Neil Osterweil

Picture this: Creating visual representations of symptom clusters may help oncologists identify and treat sentinel symptoms in patients who are receiving cancer therapies and potentially avoid costly and unnecessary acute hospitalizations.

Network visualizations – graphic representations of the frequency of individual symptoms and the strength of their co-occurrence with other symptoms – could be used by clinicians in urgent-care settings to determine whether a presenting symptom or cluster of symptoms could be safely managed in the outpatient setting or requires hospitalization, according to Bobby Daly, MD, and his colleagues at Memorial Sloan Kettering Cancer Center in New York.

“Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co-occurrence can drive improved management strategies,” the investigators wrote. The report was published in the Journal of Oncology Practice.

Preventing hospitalizations related to treatment toxicities is both sound clinical and financial practice.

“Patients who receive chemotherapy have, on average, one hospital admission and two emergency department visits per year, and 40%-50% of these stem from symptoms related to their treatment. Acute hospitalizations account for 48% of total cancer expenditures. Considerable regional variation exists, which suggests that these hospitalizations may be avoidable,” they wrote.

The Centers for Medicare & Medicaid Services has identified 10 potentially preventable conditions that may result in hospitalizations, and plans to measure the performance of cancer centers based on the frequency of urgent care visits and admissions for each condition.

The conditions (in alphabetical order) are: anemia, dehydration, diarrhea, emesis, fever, nausea, neutropenia, pain, pneumonia, and sepsis.

To get a better handle on symptom clusters in patients undergoing active cancer therapy, the investigators used an analytical method involving creation of network visualizations of symptom clusters.

“It has been established that physicians are uncomfortable with managing symptom clusters, and by better elucidating these clusters, we can improve management strategies,” Dr. Daly and his associates wrote.

They identified 23,341 unique patient visits to their center’s urgent care department in 2016, and included in their analysis only those patients who had received an intravenous chemotherapy agent, oral antineoplastic therapy, or immunotherapy within 30 days of presentation. They drew on the electronic health record (EHR) for information about the chief complaint and primary diagnosis for each visit.

They then created three patient cohorts for identifying and mapping potentially preventable symptom clusters.

Cohort 1 comprised patients who were receiving active treatment and presented to the urgent care center with one of the CMS-defined symptoms.

Cohort 2 comprised patients who were receiving active treatment and were evaluated with a clinician-developed definition of a potentially preventable symptom, defined as “a symptom that could be managed safely in the outpatient setting if the clinical team identified said symptom early and managed it proactively.”

Cohort 3 was similar to cohort 2, but included only those patients who started treatment for the first time.

The authors identified 6,429 presentations in cohort 1, and in this group of patients the network analysis identified two distinct symptom clusters centered around pain and fever.

In cohort 2, there were 5,731 visits and six symptom clusters centered around fever, nausea/emesis, fatigue, deep vein thrombosis, pain, and ascites.

In cohort 3, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis.

“By using EHR data fields for [urgent care center] primary diagnoses and chief complaints, we elicited symptom information and linked it to unplanned acute care. Unplanned acute care is of increasing importance to patients because it disrupts patients’ treatment trajectories as well as their lives outside the clinic. Use of the EHR also allowed for granular symptom data, such as a particular site of pain rather than just pain itself, which is absent from traditional sources of patient-reported symptom assessments,” Dr. Daly and his colleagues said.

The investigators recommend using data from the EHR in combination with “big data” artificial intelligence techniques to allow early detection of patients at risk for symptom clusters.

The study was supported by an ASCO Health Policy Fellowship to Dr. Daly. He disclosed employment and stock ownership with Quadrant Holdings Corporation, and stock ownership in CVS Health, Johnson & Johnson, McKesson, Lilly and the Walgreens Boots Alliance.

SOURCE: Daly B et al. J Oncol Practice, 2018 Jul 17. doi: 10.1200/JOP.18.00199.

Picture this: Creating visual representations of symptom clusters may help oncologists identify and treat sentinel symptoms in patients who are receiving cancer therapies and potentially avoid costly and unnecessary acute hospitalizations.

Network visualizations – graphic representations of the frequency of individual symptoms and the strength of their co-occurrence with other symptoms – could be used by clinicians in urgent-care settings to determine whether a presenting symptom or cluster of symptoms could be safely managed in the outpatient setting or requires hospitalization, according to Bobby Daly, MD, and his colleagues at Memorial Sloan Kettering Cancer Center in New York.

“Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co-occurrence can drive improved management strategies,” the investigators wrote. The report was published in the Journal of Oncology Practice.

Preventing hospitalizations related to treatment toxicities is both sound clinical and financial practice.

“Patients who receive chemotherapy have, on average, one hospital admission and two emergency department visits per year, and 40%-50% of these stem from symptoms related to their treatment. Acute hospitalizations account for 48% of total cancer expenditures. Considerable regional variation exists, which suggests that these hospitalizations may be avoidable,” they wrote.

The Centers for Medicare & Medicaid Services has identified 10 potentially preventable conditions that may result in hospitalizations, and plans to measure the performance of cancer centers based on the frequency of urgent care visits and admissions for each condition.

The conditions (in alphabetical order) are: anemia, dehydration, diarrhea, emesis, fever, nausea, neutropenia, pain, pneumonia, and sepsis.

To get a better handle on symptom clusters in patients undergoing active cancer therapy, the investigators used an analytical method involving creation of network visualizations of symptom clusters.

“It has been established that physicians are uncomfortable with managing symptom clusters, and by better elucidating these clusters, we can improve management strategies,” Dr. Daly and his associates wrote.

They identified 23,341 unique patient visits to their center’s urgent care department in 2016, and included in their analysis only those patients who had received an intravenous chemotherapy agent, oral antineoplastic therapy, or immunotherapy within 30 days of presentation. They drew on the electronic health record (EHR) for information about the chief complaint and primary diagnosis for each visit.

They then created three patient cohorts for identifying and mapping potentially preventable symptom clusters.

Cohort 1 comprised patients who were receiving active treatment and presented to the urgent care center with one of the CMS-defined symptoms.

Cohort 2 comprised patients who were receiving active treatment and were evaluated with a clinician-developed definition of a potentially preventable symptom, defined as “a symptom that could be managed safely in the outpatient setting if the clinical team identified said symptom early and managed it proactively.”

Cohort 3 was similar to cohort 2, but included only those patients who started treatment for the first time.

The authors identified 6,429 presentations in cohort 1, and in this group of patients the network analysis identified two distinct symptom clusters centered around pain and fever.

In cohort 2, there were 5,731 visits and six symptom clusters centered around fever, nausea/emesis, fatigue, deep vein thrombosis, pain, and ascites.

In cohort 3, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis.

“By using EHR data fields for [urgent care center] primary diagnoses and chief complaints, we elicited symptom information and linked it to unplanned acute care. Unplanned acute care is of increasing importance to patients because it disrupts patients’ treatment trajectories as well as their lives outside the clinic. Use of the EHR also allowed for granular symptom data, such as a particular site of pain rather than just pain itself, which is absent from traditional sources of patient-reported symptom assessments,” Dr. Daly and his colleagues said.

The investigators recommend using data from the EHR in combination with “big data” artificial intelligence techniques to allow early detection of patients at risk for symptom clusters.

The study was supported by an ASCO Health Policy Fellowship to Dr. Daly. He disclosed employment and stock ownership with Quadrant Holdings Corporation, and stock ownership in CVS Health, Johnson & Johnson, McKesson, Lilly and the Walgreens Boots Alliance.

SOURCE: Daly B et al. J Oncol Practice, 2018 Jul 17. doi: 10.1200/JOP.18.00199.

Picture this: Creating visual representations of symptom clusters may help oncologists identify and treat sentinel symptoms in patients who are receiving cancer therapies and potentially avoid costly and unnecessary acute hospitalizations.

Network visualizations – graphic representations of the frequency of individual symptoms and the strength of their co-occurrence with other symptoms – could be used by clinicians in urgent-care settings to determine whether a presenting symptom or cluster of symptoms could be safely managed in the outpatient setting or requires hospitalization, according to Bobby Daly, MD, and his colleagues at Memorial Sloan Kettering Cancer Center in New York.

“Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co-occurrence can drive improved management strategies,” the investigators wrote. The report was published in the Journal of Oncology Practice.

Preventing hospitalizations related to treatment toxicities is both sound clinical and financial practice.

“Patients who receive chemotherapy have, on average, one hospital admission and two emergency department visits per year, and 40%-50% of these stem from symptoms related to their treatment. Acute hospitalizations account for 48% of total cancer expenditures. Considerable regional variation exists, which suggests that these hospitalizations may be avoidable,” they wrote.

The Centers for Medicare & Medicaid Services has identified 10 potentially preventable conditions that may result in hospitalizations, and plans to measure the performance of cancer centers based on the frequency of urgent care visits and admissions for each condition.

The conditions (in alphabetical order) are: anemia, dehydration, diarrhea, emesis, fever, nausea, neutropenia, pain, pneumonia, and sepsis.

To get a better handle on symptom clusters in patients undergoing active cancer therapy, the investigators used an analytical method involving creation of network visualizations of symptom clusters.

“It has been established that physicians are uncomfortable with managing symptom clusters, and by better elucidating these clusters, we can improve management strategies,” Dr. Daly and his associates wrote.

They identified 23,341 unique patient visits to their center’s urgent care department in 2016, and included in their analysis only those patients who had received an intravenous chemotherapy agent, oral antineoplastic therapy, or immunotherapy within 30 days of presentation. They drew on the electronic health record (EHR) for information about the chief complaint and primary diagnosis for each visit.

They then created three patient cohorts for identifying and mapping potentially preventable symptom clusters.

Cohort 1 comprised patients who were receiving active treatment and presented to the urgent care center with one of the CMS-defined symptoms.

Cohort 2 comprised patients who were receiving active treatment and were evaluated with a clinician-developed definition of a potentially preventable symptom, defined as “a symptom that could be managed safely in the outpatient setting if the clinical team identified said symptom early and managed it proactively.”

Cohort 3 was similar to cohort 2, but included only those patients who started treatment for the first time.

The authors identified 6,429 presentations in cohort 1, and in this group of patients the network analysis identified two distinct symptom clusters centered around pain and fever.

In cohort 2, there were 5,731 visits and six symptom clusters centered around fever, nausea/emesis, fatigue, deep vein thrombosis, pain, and ascites.

In cohort 3, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis.

“By using EHR data fields for [urgent care center] primary diagnoses and chief complaints, we elicited symptom information and linked it to unplanned acute care. Unplanned acute care is of increasing importance to patients because it disrupts patients’ treatment trajectories as well as their lives outside the clinic. Use of the EHR also allowed for granular symptom data, such as a particular site of pain rather than just pain itself, which is absent from traditional sources of patient-reported symptom assessments,” Dr. Daly and his colleagues said.

The investigators recommend using data from the EHR in combination with “big data” artificial intelligence techniques to allow early detection of patients at risk for symptom clusters.

The study was supported by an ASCO Health Policy Fellowship to Dr. Daly. He disclosed employment and stock ownership with Quadrant Holdings Corporation, and stock ownership in CVS Health, Johnson & Johnson, McKesson, Lilly and the Walgreens Boots Alliance.

SOURCE: Daly B et al. J Oncol Practice, 2018 Jul 17. doi: 10.1200/JOP.18.00199.

Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.

Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.

“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.

Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”

Both studies were published online in The Lancet Oncology: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7, and Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

SOLO2 QOL summary

In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).

The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.

In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).

The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).

In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.

“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
 

ENGOT-OV16/NOVA QOL summary

Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.

The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).

The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.

The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.

They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.

In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.

Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.

“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.

SOURCE: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.

Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.

“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.

Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”

Both studies were published online in The Lancet Oncology: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7, and Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

SOLO2 QOL summary

In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).

The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.

In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).

The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).

In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.

“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
 

ENGOT-OV16/NOVA QOL summary

Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.

The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).

The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.

The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.

They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.

In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.

Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.

“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.

SOURCE: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.

Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.

“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.

Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”

Both studies were published online in The Lancet Oncology: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7, and Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

SOLO2 QOL summary

In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).

The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.

In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).

The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).

In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.

“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
 

ENGOT-OV16/NOVA QOL summary

Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.

The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).

The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.

The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.

They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.

In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.

Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.

“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.

SOURCE: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.

STOCKHOLM –Adding the monoclonal antibody elotuzumab to pomalidomide and dexamethasone nearly doubled the overall response rate and median progression-free survival in patients with relapsed/refractory multiple myeloma compared with pomalidomide and dexamethasone alone, results of the phase 2 ELOQUENT-3 trial showed.

Neil Osterweil/MDedge News

After a minimum follow-up of 9.1 months, median progression-free survival (PFS) for 60 patients assigned to receive elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone (EPd) was 10.3 months, compared with 4.7 months for 60 patients assigned to pomalidomide and dexamethasone (Pd). This difference translated into a hazard ratio (HR) of 0.54 (P = .0078) favoring EPd, reported Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens (Greece).

“The study met its primary endpoint, which was specifically designed to detect a large treatment effect in a relatively small sample of patients. Elotuzumab with pomalidomide and dexamethasone showed a significant and clinically meaningful 46% reduction in the risk of progression or death,” he said at the annual congress of the European Hematology Association.

Elotuzumab is an immunoglobulin G (IgG) monoclonal antibody that targets signaling lymphocytic activation molecule F7 (SLAMF7) expressed on multiple myeloma cells. Pomalidomide, an immunomodulator, may act synergistically with elotuzumab through several different mechanisms to increase killing of multiple myeloma cells, Dr. Dimopoulos said.

In ELOQUENT-3, patients with relapsed or refractory multiple myeloma after 2 or more prior lines of therapy, including lenalidomide (Revlimid) and a proteasome inhibitor and no prior pomalidomide were enrolled and randomly assigned to receive either pomalidomide 4 mg orally on days 1-21 of each 28-day cycle plus oral dexamethasone 40 mg equivalent weekly, or to the same regimen plus intravenous elotuzumab 10 mg/kg weekly for cycles 1 and 2, and 20 mg/kg every 4 weeks for cycle 3 and subsequent cycles.

The trial met its primary endpoint of investigator-assessed PFS, with a 46% reduction in the risk of progression or death with EPd compared with Pd.

An analysis of PFS by subgroups showed that EPd was significantly superior to Pd for patients younger than 65 years, those with International Staging System stage I-II at study entry, patients with lactate dehydrogenase levels below 300 IU/L at baseline, patients who had two or three prior lines of therapy vs. four or more, and those who had disease that was refractory to both lenalidomide and a proteasome inhibitor.

EPd was also associated with a trend toward better PFS in an analysis combining patients with high-risk cytogenetics (deletion 17p or translocation 14;16) or high LDH levels, with a median of 7.7 months compared with 3.6 months for Pd. However, the HR, 0.55, was not statistically significant, likely because of the small sample size.

Similarly, the elotuzumab-containing combination showed a nonsignificant trend toward better PFS among patients without high risk disease, with a median PFS not reached, vs. not reached, vs. 4.7 months for patients treated with Pd.

The overall response rate with EPd was 53%, compared with 26% for Pd (odds ratio 3.5, P = .0029). The responses in the elotuzumab arm consisted of 8% complete response, 12% very good partial responses, and 33% partial responses. The respective rates in the Pd group were 2%, 7%, and 18%.

The median duration of response with EPd was not reached at the time of the database lock, compared with 8.3 months with Pd.

A preliminary analysis of overall survival showed a trend favoring EPd (13 deaths out to 22 months of follow-up, compared with 18 deaths out to 20 months in the Pd arm; HR 0.62, nonsignificant).

There were five treatment-related deaths in the EPd arm, and eight in the Pd arm. Grade 1 or 2 infusion reactions occurred in three patients in the EPd arm.

Other adverse events were comparable between the arms, with 57% of patients in the EPd arm and 60% in the Pd arm having at least one grade 3 or 4 adverse event.

“The hematologic toxicity was driven by pomalidomide and low-dose dexamethasone. For unclear reasons, there was less grade 3 or 4 neutropenia with the addition of elotuzumab to pomalidomide/dexamethasone, and also the infection rate was lower in the EPd arm,” Dr. Dimopoulos said.
 

SOURCE: Dimopoulos MA et al. EHA Congress, Abstract LB2606.

STOCKHOLM –Adding the monoclonal antibody elotuzumab to pomalidomide and dexamethasone nearly doubled the overall response rate and median progression-free survival in patients with relapsed/refractory multiple myeloma compared with pomalidomide and dexamethasone alone, results of the phase 2 ELOQUENT-3 trial showed.

Neil Osterweil/MDedge News

After a minimum follow-up of 9.1 months, median progression-free survival (PFS) for 60 patients assigned to receive elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone (EPd) was 10.3 months, compared with 4.7 months for 60 patients assigned to pomalidomide and dexamethasone (Pd). This difference translated into a hazard ratio (HR) of 0.54 (P = .0078) favoring EPd, reported Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens (Greece).

“The study met its primary endpoint, which was specifically designed to detect a large treatment effect in a relatively small sample of patients. Elotuzumab with pomalidomide and dexamethasone showed a significant and clinically meaningful 46% reduction in the risk of progression or death,” he said at the annual congress of the European Hematology Association.

Elotuzumab is an immunoglobulin G (IgG) monoclonal antibody that targets signaling lymphocytic activation molecule F7 (SLAMF7) expressed on multiple myeloma cells. Pomalidomide, an immunomodulator, may act synergistically with elotuzumab through several different mechanisms to increase killing of multiple myeloma cells, Dr. Dimopoulos said.

In ELOQUENT-3, patients with relapsed or refractory multiple myeloma after 2 or more prior lines of therapy, including lenalidomide (Revlimid) and a proteasome inhibitor and no prior pomalidomide were enrolled and randomly assigned to receive either pomalidomide 4 mg orally on days 1-21 of each 28-day cycle plus oral dexamethasone 40 mg equivalent weekly, or to the same regimen plus intravenous elotuzumab 10 mg/kg weekly for cycles 1 and 2, and 20 mg/kg every 4 weeks for cycle 3 and subsequent cycles.

The trial met its primary endpoint of investigator-assessed PFS, with a 46% reduction in the risk of progression or death with EPd compared with Pd.

An analysis of PFS by subgroups showed that EPd was significantly superior to Pd for patients younger than 65 years, those with International Staging System stage I-II at study entry, patients with lactate dehydrogenase levels below 300 IU/L at baseline, patients who had two or three prior lines of therapy vs. four or more, and those who had disease that was refractory to both lenalidomide and a proteasome inhibitor.

EPd was also associated with a trend toward better PFS in an analysis combining patients with high-risk cytogenetics (deletion 17p or translocation 14;16) or high LDH levels, with a median of 7.7 months compared with 3.6 months for Pd. However, the HR, 0.55, was not statistically significant, likely because of the small sample size.

Similarly, the elotuzumab-containing combination showed a nonsignificant trend toward better PFS among patients without high risk disease, with a median PFS not reached, vs. not reached, vs. 4.7 months for patients treated with Pd.

The overall response rate with EPd was 53%, compared with 26% for Pd (odds ratio 3.5, P = .0029). The responses in the elotuzumab arm consisted of 8% complete response, 12% very good partial responses, and 33% partial responses. The respective rates in the Pd group were 2%, 7%, and 18%.

The median duration of response with EPd was not reached at the time of the database lock, compared with 8.3 months with Pd.

A preliminary analysis of overall survival showed a trend favoring EPd (13 deaths out to 22 months of follow-up, compared with 18 deaths out to 20 months in the Pd arm; HR 0.62, nonsignificant).

There were five treatment-related deaths in the EPd arm, and eight in the Pd arm. Grade 1 or 2 infusion reactions occurred in three patients in the EPd arm.

Other adverse events were comparable between the arms, with 57% of patients in the EPd arm and 60% in the Pd arm having at least one grade 3 or 4 adverse event.

“The hematologic toxicity was driven by pomalidomide and low-dose dexamethasone. For unclear reasons, there was less grade 3 or 4 neutropenia with the addition of elotuzumab to pomalidomide/dexamethasone, and also the infection rate was lower in the EPd arm,” Dr. Dimopoulos said.
 

SOURCE: Dimopoulos MA et al. EHA Congress, Abstract LB2606.

STOCKHOLM –Adding the monoclonal antibody elotuzumab to pomalidomide and dexamethasone nearly doubled the overall response rate and median progression-free survival in patients with relapsed/refractory multiple myeloma compared with pomalidomide and dexamethasone alone, results of the phase 2 ELOQUENT-3 trial showed.

Neil Osterweil/MDedge News

After a minimum follow-up of 9.1 months, median progression-free survival (PFS) for 60 patients assigned to receive elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone (EPd) was 10.3 months, compared with 4.7 months for 60 patients assigned to pomalidomide and dexamethasone (Pd). This difference translated into a hazard ratio (HR) of 0.54 (P = .0078) favoring EPd, reported Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens (Greece).

“The study met its primary endpoint, which was specifically designed to detect a large treatment effect in a relatively small sample of patients. Elotuzumab with pomalidomide and dexamethasone showed a significant and clinically meaningful 46% reduction in the risk of progression or death,” he said at the annual congress of the European Hematology Association.

Elotuzumab is an immunoglobulin G (IgG) monoclonal antibody that targets signaling lymphocytic activation molecule F7 (SLAMF7) expressed on multiple myeloma cells. Pomalidomide, an immunomodulator, may act synergistically with elotuzumab through several different mechanisms to increase killing of multiple myeloma cells, Dr. Dimopoulos said.

In ELOQUENT-3, patients with relapsed or refractory multiple myeloma after 2 or more prior lines of therapy, including lenalidomide (Revlimid) and a proteasome inhibitor and no prior pomalidomide were enrolled and randomly assigned to receive either pomalidomide 4 mg orally on days 1-21 of each 28-day cycle plus oral dexamethasone 40 mg equivalent weekly, or to the same regimen plus intravenous elotuzumab 10 mg/kg weekly for cycles 1 and 2, and 20 mg/kg every 4 weeks for cycle 3 and subsequent cycles.

The trial met its primary endpoint of investigator-assessed PFS, with a 46% reduction in the risk of progression or death with EPd compared with Pd.

An analysis of PFS by subgroups showed that EPd was significantly superior to Pd for patients younger than 65 years, those with International Staging System stage I-II at study entry, patients with lactate dehydrogenase levels below 300 IU/L at baseline, patients who had two or three prior lines of therapy vs. four or more, and those who had disease that was refractory to both lenalidomide and a proteasome inhibitor.

EPd was also associated with a trend toward better PFS in an analysis combining patients with high-risk cytogenetics (deletion 17p or translocation 14;16) or high LDH levels, with a median of 7.7 months compared with 3.6 months for Pd. However, the HR, 0.55, was not statistically significant, likely because of the small sample size.

Similarly, the elotuzumab-containing combination showed a nonsignificant trend toward better PFS among patients without high risk disease, with a median PFS not reached, vs. not reached, vs. 4.7 months for patients treated with Pd.

The overall response rate with EPd was 53%, compared with 26% for Pd (odds ratio 3.5, P = .0029). The responses in the elotuzumab arm consisted of 8% complete response, 12% very good partial responses, and 33% partial responses. The respective rates in the Pd group were 2%, 7%, and 18%.

The median duration of response with EPd was not reached at the time of the database lock, compared with 8.3 months with Pd.

A preliminary analysis of overall survival showed a trend favoring EPd (13 deaths out to 22 months of follow-up, compared with 18 deaths out to 20 months in the Pd arm; HR 0.62, nonsignificant).

There were five treatment-related deaths in the EPd arm, and eight in the Pd arm. Grade 1 or 2 infusion reactions occurred in three patients in the EPd arm.

Other adverse events were comparable between the arms, with 57% of patients in the EPd arm and 60% in the Pd arm having at least one grade 3 or 4 adverse event.

“The hematologic toxicity was driven by pomalidomide and low-dose dexamethasone. For unclear reasons, there was less grade 3 or 4 neutropenia with the addition of elotuzumab to pomalidomide/dexamethasone, and also the infection rate was lower in the EPd arm,” Dr. Dimopoulos said.
 

SOURCE: Dimopoulos MA et al. EHA Congress, Abstract LB2606.

BARCELONA – There was no overall survival advantage for patients with metastatic colorectal cancer treated with the immune checkpoint inhibitor atezolizumab (Tencentriq) either in combination with cobimetinib (Cotellic) or as monotherapy compared with regorafenib (Stivarga), results of the randomized phase 3 IMblaze370 trial showed.

Neil Osterweil/MDedge News

Median overall survival (OS, the primary endpoint) for 183 patients treated with atezolizumab and cobimetinib was 8.9 months, compared with 7.1 months for 90 patients treated with atezolizumab monotherapy, and 8.5 months for 90 patients treated with regorafenib. None of the differences were statistically significant, reported Johanna C. Bendell, MD, of the Sarah Cannon Research Institute in Nashville, Tenn.

“The lack of clinical activity may be due to the immune-excluded phenotype of metastatic colorectal cancer. The dual inhibition of the PD-L1 immune checkpoint and MAP kinase–mediated immune suppression may not be sufficient to generate that immune response that we need for antitumor activity,” she said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

In an interview, Dr. Bendell said that “we were all hoping that we were going to see some benefit, and we had some preliminary data suggesting that we would. What we still need to see is whether there are potentially populations of patients who might have benefited more, which hopefully will come out of the biomarker analysis.”

The results demonstrate the need for controlled comparison trials to detect true clinical benefits from a specific agent or combination, she added.

Microsatellite-stable disease, which accounts for approximately 95% of cases of metastatic colorectal cancer (MSS mCRC) is considered to be an immune-excluded or “cold” tumor type due to a lack of tumor-infiltrating lymphocytes. Single agent inhibitors of the programmed death 1 protein and its ligand (PD1/PD-L1) have only minimal activity in MSS mCRC, she noted.

In preclinical studies, there was evidence to suggest that the combination of atezolizumab and cobimetinib could augment antitumor T-cell responses. The combination also was shown to be safe and to demonstrate “promising” clinical activity in a phase 1b trial conducted by Dr. Bendell and her colleagues.

To see whether the initial promise of atezolizumab in this population held up under closer scrutiny, the investigators enrolled patients with MSS mCRC refractory to chemotherapy and randomly assigned them on a 2:1:1 basis to receive either atezolizumab plus cobimetinib, atezolizumab monotherapy, or regorafenib.

Atezolizumab was administered intravenously at 840 mg every 2 weeks in the combination arm, and at 1,200 mg every 3 weeks in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule. Regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule.

As noted, the trial did not meet its primary endpoint of an OS benefit in the intention-to-treat population. In addition, there were no significant differences in either median progression-free survival, overall response rates, or duration of response.

Response rates for both the atezolizumab/cobimetinib combination and atezolizumab monotherapy arms were consistent with published data for other PD-1/PD-L1 inhibitors, and the safety of the combination was consistent with the known safety profiles of the individual agents, Dr. Bendell said.

The investigators are conducting extensive biomarker evaluations and gene expression profiles, and hope to present the results of these studies at a future conference, she added.

SOURCE: Bendell J et al. ESMO GI 2018. Abstract LBA-004.

BARCELONA – There was no overall survival advantage for patients with metastatic colorectal cancer treated with the immune checkpoint inhibitor atezolizumab (Tencentriq) either in combination with cobimetinib (Cotellic) or as monotherapy compared with regorafenib (Stivarga), results of the randomized phase 3 IMblaze370 trial showed.

Neil Osterweil/MDedge News

Median overall survival (OS, the primary endpoint) for 183 patients treated with atezolizumab and cobimetinib was 8.9 months, compared with 7.1 months for 90 patients treated with atezolizumab monotherapy, and 8.5 months for 90 patients treated with regorafenib. None of the differences were statistically significant, reported Johanna C. Bendell, MD, of the Sarah Cannon Research Institute in Nashville, Tenn.

“The lack of clinical activity may be due to the immune-excluded phenotype of metastatic colorectal cancer. The dual inhibition of the PD-L1 immune checkpoint and MAP kinase–mediated immune suppression may not be sufficient to generate that immune response that we need for antitumor activity,” she said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

In an interview, Dr. Bendell said that “we were all hoping that we were going to see some benefit, and we had some preliminary data suggesting that we would. What we still need to see is whether there are potentially populations of patients who might have benefited more, which hopefully will come out of the biomarker analysis.”

The results demonstrate the need for controlled comparison trials to detect true clinical benefits from a specific agent or combination, she added.

Microsatellite-stable disease, which accounts for approximately 95% of cases of metastatic colorectal cancer (MSS mCRC) is considered to be an immune-excluded or “cold” tumor type due to a lack of tumor-infiltrating lymphocytes. Single agent inhibitors of the programmed death 1 protein and its ligand (PD1/PD-L1) have only minimal activity in MSS mCRC, she noted.

In preclinical studies, there was evidence to suggest that the combination of atezolizumab and cobimetinib could augment antitumor T-cell responses. The combination also was shown to be safe and to demonstrate “promising” clinical activity in a phase 1b trial conducted by Dr. Bendell and her colleagues.

To see whether the initial promise of atezolizumab in this population held up under closer scrutiny, the investigators enrolled patients with MSS mCRC refractory to chemotherapy and randomly assigned them on a 2:1:1 basis to receive either atezolizumab plus cobimetinib, atezolizumab monotherapy, or regorafenib.

Atezolizumab was administered intravenously at 840 mg every 2 weeks in the combination arm, and at 1,200 mg every 3 weeks in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule. Regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule.

As noted, the trial did not meet its primary endpoint of an OS benefit in the intention-to-treat population. In addition, there were no significant differences in either median progression-free survival, overall response rates, or duration of response.

Response rates for both the atezolizumab/cobimetinib combination and atezolizumab monotherapy arms were consistent with published data for other PD-1/PD-L1 inhibitors, and the safety of the combination was consistent with the known safety profiles of the individual agents, Dr. Bendell said.

The investigators are conducting extensive biomarker evaluations and gene expression profiles, and hope to present the results of these studies at a future conference, she added.

SOURCE: Bendell J et al. ESMO GI 2018. Abstract LBA-004.

BARCELONA – There was no overall survival advantage for patients with metastatic colorectal cancer treated with the immune checkpoint inhibitor atezolizumab (Tencentriq) either in combination with cobimetinib (Cotellic) or as monotherapy compared with regorafenib (Stivarga), results of the randomized phase 3 IMblaze370 trial showed.

Neil Osterweil/MDedge News

Median overall survival (OS, the primary endpoint) for 183 patients treated with atezolizumab and cobimetinib was 8.9 months, compared with 7.1 months for 90 patients treated with atezolizumab monotherapy, and 8.5 months for 90 patients treated with regorafenib. None of the differences were statistically significant, reported Johanna C. Bendell, MD, of the Sarah Cannon Research Institute in Nashville, Tenn.

“The lack of clinical activity may be due to the immune-excluded phenotype of metastatic colorectal cancer. The dual inhibition of the PD-L1 immune checkpoint and MAP kinase–mediated immune suppression may not be sufficient to generate that immune response that we need for antitumor activity,” she said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

In an interview, Dr. Bendell said that “we were all hoping that we were going to see some benefit, and we had some preliminary data suggesting that we would. What we still need to see is whether there are potentially populations of patients who might have benefited more, which hopefully will come out of the biomarker analysis.”

The results demonstrate the need for controlled comparison trials to detect true clinical benefits from a specific agent or combination, she added.

Microsatellite-stable disease, which accounts for approximately 95% of cases of metastatic colorectal cancer (MSS mCRC) is considered to be an immune-excluded or “cold” tumor type due to a lack of tumor-infiltrating lymphocytes. Single agent inhibitors of the programmed death 1 protein and its ligand (PD1/PD-L1) have only minimal activity in MSS mCRC, she noted.

In preclinical studies, there was evidence to suggest that the combination of atezolizumab and cobimetinib could augment antitumor T-cell responses. The combination also was shown to be safe and to demonstrate “promising” clinical activity in a phase 1b trial conducted by Dr. Bendell and her colleagues.

To see whether the initial promise of atezolizumab in this population held up under closer scrutiny, the investigators enrolled patients with MSS mCRC refractory to chemotherapy and randomly assigned them on a 2:1:1 basis to receive either atezolizumab plus cobimetinib, atezolizumab monotherapy, or regorafenib.

Atezolizumab was administered intravenously at 840 mg every 2 weeks in the combination arm, and at 1,200 mg every 3 weeks in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule. Regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule.

As noted, the trial did not meet its primary endpoint of an OS benefit in the intention-to-treat population. In addition, there were no significant differences in either median progression-free survival, overall response rates, or duration of response.

Response rates for both the atezolizumab/cobimetinib combination and atezolizumab monotherapy arms were consistent with published data for other PD-1/PD-L1 inhibitors, and the safety of the combination was consistent with the known safety profiles of the individual agents, Dr. Bendell said.

The investigators are conducting extensive biomarker evaluations and gene expression profiles, and hope to present the results of these studies at a future conference, she added.

SOURCE: Bendell J et al. ESMO GI 2018. Abstract LBA-004.

A large observational study from Great Britain paints a mixed picture of cancer risks associated with assisted reproduction technologies such as in vitro fertilization (IVF).

Among nearly 256,000 women who had assisted reproduction over a 2-decade period and were followed for more than 2.25 million person-years, there was no significant increase in risk of uterine cancers or invasive breast cancers.

However, these women were at slight but significantly increased risk for in situ breast cancers and invasive or borderline ovarian cancers, although the ovarian tumors may be related more to patient factors than to the assisted reproduction technology itself, reported Alastair Sutcliffe, MD, PhD, from University College London, and his colleagues.

“We were not able to distinguish between a genuine increase in risk of borderline ovarian tumors and other explanations including surveillance bias. Further investigation of this and longer follow-up is warranted to continue monitoring these important outcomes in this ever-growing population,” they wrote in BMJ.

Women who undergo IVF and related procedures are typically exposed to high levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and multiple ovarian punctures, all of which are potentially carcinogenic, the authors noted.

Previous studies of cancer risk in women who undergo assisted reproduction treatment have had conflicting or inconsistent results and lacked information on potential confounders, they pointed out.

To get a better sense of the potential risks, the investigators looked at linked data from the United Kingdom’s Human Fertilization and Embryology Authority and national cancer registries. They identified a total of 255,786 women treated from 1991 through 2010. Total follow-up was for 2,257,789 person-years.

They found that, during an average 8.8 years of follow-up, women had no significant increase in risk of tumors of the uterine corpus, with 164 cancers observed vs. 146.9 expected, for a standardized incidence ratio (SIR) of 1.12 (95% confidence interval, 0.95-1.30).

Similarly, there was no significant increase in risk of either breast cancer overall (2,578 observed vs. 2,641.2 expected; SIR, 0.98; 95% CI, 0.94-1.01) or invasive breast cancer (2,272 observed vs. 2,371.4 expected; SIR, 0.96; 95% CI, 0.92-1.00).

As noted, however, there was an increased risk of in situ breast cancer with 291 vs. 253.5 cases, respectively, translating into a SIR of 1.15 (95% CI, 1.02-1.29), for an absolute excess risk (AER) of 1.7 cases per 100,000 person-years, associated with an increasing number of treatment cycles (P = .03).

Additionally, the women in the study had an increased risk of ovarian cancer with an observed incidence of 405 vs. 291.82 expected, for an SIR of 1.39 (95% CI, 1.26-1.53) and an AER of 5.0 cases per 100,000 person-years.

There was a significantly increased risk for both invasive tumors, with 264 cases vs. 188.1 expected, for an SIR of 1.40 (95% CI, 1.24-1.58) and an AER of 3.4 cases per 100,000 person-years, and borderline ovarian cancers, with 141 vs. 103.7, for an SIR of 1.36 (95% CI, 1.15-1.60) and an AER of 1.7 cases per 100,000 person-years.

Increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male-factor or unexplained infertility.

Women who had previously given birth and did not have a diagnosis of endometriosis had no increase in risk for ovarian cancer. Instead, increased risk appeared to be limited to women with endometriosis, few or no births (low parity), or both.

The authors emphasized that ongoing monitoring of outcomes for women who have undergone assisted reproduction is essential.

The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.

SOURCE: Williams CL et al. BMJ. 2018;362:k2644.

A large observational study from Great Britain paints a mixed picture of cancer risks associated with assisted reproduction technologies such as in vitro fertilization (IVF).

Among nearly 256,000 women who had assisted reproduction over a 2-decade period and were followed for more than 2.25 million person-years, there was no significant increase in risk of uterine cancers or invasive breast cancers.

However, these women were at slight but significantly increased risk for in situ breast cancers and invasive or borderline ovarian cancers, although the ovarian tumors may be related more to patient factors than to the assisted reproduction technology itself, reported Alastair Sutcliffe, MD, PhD, from University College London, and his colleagues.

“We were not able to distinguish between a genuine increase in risk of borderline ovarian tumors and other explanations including surveillance bias. Further investigation of this and longer follow-up is warranted to continue monitoring these important outcomes in this ever-growing population,” they wrote in BMJ.

Women who undergo IVF and related procedures are typically exposed to high levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and multiple ovarian punctures, all of which are potentially carcinogenic, the authors noted.

Previous studies of cancer risk in women who undergo assisted reproduction treatment have had conflicting or inconsistent results and lacked information on potential confounders, they pointed out.

To get a better sense of the potential risks, the investigators looked at linked data from the United Kingdom’s Human Fertilization and Embryology Authority and national cancer registries. They identified a total of 255,786 women treated from 1991 through 2010. Total follow-up was for 2,257,789 person-years.

They found that, during an average 8.8 years of follow-up, women had no significant increase in risk of tumors of the uterine corpus, with 164 cancers observed vs. 146.9 expected, for a standardized incidence ratio (SIR) of 1.12 (95% confidence interval, 0.95-1.30).

Similarly, there was no significant increase in risk of either breast cancer overall (2,578 observed vs. 2,641.2 expected; SIR, 0.98; 95% CI, 0.94-1.01) or invasive breast cancer (2,272 observed vs. 2,371.4 expected; SIR, 0.96; 95% CI, 0.92-1.00).

As noted, however, there was an increased risk of in situ breast cancer with 291 vs. 253.5 cases, respectively, translating into a SIR of 1.15 (95% CI, 1.02-1.29), for an absolute excess risk (AER) of 1.7 cases per 100,000 person-years, associated with an increasing number of treatment cycles (P = .03).

Additionally, the women in the study had an increased risk of ovarian cancer with an observed incidence of 405 vs. 291.82 expected, for an SIR of 1.39 (95% CI, 1.26-1.53) and an AER of 5.0 cases per 100,000 person-years.

There was a significantly increased risk for both invasive tumors, with 264 cases vs. 188.1 expected, for an SIR of 1.40 (95% CI, 1.24-1.58) and an AER of 3.4 cases per 100,000 person-years, and borderline ovarian cancers, with 141 vs. 103.7, for an SIR of 1.36 (95% CI, 1.15-1.60) and an AER of 1.7 cases per 100,000 person-years.

Increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male-factor or unexplained infertility.

Women who had previously given birth and did not have a diagnosis of endometriosis had no increase in risk for ovarian cancer. Instead, increased risk appeared to be limited to women with endometriosis, few or no births (low parity), or both.

The authors emphasized that ongoing monitoring of outcomes for women who have undergone assisted reproduction is essential.

The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.

SOURCE: Williams CL et al. BMJ. 2018;362:k2644.

A large observational study from Great Britain paints a mixed picture of cancer risks associated with assisted reproduction technologies such as in vitro fertilization (IVF).

Among nearly 256,000 women who had assisted reproduction over a 2-decade period and were followed for more than 2.25 million person-years, there was no significant increase in risk of uterine cancers or invasive breast cancers.

However, these women were at slight but significantly increased risk for in situ breast cancers and invasive or borderline ovarian cancers, although the ovarian tumors may be related more to patient factors than to the assisted reproduction technology itself, reported Alastair Sutcliffe, MD, PhD, from University College London, and his colleagues.

“We were not able to distinguish between a genuine increase in risk of borderline ovarian tumors and other explanations including surveillance bias. Further investigation of this and longer follow-up is warranted to continue monitoring these important outcomes in this ever-growing population,” they wrote in BMJ.

Women who undergo IVF and related procedures are typically exposed to high levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and multiple ovarian punctures, all of which are potentially carcinogenic, the authors noted.

Previous studies of cancer risk in women who undergo assisted reproduction treatment have had conflicting or inconsistent results and lacked information on potential confounders, they pointed out.

To get a better sense of the potential risks, the investigators looked at linked data from the United Kingdom’s Human Fertilization and Embryology Authority and national cancer registries. They identified a total of 255,786 women treated from 1991 through 2010. Total follow-up was for 2,257,789 person-years.

They found that, during an average 8.8 years of follow-up, women had no significant increase in risk of tumors of the uterine corpus, with 164 cancers observed vs. 146.9 expected, for a standardized incidence ratio (SIR) of 1.12 (95% confidence interval, 0.95-1.30).

Similarly, there was no significant increase in risk of either breast cancer overall (2,578 observed vs. 2,641.2 expected; SIR, 0.98; 95% CI, 0.94-1.01) or invasive breast cancer (2,272 observed vs. 2,371.4 expected; SIR, 0.96; 95% CI, 0.92-1.00).

As noted, however, there was an increased risk of in situ breast cancer with 291 vs. 253.5 cases, respectively, translating into a SIR of 1.15 (95% CI, 1.02-1.29), for an absolute excess risk (AER) of 1.7 cases per 100,000 person-years, associated with an increasing number of treatment cycles (P = .03).

Additionally, the women in the study had an increased risk of ovarian cancer with an observed incidence of 405 vs. 291.82 expected, for an SIR of 1.39 (95% CI, 1.26-1.53) and an AER of 5.0 cases per 100,000 person-years.

There was a significantly increased risk for both invasive tumors, with 264 cases vs. 188.1 expected, for an SIR of 1.40 (95% CI, 1.24-1.58) and an AER of 3.4 cases per 100,000 person-years, and borderline ovarian cancers, with 141 vs. 103.7, for an SIR of 1.36 (95% CI, 1.15-1.60) and an AER of 1.7 cases per 100,000 person-years.

Increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male-factor or unexplained infertility.

Women who had previously given birth and did not have a diagnosis of endometriosis had no increase in risk for ovarian cancer. Instead, increased risk appeared to be limited to women with endometriosis, few or no births (low parity), or both.

The authors emphasized that ongoing monitoring of outcomes for women who have undergone assisted reproduction is essential.

The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.

SOURCE: Williams CL et al. BMJ. 2018;362:k2644.

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Neil Osterweil/MDedge News

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.

The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Neil Osterweil/MDedge News

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.

The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Neil Osterweil/MDedge News

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.

The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).

Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.

“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.

ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.

Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,

Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.

In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.

The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.

However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.

SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.

In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).

Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.

“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.

ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.

Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,

Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.

In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.

The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.

However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.

SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.

In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).

Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.

“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.

ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.

Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,

Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.

In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.

The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.

However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.

SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

For men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), a docetaxel-containing nanoparticle directed against prostate-specific membrane antigen (PSMA) was both active and well tolerated.

Among 42 men with mCRPC that had progressed after treatment with abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi), the 6-month radiographic progression-free survival (PFS) rate, the primary endpoint, was 65%, and approximately one-third of evaluable patients had a prostate-specific antigen (PSA) response and measurable disease response, reported Karen A. Autio, MD, MSc, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues.

Treatment with the PSMA-directed docetaxel-containing nanoparticle, called BIND-014, was also associated in some patients with a rapid and robust decline in PSMA-positive circulating tumor cells (CTCs), the investigators noted. The report was published in JAMA Oncology.

“Many aspects of our study – reductions in PSA, radiographically confirmed disease control in bone and visceral metastatic disease, favorable CTC conversions, and an acceptable adverse effect profile – were promising for BIND-014. However, standard therapy with docetaxel is widely used and effective in treating this disease, and as a natural comparator for a phase 3 randomized clinical trial with BIND-014, it sets a high bar for efficacy in an unselected population,” they wrote.

Their findings suggest that patients with PSMA-positive CTCs might be good candidates for treatment with BIND-014, which is associated with lower toxicities than standard docetaxel, the investigators said.

In the open-label phase 2 trial, 42 men (median age 66) with chemotherapy-naive mCRPC that had progressed on abiraterone and/or enzalutamide were treated with intravenous BIND-014 at dosages of 60 mg/m² on the first day of each 21-day cycle, plus prednisone 5 mg twice daily, until disease progression, intolerable toxicity, or treatment discontinuation at the treating physician’s discretion.

The median number of doses delivered was six.

Of 40 evaluable patients, 12 (30%) had a PSA response, defined as a decrease of 50% or greater from baseline. Among 19 patients with disease measurable according to Response Evaluation Criteria in Solid Tumors, version 1.1, six (32%) had responses, including one complete response and five partial responses. Nine other patients had stable disease.

The median PFS was 9.9 months. As noted, the radiographic PFS rate at 6 months was 65% (26 of 40 patients).

CTC enumeration was performed on samples from 39 patients, of whom 67% had unfavorable counts at baseline, defined as 5 or more CTCs per 7.5 mL of blood.

After treatment, 13 of the patients had a conversion to a favorable count, including 6 whose CTCs became undetectable.

The most common treatment-related adverse events were fatigue, occurring in 69% of patients, nausea in 55%, diarrhea in 45%, and patient-reported neuropathy in 33%. Most toxicities were grade 1 or 2.

Grade 3 or 4 hematological toxicities included lymphopenia in five patients, anemia in three, neutropenia in one, leukopenia in one, and febrile neutropenia in one.

Nonhematological grade 3 or 4 events included fatigue and nausea in two patients each, and dyspnea and decreased appetite in one patient each.

“In this trial, two principal lessons are worth highlighting: the reduction in both total CTCs, which is a marker of clinical benefit, and specifically PSMA-positive CTCs, suggests that the detection of PSMA-positive CTCs before treatment can be used to identify patients who are most likely to benefit in addition to serving as a pharmacodynamic measure,” the investigators wrote.

“Second, there was marked intrapatient and interpatient heterogeneity of PSMA expression on CTCs. This underscores the complexity of targeting tumors with single cell-surface markers,” they wrote.
 

SOURCE: Autio KA et al. JAMA Oncol. 2018 July 5 doi: 10.1001/jamaoncol.2018.2168.

For men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), a docetaxel-containing nanoparticle directed against prostate-specific membrane antigen (PSMA) was both active and well tolerated.

Among 42 men with mCRPC that had progressed after treatment with abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi), the 6-month radiographic progression-free survival (PFS) rate, the primary endpoint, was 65%, and approximately one-third of evaluable patients had a prostate-specific antigen (PSA) response and measurable disease response, reported Karen A. Autio, MD, MSc, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues.

Treatment with the PSMA-directed docetaxel-containing nanoparticle, called BIND-014, was also associated in some patients with a rapid and robust decline in PSMA-positive circulating tumor cells (CTCs), the investigators noted. The report was published in JAMA Oncology.

“Many aspects of our study – reductions in PSA, radiographically confirmed disease control in bone and visceral metastatic disease, favorable CTC conversions, and an acceptable adverse effect profile – were promising for BIND-014. However, standard therapy with docetaxel is widely used and effective in treating this disease, and as a natural comparator for a phase 3 randomized clinical trial with BIND-014, it sets a high bar for efficacy in an unselected population,” they wrote.

Their findings suggest that patients with PSMA-positive CTCs might be good candidates for treatment with BIND-014, which is associated with lower toxicities than standard docetaxel, the investigators said.

In the open-label phase 2 trial, 42 men (median age 66) with chemotherapy-naive mCRPC that had progressed on abiraterone and/or enzalutamide were treated with intravenous BIND-014 at dosages of 60 mg/m² on the first day of each 21-day cycle, plus prednisone 5 mg twice daily, until disease progression, intolerable toxicity, or treatment discontinuation at the treating physician’s discretion.

The median number of doses delivered was six.

Of 40 evaluable patients, 12 (30%) had a PSA response, defined as a decrease of 50% or greater from baseline. Among 19 patients with disease measurable according to Response Evaluation Criteria in Solid Tumors, version 1.1, six (32%) had responses, including one complete response and five partial responses. Nine other patients had stable disease.

The median PFS was 9.9 months. As noted, the radiographic PFS rate at 6 months was 65% (26 of 40 patients).

CTC enumeration was performed on samples from 39 patients, of whom 67% had unfavorable counts at baseline, defined as 5 or more CTCs per 7.5 mL of blood.

After treatment, 13 of the patients had a conversion to a favorable count, including 6 whose CTCs became undetectable.

The most common treatment-related adverse events were fatigue, occurring in 69% of patients, nausea in 55%, diarrhea in 45%, and patient-reported neuropathy in 33%. Most toxicities were grade 1 or 2.

Grade 3 or 4 hematological toxicities included lymphopenia in five patients, anemia in three, neutropenia in one, leukopenia in one, and febrile neutropenia in one.

Nonhematological grade 3 or 4 events included fatigue and nausea in two patients each, and dyspnea and decreased appetite in one patient each.

“In this trial, two principal lessons are worth highlighting: the reduction in both total CTCs, which is a marker of clinical benefit, and specifically PSMA-positive CTCs, suggests that the detection of PSMA-positive CTCs before treatment can be used to identify patients who are most likely to benefit in addition to serving as a pharmacodynamic measure,” the investigators wrote.

“Second, there was marked intrapatient and interpatient heterogeneity of PSMA expression on CTCs. This underscores the complexity of targeting tumors with single cell-surface markers,” they wrote.
 

SOURCE: Autio KA et al. JAMA Oncol. 2018 July 5 doi: 10.1001/jamaoncol.2018.2168.

For men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), a docetaxel-containing nanoparticle directed against prostate-specific membrane antigen (PSMA) was both active and well tolerated.

Among 42 men with mCRPC that had progressed after treatment with abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi), the 6-month radiographic progression-free survival (PFS) rate, the primary endpoint, was 65%, and approximately one-third of evaluable patients had a prostate-specific antigen (PSA) response and measurable disease response, reported Karen A. Autio, MD, MSc, of Memorial Sloan Kettering Cancer Center, New York, and her colleagues.

Treatment with the PSMA-directed docetaxel-containing nanoparticle, called BIND-014, was also associated in some patients with a rapid and robust decline in PSMA-positive circulating tumor cells (CTCs), the investigators noted. The report was published in JAMA Oncology.

“Many aspects of our study – reductions in PSA, radiographically confirmed disease control in bone and visceral metastatic disease, favorable CTC conversions, and an acceptable adverse effect profile – were promising for BIND-014. However, standard therapy with docetaxel is widely used and effective in treating this disease, and as a natural comparator for a phase 3 randomized clinical trial with BIND-014, it sets a high bar for efficacy in an unselected population,” they wrote.

Their findings suggest that patients with PSMA-positive CTCs might be good candidates for treatment with BIND-014, which is associated with lower toxicities than standard docetaxel, the investigators said.

In the open-label phase 2 trial, 42 men (median age 66) with chemotherapy-naive mCRPC that had progressed on abiraterone and/or enzalutamide were treated with intravenous BIND-014 at dosages of 60 mg/m² on the first day of each 21-day cycle, plus prednisone 5 mg twice daily, until disease progression, intolerable toxicity, or treatment discontinuation at the treating physician’s discretion.

The median number of doses delivered was six.

Of 40 evaluable patients, 12 (30%) had a PSA response, defined as a decrease of 50% or greater from baseline. Among 19 patients with disease measurable according to Response Evaluation Criteria in Solid Tumors, version 1.1, six (32%) had responses, including one complete response and five partial responses. Nine other patients had stable disease.

The median PFS was 9.9 months. As noted, the radiographic PFS rate at 6 months was 65% (26 of 40 patients).

CTC enumeration was performed on samples from 39 patients, of whom 67% had unfavorable counts at baseline, defined as 5 or more CTCs per 7.5 mL of blood.

After treatment, 13 of the patients had a conversion to a favorable count, including 6 whose CTCs became undetectable.

The most common treatment-related adverse events were fatigue, occurring in 69% of patients, nausea in 55%, diarrhea in 45%, and patient-reported neuropathy in 33%. Most toxicities were grade 1 or 2.

Grade 3 or 4 hematological toxicities included lymphopenia in five patients, anemia in three, neutropenia in one, leukopenia in one, and febrile neutropenia in one.

Nonhematological grade 3 or 4 events included fatigue and nausea in two patients each, and dyspnea and decreased appetite in one patient each.

“In this trial, two principal lessons are worth highlighting: the reduction in both total CTCs, which is a marker of clinical benefit, and specifically PSMA-positive CTCs, suggests that the detection of PSMA-positive CTCs before treatment can be used to identify patients who are most likely to benefit in addition to serving as a pharmacodynamic measure,” the investigators wrote.

“Second, there was marked intrapatient and interpatient heterogeneity of PSMA expression on CTCs. This underscores the complexity of targeting tumors with single cell-surface markers,” they wrote.
 

SOURCE: Autio KA et al. JAMA Oncol. 2018 July 5 doi: 10.1001/jamaoncol.2018.2168.