP or FFP and recombined with the packed red blood cells to create reconstituted whole blood with hematocrit of 34%-40% and 150,000-250,000 platelets per mcL.

After fluorescent labeling, the samples were flowed through a type I collagen-coated microchannel and still images of adherent platelets and thrombi were captured in order to calculate surface area coverage along the length of the channel. Next, the investigators used a ratio paired t-test to compare surface area coverage in SpDP versus FFP. The margin of noninferiority was 20% (SpDP/FFP greater than 0.8).

A total of six batches of SpDP and FFP were evaluated with 17 donors, and there was no statistical difference between the SpDP versus FFP pairs (P = .7558).

The mean ratio of SpDP versus FFP was 1.21 with a 95% confidence interval of 0.84-1.57. The surface area coverage in samples that were reconstituted with SpDP were, on average, 20% greater than in samples reconstituted with FFP. The lower limit of the 95% confidence interval was a difference of 16%, and therefore lower than the a priori determined margin of noninferiority of 20%.

“We found that SpDP is not inferior to FFP in supporting platelet adhesion and thrombus formation in our in vitro model,” Dr. Bercovitz said. “We feel that these in vitro assays support further in vivo studies of safety and efficacy of spray dried plasma.”

In a second study, Michael A. Meledeo, PhD, of the U.S. Army Institute of Surgical Research (coagulation and blood research), and his colleagues examined methods of reconstituting SpDP. They noted that a single unit process has been developed that produces a long-lived and readily stored SpDP product, which decreased high-molecular-weight multimers of vWF but increased low-molecular-weight multimers. vWF is critical in the process of platelet adhesion and thrombus formation, Dr. Meledeo said.

The researchers examined different reconstitution solutions: FFP, FFP with glycine, regular SpDP without pretreatment and rehydrated with glycine-hydrochloride:glycine, SpDP pretreated with glycine-HCl, or glycine-HCl:glycine and rehydrated with water.

Several in vitro analyses were performed, including measurement of vWF activity, fibrin polymerization kinetics, thrombin generation, coagulation properties and platelet adhesion to collagen.

Pretreated SpDP had better vWF activity, compared with regular SpDP (P less than .05). As compared with FFP, fibrin polymerization density was slightly lower in regular SpDP (0.879 vs. 0.742 optical density; P less than .01), although generation of thrombin was similar.

The researchers also found that the bicarbonate/base excess were lower in SpDP samples versus FFP (P less than .001). Thromboelastography results (used to measure coagulation properties) remained unchanged in plasma-only samples, but clot strength in reconstructed whole blood was reduced in all SpDP samples, compared with FFP (63.82 vs. 55-59.38; P less than .01).

Finally, platelet adhesion was equivalent in pretreated SpDP samples and FFP, while with regular SpDP, it was improved as compared with all other samples (71.53% surface coverage vs. 30.26%-43.87%; P less than .05).

“Based on these results, spray dried plasma was equivalent or superior to FFP in most of the in vitro hemostasis assays,” Dr. Meledeo said. “Reconstitution with glycine-HCl or glycine-HCl:glycine induced a superior von Willebrand function, but it was inferior in terms of supporting a flowing platelet adhesion to collagen.”

Dr. Bercovitz and Dr. Meledeo reported having no financial disclosures.

[email protected]

SOURCES: Bercovitz R et al. AABB 17 Abstract C20-A02B; Meledeo M et al. AABB 17 Abstract C21-A02B.

SAN DIEGO – Spray-dried plasma compared well with fresh frozen plasma in two in vitro studies, but clinical studies are needed to confirm the findings, researchers reported at the annual meeting of the American Association of Blood Banks.

The product’s logistical benefits include ease of transport, stability at room temperature, and the ability to be rapidly reconstituted – attributes that make it particularly useful in combat situations and prehospital settings where it is impractical to administer fresh frozen plasma (FFP).

The advantages of reconstituted blood products in combat settings have prompted recent efforts to speed their availability. The Food and Drug Administration and the Department of Defense recently announced a joint program to expedite the FDA’s review of products that could diagnose, treat, or prevent life-threatening conditions facing U.S. military personnel. It would be a fast-track process similar to how the FDA handles the breakthrough designation program.

In the first study, the investigators compared spray-dried plasma (SpDP) and FFP in reconstituted whole blood to test their hypothesis that SpDP is not inferior to FFP in facilitating platelet adhesion and thrombus formation, as evaluated by using a microfusion assay.

“Trauma is frequently associated with the use of plasma,” said Rachel S. Bercovitz, MD, MS, of the BloodCenter of Wisconsin and associate professor of pediatrics (hematology, oncology, and stem cell transplantation) at Northwestern University, Chicago.

Compared with FFP, SpDP can be reconstituted in 5 minutes and has more than 80% of the procoagulation and anticoagulation proteins, she explained. “Factor 8 levels were lower in the spray-dried plasma and were about at the 70% level of FFP. The other factor that was reduced, as compared to the FFP, was the von Willebrand factor (vWF), which was about 60% in SpDP compared to FFP.”

Whole blood was obtained from healthy volunteers and red blood cells (RBCs) were separated from platelet-rich plasma, and following standard procedures, resuspended in either SpDP or FFP and recombined with the packed red blood cells to create reconstituted whole blood with hematocrit of 34%-40% and 150,000-250,000 platelets per mcL.

After fluorescent labeling, the samples were flowed through a type I collagen-coated microchannel and still images of adherent platelets and thrombi were captured in order to calculate surface area coverage along the length of the channel. Next, the investigators used a ratio paired t-test to compare surface area coverage in SpDP versus FFP. The margin of noninferiority was 20% (SpDP/FFP greater than 0.8).

A total of six batches of SpDP and FFP were evaluated with 17 donors, and there was no statistical difference between the SpDP versus FFP pairs (P = .7558).

The mean ratio of SpDP versus FFP was 1.21 with a 95% confidence interval of 0.84-1.57. The surface area coverage in samples that were reconstituted with SpDP were, on average, 20% greater than in samples reconstituted with FFP. The lower limit of the 95% confidence interval was a difference of 16%, and therefore lower than the a priori determined margin of noninferiority of 20%.

“We found that SpDP is not inferior to FFP in supporting platelet adhesion and thrombus formation in our in vitro model,” Dr. Bercovitz said. “We feel that these in vitro assays support further in vivo studies of safety and efficacy of spray dried plasma.”

In a second study, Michael A. Meledeo, PhD, of the U.S. Army Institute of Surgical Research (coagulation and blood research), and his colleagues examined methods of reconstituting SpDP. They noted that a single unit process has been developed that produces a long-lived and readily stored SpDP product, which decreased high-molecular-weight multimers of vWF but increased low-molecular-weight multimers. vWF is critical in the process of platelet adhesion and thrombus formation, Dr. Meledeo said.

The researchers examined different reconstitution solutions: FFP, FFP with glycine, regular SpDP without pretreatment and rehydrated with glycine-hydrochloride:glycine, SpDP pretreated with glycine-HCl, or glycine-HCl:glycine and rehydrated with water.

Several in vitro analyses were performed, including measurement of vWF activity, fibrin polymerization kinetics, thrombin generation, coagulation properties and platelet adhesion to collagen.

Pretreated SpDP had better vWF activity, compared with regular SpDP (P less than .05). As compared with FFP, fibrin polymerization density was slightly lower in regular SpDP (0.879 vs. 0.742 optical density; P less than .01), although generation of thrombin was similar.

The researchers also found that the bicarbonate/base excess were lower in SpDP samples versus FFP (P less than .001). Thromboelastography results (used to measure coagulation properties) remained unchanged in plasma-only samples, but clot strength in reconstructed whole blood was reduced in all SpDP samples, compared with FFP (63.82 vs. 55-59.38; P less than .01).

Finally, platelet adhesion was equivalent in pretreated SpDP samples and FFP, while with regular SpDP, it was improved as compared with all other samples (71.53% surface coverage vs. 30.26%-43.87%; P less than .05).

“Based on these results, spray dried plasma was equivalent or superior to FFP in most of the in vitro hemostasis assays,” Dr. Meledeo said. “Reconstitution with glycine-HCl or glycine-HCl:glycine induced a superior von Willebrand function, but it was inferior in terms of supporting a flowing platelet adhesion to collagen.”

Dr. Bercovitz and Dr. Meledeo reported having no financial disclosures.

[email protected]

SOURCES: Bercovitz R et al. AABB 17 Abstract C20-A02B; Meledeo M et al. AABB 17 Abstract C21-A02B.

SAN DIEGO – Spray-dried plasma compared well with fresh frozen plasma in two in vitro studies, but clinical studies are needed to confirm the findings, researchers reported at the annual meeting of the American Association of Blood Banks.

The product’s logistical benefits include ease of transport, stability at room temperature, and the ability to be rapidly reconstituted – attributes that make it particularly useful in combat situations and prehospital settings where it is impractical to administer fresh frozen plasma (FFP).

The advantages of reconstituted blood products in combat settings have prompted recent efforts to speed their availability. The Food and Drug Administration and the Department of Defense recently announced a joint program to expedite the FDA’s review of products that could diagnose, treat, or prevent life-threatening conditions facing U.S. military personnel. It would be a fast-track process similar to how the FDA handles the breakthrough designation program.

In the first study, the investigators compared spray-dried plasma (SpDP) and FFP in reconstituted whole blood to test their hypothesis that SpDP is not inferior to FFP in facilitating platelet adhesion and thrombus formation, as evaluated by using a microfusion assay.

“Trauma is frequently associated with the use of plasma,” said Rachel S. Bercovitz, MD, MS, of the BloodCenter of Wisconsin and associate professor of pediatrics (hematology, oncology, and stem cell transplantation) at Northwestern University, Chicago.

Compared with FFP, SpDP can be reconstituted in 5 minutes and has more than 80% of the procoagulation and anticoagulation proteins, she explained. “Factor 8 levels were lower in the spray-dried plasma and were about at the 70% level of FFP. The other factor that was reduced, as compared to the FFP, was the von Willebrand factor (vWF), which was about 60% in SpDP compared to FFP.”

Whole blood was obtained from healthy volunteers and red blood cells (RBCs) were separated from platelet-rich plasma, and following standard procedures, resuspended in either SpDP or FFP and recombined with the packed red blood cells to create reconstituted whole blood with hematocrit of 34%-40% and 150,000-250,000 platelets per mcL.

After fluorescent labeling, the samples were flowed through a type I collagen-coated microchannel and still images of adherent platelets and thrombi were captured in order to calculate surface area coverage along the length of the channel. Next, the investigators used a ratio paired t-test to compare surface area coverage in SpDP versus FFP. The margin of noninferiority was 20% (SpDP/FFP greater than 0.8).

A total of six batches of SpDP and FFP were evaluated with 17 donors, and there was no statistical difference between the SpDP versus FFP pairs (P = .7558).

The mean ratio of SpDP versus FFP was 1.21 with a 95% confidence interval of 0.84-1.57. The surface area coverage in samples that were reconstituted with SpDP were, on average, 20% greater than in samples reconstituted with FFP. The lower limit of the 95% confidence interval was a difference of 16%, and therefore lower than the a priori determined margin of noninferiority of 20%.

“We found that SpDP is not inferior to FFP in supporting platelet adhesion and thrombus formation in our in vitro model,” Dr. Bercovitz said. “We feel that these in vitro assays support further in vivo studies of safety and efficacy of spray dried plasma.”

In a second study, Michael A. Meledeo, PhD, of the U.S. Army Institute of Surgical Research (coagulation and blood research), and his colleagues examined methods of reconstituting SpDP. They noted that a single unit process has been developed that produces a long-lived and readily stored SpDP product, which decreased high-molecular-weight multimers of vWF but increased low-molecular-weight multimers. vWF is critical in the process of platelet adhesion and thrombus formation, Dr. Meledeo said.

The researchers examined different reconstitution solutions: FFP, FFP with glycine, regular SpDP without pretreatment and rehydrated with glycine-hydrochloride:glycine, SpDP pretreated with glycine-HCl, or glycine-HCl:glycine and rehydrated with water.

Several in vitro analyses were performed, including measurement of vWF activity, fibrin polymerization kinetics, thrombin generation, coagulation properties and platelet adhesion to collagen.

Pretreated SpDP had better vWF activity, compared with regular SpDP (P less than .05). As compared with FFP, fibrin polymerization density was slightly lower in regular SpDP (0.879 vs. 0.742 optical density; P less than .01), although generation of thrombin was similar.

The researchers also found that the bicarbonate/base excess were lower in SpDP samples versus FFP (P less than .001). Thromboelastography results (used to measure coagulation properties) remained unchanged in plasma-only samples, but clot strength in reconstructed whole blood was reduced in all SpDP samples, compared with FFP (63.82 vs. 55-59.38; P less than .01).

Finally, platelet adhesion was equivalent in pretreated SpDP samples and FFP, while with regular SpDP, it was improved as compared with all other samples (71.53% surface coverage vs. 30.26%-43.87%; P less than .05).

“Based on these results, spray dried plasma was equivalent or superior to FFP in most of the in vitro hemostasis assays,” Dr. Meledeo said. “Reconstitution with glycine-HCl or glycine-HCl:glycine induced a superior von Willebrand function, but it was inferior in terms of supporting a flowing platelet adhesion to collagen.”

Dr. Bercovitz and Dr. Meledeo reported having no financial disclosures.

[email protected]

SOURCES: Bercovitz R et al. AABB 17 Abstract C20-A02B; Meledeo M et al. AABB 17 Abstract C21-A02B.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

Carriers of the BRCA1/2 mutation who undergo risk-reducing salpingo-oophorectomy (RRSO) still face a risk of developing metachronous peritoneal carcinomatosis, according to new findings published in Cancer.

The risk was predominantly observed in BRCA1 mutation carriers, and disease development generally occurred within 5 years following RRSO. Women who underwent RRSO at an age older than that currently recommended also had a higher risk of developing peritoneal carcinoma.

Their median age was 52 years at the time they underwent surgery, and 60 years when they were diagnosed with peritoneal carcinomatosis. As compared with the control group, the patients were older at the time they underwent RRSO (P = .025).

In eight RRSO specimens that were obtained from women who subsequently developed peritoneal carcinomatosis, five (62.5%), had serous tubal intraepithelial carcinoma (STIC) and one had epithelial atypia.

“The findings of the current study can be used to refine gynecologic counseling for BRCA1/2 mutation carriers who consider risk-reducing surgery and to stress the importance of complete RRSO at the recommended ages,” wrote lead author Marline G. Harmsen, MD, PhD, of the Radboud University Medical Center, Nijmegen, the Netherlands.

BRCA1/2 mutation carriers face a higher risk of developing ovarian carcinoma, and RRSO can reduce that risk by 80%-96%. Surgery is recommended for carriers of BRCA1 mutations aged 35-40 years and for BRCA2 mutation carriers aged 40-45 years.

In this study, Dr. Harmsen and her colleagues conducted a literature search in order to collect and analyze clinical and pathological data from women with BRCA1/2 mutation who developed peritoneal carcinomatosis following RRSO. The cases that were identified were then compared with a cohort from a single institution.

Of the 36 cases that were identified, 86.1% were BRCA1 mutation carriers and the remaining 5 patients had a BRCA2 mutation. The median age at the time of surgery differed significantly between BRCA1 (51 years; range, 30-71 years) and BRCA2 mutation carriers (57 years; range, 56-65 years) (P = .006).

The majority of women had undergone salpingo-oophorectomy (31; 86.1%), and 16 (44.4%) had also had a hysterectomy.

The authors found that several statistically significant differences between the case studies and the control group: the median age surgery (52 vs. 46 years), percentage of BRCA1 mutation carriers (86.1% vs. 53.1%, P less than .001), and percentage of serous tubal intraepithelial carcinomas in the RRSO specimens (62.5% vs. 0%; P less than .001).

SOURCE: Hamsen MG et al. Cancer. 2018 Jan 9. doi: 10.1002/cncr.31211.

[email protected]

Carriers of the BRCA1/2 mutation who undergo risk-reducing salpingo-oophorectomy (RRSO) still face a risk of developing metachronous peritoneal carcinomatosis, according to new findings published in Cancer.

The risk was predominantly observed in BRCA1 mutation carriers, and disease development generally occurred within 5 years following RRSO. Women who underwent RRSO at an age older than that currently recommended also had a higher risk of developing peritoneal carcinoma.

Their median age was 52 years at the time they underwent surgery, and 60 years when they were diagnosed with peritoneal carcinomatosis. As compared with the control group, the patients were older at the time they underwent RRSO (P = .025).

In eight RRSO specimens that were obtained from women who subsequently developed peritoneal carcinomatosis, five (62.5%), had serous tubal intraepithelial carcinoma (STIC) and one had epithelial atypia.

“The findings of the current study can be used to refine gynecologic counseling for BRCA1/2 mutation carriers who consider risk-reducing surgery and to stress the importance of complete RRSO at the recommended ages,” wrote lead author Marline G. Harmsen, MD, PhD, of the Radboud University Medical Center, Nijmegen, the Netherlands.

BRCA1/2 mutation carriers face a higher risk of developing ovarian carcinoma, and RRSO can reduce that risk by 80%-96%. Surgery is recommended for carriers of BRCA1 mutations aged 35-40 years and for BRCA2 mutation carriers aged 40-45 years.

In this study, Dr. Harmsen and her colleagues conducted a literature search in order to collect and analyze clinical and pathological data from women with BRCA1/2 mutation who developed peritoneal carcinomatosis following RRSO. The cases that were identified were then compared with a cohort from a single institution.

Of the 36 cases that were identified, 86.1% were BRCA1 mutation carriers and the remaining 5 patients had a BRCA2 mutation. The median age at the time of surgery differed significantly between BRCA1 (51 years; range, 30-71 years) and BRCA2 mutation carriers (57 years; range, 56-65 years) (P = .006).

The majority of women had undergone salpingo-oophorectomy (31; 86.1%), and 16 (44.4%) had also had a hysterectomy.

The authors found that several statistically significant differences between the case studies and the control group: the median age surgery (52 vs. 46 years), percentage of BRCA1 mutation carriers (86.1% vs. 53.1%, P less than .001), and percentage of serous tubal intraepithelial carcinomas in the RRSO specimens (62.5% vs. 0%; P less than .001).

SOURCE: Hamsen MG et al. Cancer. 2018 Jan 9. doi: 10.1002/cncr.31211.

[email protected]

Carriers of the BRCA1/2 mutation who undergo risk-reducing salpingo-oophorectomy (RRSO) still face a risk of developing metachronous peritoneal carcinomatosis, according to new findings published in Cancer.

The risk was predominantly observed in BRCA1 mutation carriers, and disease development generally occurred within 5 years following RRSO. Women who underwent RRSO at an age older than that currently recommended also had a higher risk of developing peritoneal carcinoma.

Their median age was 52 years at the time they underwent surgery, and 60 years when they were diagnosed with peritoneal carcinomatosis. As compared with the control group, the patients were older at the time they underwent RRSO (P = .025).

In eight RRSO specimens that were obtained from women who subsequently developed peritoneal carcinomatosis, five (62.5%), had serous tubal intraepithelial carcinoma (STIC) and one had epithelial atypia.

“The findings of the current study can be used to refine gynecologic counseling for BRCA1/2 mutation carriers who consider risk-reducing surgery and to stress the importance of complete RRSO at the recommended ages,” wrote lead author Marline G. Harmsen, MD, PhD, of the Radboud University Medical Center, Nijmegen, the Netherlands.

BRCA1/2 mutation carriers face a higher risk of developing ovarian carcinoma, and RRSO can reduce that risk by 80%-96%. Surgery is recommended for carriers of BRCA1 mutations aged 35-40 years and for BRCA2 mutation carriers aged 40-45 years.

In this study, Dr. Harmsen and her colleagues conducted a literature search in order to collect and analyze clinical and pathological data from women with BRCA1/2 mutation who developed peritoneal carcinomatosis following RRSO. The cases that were identified were then compared with a cohort from a single institution.

Of the 36 cases that were identified, 86.1% were BRCA1 mutation carriers and the remaining 5 patients had a BRCA2 mutation. The median age at the time of surgery differed significantly between BRCA1 (51 years; range, 30-71 years) and BRCA2 mutation carriers (57 years; range, 56-65 years) (P = .006).

The majority of women had undergone salpingo-oophorectomy (31; 86.1%), and 16 (44.4%) had also had a hysterectomy.

The authors found that several statistically significant differences between the case studies and the control group: the median age surgery (52 vs. 46 years), percentage of BRCA1 mutation carriers (86.1% vs. 53.1%, P less than .001), and percentage of serous tubal intraepithelial carcinomas in the RRSO specimens (62.5% vs. 0%; P less than .001).

SOURCE: Hamsen MG et al. Cancer. 2018 Jan 9. doi: 10.1002/cncr.31211.

[email protected]

Undergoing a second allogeneic bone or marrow transplant (BMT) is a feasible strategy for patients who have relapsed after their first transplantation, according to findings reported in Biology of Blood and Marrow Transplantation.

Specifically, there may be an advantage to selecting a donor with a new mismatched haplotype after a failed HLA-matched allograft. Among patients who had a second graft transplanted that did not harbor a new mismatched haplotype, median survival was 552 days (95% CI, 376-2,950+). But median survival was not reached in the cohort whose allograft contained a new mismatched haplotype (hazard ratio, 0.36; 95% confidence interval, 0.14-0.9; P = .02).

“In the case of a failed HLA-matched transplantation, when haplotype loss would not be favored through selective pressure and thus would not provide a mechanism of relapse, switching to a different haploidentical donor may be beneficial by increasing major histocompatibility mismatch,” Philip H. Imus, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and colleagues wrote.

For this retrospective review, the researchers examined 40 consecutive patients who underwent a second BMT for a relapsed hematologic malignancy at a single institution between 2005 and 2014. In all, 21 patients had their first allograft from a haploidentical donor, with 14 of these patients receiving a second haploidentical transplant (8 from a donor sharing the same shared haplotype as the first donor and 6 from a second donor sharing the other haplotype).

The other 19 patients received their first allograft from a fully matched donor, with 14 patients receiving a haploidentical allograft at the second transplantation and 5 receiving a second matched allograft. Overall, a total of 20 patients had a second allograft with a new mismatched haplotype.

The median overall survival for the six patients who were retransplantated with an HLA-haploidentical donor sharing the different haplotype from the first haploidentical donor had not been reached, compared with 502 days (95% CI, 317-2,950+) for the eight patients with a second haplo allograft that shared the same haplotype (HR, 0.37; 95% CI, 0.08 to 1.7; P = .16).

The median event free survival was also superior among those retransplanted with a new mismatched haplotype (not reached vs. 401 days; HR, .50; 95% CI, .22-1.14, P = .09).

A higher risk of mortality was observed in patients who had relapsed within 6 months of their first transplantation (HR, 2.49; 95% CI, 1.0-6.2; P = .07), as well as in those who had progressive or refractory disease prior to their second alloBMT (HR, 2.56; 95% CI, 1.03-6.25; P = .06).

“For patients who relapse more than 6 months after a BMT and who achieve remission with salvage therapy, results are very encouraging,” the researchers wrote. “Although a randomized trial to study selecting donors with a new mismatched haplotype may be impractical, larger numbers should provide additional information on the effectiveness of such an approach.”

The researchers reported having no financial disclosures.

SOURCE: Imus P et al. Biol Blood Marrow Transplant. 2017;23:1887-94.

Undergoing a second allogeneic bone or marrow transplant (BMT) is a feasible strategy for patients who have relapsed after their first transplantation, according to findings reported in Biology of Blood and Marrow Transplantation.

Specifically, there may be an advantage to selecting a donor with a new mismatched haplotype after a failed HLA-matched allograft. Among patients who had a second graft transplanted that did not harbor a new mismatched haplotype, median survival was 552 days (95% CI, 376-2,950+). But median survival was not reached in the cohort whose allograft contained a new mismatched haplotype (hazard ratio, 0.36; 95% confidence interval, 0.14-0.9; P = .02).

“In the case of a failed HLA-matched transplantation, when haplotype loss would not be favored through selective pressure and thus would not provide a mechanism of relapse, switching to a different haploidentical donor may be beneficial by increasing major histocompatibility mismatch,” Philip H. Imus, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and colleagues wrote.

For this retrospective review, the researchers examined 40 consecutive patients who underwent a second BMT for a relapsed hematologic malignancy at a single institution between 2005 and 2014. In all, 21 patients had their first allograft from a haploidentical donor, with 14 of these patients receiving a second haploidentical transplant (8 from a donor sharing the same shared haplotype as the first donor and 6 from a second donor sharing the other haplotype).

The other 19 patients received their first allograft from a fully matched donor, with 14 patients receiving a haploidentical allograft at the second transplantation and 5 receiving a second matched allograft. Overall, a total of 20 patients had a second allograft with a new mismatched haplotype.

The median overall survival for the six patients who were retransplantated with an HLA-haploidentical donor sharing the different haplotype from the first haploidentical donor had not been reached, compared with 502 days (95% CI, 317-2,950+) for the eight patients with a second haplo allograft that shared the same haplotype (HR, 0.37; 95% CI, 0.08 to 1.7; P = .16).

The median event free survival was also superior among those retransplanted with a new mismatched haplotype (not reached vs. 401 days; HR, .50; 95% CI, .22-1.14, P = .09).

A higher risk of mortality was observed in patients who had relapsed within 6 months of their first transplantation (HR, 2.49; 95% CI, 1.0-6.2; P = .07), as well as in those who had progressive or refractory disease prior to their second alloBMT (HR, 2.56; 95% CI, 1.03-6.25; P = .06).

“For patients who relapse more than 6 months after a BMT and who achieve remission with salvage therapy, results are very encouraging,” the researchers wrote. “Although a randomized trial to study selecting donors with a new mismatched haplotype may be impractical, larger numbers should provide additional information on the effectiveness of such an approach.”

The researchers reported having no financial disclosures.

SOURCE: Imus P et al. Biol Blood Marrow Transplant. 2017;23:1887-94.

Undergoing a second allogeneic bone or marrow transplant (BMT) is a feasible strategy for patients who have relapsed after their first transplantation, according to findings reported in Biology of Blood and Marrow Transplantation.

Specifically, there may be an advantage to selecting a donor with a new mismatched haplotype after a failed HLA-matched allograft. Among patients who had a second graft transplanted that did not harbor a new mismatched haplotype, median survival was 552 days (95% CI, 376-2,950+). But median survival was not reached in the cohort whose allograft contained a new mismatched haplotype (hazard ratio, 0.36; 95% confidence interval, 0.14-0.9; P = .02).

“In the case of a failed HLA-matched transplantation, when haplotype loss would not be favored through selective pressure and thus would not provide a mechanism of relapse, switching to a different haploidentical donor may be beneficial by increasing major histocompatibility mismatch,” Philip H. Imus, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and colleagues wrote.

For this retrospective review, the researchers examined 40 consecutive patients who underwent a second BMT for a relapsed hematologic malignancy at a single institution between 2005 and 2014. In all, 21 patients had their first allograft from a haploidentical donor, with 14 of these patients receiving a second haploidentical transplant (8 from a donor sharing the same shared haplotype as the first donor and 6 from a second donor sharing the other haplotype).

The other 19 patients received their first allograft from a fully matched donor, with 14 patients receiving a haploidentical allograft at the second transplantation and 5 receiving a second matched allograft. Overall, a total of 20 patients had a second allograft with a new mismatched haplotype.

The median overall survival for the six patients who were retransplantated with an HLA-haploidentical donor sharing the different haplotype from the first haploidentical donor had not been reached, compared with 502 days (95% CI, 317-2,950+) for the eight patients with a second haplo allograft that shared the same haplotype (HR, 0.37; 95% CI, 0.08 to 1.7; P = .16).

The median event free survival was also superior among those retransplanted with a new mismatched haplotype (not reached vs. 401 days; HR, .50; 95% CI, .22-1.14, P = .09).

A higher risk of mortality was observed in patients who had relapsed within 6 months of their first transplantation (HR, 2.49; 95% CI, 1.0-6.2; P = .07), as well as in those who had progressive or refractory disease prior to their second alloBMT (HR, 2.56; 95% CI, 1.03-6.25; P = .06).

“For patients who relapse more than 6 months after a BMT and who achieve remission with salvage therapy, results are very encouraging,” the researchers wrote. “Although a randomized trial to study selecting donors with a new mismatched haplotype may be impractical, larger numbers should provide additional information on the effectiveness of such an approach.”

The researchers reported having no financial disclosures.

SOURCE: Imus P et al. Biol Blood Marrow Transplant. 2017;23:1887-94.

SAN ANTONIO – A margin width beyond ‘no tumor on ink’ may reduce local recurrence in certain subsets of patients undergoing breast-conserving treatment for early-stage breast cancer, according to findings from a meta-analysis.

“Further prospective studies are required to validate the appropriate margin width,” study author Frank A. Vicini, MD, of 21st Century Oncology/Michigan Healthcare Professionals in Farmington Hills, Michigan, said at the San Antonio Breast Cancer Symposium.

Dr. Vicini pointed out that the medical community has been addressing the question of “what is the appropriate margin for breast conserving therapy” for about 3 or 4 decades. A meta-analysis of 33 studies (Ann Surg Oncol. 2014 Mar;21[3]:717-30. doi: 10.1245/s10434-014-3480-5) showed that wider margins are unlikely to have a substantial benefit over “no tumor on ink.”

The results of the meta-analysis led to guidelines published by the Society of Surgical Oncology–American Society for Radiation Oncology that supported those conclusions.

“So the question now is that with additional patients and additional modeling, is this conclusion still correct?” Dr. Vicini said.

The 2014 meta-analysis had significant limitations, and to address them, Dr. Vicini and his colleagues conducted an updated analysis of all available data that included 31 of the initial studies. However, stricter criteria were used for inclusion into their review. The authors reviewed all studies published between 1995 and 2016 that had a minimum follow-up of 50 months, and that included explicit pathologic definitions of margin status and local recurrence in relation to margin status.

The final meta-analysis included 55,302 patients (74% T1 tumors; 72% node-negative disease) from a total of 38 studies, and the median follow up was 7.2 years.

The analysis used three generalized linear mixed models for the outcome of local recurrence, and random effects for study and fixed effects for various patient and study characteristics.

In model 1, all patients with at or equal margin width were compared with those who had wider margins. Model 2 examined the impact of margin width “range” as opposed to a set margin width of 0 mm to 2 mm, 2 mm to 5 mm, or greater than 5 mm. Model 3 divided margin distance by cut points of –1 mm, 2 mm, and 5 mm.

The crude rate of local recurrence was 10.3% for patients with positive margins versus 3.8% for those with negative margins that were defined as no tumor on ink or wider (P less than .001). Local recurrence rates declined as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each). The use of endocrine therapy and increasing median study year were associated with decreased rates of local recurrence in univariate models but not in multivariable analyses.

For local recurrence in model 1, a benefit for wider margins was observed, with the greatest benefit seen at 1 mm. The odds ratio (OR) for local recurrence for negative vs. close/positive margins was 0.46 (95% confidence interval, 0.4-0.53) for margins larger than 0 mm, 0.43 (95% CI, 0.36-0.51) for those greater than 1 mm, 0.49 (95% CI, 0.42-0.55) for those larger than 2 mm, and 0.53 (95% CI, 0.43-0.66) for greater than 5 mm. Upon multivariate analysis, the only significant predictive variable was margin status.

For model 2, margin width turned out to be the significant variable, and only wider margins were associated with a decrease in local recurrence.

Finally, in model 3, both margin status and margin width were significantly associated with local recurrence. When modeling as negative, close, or positive margins, the lowest rates were at 2 mm (negative, 3.6%; close, 5.5%; positive, 9.5%) and 5 mm (negative, 2.9%; close, 4.1%; positive, 12.8%).

“So the initial question is the same – should we achieve a 1- to 2-mm margin for our patients as compared to a no tumor on ink, taking into account the potential for local control benefits versus morbidity and time, and cost?” said Dr. Vicini.

“The real question in my mind, is which patients with no tumor on ink require additional surgery,” he concluded. “In my opinion, it may not only be related to the margin status itself, but to the volume of disease near the margin but these meta-analyses were not designed to look at that point.”

SOURCE: Vicini et al. SABCS Abstract GS5-01

SAN ANTONIO – A margin width beyond ‘no tumor on ink’ may reduce local recurrence in certain subsets of patients undergoing breast-conserving treatment for early-stage breast cancer, according to findings from a meta-analysis.

“Further prospective studies are required to validate the appropriate margin width,” study author Frank A. Vicini, MD, of 21st Century Oncology/Michigan Healthcare Professionals in Farmington Hills, Michigan, said at the San Antonio Breast Cancer Symposium.

Dr. Vicini pointed out that the medical community has been addressing the question of “what is the appropriate margin for breast conserving therapy” for about 3 or 4 decades. A meta-analysis of 33 studies (Ann Surg Oncol. 2014 Mar;21[3]:717-30. doi: 10.1245/s10434-014-3480-5) showed that wider margins are unlikely to have a substantial benefit over “no tumor on ink.”

The results of the meta-analysis led to guidelines published by the Society of Surgical Oncology–American Society for Radiation Oncology that supported those conclusions.

“So the question now is that with additional patients and additional modeling, is this conclusion still correct?” Dr. Vicini said.

The 2014 meta-analysis had significant limitations, and to address them, Dr. Vicini and his colleagues conducted an updated analysis of all available data that included 31 of the initial studies. However, stricter criteria were used for inclusion into their review. The authors reviewed all studies published between 1995 and 2016 that had a minimum follow-up of 50 months, and that included explicit pathologic definitions of margin status and local recurrence in relation to margin status.

The final meta-analysis included 55,302 patients (74% T1 tumors; 72% node-negative disease) from a total of 38 studies, and the median follow up was 7.2 years.

The analysis used three generalized linear mixed models for the outcome of local recurrence, and random effects for study and fixed effects for various patient and study characteristics.

In model 1, all patients with at or equal margin width were compared with those who had wider margins. Model 2 examined the impact of margin width “range” as opposed to a set margin width of 0 mm to 2 mm, 2 mm to 5 mm, or greater than 5 mm. Model 3 divided margin distance by cut points of –1 mm, 2 mm, and 5 mm.

The crude rate of local recurrence was 10.3% for patients with positive margins versus 3.8% for those with negative margins that were defined as no tumor on ink or wider (P less than .001). Local recurrence rates declined as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each). The use of endocrine therapy and increasing median study year were associated with decreased rates of local recurrence in univariate models but not in multivariable analyses.

For local recurrence in model 1, a benefit for wider margins was observed, with the greatest benefit seen at 1 mm. The odds ratio (OR) for local recurrence for negative vs. close/positive margins was 0.46 (95% confidence interval, 0.4-0.53) for margins larger than 0 mm, 0.43 (95% CI, 0.36-0.51) for those greater than 1 mm, 0.49 (95% CI, 0.42-0.55) for those larger than 2 mm, and 0.53 (95% CI, 0.43-0.66) for greater than 5 mm. Upon multivariate analysis, the only significant predictive variable was margin status.

For model 2, margin width turned out to be the significant variable, and only wider margins were associated with a decrease in local recurrence.

Finally, in model 3, both margin status and margin width were significantly associated with local recurrence. When modeling as negative, close, or positive margins, the lowest rates were at 2 mm (negative, 3.6%; close, 5.5%; positive, 9.5%) and 5 mm (negative, 2.9%; close, 4.1%; positive, 12.8%).

“So the initial question is the same – should we achieve a 1- to 2-mm margin for our patients as compared to a no tumor on ink, taking into account the potential for local control benefits versus morbidity and time, and cost?” said Dr. Vicini.

“The real question in my mind, is which patients with no tumor on ink require additional surgery,” he concluded. “In my opinion, it may not only be related to the margin status itself, but to the volume of disease near the margin but these meta-analyses were not designed to look at that point.”

SOURCE: Vicini et al. SABCS Abstract GS5-01

SAN ANTONIO – A margin width beyond ‘no tumor on ink’ may reduce local recurrence in certain subsets of patients undergoing breast-conserving treatment for early-stage breast cancer, according to findings from a meta-analysis.

“Further prospective studies are required to validate the appropriate margin width,” study author Frank A. Vicini, MD, of 21st Century Oncology/Michigan Healthcare Professionals in Farmington Hills, Michigan, said at the San Antonio Breast Cancer Symposium.

Dr. Vicini pointed out that the medical community has been addressing the question of “what is the appropriate margin for breast conserving therapy” for about 3 or 4 decades. A meta-analysis of 33 studies (Ann Surg Oncol. 2014 Mar;21[3]:717-30. doi: 10.1245/s10434-014-3480-5) showed that wider margins are unlikely to have a substantial benefit over “no tumor on ink.”

The results of the meta-analysis led to guidelines published by the Society of Surgical Oncology–American Society for Radiation Oncology that supported those conclusions.

“So the question now is that with additional patients and additional modeling, is this conclusion still correct?” Dr. Vicini said.

The 2014 meta-analysis had significant limitations, and to address them, Dr. Vicini and his colleagues conducted an updated analysis of all available data that included 31 of the initial studies. However, stricter criteria were used for inclusion into their review. The authors reviewed all studies published between 1995 and 2016 that had a minimum follow-up of 50 months, and that included explicit pathologic definitions of margin status and local recurrence in relation to margin status.

The final meta-analysis included 55,302 patients (74% T1 tumors; 72% node-negative disease) from a total of 38 studies, and the median follow up was 7.2 years.

The analysis used three generalized linear mixed models for the outcome of local recurrence, and random effects for study and fixed effects for various patient and study characteristics.

In model 1, all patients with at or equal margin width were compared with those who had wider margins. Model 2 examined the impact of margin width “range” as opposed to a set margin width of 0 mm to 2 mm, 2 mm to 5 mm, or greater than 5 mm. Model 3 divided margin distance by cut points of –1 mm, 2 mm, and 5 mm.

The crude rate of local recurrence was 10.3% for patients with positive margins versus 3.8% for those with negative margins that were defined as no tumor on ink or wider (P less than .001). Local recurrence rates declined as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each). The use of endocrine therapy and increasing median study year were associated with decreased rates of local recurrence in univariate models but not in multivariable analyses.

For local recurrence in model 1, a benefit for wider margins was observed, with the greatest benefit seen at 1 mm. The odds ratio (OR) for local recurrence for negative vs. close/positive margins was 0.46 (95% confidence interval, 0.4-0.53) for margins larger than 0 mm, 0.43 (95% CI, 0.36-0.51) for those greater than 1 mm, 0.49 (95% CI, 0.42-0.55) for those larger than 2 mm, and 0.53 (95% CI, 0.43-0.66) for greater than 5 mm. Upon multivariate analysis, the only significant predictive variable was margin status.

For model 2, margin width turned out to be the significant variable, and only wider margins were associated with a decrease in local recurrence.

Finally, in model 3, both margin status and margin width were significantly associated with local recurrence. When modeling as negative, close, or positive margins, the lowest rates were at 2 mm (negative, 3.6%; close, 5.5%; positive, 9.5%) and 5 mm (negative, 2.9%; close, 4.1%; positive, 12.8%).

“So the initial question is the same – should we achieve a 1- to 2-mm margin for our patients as compared to a no tumor on ink, taking into account the potential for local control benefits versus morbidity and time, and cost?” said Dr. Vicini.

“The real question in my mind, is which patients with no tumor on ink require additional surgery,” he concluded. “In my opinion, it may not only be related to the margin status itself, but to the volume of disease near the margin but these meta-analyses were not designed to look at that point.”

SOURCE: Vicini et al. SABCS Abstract GS5-01

SAN ANTONIO – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.

Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.

Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.

However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.

“The study met its primary endpoint in improving PFS in the enzalutamide plus exemestane-treated patients who were biomarker positive and HR positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.

“The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation,” said Dr. Yardley.

SOURCE: Yardley et al. SABCS Abstract GS4-07

SAN ANTONIO – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.

Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.

Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.

However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.

“The study met its primary endpoint in improving PFS in the enzalutamide plus exemestane-treated patients who were biomarker positive and HR positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.

“The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation,” said Dr. Yardley.

SOURCE: Yardley et al. SABCS Abstract GS4-07

SAN ANTONIO – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.

Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.

Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.

However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.

“The study met its primary endpoint in improving PFS in the enzalutamide plus exemestane-treated patients who were biomarker positive and HR positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.

“The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation,” said Dr. Yardley.

SOURCE: Yardley et al. SABCS Abstract GS4-07

SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.

SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.

SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02