Metastatic Breast Cancer

The relationship between obesity and overweight and breast cancer has some elements of mystery. But this is not one of them: in metastatic breast cancer (MBC), excess body weight does not negatively influence outcomes.

Multiple small studies have demonstrated this point, and now, for the first time, a large multicenter cohort analysis indicates the same.

Using medical records from 18 French comprehensive cancer centers, investigators reviewed body mass index (BMI) and overall survival (OS) data for nearly 13,000 women. The median OS was 47.4 months, and the median follow-up was about the same length of time. The team reports that obesity and overweight “were clearly not associated with prognosis.”

However, underweight was independently associated with worse OS (median, 33 months; hazard ratio, 1.14; 95% confidence interval, 1.02-1.27), report Khalil Saleh, MD, of Gustave Roussy in Villejuif, France, and colleagues.

In short, obesity or overweight had no effect on the primary outcome of OS, but underweight did.

“Underweight should be the subject of clinical attention at the time of diagnosis of MBC, and specific management should be implemented,” said study author Elise Deluche, MD, of CHU de Limoges, in an email to this news organization.

The study was published online Dec. 1 in The Breast.

“It’s really wonderful to have such a large cohort to look at this question,” said Jennifer Ligibel, MD, of the Dana-Farber Cancer Institute, Boston, who was asked for comment.

Is this another case of obesity paradox in cancer (as in renal cell carcinoma and melanoma, where excess weight is tied to better cancer-specific survival)?

No, said Dr. Ligibel: “There’s no hint at all [in this study] that people with obesity and overweight did better. … They just didn’t have worse outcomes.”

The study authors point out that the opposite is true in early-stage breast cancer. In this patient population, excess weight is associated with worse outcomes.

For example, in a 2014 meta-analysis of 82 follow-up studies in early-stage disease, obesity was associated with higher total mortality (relative risk, 1.41) and breast cancer–specific mortality (RR, 1.35) as compared to normal weight.

Why is there such a contrast between early- and late-stage disease?

“I don’t think we know exactly,” answered Dr. Ligibel. “It may be that, with breast cancer, as disease progresses, the pathways through which lifestyle may impact breast cancer may become less important.

“Obesity and overweight are associated with cancer risk in general,” said Dr. Ligibel, citing more than a dozen malignancies, including breast cancer.

But there is also an age element. Overweight or obesity is an independent predictor of breast cancer risk in postmenopausal women, but in premenopausal women, it appears to be protective. “Historically, there has been a lower risk of hormone receptor–positive breast cancer in women with obesity at younger ages that we don’t completely understand,” Dr. Ligibel noted.

That age-based difference is a conundrum, said Dr. Ligibel: “People have been trying to figure that out for a long time.”

Dr. Ligibel summarized as follows:

“There is a clear relationship between obesity and the risk of developing breast cancer; there is a clear relationship in early breast cancer that obesity is related to an increased risk of occurrence and mortality. What we are seeing from this study is that, by the time you get to metastatic breast cancer, body weight does not seem to play as important a role.”
 

More study details

The findings come from the French National Epidemiological Strategy and Medical Economics–Metastatic Breast Cancer observational cohort, which includes 22,000-plus consecutive patients who were newly diagnosed with metastatic disease between 2008 and 2016.

A total of 12,999 women for whom BMI data were available when they were diagnosed with metastatic breast cancer were selected for analysis. They were divided into four groups, according to World Health Organization classification: underweight (BMI <18.5 kg/m²), normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0).

A total of 20% of women were obese, which is a much lower percentage than the 40%-50% that would be expected in a comparable American cohort, said Dr. Ligibel. Also, 5% of the French cohort was underweight.

Multivariate Cox analyses were carried out for OS and for first-line progression-free survival (PFS).

As noted above, underweight was independently associated with a worse OS. It was also tied to worse first-line PFS (HR, 1.11; 95% CI, 1.01-1.22). Overweight or obesity had no effect.

“Patients with a low BMI had more visceral metastases and a greater number of metastatic sites,” pointed out study author Dr. Deluche. “We attribute the fat loss in patients with metastatic breast cancer to aggressive tumor behavior with a higher energy requirement.”

The study authors also observe that in early-stage breast cancer, underweight is not associated with overall or breast cancer–specific survival. “Underweight at metastatic diagnosis seems to have a different significance and impact,” they write. The French team also observes that, in other cancers, underweight is also an adverse prognostic factor and has been associated with a higher risk for death.

The study authors acknowledge that BMI has limitations as a measure of body type. “BMI alone cannot estimate a woman’s muscle mass and adiposity,” they observe. The suggestion is that, among women with a similar BMI, some might be muscular, whereas others might have more body fat.

Multiple study authors report financial ties to industry, including pharmaceutical companies with drugs used in breast cancer. The database used in the study receives financial support from AstraZeneca, Daiichi Sankyo, Eisai, MSD, Pfizer, and Roche. Dr. Ligibel reports no relevant financial relationships.

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

The relationship between obesity and overweight and breast cancer has some elements of mystery. But this is not one of them: in metastatic breast cancer (MBC), excess body weight does not negatively influence outcomes.

Multiple small studies have demonstrated this point, and now, for the first time, a large multicenter cohort analysis indicates the same.

Using medical records from 18 French comprehensive cancer centers, investigators reviewed body mass index (BMI) and overall survival (OS) data for nearly 13,000 women. The median OS was 47.4 months, and the median follow-up was about the same length of time. The team reports that obesity and overweight “were clearly not associated with prognosis.”

However, underweight was independently associated with worse OS (median, 33 months; hazard ratio, 1.14; 95% confidence interval, 1.02-1.27), report Khalil Saleh, MD, of Gustave Roussy in Villejuif, France, and colleagues.

In short, obesity or overweight had no effect on the primary outcome of OS, but underweight did.

“Underweight should be the subject of clinical attention at the time of diagnosis of MBC, and specific management should be implemented,” said study author Elise Deluche, MD, of CHU de Limoges, in an email to this news organization.

The study was published online Dec. 1 in The Breast.

“It’s really wonderful to have such a large cohort to look at this question,” said Jennifer Ligibel, MD, of the Dana-Farber Cancer Institute, Boston, who was asked for comment.

Is this another case of obesity paradox in cancer (as in renal cell carcinoma and melanoma, where excess weight is tied to better cancer-specific survival)?

No, said Dr. Ligibel: “There’s no hint at all [in this study] that people with obesity and overweight did better. … They just didn’t have worse outcomes.”

The study authors point out that the opposite is true in early-stage breast cancer. In this patient population, excess weight is associated with worse outcomes.

For example, in a 2014 meta-analysis of 82 follow-up studies in early-stage disease, obesity was associated with higher total mortality (relative risk, 1.41) and breast cancer–specific mortality (RR, 1.35) as compared to normal weight.

Why is there such a contrast between early- and late-stage disease?

“I don’t think we know exactly,” answered Dr. Ligibel. “It may be that, with breast cancer, as disease progresses, the pathways through which lifestyle may impact breast cancer may become less important.

“Obesity and overweight are associated with cancer risk in general,” said Dr. Ligibel, citing more than a dozen malignancies, including breast cancer.

But there is also an age element. Overweight or obesity is an independent predictor of breast cancer risk in postmenopausal women, but in premenopausal women, it appears to be protective. “Historically, there has been a lower risk of hormone receptor–positive breast cancer in women with obesity at younger ages that we don’t completely understand,” Dr. Ligibel noted.

That age-based difference is a conundrum, said Dr. Ligibel: “People have been trying to figure that out for a long time.”

Dr. Ligibel summarized as follows:

“There is a clear relationship between obesity and the risk of developing breast cancer; there is a clear relationship in early breast cancer that obesity is related to an increased risk of occurrence and mortality. What we are seeing from this study is that, by the time you get to metastatic breast cancer, body weight does not seem to play as important a role.”
 

More study details

The findings come from the French National Epidemiological Strategy and Medical Economics–Metastatic Breast Cancer observational cohort, which includes 22,000-plus consecutive patients who were newly diagnosed with metastatic disease between 2008 and 2016.

A total of 12,999 women for whom BMI data were available when they were diagnosed with metastatic breast cancer were selected for analysis. They were divided into four groups, according to World Health Organization classification: underweight (BMI <18.5 kg/m²), normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0).

A total of 20% of women were obese, which is a much lower percentage than the 40%-50% that would be expected in a comparable American cohort, said Dr. Ligibel. Also, 5% of the French cohort was underweight.

Multivariate Cox analyses were carried out for OS and for first-line progression-free survival (PFS).

As noted above, underweight was independently associated with a worse OS. It was also tied to worse first-line PFS (HR, 1.11; 95% CI, 1.01-1.22). Overweight or obesity had no effect.

“Patients with a low BMI had more visceral metastases and a greater number of metastatic sites,” pointed out study author Dr. Deluche. “We attribute the fat loss in patients with metastatic breast cancer to aggressive tumor behavior with a higher energy requirement.”

The study authors also observe that in early-stage breast cancer, underweight is not associated with overall or breast cancer–specific survival. “Underweight at metastatic diagnosis seems to have a different significance and impact,” they write. The French team also observes that, in other cancers, underweight is also an adverse prognostic factor and has been associated with a higher risk for death.

The study authors acknowledge that BMI has limitations as a measure of body type. “BMI alone cannot estimate a woman’s muscle mass and adiposity,” they observe. The suggestion is that, among women with a similar BMI, some might be muscular, whereas others might have more body fat.

Multiple study authors report financial ties to industry, including pharmaceutical companies with drugs used in breast cancer. The database used in the study receives financial support from AstraZeneca, Daiichi Sankyo, Eisai, MSD, Pfizer, and Roche. Dr. Ligibel reports no relevant financial relationships.

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

The relationship between obesity and overweight and breast cancer has some elements of mystery. But this is not one of them: in metastatic breast cancer (MBC), excess body weight does not negatively influence outcomes.

Multiple small studies have demonstrated this point, and now, for the first time, a large multicenter cohort analysis indicates the same.

Using medical records from 18 French comprehensive cancer centers, investigators reviewed body mass index (BMI) and overall survival (OS) data for nearly 13,000 women. The median OS was 47.4 months, and the median follow-up was about the same length of time. The team reports that obesity and overweight “were clearly not associated with prognosis.”

However, underweight was independently associated with worse OS (median, 33 months; hazard ratio, 1.14; 95% confidence interval, 1.02-1.27), report Khalil Saleh, MD, of Gustave Roussy in Villejuif, France, and colleagues.

In short, obesity or overweight had no effect on the primary outcome of OS, but underweight did.

“Underweight should be the subject of clinical attention at the time of diagnosis of MBC, and specific management should be implemented,” said study author Elise Deluche, MD, of CHU de Limoges, in an email to this news organization.

The study was published online Dec. 1 in The Breast.

“It’s really wonderful to have such a large cohort to look at this question,” said Jennifer Ligibel, MD, of the Dana-Farber Cancer Institute, Boston, who was asked for comment.

Is this another case of obesity paradox in cancer (as in renal cell carcinoma and melanoma, where excess weight is tied to better cancer-specific survival)?

No, said Dr. Ligibel: “There’s no hint at all [in this study] that people with obesity and overweight did better. … They just didn’t have worse outcomes.”

The study authors point out that the opposite is true in early-stage breast cancer. In this patient population, excess weight is associated with worse outcomes.

For example, in a 2014 meta-analysis of 82 follow-up studies in early-stage disease, obesity was associated with higher total mortality (relative risk, 1.41) and breast cancer–specific mortality (RR, 1.35) as compared to normal weight.

Why is there such a contrast between early- and late-stage disease?

“I don’t think we know exactly,” answered Dr. Ligibel. “It may be that, with breast cancer, as disease progresses, the pathways through which lifestyle may impact breast cancer may become less important.

“Obesity and overweight are associated with cancer risk in general,” said Dr. Ligibel, citing more than a dozen malignancies, including breast cancer.

But there is also an age element. Overweight or obesity is an independent predictor of breast cancer risk in postmenopausal women, but in premenopausal women, it appears to be protective. “Historically, there has been a lower risk of hormone receptor–positive breast cancer in women with obesity at younger ages that we don’t completely understand,” Dr. Ligibel noted.

That age-based difference is a conundrum, said Dr. Ligibel: “People have been trying to figure that out for a long time.”

Dr. Ligibel summarized as follows:

“There is a clear relationship between obesity and the risk of developing breast cancer; there is a clear relationship in early breast cancer that obesity is related to an increased risk of occurrence and mortality. What we are seeing from this study is that, by the time you get to metastatic breast cancer, body weight does not seem to play as important a role.”
 

More study details

The findings come from the French National Epidemiological Strategy and Medical Economics–Metastatic Breast Cancer observational cohort, which includes 22,000-plus consecutive patients who were newly diagnosed with metastatic disease between 2008 and 2016.

A total of 12,999 women for whom BMI data were available when they were diagnosed with metastatic breast cancer were selected for analysis. They were divided into four groups, according to World Health Organization classification: underweight (BMI <18.5 kg/m²), normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0).

A total of 20% of women were obese, which is a much lower percentage than the 40%-50% that would be expected in a comparable American cohort, said Dr. Ligibel. Also, 5% of the French cohort was underweight.

Multivariate Cox analyses were carried out for OS and for first-line progression-free survival (PFS).

As noted above, underweight was independently associated with a worse OS. It was also tied to worse first-line PFS (HR, 1.11; 95% CI, 1.01-1.22). Overweight or obesity had no effect.

“Patients with a low BMI had more visceral metastases and a greater number of metastatic sites,” pointed out study author Dr. Deluche. “We attribute the fat loss in patients with metastatic breast cancer to aggressive tumor behavior with a higher energy requirement.”

The study authors also observe that in early-stage breast cancer, underweight is not associated with overall or breast cancer–specific survival. “Underweight at metastatic diagnosis seems to have a different significance and impact,” they write. The French team also observes that, in other cancers, underweight is also an adverse prognostic factor and has been associated with a higher risk for death.

The study authors acknowledge that BMI has limitations as a measure of body type. “BMI alone cannot estimate a woman’s muscle mass and adiposity,” they observe. The suggestion is that, among women with a similar BMI, some might be muscular, whereas others might have more body fat.

Multiple study authors report financial ties to industry, including pharmaceutical companies with drugs used in breast cancer. The database used in the study receives financial support from AstraZeneca, Daiichi Sankyo, Eisai, MSD, Pfizer, and Roche. Dr. Ligibel reports no relevant financial relationships.

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

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.

“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
 

Why HDAC inhibitors in advanced breast cancer?

“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
 

Phase 3 trial details and results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
 

Implications and next steps

“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.

“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.

Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”

When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”

Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.

“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”

The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.

“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
 

Why HDAC inhibitors in advanced breast cancer?

“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
 

Phase 3 trial details and results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
 

Implications and next steps

“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.

“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.

Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”

When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”

Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.

“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”

The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.

“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
 

Why HDAC inhibitors in advanced breast cancer?

“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
 

Phase 3 trial details and results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
 

Implications and next steps

“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.

“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.

Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”

When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”

Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.

“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”

The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.

Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.

“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.

But those statistics have not been available from a robust population-based source.

Now, there is hope that they will – at last – be collected.

A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.

But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.

“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.

“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.

But this database has never included information on cancer recurrence.

In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
 

New project

The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.

The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.

She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.

“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
 

Why the change now?

“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.

Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.

Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.

In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
 

Tracking recurrences

In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.

Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.

“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.

To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.

On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.

Nonetheless, these clinical trials provide a starting place.

The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.

The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.

“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.

The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.

The study was supported by NCI.

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

Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.

“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.

But those statistics have not been available from a robust population-based source.

Now, there is hope that they will – at last – be collected.

A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.

But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.

“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.

“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.

But this database has never included information on cancer recurrence.

In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
 

New project

The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.

The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.

She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.

“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
 

Why the change now?

“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.

Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.

Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.

In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
 

Tracking recurrences

In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.

Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.

“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.

To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.

On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.

Nonetheless, these clinical trials provide a starting place.

The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.

The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.

“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.

The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.

The study was supported by NCI.

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

Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.

“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.

But those statistics have not been available from a robust population-based source.

Now, there is hope that they will – at last – be collected.

A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.

But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.

“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.

“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.

But this database has never included information on cancer recurrence.

In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
 

New project

The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.

The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.

She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.

“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
 

Why the change now?

“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.

Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.

Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.

In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
 

Tracking recurrences

In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.

Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.

“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.

To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.

On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.

Nonetheless, these clinical trials provide a starting place.

The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.

The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.

“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.

The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.

The study was supported by NCI.

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

A new monoclonal antibody that targets HER2 in breast cancer, margetuximab-cmkb (Margenza), has been approved by the Food and Drug Administration.

The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.

Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first-ever HER2-targeted agent, trastuzumab in a head-to-head, phase 3 clinical trial (known as SOPHIA).

“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” said Hope S. Rugo, MD, director of breast oncology and clinical trials education, University of California, San Francisco, Diller Family Comprehensive Cancer Center, in a press release.

“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Dr. Rugo, who is an investigator in the SOPHIA trial.

Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer, MacroGenics.
 

Details of the pivotal trial

The SOPHIA trial was a randomized, open-label, phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy with trastuzumab plus chemotherapy in both arms in patients with HER2-positive metastatic breast cancer who had previously been treated with anti–HER2-targeted therapies.

All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.

The trial randomly assigned 536 patients to receive either margetuximab-cmkb (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine, given at the standard doses.

As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death (hazard ratio, 0.76).

The median PFS also favored margetuximab (5.8 months vs. 4.9 months), as did the overall response rate (22% vs. 16%).

The final overall survival analysis is expected in the second half of 2021.

Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.

The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.

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

A new monoclonal antibody that targets HER2 in breast cancer, margetuximab-cmkb (Margenza), has been approved by the Food and Drug Administration.

The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.

Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first-ever HER2-targeted agent, trastuzumab in a head-to-head, phase 3 clinical trial (known as SOPHIA).

“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” said Hope S. Rugo, MD, director of breast oncology and clinical trials education, University of California, San Francisco, Diller Family Comprehensive Cancer Center, in a press release.

“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Dr. Rugo, who is an investigator in the SOPHIA trial.

Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer, MacroGenics.
 

Details of the pivotal trial

The SOPHIA trial was a randomized, open-label, phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy with trastuzumab plus chemotherapy in both arms in patients with HER2-positive metastatic breast cancer who had previously been treated with anti–HER2-targeted therapies.

All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.

The trial randomly assigned 536 patients to receive either margetuximab-cmkb (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine, given at the standard doses.

As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death (hazard ratio, 0.76).

The median PFS also favored margetuximab (5.8 months vs. 4.9 months), as did the overall response rate (22% vs. 16%).

The final overall survival analysis is expected in the second half of 2021.

Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.

The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.

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

A new monoclonal antibody that targets HER2 in breast cancer, margetuximab-cmkb (Margenza), has been approved by the Food and Drug Administration.

The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.

Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first-ever HER2-targeted agent, trastuzumab in a head-to-head, phase 3 clinical trial (known as SOPHIA).

“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” said Hope S. Rugo, MD, director of breast oncology and clinical trials education, University of California, San Francisco, Diller Family Comprehensive Cancer Center, in a press release.

“As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Dr. Rugo, who is an investigator in the SOPHIA trial.

Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer, MacroGenics.
 

Details of the pivotal trial

The SOPHIA trial was a randomized, open-label, phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy with trastuzumab plus chemotherapy in both arms in patients with HER2-positive metastatic breast cancer who had previously been treated with anti–HER2-targeted therapies.

All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.

The trial randomly assigned 536 patients to receive either margetuximab-cmkb (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine, given at the standard doses.

As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death (hazard ratio, 0.76).

The median PFS also favored margetuximab (5.8 months vs. 4.9 months), as did the overall response rate (22% vs. 16%).

The final overall survival analysis is expected in the second half of 2021.

Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.

The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.

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

Adding the oral taxane tesetaxel to capecitabine prolonged progression-free survival (PFS) by almost 3 months in patients with hormone receptor–positive, HER2-negative metastatic breast cancer in the ongoing phase 3 CONTESSA study.

These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.

“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.

Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.

“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.

At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.

Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.

Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.

“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.

“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”

The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.

“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”

 

Trial design

CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.

Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.

Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m² only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m² dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.

The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m² given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
 

Efficacy and safety

PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).

A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.

The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).

The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).

The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.

She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.

The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.

“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.

“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.

This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.

SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.

Adding the oral taxane tesetaxel to capecitabine prolonged progression-free survival (PFS) by almost 3 months in patients with hormone receptor–positive, HER2-negative metastatic breast cancer in the ongoing phase 3 CONTESSA study.

These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.

“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.

Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.

“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.

At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.

Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.

Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.

“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.

“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”

The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.

“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”

 

Trial design

CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.

Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.

Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m² only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m² dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.

The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m² given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
 

Efficacy and safety

PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).

A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.

The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).

The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).

The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.

She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.

The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.

“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.

“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.

This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.

SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.

Adding the oral taxane tesetaxel to capecitabine prolonged progression-free survival (PFS) by almost 3 months in patients with hormone receptor–positive, HER2-negative metastatic breast cancer in the ongoing phase 3 CONTESSA study.

These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.

“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.

Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.

“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.

At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.

Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.

Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.

“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.

“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”

The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.

“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”

 

Trial design

CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.

Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.

Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m² only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m² dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.

The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m² given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
 

Efficacy and safety

PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).

A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.

The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).

The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).

The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.

She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.

The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.

“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.

“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.

This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.

SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.

Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.

There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).

“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.

Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.

For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.

In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).

PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.

A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.

Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.

Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”

She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”

Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.

Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”

Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
 

Study details

For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.

They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.

Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.

Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.

Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.

The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.

After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.

This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.

The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.

Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.

Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.

In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.

Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”

This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.

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

Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.

There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).

“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.

Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.

For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.

In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).

PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.

A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.

Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.

Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”

She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”

Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.

Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”

Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
 

Study details

For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.

They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.

Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.

Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.

Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.

The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.

After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.

This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.

The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.

Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.

Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.

In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.

Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”

This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.

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

Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.

There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).

“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.

Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.

For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.

In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).

PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.

A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.

Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.

Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”

She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”

Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.

Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”

Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
 

Study details

For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.

They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.

Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.

Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.

Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.

The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.

After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.

This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.

The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.

Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.

Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.

In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.

Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”

This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.

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

The antibody–drug conjugate sacituzumab govitecan (SG) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”

She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”

Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
 

Study details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.

A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.

This article first appeared on Medscape.com.

The antibody–drug conjugate sacituzumab govitecan (SG) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”

She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”

Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
 

Study details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.

A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.

This article first appeared on Medscape.com.

The antibody–drug conjugate sacituzumab govitecan (SG) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”

She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”

Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
 

Study details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.

A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.

This article first appeared on Medscape.com.

A new meta-analysis adds to data supporting the use of a blood test that measures circulating tumor cells (CTCs) as a quick way to find out whether or not a treatment for metastatic breast cancer is working.

The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.

But an expert is not convinced that this approach is currently ready for clinical use and suggests that, for now, it should remain a tool for use in research.

The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs “strongly” predicts overall survival (OS).

Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.

The risk for death was more than 200% greater for patients in the latter group than in the former group.

The results “suggest the potential for clinical utility” of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.

The investigators say the findings from this meta-analysis add to literature in which “several studies suggest clinical utility” of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.

Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.

“Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing),” Kaklamani told Medscape Medical News.

Kaklamani explained how CTC assessments have worked in practice. “You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment’s not working. So you switch treatments around,” she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which, in turn, may nullify any treatment benefit.

However, she noted that, so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.

Currently, CTCs are best used by researchers, Kaklamani said during the press conference, because they have not been definitively proven to improve patient results.

Investigator Janni did not object to that description.

But in a press statement, he suggested that CTCs can be used currently by clinicians.

“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” Janni said in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued.”

But, to Kaklamani’s point, an article published in November in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER2-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.
 

Details of the study results

For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.

The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.

Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).

Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).

As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).

Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).

These CTC dynamics were found across all breast cancer subtypes, said Janni.

“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” said Janni in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”

The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.

This article first appeared on Medscape.com.

A new meta-analysis adds to data supporting the use of a blood test that measures circulating tumor cells (CTCs) as a quick way to find out whether or not a treatment for metastatic breast cancer is working.

The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.

But an expert is not convinced that this approach is currently ready for clinical use and suggests that, for now, it should remain a tool for use in research.

The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs “strongly” predicts overall survival (OS).

Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.

The risk for death was more than 200% greater for patients in the latter group than in the former group.

The results “suggest the potential for clinical utility” of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.

The investigators say the findings from this meta-analysis add to literature in which “several studies suggest clinical utility” of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.

Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.

“Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing),” Kaklamani told Medscape Medical News.

Kaklamani explained how CTC assessments have worked in practice. “You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment’s not working. So you switch treatments around,” she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which, in turn, may nullify any treatment benefit.

However, she noted that, so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.

Currently, CTCs are best used by researchers, Kaklamani said during the press conference, because they have not been definitively proven to improve patient results.

Investigator Janni did not object to that description.

But in a press statement, he suggested that CTCs can be used currently by clinicians.

“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” Janni said in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued.”

But, to Kaklamani’s point, an article published in November in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER2-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.
 

Details of the study results

For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.

The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.

Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).

Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).

As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).

Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).

These CTC dynamics were found across all breast cancer subtypes, said Janni.

“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” said Janni in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”

The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.

This article first appeared on Medscape.com.

A new meta-analysis adds to data supporting the use of a blood test that measures circulating tumor cells (CTCs) as a quick way to find out whether or not a treatment for metastatic breast cancer is working.

The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.

But an expert is not convinced that this approach is currently ready for clinical use and suggests that, for now, it should remain a tool for use in research.

The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs “strongly” predicts overall survival (OS).

Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.

The risk for death was more than 200% greater for patients in the latter group than in the former group.

The results “suggest the potential for clinical utility” of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.

The investigators say the findings from this meta-analysis add to literature in which “several studies suggest clinical utility” of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.

Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.

“Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing),” Kaklamani told Medscape Medical News.

Kaklamani explained how CTC assessments have worked in practice. “You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment’s not working. So you switch treatments around,” she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which, in turn, may nullify any treatment benefit.

However, she noted that, so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.

Currently, CTCs are best used by researchers, Kaklamani said during the press conference, because they have not been definitively proven to improve patient results.

Investigator Janni did not object to that description.

But in a press statement, he suggested that CTCs can be used currently by clinicians.

“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” Janni said in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued.”

But, to Kaklamani’s point, an article published in November in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER2-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.
 

Details of the study results

For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.

The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.

Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).

Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).

As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).

Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).

These CTC dynamics were found across all breast cancer subtypes, said Janni.

“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” said Janni in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”

The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.

This article first appeared on Medscape.com.

Trial results suggest circulating tumor cell (CTC) counts may be a reliable biomarker for guiding the choice of first-line treatment in patients with hormone receptor–positive, HER2-negative metastatic breast cancer, investigators wrote in JAMA Oncology.

However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.

In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.

“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.

The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.

The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
 

Study results

The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).

Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.

The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.

Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.

The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).

Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.

As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
 

‘Not good enough’

The investigators behind this study had “a worthy goal,” according to authors of a related editorial.

Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.

However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.

“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.

In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.

“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.

The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”

Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.

This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.

SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.

Trial results suggest circulating tumor cell (CTC) counts may be a reliable biomarker for guiding the choice of first-line treatment in patients with hormone receptor–positive, HER2-negative metastatic breast cancer, investigators wrote in JAMA Oncology.

However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.

In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.

“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.

The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.

The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
 

Study results

The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).

Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.

The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.

Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.

The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).

Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.

As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
 

‘Not good enough’

The investigators behind this study had “a worthy goal,” according to authors of a related editorial.

Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.

However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.

“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.

In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.

“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.

The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”

Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.

This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.

SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.

Trial results suggest circulating tumor cell (CTC) counts may be a reliable biomarker for guiding the choice of first-line treatment in patients with hormone receptor–positive, HER2-negative metastatic breast cancer, investigators wrote in JAMA Oncology.

However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.

In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.

“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.

The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.

The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
 

Study results

The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).

Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.

The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.

Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.

The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).

Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.

As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
 

‘Not good enough’

The investigators behind this study had “a worthy goal,” according to authors of a related editorial.

Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.

However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.

“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.

In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.

“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.

The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”

Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.

This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.

SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.

The Food and Drug Administration has granted accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy to treat locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that expresses PD-L1, as determined by a combined positive score of 10 or greater on an FDA-approved assay.

The FDA also approved a PD-L1 assay for selecting TNBC patients for pembrolizumab, the PD-L1 IHC 22C3 pharmDx.

Pembrolizumab is approved for numerous indications in the United States, but the new approval is its first breast cancer indication.

The accelerated approval for pembrolizumab in TNBC was based on progression-free survival (PFS) in the KEYNOTE-355 trial. The FDA noted that continued approval of pembrolizumab in TNBC “may be contingent upon verification and description of clinical benefit in the confirmatory trials.”

KEYNOTE-355 enrolled patients with locally recurrent unresectable or metastatic TNBC who had not received chemotherapy in the metastatic setting. Patients were randomized to chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) plus placebo (n = 281) or chemotherapy plus pembrolizumab at 200 mg on day 1 every 3 weeks (n = 562).

Among PD-L1-positive patients (n = 323), the median PFS was 5.6 months in the placebo arm and 9.7 months in the pembrolizumab arm (hazard ratio, 0.65; P = .0012).

The recommended pembrolizumab dose in TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.

Pembrolizumab can cause immune-mediated adverse reactions that may be severe or fatal, according to Merck, the manufacturer of pembrolizumab. These adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplant.

“Based on the severity of the adverse reaction, [pembrolizumab] should be withheld or discontinued and corticosteroids administered if appropriate,” the company noted.

For more details on pembrolizumab, see the full prescribing information.

[email protected]

The Food and Drug Administration has granted accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy to treat locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that expresses PD-L1, as determined by a combined positive score of 10 or greater on an FDA-approved assay.

The FDA also approved a PD-L1 assay for selecting TNBC patients for pembrolizumab, the PD-L1 IHC 22C3 pharmDx.

Pembrolizumab is approved for numerous indications in the United States, but the new approval is its first breast cancer indication.

The accelerated approval for pembrolizumab in TNBC was based on progression-free survival (PFS) in the KEYNOTE-355 trial. The FDA noted that continued approval of pembrolizumab in TNBC “may be contingent upon verification and description of clinical benefit in the confirmatory trials.”

KEYNOTE-355 enrolled patients with locally recurrent unresectable or metastatic TNBC who had not received chemotherapy in the metastatic setting. Patients were randomized to chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) plus placebo (n = 281) or chemotherapy plus pembrolizumab at 200 mg on day 1 every 3 weeks (n = 562).

Among PD-L1-positive patients (n = 323), the median PFS was 5.6 months in the placebo arm and 9.7 months in the pembrolizumab arm (hazard ratio, 0.65; P = .0012).

The recommended pembrolizumab dose in TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.

Pembrolizumab can cause immune-mediated adverse reactions that may be severe or fatal, according to Merck, the manufacturer of pembrolizumab. These adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplant.

“Based on the severity of the adverse reaction, [pembrolizumab] should be withheld or discontinued and corticosteroids administered if appropriate,” the company noted.

For more details on pembrolizumab, see the full prescribing information.

[email protected]

The Food and Drug Administration has granted accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy to treat locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) that expresses PD-L1, as determined by a combined positive score of 10 or greater on an FDA-approved assay.

The FDA also approved a PD-L1 assay for selecting TNBC patients for pembrolizumab, the PD-L1 IHC 22C3 pharmDx.

Pembrolizumab is approved for numerous indications in the United States, but the new approval is its first breast cancer indication.

The accelerated approval for pembrolizumab in TNBC was based on progression-free survival (PFS) in the KEYNOTE-355 trial. The FDA noted that continued approval of pembrolizumab in TNBC “may be contingent upon verification and description of clinical benefit in the confirmatory trials.”

KEYNOTE-355 enrolled patients with locally recurrent unresectable or metastatic TNBC who had not received chemotherapy in the metastatic setting. Patients were randomized to chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) plus placebo (n = 281) or chemotherapy plus pembrolizumab at 200 mg on day 1 every 3 weeks (n = 562).

Among PD-L1-positive patients (n = 323), the median PFS was 5.6 months in the placebo arm and 9.7 months in the pembrolizumab arm (hazard ratio, 0.65; P = .0012).

The recommended pembrolizumab dose in TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months.

Pembrolizumab can cause immune-mediated adverse reactions that may be severe or fatal, according to Merck, the manufacturer of pembrolizumab. These adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplant.

“Based on the severity of the adverse reaction, [pembrolizumab] should be withheld or discontinued and corticosteroids administered if appropriate,” the company noted.

For more details on pembrolizumab, see the full prescribing information.

[email protected]