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CTCs linked to late recurrence in HER2–, HR+ breast cancer
Circulating tumor cells could be used to stratify patients with hormone receptor (HR)–positive, HER2-negative breast cancer for late recurrence risk, results of a secondary analysis of a randomized clinical trial suggest.
Risk of late clinical recurrence was about 13-fold higher among HR-positive patients with a positive circulating tumor cell (CTC) assay result, according to results of the study, published in JAMA Oncology.
“This prospectively conducted study offers a high level of evidence supporting the association between a positive CTC assay result and risk of clinical recurrence,” said Joseph A. Sparano, MD, of Albert Einstein College of Medicine, New York, and his coauthors.
The present study is the first to show that this CTC assay may play a role in determining late clinical recurrence after local and systemic adjuvant therapy, according to the investigators.
The study is a secondary analysis of E5103, a phase 3 trial of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel with bevacizumab in patients with HER2-negative stage II-III breast cancer. Investigators included a total of 547 patients who had no clinical evidence of recurrence between 4.5 and 7.5 years of registration in that trial.
Positive CTC assay results occurred in 26 of those patients (4.8%), they found.
At a median follow-up of 2.6 years, 24 patients had a clinical recurrence, including 23 HR-positive patients and just 1 HR-negative patient. Accordingly, the investigators focused most of their further analysis on the HR-positive subset.
A total of 7 of 23 patients with HR-positive disease (30.4%) had a positive CTC assay result.
A positive CTC result in HR-positive patients was associated with a 13.1-fold increased risk of recurrence, multivariate analysis showed.
Higher CTC burden appeared to be associated with a numerically higher recurrence risk in HR-positive patients, the investigators found. They saw recurrences in 16 of 335 patients with a CTC count of 0 cells per 7.5 mL blood (4.8%), compared with 2 of 12 patients with 1 cell per 7.5 mL blood (16.7%), and 5 of 6 patients with 2 or more cells per 7.5 mL (83.3%).
Taken together, these results provided proof of concept to support additional investigations of the CTC assay and other blood-based biomarker tests in the setting of late clinical recurrence in HR-positive patients, the researchers said.
They acknowledged several limitations of this study: It was small, it had relatively short follow-up, and it did not evaluate the CTC assay in the context of other assays.
“Notwithstanding proof of concept, further evaluation is required to confirm the clinical validity and determine the clinical utility of performing the CTC assay in this context,” Dr. Sparano and his coauthors wrote.
Late recurrences, or those that occur more than 5 years after diagnosis, account for about half of all recurrences among HR-positive receptive breast cancers, Dr. Sparano and his colleagues said.
The researchers had no conflicts of interest to report. The study was supported by grants from the National Cancer Institute, National Institutes of Health, Breast Cancer Research Foundation, and Susan G. Komen Foundation.
SOURCE: Sparano J et al. JAMA Oncol. 2018 Jul 26. doi: 10.1001/jamaoncol.2018.2574.
Circulating tumor cells could be used to stratify patients with hormone receptor (HR)–positive, HER2-negative breast cancer for late recurrence risk, results of a secondary analysis of a randomized clinical trial suggest.
Risk of late clinical recurrence was about 13-fold higher among HR-positive patients with a positive circulating tumor cell (CTC) assay result, according to results of the study, published in JAMA Oncology.
“This prospectively conducted study offers a high level of evidence supporting the association between a positive CTC assay result and risk of clinical recurrence,” said Joseph A. Sparano, MD, of Albert Einstein College of Medicine, New York, and his coauthors.
The present study is the first to show that this CTC assay may play a role in determining late clinical recurrence after local and systemic adjuvant therapy, according to the investigators.
The study is a secondary analysis of E5103, a phase 3 trial of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel with bevacizumab in patients with HER2-negative stage II-III breast cancer. Investigators included a total of 547 patients who had no clinical evidence of recurrence between 4.5 and 7.5 years of registration in that trial.
Positive CTC assay results occurred in 26 of those patients (4.8%), they found.
At a median follow-up of 2.6 years, 24 patients had a clinical recurrence, including 23 HR-positive patients and just 1 HR-negative patient. Accordingly, the investigators focused most of their further analysis on the HR-positive subset.
A total of 7 of 23 patients with HR-positive disease (30.4%) had a positive CTC assay result.
A positive CTC result in HR-positive patients was associated with a 13.1-fold increased risk of recurrence, multivariate analysis showed.
Higher CTC burden appeared to be associated with a numerically higher recurrence risk in HR-positive patients, the investigators found. They saw recurrences in 16 of 335 patients with a CTC count of 0 cells per 7.5 mL blood (4.8%), compared with 2 of 12 patients with 1 cell per 7.5 mL blood (16.7%), and 5 of 6 patients with 2 or more cells per 7.5 mL (83.3%).
Taken together, these results provided proof of concept to support additional investigations of the CTC assay and other blood-based biomarker tests in the setting of late clinical recurrence in HR-positive patients, the researchers said.
They acknowledged several limitations of this study: It was small, it had relatively short follow-up, and it did not evaluate the CTC assay in the context of other assays.
“Notwithstanding proof of concept, further evaluation is required to confirm the clinical validity and determine the clinical utility of performing the CTC assay in this context,” Dr. Sparano and his coauthors wrote.
Late recurrences, or those that occur more than 5 years after diagnosis, account for about half of all recurrences among HR-positive receptive breast cancers, Dr. Sparano and his colleagues said.
The researchers had no conflicts of interest to report. The study was supported by grants from the National Cancer Institute, National Institutes of Health, Breast Cancer Research Foundation, and Susan G. Komen Foundation.
SOURCE: Sparano J et al. JAMA Oncol. 2018 Jul 26. doi: 10.1001/jamaoncol.2018.2574.
Circulating tumor cells could be used to stratify patients with hormone receptor (HR)–positive, HER2-negative breast cancer for late recurrence risk, results of a secondary analysis of a randomized clinical trial suggest.
Risk of late clinical recurrence was about 13-fold higher among HR-positive patients with a positive circulating tumor cell (CTC) assay result, according to results of the study, published in JAMA Oncology.
“This prospectively conducted study offers a high level of evidence supporting the association between a positive CTC assay result and risk of clinical recurrence,” said Joseph A. Sparano, MD, of Albert Einstein College of Medicine, New York, and his coauthors.
The present study is the first to show that this CTC assay may play a role in determining late clinical recurrence after local and systemic adjuvant therapy, according to the investigators.
The study is a secondary analysis of E5103, a phase 3 trial of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel with bevacizumab in patients with HER2-negative stage II-III breast cancer. Investigators included a total of 547 patients who had no clinical evidence of recurrence between 4.5 and 7.5 years of registration in that trial.
Positive CTC assay results occurred in 26 of those patients (4.8%), they found.
At a median follow-up of 2.6 years, 24 patients had a clinical recurrence, including 23 HR-positive patients and just 1 HR-negative patient. Accordingly, the investigators focused most of their further analysis on the HR-positive subset.
A total of 7 of 23 patients with HR-positive disease (30.4%) had a positive CTC assay result.
A positive CTC result in HR-positive patients was associated with a 13.1-fold increased risk of recurrence, multivariate analysis showed.
Higher CTC burden appeared to be associated with a numerically higher recurrence risk in HR-positive patients, the investigators found. They saw recurrences in 16 of 335 patients with a CTC count of 0 cells per 7.5 mL blood (4.8%), compared with 2 of 12 patients with 1 cell per 7.5 mL blood (16.7%), and 5 of 6 patients with 2 or more cells per 7.5 mL (83.3%).
Taken together, these results provided proof of concept to support additional investigations of the CTC assay and other blood-based biomarker tests in the setting of late clinical recurrence in HR-positive patients, the researchers said.
They acknowledged several limitations of this study: It was small, it had relatively short follow-up, and it did not evaluate the CTC assay in the context of other assays.
“Notwithstanding proof of concept, further evaluation is required to confirm the clinical validity and determine the clinical utility of performing the CTC assay in this context,” Dr. Sparano and his coauthors wrote.
Late recurrences, or those that occur more than 5 years after diagnosis, account for about half of all recurrences among HR-positive receptive breast cancers, Dr. Sparano and his colleagues said.
The researchers had no conflicts of interest to report. The study was supported by grants from the National Cancer Institute, National Institutes of Health, Breast Cancer Research Foundation, and Susan G. Komen Foundation.
SOURCE: Sparano J et al. JAMA Oncol. 2018 Jul 26. doi: 10.1001/jamaoncol.2018.2574.
FROM JAMA ONCOLOGY
Key clinical point: Circulating tumor cells (CTC) may help to evaluate late recurrence risk in patients with HER2-negative breast cancer.
Major finding: A positive CTC result was associated with a 13.1-fold increased risk of recurrence in hormone receptor–positive patients.
Study details: Secondary analysis of a randomized clinical trial including 547 patients with HER2-negative stage II-III breast cancer.
Disclosures: The study was supported by grants from the National Cancer Institute, National Institutes of Health, Breast Cancer Research Foundation, and Susan G. Komen Foundation. The authors reported no conflicts of interest.
Source: Sparano J et al. JAMA Oncol. 2018 Jul 26. doi: 10.1001/jamaoncol.2018.2574.
Lower CTC count IDs indolent MBC disease subset
CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.
The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.
In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.
Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IVindolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.
For example, median OS in patients with stage IVindolent vs. stage IVaggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IVindolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.
In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.
“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.
This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
SOURCE: Davis A et al., ASCO 2018 Poster 1019.
CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.
The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.
In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.
Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IVindolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.
For example, median OS in patients with stage IVindolent vs. stage IVaggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IVindolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.
In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.
“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.
This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
SOURCE: Davis A et al., ASCO 2018 Poster 1019.
CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.
The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.
In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.
Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IVindolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.
For example, median OS in patients with stage IVindolent vs. stage IVaggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IVindolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.
In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.
“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.
This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
SOURCE: Davis A et al., ASCO 2018 Poster 1019.
REPORTING FROM ASCO 2018
Key clinical point: A CTC count less than 5 per 7.5 mL of blood in patients with MBC indicates an indolent disease subset.
Major finding: Median OS for stage IVindolent vs. stage IVaggressive disease was 4.0 vs. 17.3 months in HER2-negative patients, 23.8 vs. 9.0 months in TNBC patients, and 36.7 vs. 20.4 months in HER2-positive disease.
Study details: A pooled analysis of data from two cohort studies including 2,436 patients.
Disclosures: This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.
Source: Davis A et al. ASCO 2018 Poster 1019.
Breast cancer patients don’t get the financial counseling they want from their clinicians
About half of medical oncologists – and even fewer surgeons and radiation oncologists – have someone in their practice to discuss the financial implications of treating breast cancer, a physician-patient survey has found.
Patients are feeling that lack of service, too; 73% of women in the survey said their providers didn’t offer much, or even any, help in tackling the potentially devastating financial impact of their cancer. Women reported a variety of these issues, including increased debt, lost time at work, skimping on their food budget, and even losing their homes as the medical bills added up.
“The privations observed in the current study are sobering and consistent with studies published before the widespread awareness of the potential for financial toxicity after the diagnosis and treatment of cancer,” wrote Reshma Jagsi, MD, and coauthors. The report was published in Cancer. 
“… Unfortunately, unmet needs for discussion persist, as does unresolved worry. The percentage of patients who perceive meaningful clinician engagement is low, with far fewer than one-quarter of respondents reporting more than a little discussion of these issues, which is strikingly lower than the percentage of providers who perceive routinely making services available,” they wrote.
Dr. Jagsi, of the University of Michigan, Ann Arbor, and her colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to identify 2,502 women in Georgia and Los Angeles County who were diagnosed with early-stage breast cancer from 2013 to 2015. They contacted these women, who were at least 1 year out from diagnosis, and their oncology providers with a survey designed to determine how both groups communicated about financial issues, and how those issues affected patients’ day-to-day lives.
Most of the clinicians were surgeons (370); the rest were medical oncologists (306) or radiation oncologists (169). About a quarter of each group was in a teaching practice.
Among the medical oncologists, 50.9% reported that someone in their practice often or always discussed financial burden with patients, as did 15.6% of surgeons and 43.2% of radiation oncologists. Medical oncologists were also more likely to respond that they were very aware of out-of-pocket costs for patients, as did 27.3% of surgeons and 34.3% of radiation oncologists.
About 57% of medical oncologists thought it was quite or extremely important to save their patients money; 35.3% of surgeons and 55.8% of radiation oncologists also responded so.
Many women reported at least some measure of financial toxicity related to their cancer and its treatment, and this varied widely by ethnicity and race. Debt was common, noted by 58.9% of black patients, 33.5% of Latina patients, and about 28% of both white and Asian patients.
“Many patients also had substantial lost income and out-of-pocket expenses that they attributed to breast cancer,” the authors wrote. “Overall, 14% of patients reported lost income that was [at least] 10% of their household income, 17% of patients reported spending [at least] 10% of household income on out-of-pocket medical expenses, and 7% of patients reported spending [at least] 10% of household income on out-of-pocket nonmedical expenses.
Housing loss attributed to breast cancer was most common among blacks (6%) and Latinas (4.7%), and less so among whites and Asians (about 1% each).
Blacks and Latinas also were more likely to report a utility disconnection due to unpaid bills (5.9% and 3.2%, respectively) compared with whites and Asians (1.7% and 0.5%).
One way women financially coped, the survey found, was to cut the food budget. “One in five whites [21.5%] and Asians [22.5%] cut down spending on food, as did nearly one-half of black individuals [45.2%] and greater than one-third of Latinas [35.8%].”
Worry about finances was most common among blacks and Latinas (about 50%), but about a third of white and Asian women also reported worry. Survey results suggested that clinicians were not addressing these issues.
Women – especially nonwhite women – wanted to have these talks, with 15.2% of whites, 31.1% of blacks, 30.3% of Latinas, and 25.4% of Asians reporting this desire.
“Unmet patient needs for engagement with physicians regarding financial concerns were common. Of the 945 women who expressed worrying at least somewhat, 679 (72.8%) indicated that cancer physicians and their staff did not help at least somewhat,” the authors said.
More than half of the 523 women who expressed a desire to talk to health care providers regarding the impact of breast cancer on employment or finances (55.4%) reported that this discussion never took place, either with the oncologist, primary care provider, social worker, or any other professional involved in their care.
A multivariate analysis examined patient characteristics associated with the desire to discuss financial toxicity with a health care provider. Younger age, nonwhite race, lower income, being employed, receiving chemotherapy, and living in Georgia all showed significant, independent interaction.
“Given these findings, it is clear that thoughtfully designed, prospective interventions are necessary to address the remarkably common experiences of financial burden that patients report even in the modern era,” the investigators wrote. “These interventions might include training for physicians and their staff regarding how to have effective conversations in this context, in ways that are sensitive to cultural differences and needs. Other promising approaches might include the use of advanced technology to engage patients in interactive exercises that elicit their financial concerns and experiences and alert providers to their needs.”
The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
SOURCE: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
About half of medical oncologists – and even fewer surgeons and radiation oncologists – have someone in their practice to discuss the financial implications of treating breast cancer, a physician-patient survey has found.
Patients are feeling that lack of service, too; 73% of women in the survey said their providers didn’t offer much, or even any, help in tackling the potentially devastating financial impact of their cancer. Women reported a variety of these issues, including increased debt, lost time at work, skimping on their food budget, and even losing their homes as the medical bills added up.
“The privations observed in the current study are sobering and consistent with studies published before the widespread awareness of the potential for financial toxicity after the diagnosis and treatment of cancer,” wrote Reshma Jagsi, MD, and coauthors. The report was published in Cancer.
“… Unfortunately, unmet needs for discussion persist, as does unresolved worry. The percentage of patients who perceive meaningful clinician engagement is low, with far fewer than one-quarter of respondents reporting more than a little discussion of these issues, which is strikingly lower than the percentage of providers who perceive routinely making services available,” they wrote.
Dr. Jagsi, of the University of Michigan, Ann Arbor, and her colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to identify 2,502 women in Georgia and Los Angeles County who were diagnosed with early-stage breast cancer from 2013 to 2015. They contacted these women, who were at least 1 year out from diagnosis, and their oncology providers with a survey designed to determine how both groups communicated about financial issues, and how those issues affected patients’ day-to-day lives.
Most of the clinicians were surgeons (370); the rest were medical oncologists (306) or radiation oncologists (169). About a quarter of each group was in a teaching practice.
Among the medical oncologists, 50.9% reported that someone in their practice often or always discussed financial burden with patients, as did 15.6% of surgeons and 43.2% of radiation oncologists. Medical oncologists were also more likely to respond that they were very aware of out-of-pocket costs for patients, as did 27.3% of surgeons and 34.3% of radiation oncologists.
About 57% of medical oncologists thought it was quite or extremely important to save their patients money; 35.3% of surgeons and 55.8% of radiation oncologists also responded so.
Many women reported at least some measure of financial toxicity related to their cancer and its treatment, and this varied widely by ethnicity and race. Debt was common, noted by 58.9% of black patients, 33.5% of Latina patients, and about 28% of both white and Asian patients.
“Many patients also had substantial lost income and out-of-pocket expenses that they attributed to breast cancer,” the authors wrote. “Overall, 14% of patients reported lost income that was [at least] 10% of their household income, 17% of patients reported spending [at least] 10% of household income on out-of-pocket medical expenses, and 7% of patients reported spending [at least] 10% of household income on out-of-pocket nonmedical expenses.
Housing loss attributed to breast cancer was most common among blacks (6%) and Latinas (4.7%), and less so among whites and Asians (about 1% each).
Blacks and Latinas also were more likely to report a utility disconnection due to unpaid bills (5.9% and 3.2%, respectively) compared with whites and Asians (1.7% and 0.5%).
One way women financially coped, the survey found, was to cut the food budget. “One in five whites [21.5%] and Asians [22.5%] cut down spending on food, as did nearly one-half of black individuals [45.2%] and greater than one-third of Latinas [35.8%].”
Worry about finances was most common among blacks and Latinas (about 50%), but about a third of white and Asian women also reported worry. Survey results suggested that clinicians were not addressing these issues.
Women – especially nonwhite women – wanted to have these talks, with 15.2% of whites, 31.1% of blacks, 30.3% of Latinas, and 25.4% of Asians reporting this desire.
“Unmet patient needs for engagement with physicians regarding financial concerns were common. Of the 945 women who expressed worrying at least somewhat, 679 (72.8%) indicated that cancer physicians and their staff did not help at least somewhat,” the authors said.
More than half of the 523 women who expressed a desire to talk to health care providers regarding the impact of breast cancer on employment or finances (55.4%) reported that this discussion never took place, either with the oncologist, primary care provider, social worker, or any other professional involved in their care.
A multivariate analysis examined patient characteristics associated with the desire to discuss financial toxicity with a health care provider. Younger age, nonwhite race, lower income, being employed, receiving chemotherapy, and living in Georgia all showed significant, independent interaction.
“Given these findings, it is clear that thoughtfully designed, prospective interventions are necessary to address the remarkably common experiences of financial burden that patients report even in the modern era,” the investigators wrote. “These interventions might include training for physicians and their staff regarding how to have effective conversations in this context, in ways that are sensitive to cultural differences and needs. Other promising approaches might include the use of advanced technology to engage patients in interactive exercises that elicit their financial concerns and experiences and alert providers to their needs.”
The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
SOURCE: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
About half of medical oncologists – and even fewer surgeons and radiation oncologists – have someone in their practice to discuss the financial implications of treating breast cancer, a physician-patient survey has found.
Patients are feeling that lack of service, too; 73% of women in the survey said their providers didn’t offer much, or even any, help in tackling the potentially devastating financial impact of their cancer. Women reported a variety of these issues, including increased debt, lost time at work, skimping on their food budget, and even losing their homes as the medical bills added up.
“The privations observed in the current study are sobering and consistent with studies published before the widespread awareness of the potential for financial toxicity after the diagnosis and treatment of cancer,” wrote Reshma Jagsi, MD, and coauthors. The report was published in Cancer.
“… Unfortunately, unmet needs for discussion persist, as does unresolved worry. The percentage of patients who perceive meaningful clinician engagement is low, with far fewer than one-quarter of respondents reporting more than a little discussion of these issues, which is strikingly lower than the percentage of providers who perceive routinely making services available,” they wrote.
Dr. Jagsi, of the University of Michigan, Ann Arbor, and her colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to identify 2,502 women in Georgia and Los Angeles County who were diagnosed with early-stage breast cancer from 2013 to 2015. They contacted these women, who were at least 1 year out from diagnosis, and their oncology providers with a survey designed to determine how both groups communicated about financial issues, and how those issues affected patients’ day-to-day lives.
Most of the clinicians were surgeons (370); the rest were medical oncologists (306) or radiation oncologists (169). About a quarter of each group was in a teaching practice.
Among the medical oncologists, 50.9% reported that someone in their practice often or always discussed financial burden with patients, as did 15.6% of surgeons and 43.2% of radiation oncologists. Medical oncologists were also more likely to respond that they were very aware of out-of-pocket costs for patients, as did 27.3% of surgeons and 34.3% of radiation oncologists.
About 57% of medical oncologists thought it was quite or extremely important to save their patients money; 35.3% of surgeons and 55.8% of radiation oncologists also responded so.
Many women reported at least some measure of financial toxicity related to their cancer and its treatment, and this varied widely by ethnicity and race. Debt was common, noted by 58.9% of black patients, 33.5% of Latina patients, and about 28% of both white and Asian patients.
“Many patients also had substantial lost income and out-of-pocket expenses that they attributed to breast cancer,” the authors wrote. “Overall, 14% of patients reported lost income that was [at least] 10% of their household income, 17% of patients reported spending [at least] 10% of household income on out-of-pocket medical expenses, and 7% of patients reported spending [at least] 10% of household income on out-of-pocket nonmedical expenses.
Housing loss attributed to breast cancer was most common among blacks (6%) and Latinas (4.7%), and less so among whites and Asians (about 1% each).
Blacks and Latinas also were more likely to report a utility disconnection due to unpaid bills (5.9% and 3.2%, respectively) compared with whites and Asians (1.7% and 0.5%).
One way women financially coped, the survey found, was to cut the food budget. “One in five whites [21.5%] and Asians [22.5%] cut down spending on food, as did nearly one-half of black individuals [45.2%] and greater than one-third of Latinas [35.8%].”
Worry about finances was most common among blacks and Latinas (about 50%), but about a third of white and Asian women also reported worry. Survey results suggested that clinicians were not addressing these issues.
Women – especially nonwhite women – wanted to have these talks, with 15.2% of whites, 31.1% of blacks, 30.3% of Latinas, and 25.4% of Asians reporting this desire.
“Unmet patient needs for engagement with physicians regarding financial concerns were common. Of the 945 women who expressed worrying at least somewhat, 679 (72.8%) indicated that cancer physicians and their staff did not help at least somewhat,” the authors said.
More than half of the 523 women who expressed a desire to talk to health care providers regarding the impact of breast cancer on employment or finances (55.4%) reported that this discussion never took place, either with the oncologist, primary care provider, social worker, or any other professional involved in their care.
A multivariate analysis examined patient characteristics associated with the desire to discuss financial toxicity with a health care provider. Younger age, nonwhite race, lower income, being employed, receiving chemotherapy, and living in Georgia all showed significant, independent interaction.
“Given these findings, it is clear that thoughtfully designed, prospective interventions are necessary to address the remarkably common experiences of financial burden that patients report even in the modern era,” the investigators wrote. “These interventions might include training for physicians and their staff regarding how to have effective conversations in this context, in ways that are sensitive to cultural differences and needs. Other promising approaches might include the use of advanced technology to engage patients in interactive exercises that elicit their financial concerns and experiences and alert providers to their needs.”
The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
SOURCE: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
FROM CANCER
Key clinical point: Oncology care providers aren’t providing adequate financial counseling for patients with breast cancer.
Major finding: Half of medical oncologists say they don’t have a staff member routinely discuss the financial impact of breast cancer, and 73% of patients say they’ve never had this discussion with their doctor.
Study details: The survey comprised 2,502 patients and 845 physicians.
Disclosures: The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
Source: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
Trio of biosimilars have good showing
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
REPORTING FROM ASCO 2018
Key clinical point: Biosimilars for bevacizumab, trastuzumab, and filgrastim showed similar efficacy and safety.
Major finding: In patients with advanced nonsquamous NSCLC, the overall response rate was 45.3% with a candidate bevacizumab biosimilar and 44.6% with bevacizumab. In patients with HER2+ advanced breast cancer, 48-week median progression-free survival was 11.1 months for both trastuzumab-dkst and trastuzumab. The rate of chemotherapy-induced febrile neutropenia among breast cancer patients given a biosimilar for filgrastim was 5.1% in a trial population and 6.2% in a real-world population.
Study details: Randomized, controlled trials of first-line therapy among 719 patients with advanced nonsquamous NSCLC (REFLECTIONS trial) and among 458 patients with HER2+ advanced breast cancer (HERITAGE trial). Comparison of outcomes in a randomized, controlled trial among 217 patients with nonmetastatic breast cancer (PIONEER trial) and a real-world cohort study of 466 patients with any-stage breast cancer (MONITOR-GCSF).
Disclosures: Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were sponsored by Sandoz.
Source: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
Could High BMI Reduce Premenopausal Breast Cancer Risk?
Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.
The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.
The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.
Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.
Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.
Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.
The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.
The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.
Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.
Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.
Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.
The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.
The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.
Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.
Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.
FDA expands indication for ribociclib for advanced breast cancer
The Food and Drug Administration has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy.
Ribociclib was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative advanced breast cancer in postmenopausal women.
Approval for ribociclib in combination with an AI for pre/perimenopausal women was based on progression-free survival (PFS) in MONALEESA-7, a trial of premenopausal women with HR-positive, HER2-negative, advanced breast cancer. The women received either ribociclib and an AI, or placebo and an AI, and all also received ovarian suppression with goserelin (Zoladex). Of 495 women who received nonsteroidal AIs, median PFS was 27.5 months for women also receiving ribociclib, versus 13.8 months for women who received placebo plus the AI.
Approval for ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was based on PFS results from MONALEESA-3, which enrolled 726 women with HR-positive, HER2-negative, advanced breast cancer who received no or up to one line of prior endocrine therapy. Median PFS was 20.5 months for women randomized to receive ribociclib and fulvestrant, compared with 12.8 months for women randomized to receive placebo plus fulvestrant.
The common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash. Warnings include the risk of QT prolongation, serious liver problems, low white blood cell counts, and fetal harm, the FDA said.
This is the first FDA approval as part of two new pilot programs announced earlier this year: Real-Time Oncology Review allows for the FDA to review much of the data earlier, before the information is formally submitted to the FDA, and the Assessment Aid is a structured template that offers a more streamlined approach.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information,” FDA Commissioner Scott Gottlieb, MD, said in the press statement. “This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
The two pilot programs are currently being used for supplemental applications for already approved cancer drugs and could later be expanded to original drugs and biologics, the FDA said.
Ribociclib is marketed as Kisqali by Novartis Pharmaceuticals Corporation.
The Food and Drug Administration has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy.
Ribociclib was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative advanced breast cancer in postmenopausal women.
Approval for ribociclib in combination with an AI for pre/perimenopausal women was based on progression-free survival (PFS) in MONALEESA-7, a trial of premenopausal women with HR-positive, HER2-negative, advanced breast cancer. The women received either ribociclib and an AI, or placebo and an AI, and all also received ovarian suppression with goserelin (Zoladex). Of 495 women who received nonsteroidal AIs, median PFS was 27.5 months for women also receiving ribociclib, versus 13.8 months for women who received placebo plus the AI.
Approval for ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was based on PFS results from MONALEESA-3, which enrolled 726 women with HR-positive, HER2-negative, advanced breast cancer who received no or up to one line of prior endocrine therapy. Median PFS was 20.5 months for women randomized to receive ribociclib and fulvestrant, compared with 12.8 months for women randomized to receive placebo plus fulvestrant.
The common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash. Warnings include the risk of QT prolongation, serious liver problems, low white blood cell counts, and fetal harm, the FDA said.
This is the first FDA approval as part of two new pilot programs announced earlier this year: Real-Time Oncology Review allows for the FDA to review much of the data earlier, before the information is formally submitted to the FDA, and the Assessment Aid is a structured template that offers a more streamlined approach.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information,” FDA Commissioner Scott Gottlieb, MD, said in the press statement. “This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
The two pilot programs are currently being used for supplemental applications for already approved cancer drugs and could later be expanded to original drugs and biologics, the FDA said.
Ribociclib is marketed as Kisqali by Novartis Pharmaceuticals Corporation.
The Food and Drug Administration has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy.
Ribociclib was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative advanced breast cancer in postmenopausal women.
Approval for ribociclib in combination with an AI for pre/perimenopausal women was based on progression-free survival (PFS) in MONALEESA-7, a trial of premenopausal women with HR-positive, HER2-negative, advanced breast cancer. The women received either ribociclib and an AI, or placebo and an AI, and all also received ovarian suppression with goserelin (Zoladex). Of 495 women who received nonsteroidal AIs, median PFS was 27.5 months for women also receiving ribociclib, versus 13.8 months for women who received placebo plus the AI.
Approval for ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was based on PFS results from MONALEESA-3, which enrolled 726 women with HR-positive, HER2-negative, advanced breast cancer who received no or up to one line of prior endocrine therapy. Median PFS was 20.5 months for women randomized to receive ribociclib and fulvestrant, compared with 12.8 months for women randomized to receive placebo plus fulvestrant.
The common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash. Warnings include the risk of QT prolongation, serious liver problems, low white blood cell counts, and fetal harm, the FDA said.
This is the first FDA approval as part of two new pilot programs announced earlier this year: Real-Time Oncology Review allows for the FDA to review much of the data earlier, before the information is formally submitted to the FDA, and the Assessment Aid is a structured template that offers a more streamlined approach.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information,” FDA Commissioner Scott Gottlieb, MD, said in the press statement. “This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
The two pilot programs are currently being used for supplemental applications for already approved cancer drugs and could later be expanded to original drugs and biologics, the FDA said.
Ribociclib is marketed as Kisqali by Novartis Pharmaceuticals Corporation.
ABP 980 similar to trastuzumab in HER2+ breast cancer in all but name
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.
The safety analysis showed a similar incidence of grade 3 or greater adverse events during neoadjuvant therapy (15% of patients on ABP 980 vs. 14% on trastuzumab). Grade 3 or greater neutropenia occurred in 6% of patients in each group.
During adjuvant therapy, grade 3 or greater adverse events occurred in 9% of patients continuing ABP 980, 6% continuing trastuzumab, and 8% of these switched from trastuzumab to ABP 980. The most frequent grade 3 or greater events of interest were infections and neutropenia, all occurring in 1% of patients in each arm, and infusion reaction, which occurred in 1% of patients who stayed on the assigned HER2 inhibitor and in 2% of patients who were switched to ABP 980.
There were two patient deaths from adverse events, each deemed to be unrelated to treatment. One patient died from pneumonia during neoadjuvant ABP 980 therapy, and one died from septic shock during adjuvant therapy with ABP 980 after being switch from trastuzumab.
“To our knowledge, this is the first study of a trastuzumab biosimilar encompassing a single-switch design from the reference product to a biosimilar, which allowed us to assess the clinical safety and immunogenicity of this approach to treatment. Safety and immunogenicity were similar in patients who were switched and in those who continued to receive trastuzumab as adjuvant therapy,” the investigators wrote.
SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
The LILAC trial has some strengths and weaknesses and raises a curious regulatory issue. To begin with the weaknesses, only 696 of 725 randomized patients were evaluable for pathological complete response after surgery. No data about the outcomes, characteristics, or allocated treatment of the patients who did not reach surgery were provided. These lost patients should have been included in the intention-to-treat analysis and their responses classified when possible (e.g., those who did not reach surgery due to progressive disease should have been classified as nonpathological complete response). The effect of these few patients on the overall results is unknown, although it is possibly small.
Among the strengths of LILAC were that the trial was done in a sensitive population (i.e., a population in which differences in safety, immunogenicity, and efficacy could be attributed to the biosimilar or reference drug rather than patient-related or disease-related factors). Two chemotherapy choices were included that are broadly used worldwide, and thus mimicked routine clinical practice, and the study had a sensitive primary endpoint (pathological complete response). The aim of clinical trials in the regulatory pathway of biosimilars is to show an acceptable degree of similarity in clinical efficacy and safety to the reference product. For original products, endpoints in clinical trials must show benefits to patients, such as progression-free survival, disease-free survival, or overall survival, whereas for biosimilars, surrogate endpoints, such as the proportion of patients with pathological response in breast cancer neoadjuvant trials, are appropriate. The study design of LILAC, therefore, meets the main clinical requirements demanded by medicine agencies for the registration of biosimilars.
Miguel Martin, MD, PhD is with Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martin’s remarks are adapted and condensed from an editorial in The Lancet Oncology accompanying the study by von Minckwitz G et al. He disclosed grants from Novartis and Roche and personal fees from AstraZeneca, Lilly, Pfizer, and Roche.
The LILAC trial has some strengths and weaknesses and raises a curious regulatory issue. To begin with the weaknesses, only 696 of 725 randomized patients were evaluable for pathological complete response after surgery. No data about the outcomes, characteristics, or allocated treatment of the patients who did not reach surgery were provided. These lost patients should have been included in the intention-to-treat analysis and their responses classified when possible (e.g., those who did not reach surgery due to progressive disease should have been classified as nonpathological complete response). The effect of these few patients on the overall results is unknown, although it is possibly small.
Among the strengths of LILAC were that the trial was done in a sensitive population (i.e., a population in which differences in safety, immunogenicity, and efficacy could be attributed to the biosimilar or reference drug rather than patient-related or disease-related factors). Two chemotherapy choices were included that are broadly used worldwide, and thus mimicked routine clinical practice, and the study had a sensitive primary endpoint (pathological complete response). The aim of clinical trials in the regulatory pathway of biosimilars is to show an acceptable degree of similarity in clinical efficacy and safety to the reference product. For original products, endpoints in clinical trials must show benefits to patients, such as progression-free survival, disease-free survival, or overall survival, whereas for biosimilars, surrogate endpoints, such as the proportion of patients with pathological response in breast cancer neoadjuvant trials, are appropriate. The study design of LILAC, therefore, meets the main clinical requirements demanded by medicine agencies for the registration of biosimilars.
Miguel Martin, MD, PhD is with Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martin’s remarks are adapted and condensed from an editorial in The Lancet Oncology accompanying the study by von Minckwitz G et al. He disclosed grants from Novartis and Roche and personal fees from AstraZeneca, Lilly, Pfizer, and Roche.
The LILAC trial has some strengths and weaknesses and raises a curious regulatory issue. To begin with the weaknesses, only 696 of 725 randomized patients were evaluable for pathological complete response after surgery. No data about the outcomes, characteristics, or allocated treatment of the patients who did not reach surgery were provided. These lost patients should have been included in the intention-to-treat analysis and their responses classified when possible (e.g., those who did not reach surgery due to progressive disease should have been classified as nonpathological complete response). The effect of these few patients on the overall results is unknown, although it is possibly small.
Among the strengths of LILAC were that the trial was done in a sensitive population (i.e., a population in which differences in safety, immunogenicity, and efficacy could be attributed to the biosimilar or reference drug rather than patient-related or disease-related factors). Two chemotherapy choices were included that are broadly used worldwide, and thus mimicked routine clinical practice, and the study had a sensitive primary endpoint (pathological complete response). The aim of clinical trials in the regulatory pathway of biosimilars is to show an acceptable degree of similarity in clinical efficacy and safety to the reference product. For original products, endpoints in clinical trials must show benefits to patients, such as progression-free survival, disease-free survival, or overall survival, whereas for biosimilars, surrogate endpoints, such as the proportion of patients with pathological response in breast cancer neoadjuvant trials, are appropriate. The study design of LILAC, therefore, meets the main clinical requirements demanded by medicine agencies for the registration of biosimilars.
Miguel Martin, MD, PhD is with Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martin’s remarks are adapted and condensed from an editorial in The Lancet Oncology accompanying the study by von Minckwitz G et al. He disclosed grants from Novartis and Roche and personal fees from AstraZeneca, Lilly, Pfizer, and Roche.
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.
The safety analysis showed a similar incidence of grade 3 or greater adverse events during neoadjuvant therapy (15% of patients on ABP 980 vs. 14% on trastuzumab). Grade 3 or greater neutropenia occurred in 6% of patients in each group.
During adjuvant therapy, grade 3 or greater adverse events occurred in 9% of patients continuing ABP 980, 6% continuing trastuzumab, and 8% of these switched from trastuzumab to ABP 980. The most frequent grade 3 or greater events of interest were infections and neutropenia, all occurring in 1% of patients in each arm, and infusion reaction, which occurred in 1% of patients who stayed on the assigned HER2 inhibitor and in 2% of patients who were switched to ABP 980.
There were two patient deaths from adverse events, each deemed to be unrelated to treatment. One patient died from pneumonia during neoadjuvant ABP 980 therapy, and one died from septic shock during adjuvant therapy with ABP 980 after being switch from trastuzumab.
“To our knowledge, this is the first study of a trastuzumab biosimilar encompassing a single-switch design from the reference product to a biosimilar, which allowed us to assess the clinical safety and immunogenicity of this approach to treatment. Safety and immunogenicity were similar in patients who were switched and in those who continued to receive trastuzumab as adjuvant therapy,” the investigators wrote.
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.
The safety analysis showed a similar incidence of grade 3 or greater adverse events during neoadjuvant therapy (15% of patients on ABP 980 vs. 14% on trastuzumab). Grade 3 or greater neutropenia occurred in 6% of patients in each group.
During adjuvant therapy, grade 3 or greater adverse events occurred in 9% of patients continuing ABP 980, 6% continuing trastuzumab, and 8% of these switched from trastuzumab to ABP 980. The most frequent grade 3 or greater events of interest were infections and neutropenia, all occurring in 1% of patients in each arm, and infusion reaction, which occurred in 1% of patients who stayed on the assigned HER2 inhibitor and in 2% of patients who were switched to ABP 980.
There were two patient deaths from adverse events, each deemed to be unrelated to treatment. One patient died from pneumonia during neoadjuvant ABP 980 therapy, and one died from septic shock during adjuvant therapy with ABP 980 after being switch from trastuzumab.
“To our knowledge, this is the first study of a trastuzumab biosimilar encompassing a single-switch design from the reference product to a biosimilar, which allowed us to assess the clinical safety and immunogenicity of this approach to treatment. Safety and immunogenicity were similar in patients who were switched and in those who continued to receive trastuzumab as adjuvant therapy,” the investigators wrote.
SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
FROM THE LANCET ONCOLOGY
Key clinical point: The biosimilar ABP 980 appears to be comparable in efficacy and safety to trastuzumab in women with early HER2-positive breast cancer.
Major finding: According to local lab assessments, 48% of patients assigned to ABP 980 had a pathologic complete response, compared with 41% assigned to trastuzumab.
Study details: Randomized, double-blind, phase 3 trial of 696 adult women with HER2-positive breast cancer.
Disclosures: Dr. von Minckwitz is a consultant for Amgen, which funded the study. Two coauthors are employees of the company and stockholders. Other coauthors disclosed relationships with various companies.
Source: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
Trastuzumab biosimilar is equivalent on central review
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
REPORTING FROM THE ASCO ANNUAL MEETING
Key clinical point: Central review determined that ABP 980 was neither inferior nor superior to trastuzumab in breast cancer patients.
Major finding: The centrally determined pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab, with bounds of the confidence intervals for risk difference and for risk ratio falling within the predefined equivalence margins.
Study details: An analysis of a phase 3 randomized controlled trial of neoadjuvant (and adjuvant) therapy among 725 patients with HER2+ early breast cancer (LILAC trial).
Disclosures: Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
Source: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
Does hormone therapy increase breast cancer risk in BRCA1 mutation carriers?
EXPERT COMMENTARY
Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.
To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.
Details of the study
The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.
Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).
During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.
When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).
Study strengths and weaknesses
This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.
The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.
Because women with BRCA1 mutations have an elevated risk of ovarian cancer, risk-reducing gynecologic surgery is recommended for these women who have completed childbearing. In young women, BO without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. The clear reduction in breast cancer risk associated with ET (vs EPT) following BO suggests that in BRCA1 carriers who have completed childbearing, hysterectomy (which precludes the need for progestogen therapy) should be considered as part of risk-reducing gynecologic surgery. Further, the findings of this prospective study in high-risk women parallels the findings of the large randomized Women's Health Initiative trial (performed in the general population of menopausal women), which found that ET (conjugated equine estrogen) reduces the risk.1
-- Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
EXPERT COMMENTARY
Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.
To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.
Details of the study
The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.
Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).
During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.
When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).
Study strengths and weaknesses
This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.
The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.
Because women with BRCA1 mutations have an elevated risk of ovarian cancer, risk-reducing gynecologic surgery is recommended for these women who have completed childbearing. In young women, BO without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. The clear reduction in breast cancer risk associated with ET (vs EPT) following BO suggests that in BRCA1 carriers who have completed childbearing, hysterectomy (which precludes the need for progestogen therapy) should be considered as part of risk-reducing gynecologic surgery. Further, the findings of this prospective study in high-risk women parallels the findings of the large randomized Women's Health Initiative trial (performed in the general population of menopausal women), which found that ET (conjugated equine estrogen) reduces the risk.1
-- Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
EXPERT COMMENTARY
Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.
To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.
Details of the study
The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.
Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).
During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.
When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).
Study strengths and weaknesses
This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.
The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.
Because women with BRCA1 mutations have an elevated risk of ovarian cancer, risk-reducing gynecologic surgery is recommended for these women who have completed childbearing. In young women, BO without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. The clear reduction in breast cancer risk associated with ET (vs EPT) following BO suggests that in BRCA1 carriers who have completed childbearing, hysterectomy (which precludes the need for progestogen therapy) should be considered as part of risk-reducing gynecologic surgery. Further, the findings of this prospective study in high-risk women parallels the findings of the large randomized Women's Health Initiative trial (performed in the general population of menopausal women), which found that ET (conjugated equine estrogen) reduces the risk.1
-- Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
Higher BMI tied to lower breast cancer risk in women before menopause
Although obesity increases the risk of breast cancer in postmenopausal women, a large multicenter analysis has confirmed the opposite effect in premenopausal women.
The association had “a greater magnitude than previously shown and across the entire distribution of body mass index,” wrote Minouk J. Schoemaker, PhD, of the Institute of Cancer Research in London, with his associates, on behalf of the Premenopausal Breast Cancer Collaborative Group. The protective effect of adiposity was strongest during young adulthood (ages 18-24 years), when it spanned breast cancer subtypes. “Understanding the biological mechanisms underlying these associations could have important preventive potential,” they wrote in JAMA Oncology.
Prior studies have linked greater body fat with reduced risk of breast cancer in younger women, but the effect has not been well characterized. For this analysis, the investigators pooled data from 19 cohort studies that included a total of 758,592 premenopausal women; median age was 40.6 years (interquartile range, 35.2-45.5 years).
For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years. There was no BMI threshold for risk reduction: the inverse correlation existed even when women were not overweight. Risk also did vary significantly among subgroups stratified by other risk factors for breast cancer. Adiposity was more protective against estrogen receptor-positive and progesterone-receptor positive breast cancers and less protective against hormone receptor–negative breast cancers, which “implies a hormonal mechanism,” the investigators said. “Body mass index at ages 25-54 years was not consistently associated with triple-negative or hormone receptor–negative breast cancer overall.”
Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
SOURCE: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
Although obesity increases the risk of breast cancer in postmenopausal women, a large multicenter analysis has confirmed the opposite effect in premenopausal women.
The association had “a greater magnitude than previously shown and across the entire distribution of body mass index,” wrote Minouk J. Schoemaker, PhD, of the Institute of Cancer Research in London, with his associates, on behalf of the Premenopausal Breast Cancer Collaborative Group. The protective effect of adiposity was strongest during young adulthood (ages 18-24 years), when it spanned breast cancer subtypes. “Understanding the biological mechanisms underlying these associations could have important preventive potential,” they wrote in JAMA Oncology.
Prior studies have linked greater body fat with reduced risk of breast cancer in younger women, but the effect has not been well characterized. For this analysis, the investigators pooled data from 19 cohort studies that included a total of 758,592 premenopausal women; median age was 40.6 years (interquartile range, 35.2-45.5 years).
For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years. There was no BMI threshold for risk reduction: the inverse correlation existed even when women were not overweight. Risk also did vary significantly among subgroups stratified by other risk factors for breast cancer. Adiposity was more protective against estrogen receptor-positive and progesterone-receptor positive breast cancers and less protective against hormone receptor–negative breast cancers, which “implies a hormonal mechanism,” the investigators said. “Body mass index at ages 25-54 years was not consistently associated with triple-negative or hormone receptor–negative breast cancer overall.”
Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
SOURCE: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
Although obesity increases the risk of breast cancer in postmenopausal women, a large multicenter analysis has confirmed the opposite effect in premenopausal women.
The association had “a greater magnitude than previously shown and across the entire distribution of body mass index,” wrote Minouk J. Schoemaker, PhD, of the Institute of Cancer Research in London, with his associates, on behalf of the Premenopausal Breast Cancer Collaborative Group. The protective effect of adiposity was strongest during young adulthood (ages 18-24 years), when it spanned breast cancer subtypes. “Understanding the biological mechanisms underlying these associations could have important preventive potential,” they wrote in JAMA Oncology.
Prior studies have linked greater body fat with reduced risk of breast cancer in younger women, but the effect has not been well characterized. For this analysis, the investigators pooled data from 19 cohort studies that included a total of 758,592 premenopausal women; median age was 40.6 years (interquartile range, 35.2-45.5 years).
For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years. There was no BMI threshold for risk reduction: the inverse correlation existed even when women were not overweight. Risk also did vary significantly among subgroups stratified by other risk factors for breast cancer. Adiposity was more protective against estrogen receptor-positive and progesterone-receptor positive breast cancers and less protective against hormone receptor–negative breast cancers, which “implies a hormonal mechanism,” the investigators said. “Body mass index at ages 25-54 years was not consistently associated with triple-negative or hormone receptor–negative breast cancer overall.”
Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
SOURCE: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
FROM JAMA ONCOLOGY
Key clinical point: In premenopausal women, adiposity inversely correlated with risk of breast cancer, and showed a stronger protective effect than previously documented.
Major finding: For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years.
Study details: Multicenter analysis of 19 cohort studies.
Disclosures: Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
Source: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.