SABCS 2014

SAN ANTONIO – The combination of capecitabine plus the bisphosphonate ibandronate didn’t improve disease-free survival in elderly women with moderate- or high-risk breast cancers.

After 5 years, there was an absolute – but nonsignificant – difference of 3.8% in favor of the combination treatment, Dr. Gunter von Minckwitz said at the San Antonio Breast Cancer Symposium. “But thereafter, the survival curves crossed and there was no statistically significant difference between the groups.”

But the results of the 5-year Ibandronate with or without Capecitabine for Elderly Patients with Early Breast Cancer (ICE) trial do suggest that women older than 65 years can tolerate a complete chemotherapy regimen quite well, and shouldn’t be denied the chance to receive such treatment, Dr. von Minckwitz, chair of the German Breast Group , said during his presentation.

Michele G. Sullivan/Frontline Medical News

“We still see a large fraction of elderly patients who are not getting appropriate treatment. These women were about 71 years old at the beginning of this study, and after 5 years, 90% are still surviving. This shows us that the life expectancy of these patients is long. This is important information when treatment decisions are being made in these patients, who have perhaps not been considered fit enough to receive adjuvant chemotherapy, including endocrine treatment,” he said.

Investigators randomized 1,358 women aged 65 years or older to either ibandronate alone or ibandronate plus capecitabine. In each arm, patients and their physicians could decide on the ibandronate delivery mode – either 50 mg daily or 6 mg intravenously, delivered every 4 weeks. Capecitabine was delivered in six cycles of 2,000 mg/m² daily on days 1 and 4, followed by thrice weekly for six cycles in conjunction with the preferred ibandronate schedule. Both treatments continued for 2 years.

The patients were a mean of 71 years, with 25% being at least 75 years. About 10% had a Charlson comorbidity score of at least 2. About 20% of the tumors were HER2-positive, and 15%, triple negative. Most (80%) were hormone-receptor positive. About 3/4 of the cohort had only been treated with an aromatase inhibitor.

At 3 years, there was no difference in disease-free survival, with an 85% rate in the combination group and 84% in the ibandronate-only group. At 5 years, disease-free survival was 79% and 75%, respectively. Nor was there any difference in overall survival at 3 years; in fact, survival was quite good, Dr. von Minckwitz said, with 95% still alive in the combination group and 94% in the ibandronate-only group. At 5 years, patients continued to do very well, with an overall survival of 90% in the combination group and 88% in the ibandronate-only group.

There were no significant between-group differences in any subgroup analyzed, including separation by age; pN status; hormone-receptor status; hemoglobin, albumin, and creatinine clearance; comorbidity status; or body mass index.

Adverse events of grades 3 or 4 were significantly more common in the combination group (31% vs. 9%). Two individual events drove that finding – gastrointestinal problems (6.7% vs. 1%), and skin disorders, especially hand-foot syndrome (14.6% vs. 0.6%).

Other adverse events more common in the combination group included blood and lymphatic disorders (1.2% vs 0.7%); neuropathy and dizziness (2.5% vs. 0.7%) arrhythmias and cardiac ischemia (1.8% vs. 0.4%); and thromboembolic events (2.8% vs.1.3%).

Ibandronate completion was virtually identical – about 76% in each group. Most patients in the combination group (83%) also completed the treatment.

A quarter of patients in each group experienced a bone-related adverse event, excluding metastasis. These included fractures, surgery, and new osteoporosis. Because these were so frequent, Dr. von Minckwitz suggested that bisphosphonates should be part of any treatment regimen for this population.

The ICE survival curves are so good, Dr. Minckwitz said, that they raise a bit of a question, which only time can answer. “Due to the excellent survival data, we need longer follow-up to observe any potential late effect of capecitabine.”

He had no relevant financial disclosures. The German Breast Group has no financial ties with any pharmaceutical company.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – The combination of capecitabine plus the bisphosphonate ibandronate didn’t improve disease-free survival in elderly women with moderate- or high-risk breast cancers.

After 5 years, there was an absolute – but nonsignificant – difference of 3.8% in favor of the combination treatment, Dr. Gunter von Minckwitz said at the San Antonio Breast Cancer Symposium. “But thereafter, the survival curves crossed and there was no statistically significant difference between the groups.”

But the results of the 5-year Ibandronate with or without Capecitabine for Elderly Patients with Early Breast Cancer (ICE) trial do suggest that women older than 65 years can tolerate a complete chemotherapy regimen quite well, and shouldn’t be denied the chance to receive such treatment, Dr. von Minckwitz, chair of the German Breast Group , said during his presentation.

Michele G. Sullivan/Frontline Medical News

“We still see a large fraction of elderly patients who are not getting appropriate treatment. These women were about 71 years old at the beginning of this study, and after 5 years, 90% are still surviving. This shows us that the life expectancy of these patients is long. This is important information when treatment decisions are being made in these patients, who have perhaps not been considered fit enough to receive adjuvant chemotherapy, including endocrine treatment,” he said.

Investigators randomized 1,358 women aged 65 years or older to either ibandronate alone or ibandronate plus capecitabine. In each arm, patients and their physicians could decide on the ibandronate delivery mode – either 50 mg daily or 6 mg intravenously, delivered every 4 weeks. Capecitabine was delivered in six cycles of 2,000 mg/m² daily on days 1 and 4, followed by thrice weekly for six cycles in conjunction with the preferred ibandronate schedule. Both treatments continued for 2 years.

The patients were a mean of 71 years, with 25% being at least 75 years. About 10% had a Charlson comorbidity score of at least 2. About 20% of the tumors were HER2-positive, and 15%, triple negative. Most (80%) were hormone-receptor positive. About 3/4 of the cohort had only been treated with an aromatase inhibitor.

At 3 years, there was no difference in disease-free survival, with an 85% rate in the combination group and 84% in the ibandronate-only group. At 5 years, disease-free survival was 79% and 75%, respectively. Nor was there any difference in overall survival at 3 years; in fact, survival was quite good, Dr. von Minckwitz said, with 95% still alive in the combination group and 94% in the ibandronate-only group. At 5 years, patients continued to do very well, with an overall survival of 90% in the combination group and 88% in the ibandronate-only group.

There were no significant between-group differences in any subgroup analyzed, including separation by age; pN status; hormone-receptor status; hemoglobin, albumin, and creatinine clearance; comorbidity status; or body mass index.

Adverse events of grades 3 or 4 were significantly more common in the combination group (31% vs. 9%). Two individual events drove that finding – gastrointestinal problems (6.7% vs. 1%), and skin disorders, especially hand-foot syndrome (14.6% vs. 0.6%).

Other adverse events more common in the combination group included blood and lymphatic disorders (1.2% vs 0.7%); neuropathy and dizziness (2.5% vs. 0.7%) arrhythmias and cardiac ischemia (1.8% vs. 0.4%); and thromboembolic events (2.8% vs.1.3%).

Ibandronate completion was virtually identical – about 76% in each group. Most patients in the combination group (83%) also completed the treatment.

A quarter of patients in each group experienced a bone-related adverse event, excluding metastasis. These included fractures, surgery, and new osteoporosis. Because these were so frequent, Dr. von Minckwitz suggested that bisphosphonates should be part of any treatment regimen for this population.

The ICE survival curves are so good, Dr. Minckwitz said, that they raise a bit of a question, which only time can answer. “Due to the excellent survival data, we need longer follow-up to observe any potential late effect of capecitabine.”

He had no relevant financial disclosures. The German Breast Group has no financial ties with any pharmaceutical company.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – The combination of capecitabine plus the bisphosphonate ibandronate didn’t improve disease-free survival in elderly women with moderate- or high-risk breast cancers.

After 5 years, there was an absolute – but nonsignificant – difference of 3.8% in favor of the combination treatment, Dr. Gunter von Minckwitz said at the San Antonio Breast Cancer Symposium. “But thereafter, the survival curves crossed and there was no statistically significant difference between the groups.”

But the results of the 5-year Ibandronate with or without Capecitabine for Elderly Patients with Early Breast Cancer (ICE) trial do suggest that women older than 65 years can tolerate a complete chemotherapy regimen quite well, and shouldn’t be denied the chance to receive such treatment, Dr. von Minckwitz, chair of the German Breast Group , said during his presentation.

Michele G. Sullivan/Frontline Medical News

“We still see a large fraction of elderly patients who are not getting appropriate treatment. These women were about 71 years old at the beginning of this study, and after 5 years, 90% are still surviving. This shows us that the life expectancy of these patients is long. This is important information when treatment decisions are being made in these patients, who have perhaps not been considered fit enough to receive adjuvant chemotherapy, including endocrine treatment,” he said.

Investigators randomized 1,358 women aged 65 years or older to either ibandronate alone or ibandronate plus capecitabine. In each arm, patients and their physicians could decide on the ibandronate delivery mode – either 50 mg daily or 6 mg intravenously, delivered every 4 weeks. Capecitabine was delivered in six cycles of 2,000 mg/m² daily on days 1 and 4, followed by thrice weekly for six cycles in conjunction with the preferred ibandronate schedule. Both treatments continued for 2 years.

The patients were a mean of 71 years, with 25% being at least 75 years. About 10% had a Charlson comorbidity score of at least 2. About 20% of the tumors were HER2-positive, and 15%, triple negative. Most (80%) were hormone-receptor positive. About 3/4 of the cohort had only been treated with an aromatase inhibitor.

At 3 years, there was no difference in disease-free survival, with an 85% rate in the combination group and 84% in the ibandronate-only group. At 5 years, disease-free survival was 79% and 75%, respectively. Nor was there any difference in overall survival at 3 years; in fact, survival was quite good, Dr. von Minckwitz said, with 95% still alive in the combination group and 94% in the ibandronate-only group. At 5 years, patients continued to do very well, with an overall survival of 90% in the combination group and 88% in the ibandronate-only group.

There were no significant between-group differences in any subgroup analyzed, including separation by age; pN status; hormone-receptor status; hemoglobin, albumin, and creatinine clearance; comorbidity status; or body mass index.

Adverse events of grades 3 or 4 were significantly more common in the combination group (31% vs. 9%). Two individual events drove that finding – gastrointestinal problems (6.7% vs. 1%), and skin disorders, especially hand-foot syndrome (14.6% vs. 0.6%).

Other adverse events more common in the combination group included blood and lymphatic disorders (1.2% vs 0.7%); neuropathy and dizziness (2.5% vs. 0.7%) arrhythmias and cardiac ischemia (1.8% vs. 0.4%); and thromboembolic events (2.8% vs.1.3%).

Ibandronate completion was virtually identical – about 76% in each group. Most patients in the combination group (83%) also completed the treatment.

A quarter of patients in each group experienced a bone-related adverse event, excluding metastasis. These included fractures, surgery, and new osteoporosis. Because these were so frequent, Dr. von Minckwitz suggested that bisphosphonates should be part of any treatment regimen for this population.

The ICE survival curves are so good, Dr. Minckwitz said, that they raise a bit of a question, which only time can answer. “Due to the excellent survival data, we need longer follow-up to observe any potential late effect of capecitabine.”

He had no relevant financial disclosures. The German Breast Group has no financial ties with any pharmaceutical company.

[email protected]

On Twitter @alz_gal

SAN ANTONIO – Know your patient’s number: Dr. Edith A. Perez of the Mayo Clinic in Jacksonville, Fla., explains in a video interview how the level of stromal tumor infiltrating lymphocytes (TILs) in women with early-stage, HER2+ breast cancer may be useful in identifying a subset who might potentially do quite well with chemotherapy alone.

[email protected]

SAN ANTONIO – Know your patient’s number: Dr. Edith A. Perez of the Mayo Clinic in Jacksonville, Fla., explains in a video interview how the level of stromal tumor infiltrating lymphocytes (TILs) in women with early-stage, HER2+ breast cancer may be useful in identifying a subset who might potentially do quite well with chemotherapy alone.

[email protected]

SAN ANTONIO – Know your patient’s number: Dr. Edith A. Perez of the Mayo Clinic in Jacksonville, Fla., explains in a video interview how the level of stromal tumor infiltrating lymphocytes (TILs) in women with early-stage, HER2+ breast cancer may be useful in identifying a subset who might potentially do quite well with chemotherapy alone.

[email protected]

SAN ANTONIO – Roughly one in five women with heavily pretreated, advanced triple-negative breast cancer experienced a durable response to monotherapy using the novel immune checkpoint inhibitor pembrolizumab in a small proof-of-concept study.

“The acceptable safety and tolerability profile coupled with the promising antitumor activity seen in this very early trial support the further development of pembrolizumab in patients with advanced triple-negative breast cancer,” Dr. Rita Nanda declared in presenting the findings of the KEYNOTE-012 study at the San Antonio Breast Cancer Symposium.

The phase Ib study comprised 32 women with advanced triple-negative breast cancer, all with PD-L1-positive tumors. They were placed on pembrolizumab (Keytruda) at a dose of 10 mg/kg administered intravenously every 2 weeks. Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor with high affinity, thereby switching off PD-1-mediated inhibition of the antitumor immune response.

Bruce Jancin/Frontline Medical News

This was a group of patients with disease progression despite extensive earlier treatments. Median survival is about 1 year from the time of diagnosis of metastatic triple-negative breast cancer, and since receiving that diagnosis nearly half of the study participants had received three or more lines of chemotherapy for metastatic disease. So their median life expectancy at enrollment in KEYNOTE-012 was just a few months, making the durability of the responses seen in the handful of pembrolizumab responders all the more impressive, said Dr. Nanda, a medical oncologist at the University of Chicago.

The overall response rate in the 27 evaluable patients was 18.5% using RECIST version 1.1 criteria with central review. One patient had a complete response, four others had a partial response. Another seven had stable disease. One-third of patients showed tumor shrinkage upon imaging.

The median time to response was 18 weeks. At a median 9.9 months of follow-up, the median duration of response had not yet been reached. Three of five responders remained on treatment for 48 weeks or longer, while the two who discontinued pembrolizumab did so at 40 weeks. Median progression-free survival was 1.9 months, with a progression-free survival rate at 6 months of 23%.

While 56% of patients experienced one or more treatment-related adverse events, the vast majority of these were mild and easily managed without treatment discontinuation. However, four patients experienced grade 3 anemia, aseptic meningitis, headache, or pyrexia, and a fifth who had rapidly progressive disease developed fatal disseminated intravascular coagulation.

A proprietary Merck assay for PD-L1 showed that 58% of patients with advanced triple-negative breast cancer screened as a prelude to the study were deemed to have PD-L1-positive tumors. But investigators saw no correlation between the degree of PD-L1 positivity and response to treatment, so it remains unclear how to identify beforehand the patient subgroup likely to respond to pembrolizumab.

A phase II study is planned for early 2015. Tumor biopsies will routinely be obtained in this and other future trials so investigators can search fresh tissue for useful biomarkers; this was not done in KEYNOTE-012.

Plans are afoot to study pembrolizumab in patients with other subtypes of advanced breast cancer. Pembrolizumab will be assessed in combination with standard therapies, albeit not with agents requiring concomitant corticosteroid therapy, which would likely inhibit pembrolizumab’s ability to stimulate the immune system, Dr. Nanda explained.

The pembrolizumab study results received an enthusiastic response.

“I think everyone continues to be quite excited about immunotherapy in breast cancer. This study shows what we’ve seen in several other studies in other tumor types: a small portion of patients may respond, and for those that do there tends to be a long-term response with durability that we don’t see often with other therapies,” said Dr. Jennifer Litton of MD Anderson Cancer Center, Houston, who chaired a press conference highlighting the KEYNOTE-012 results.

Dr. Edith A. Perez observed that the conventional wisdom has long been that breast cancer is not typically a disease amenable to targeting with immune-modulating therapy. But the conventional wisdom was wrong.

“I’m very grateful that now we have the first proof-of-principle study showing that in a group of patients with refractory advanced metastatic breast cancer there was a signal of activity in response to immune-modulating therapy,” said Dr. Perez, deputy director at large for the Mayo Clinic Cancer Center and professor of medicine at the Mayo Clinic in Jacksonville, Fla.

“These patients have so few options that to see this glimpse of activity provides me with a lot of enthusiasm,” she added.

Discussant Mary L. Disis offered a rousing argument for moving on quickly to mount studies evaluating pembrolizumab in combination regimens with standard therapies. Dr. Disis noted that when pembrolizumab has been studied as single-agent therapy for kidney, gastric, head and neck, and lung cancers as well as in melanoma, the overall response rates have been 20%-34%.

Bruce Jancin/Frontline Medical News

“We’re right in that ballpark with advanced triple-negative breast cancer. And in melanoma, where they’re using pembrolizumab in combination with standard therapies, including chemotherapy, they’re seeing response rates of 50%-60%. So let’s not wait. Let’s move this forward so we can benefit our breast cancer patients,” argued Dr. Disis, professor of medicine at the University of Washington, Seattle.

She noted that the 18-week time to response seen in KEYNOTE-012 is consistent with how long T cells take to propagate in vivo to create an antitumor response.

“We’ve got the biology, we’ve got the monotherapy response rates, and we’ve got the toxicities that are seen with other diseases. So I say, onward to the rational combinations, so we can drive that response rate up. I think everyone needs to know about immunotherapy in the treatment of breast cancer. The time is here for us to be able to drive our patients toward a better therapy that will cause long-lasting protective immunity,” she said.

The KEYNOTE-012 study was funded by Merck, which earlier in 2014 received Food and Drug Administration marketing approval for pembrolizumab in the treatment of metastatic and progressive melanoma. Dr. Nanda reported having no financial conflicts.

[email protected]

SAN ANTONIO – Roughly one in five women with heavily pretreated, advanced triple-negative breast cancer experienced a durable response to monotherapy using the novel immune checkpoint inhibitor pembrolizumab in a small proof-of-concept study.

“The acceptable safety and tolerability profile coupled with the promising antitumor activity seen in this very early trial support the further development of pembrolizumab in patients with advanced triple-negative breast cancer,” Dr. Rita Nanda declared in presenting the findings of the KEYNOTE-012 study at the San Antonio Breast Cancer Symposium.

The phase Ib study comprised 32 women with advanced triple-negative breast cancer, all with PD-L1-positive tumors. They were placed on pembrolizumab (Keytruda) at a dose of 10 mg/kg administered intravenously every 2 weeks. Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor with high affinity, thereby switching off PD-1-mediated inhibition of the antitumor immune response.

Bruce Jancin/Frontline Medical News

This was a group of patients with disease progression despite extensive earlier treatments. Median survival is about 1 year from the time of diagnosis of metastatic triple-negative breast cancer, and since receiving that diagnosis nearly half of the study participants had received three or more lines of chemotherapy for metastatic disease. So their median life expectancy at enrollment in KEYNOTE-012 was just a few months, making the durability of the responses seen in the handful of pembrolizumab responders all the more impressive, said Dr. Nanda, a medical oncologist at the University of Chicago.

The overall response rate in the 27 evaluable patients was 18.5% using RECIST version 1.1 criteria with central review. One patient had a complete response, four others had a partial response. Another seven had stable disease. One-third of patients showed tumor shrinkage upon imaging.

The median time to response was 18 weeks. At a median 9.9 months of follow-up, the median duration of response had not yet been reached. Three of five responders remained on treatment for 48 weeks or longer, while the two who discontinued pembrolizumab did so at 40 weeks. Median progression-free survival was 1.9 months, with a progression-free survival rate at 6 months of 23%.

While 56% of patients experienced one or more treatment-related adverse events, the vast majority of these were mild and easily managed without treatment discontinuation. However, four patients experienced grade 3 anemia, aseptic meningitis, headache, or pyrexia, and a fifth who had rapidly progressive disease developed fatal disseminated intravascular coagulation.

A proprietary Merck assay for PD-L1 showed that 58% of patients with advanced triple-negative breast cancer screened as a prelude to the study were deemed to have PD-L1-positive tumors. But investigators saw no correlation between the degree of PD-L1 positivity and response to treatment, so it remains unclear how to identify beforehand the patient subgroup likely to respond to pembrolizumab.

A phase II study is planned for early 2015. Tumor biopsies will routinely be obtained in this and other future trials so investigators can search fresh tissue for useful biomarkers; this was not done in KEYNOTE-012.

Plans are afoot to study pembrolizumab in patients with other subtypes of advanced breast cancer. Pembrolizumab will be assessed in combination with standard therapies, albeit not with agents requiring concomitant corticosteroid therapy, which would likely inhibit pembrolizumab’s ability to stimulate the immune system, Dr. Nanda explained.

The pembrolizumab study results received an enthusiastic response.

“I think everyone continues to be quite excited about immunotherapy in breast cancer. This study shows what we’ve seen in several other studies in other tumor types: a small portion of patients may respond, and for those that do there tends to be a long-term response with durability that we don’t see often with other therapies,” said Dr. Jennifer Litton of MD Anderson Cancer Center, Houston, who chaired a press conference highlighting the KEYNOTE-012 results.

Dr. Edith A. Perez observed that the conventional wisdom has long been that breast cancer is not typically a disease amenable to targeting with immune-modulating therapy. But the conventional wisdom was wrong.

“I’m very grateful that now we have the first proof-of-principle study showing that in a group of patients with refractory advanced metastatic breast cancer there was a signal of activity in response to immune-modulating therapy,” said Dr. Perez, deputy director at large for the Mayo Clinic Cancer Center and professor of medicine at the Mayo Clinic in Jacksonville, Fla.

“These patients have so few options that to see this glimpse of activity provides me with a lot of enthusiasm,” she added.

Discussant Mary L. Disis offered a rousing argument for moving on quickly to mount studies evaluating pembrolizumab in combination regimens with standard therapies. Dr. Disis noted that when pembrolizumab has been studied as single-agent therapy for kidney, gastric, head and neck, and lung cancers as well as in melanoma, the overall response rates have been 20%-34%.

Bruce Jancin/Frontline Medical News

“We’re right in that ballpark with advanced triple-negative breast cancer. And in melanoma, where they’re using pembrolizumab in combination with standard therapies, including chemotherapy, they’re seeing response rates of 50%-60%. So let’s not wait. Let’s move this forward so we can benefit our breast cancer patients,” argued Dr. Disis, professor of medicine at the University of Washington, Seattle.

She noted that the 18-week time to response seen in KEYNOTE-012 is consistent with how long T cells take to propagate in vivo to create an antitumor response.

“We’ve got the biology, we’ve got the monotherapy response rates, and we’ve got the toxicities that are seen with other diseases. So I say, onward to the rational combinations, so we can drive that response rate up. I think everyone needs to know about immunotherapy in the treatment of breast cancer. The time is here for us to be able to drive our patients toward a better therapy that will cause long-lasting protective immunity,” she said.

The KEYNOTE-012 study was funded by Merck, which earlier in 2014 received Food and Drug Administration marketing approval for pembrolizumab in the treatment of metastatic and progressive melanoma. Dr. Nanda reported having no financial conflicts.

[email protected]

SAN ANTONIO – Roughly one in five women with heavily pretreated, advanced triple-negative breast cancer experienced a durable response to monotherapy using the novel immune checkpoint inhibitor pembrolizumab in a small proof-of-concept study.

“The acceptable safety and tolerability profile coupled with the promising antitumor activity seen in this very early trial support the further development of pembrolizumab in patients with advanced triple-negative breast cancer,” Dr. Rita Nanda declared in presenting the findings of the KEYNOTE-012 study at the San Antonio Breast Cancer Symposium.

The phase Ib study comprised 32 women with advanced triple-negative breast cancer, all with PD-L1-positive tumors. They were placed on pembrolizumab (Keytruda) at a dose of 10 mg/kg administered intravenously every 2 weeks. Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor with high affinity, thereby switching off PD-1-mediated inhibition of the antitumor immune response.

Bruce Jancin/Frontline Medical News

This was a group of patients with disease progression despite extensive earlier treatments. Median survival is about 1 year from the time of diagnosis of metastatic triple-negative breast cancer, and since receiving that diagnosis nearly half of the study participants had received three or more lines of chemotherapy for metastatic disease. So their median life expectancy at enrollment in KEYNOTE-012 was just a few months, making the durability of the responses seen in the handful of pembrolizumab responders all the more impressive, said Dr. Nanda, a medical oncologist at the University of Chicago.

The overall response rate in the 27 evaluable patients was 18.5% using RECIST version 1.1 criteria with central review. One patient had a complete response, four others had a partial response. Another seven had stable disease. One-third of patients showed tumor shrinkage upon imaging.

The median time to response was 18 weeks. At a median 9.9 months of follow-up, the median duration of response had not yet been reached. Three of five responders remained on treatment for 48 weeks or longer, while the two who discontinued pembrolizumab did so at 40 weeks. Median progression-free survival was 1.9 months, with a progression-free survival rate at 6 months of 23%.

While 56% of patients experienced one or more treatment-related adverse events, the vast majority of these were mild and easily managed without treatment discontinuation. However, four patients experienced grade 3 anemia, aseptic meningitis, headache, or pyrexia, and a fifth who had rapidly progressive disease developed fatal disseminated intravascular coagulation.

A proprietary Merck assay for PD-L1 showed that 58% of patients with advanced triple-negative breast cancer screened as a prelude to the study were deemed to have PD-L1-positive tumors. But investigators saw no correlation between the degree of PD-L1 positivity and response to treatment, so it remains unclear how to identify beforehand the patient subgroup likely to respond to pembrolizumab.

A phase II study is planned for early 2015. Tumor biopsies will routinely be obtained in this and other future trials so investigators can search fresh tissue for useful biomarkers; this was not done in KEYNOTE-012.

Plans are afoot to study pembrolizumab in patients with other subtypes of advanced breast cancer. Pembrolizumab will be assessed in combination with standard therapies, albeit not with agents requiring concomitant corticosteroid therapy, which would likely inhibit pembrolizumab’s ability to stimulate the immune system, Dr. Nanda explained.

The pembrolizumab study results received an enthusiastic response.

“I think everyone continues to be quite excited about immunotherapy in breast cancer. This study shows what we’ve seen in several other studies in other tumor types: a small portion of patients may respond, and for those that do there tends to be a long-term response with durability that we don’t see often with other therapies,” said Dr. Jennifer Litton of MD Anderson Cancer Center, Houston, who chaired a press conference highlighting the KEYNOTE-012 results.

Dr. Edith A. Perez observed that the conventional wisdom has long been that breast cancer is not typically a disease amenable to targeting with immune-modulating therapy. But the conventional wisdom was wrong.

“I’m very grateful that now we have the first proof-of-principle study showing that in a group of patients with refractory advanced metastatic breast cancer there was a signal of activity in response to immune-modulating therapy,” said Dr. Perez, deputy director at large for the Mayo Clinic Cancer Center and professor of medicine at the Mayo Clinic in Jacksonville, Fla.

“These patients have so few options that to see this glimpse of activity provides me with a lot of enthusiasm,” she added.

Discussant Mary L. Disis offered a rousing argument for moving on quickly to mount studies evaluating pembrolizumab in combination regimens with standard therapies. Dr. Disis noted that when pembrolizumab has been studied as single-agent therapy for kidney, gastric, head and neck, and lung cancers as well as in melanoma, the overall response rates have been 20%-34%.

Bruce Jancin/Frontline Medical News

“We’re right in that ballpark with advanced triple-negative breast cancer. And in melanoma, where they’re using pembrolizumab in combination with standard therapies, including chemotherapy, they’re seeing response rates of 50%-60%. So let’s not wait. Let’s move this forward so we can benefit our breast cancer patients,” argued Dr. Disis, professor of medicine at the University of Washington, Seattle.

She noted that the 18-week time to response seen in KEYNOTE-012 is consistent with how long T cells take to propagate in vivo to create an antitumor response.

“We’ve got the biology, we’ve got the monotherapy response rates, and we’ve got the toxicities that are seen with other diseases. So I say, onward to the rational combinations, so we can drive that response rate up. I think everyone needs to know about immunotherapy in the treatment of breast cancer. The time is here for us to be able to drive our patients toward a better therapy that will cause long-lasting protective immunity,” she said.

The KEYNOTE-012 study was funded by Merck, which earlier in 2014 received Food and Drug Administration marketing approval for pembrolizumab in the treatment of metastatic and progressive melanoma. Dr. Nanda reported having no financial conflicts.

[email protected]

SAN ANTONIO – In the FERGI trial, the combination of pictilisib and fulvestrant nearly doubled progression-free survival in a subset of patients with ER+/PR+ breast cancer, increasing the duration of response by almost 3 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

But in the entire study cohort, the combination conferred no advantage over fulvestrant alone, with less than a 2-month survival advantage going to the combination therapy arm, said Dr. Winer of the Dana-Farber Cancer Institute, Boston.

The findings raise the question of whether pictilisib, a general inhibitor of the PI3 kinase pathway, confers any meaningful clinical results, especially in light of the excess of associated adverse events (31% with combined therapy vs. 20% with fulvestrant alone), according to Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston.

In this video interview, she shared her views on the study results, the drug’s mechanism, and its possible future – especially in light of the more effective and more selective PI3k inhibitors that are now in early clinical trials.

[email protected]

SAN ANTONIO – In the FERGI trial, the combination of pictilisib and fulvestrant nearly doubled progression-free survival in a subset of patients with ER+/PR+ breast cancer, increasing the duration of response by almost 3 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

But in the entire study cohort, the combination conferred no advantage over fulvestrant alone, with less than a 2-month survival advantage going to the combination therapy arm, said Dr. Winer of the Dana-Farber Cancer Institute, Boston.

The findings raise the question of whether pictilisib, a general inhibitor of the PI3 kinase pathway, confers any meaningful clinical results, especially in light of the excess of associated adverse events (31% with combined therapy vs. 20% with fulvestrant alone), according to Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston.

In this video interview, she shared her views on the study results, the drug’s mechanism, and its possible future – especially in light of the more effective and more selective PI3k inhibitors that are now in early clinical trials.

[email protected]

SAN ANTONIO – In the FERGI trial, the combination of pictilisib and fulvestrant nearly doubled progression-free survival in a subset of patients with ER+/PR+ breast cancer, increasing the duration of response by almost 3 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

But in the entire study cohort, the combination conferred no advantage over fulvestrant alone, with less than a 2-month survival advantage going to the combination therapy arm, said Dr. Winer of the Dana-Farber Cancer Institute, Boston.

The findings raise the question of whether pictilisib, a general inhibitor of the PI3 kinase pathway, confers any meaningful clinical results, especially in light of the excess of associated adverse events (31% with combined therapy vs. 20% with fulvestrant alone), according to Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston.

In this video interview, she shared her views on the study results, the drug’s mechanism, and its possible future – especially in light of the more effective and more selective PI3k inhibitors that are now in early clinical trials.

[email protected]

SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

[email protected]

SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

[email protected]

SAN ANTONIO – The combination of pictilisib and fulvestrant improved progression-free survival in some women with advanced hormone receptor–positive breast cancer – but the jury is out on whether that benefit is clinically meaningful.

At 17 months, women taking the dual regimen were 26% less likely to experience disease progression, but that progression-free survival difference amounted to only about 2 months, Dr. Eric Winer said at the San Antonio Breast Cancer Symposium.

Results were slightly better in those with both progesterone and estrogen receptor–positive tumors, and in the small subgroup of patients with a confirmed PIK3CA mutation tumor, Dr. Winer, a coinvestigator on the study, said during a press briefing.

“There was enough action here that there is interest in pursuing research on this [investigational] drug,” said Dr. Winer of the Dana Farber Cancer Institute, Boston. “Whether or not this is the right drug remains to be seen. ... We will see if there is a stronger signal in the ongoing phase III trial.”

Pictilisib is a PI3 kinase inhibitor, under development by Genentech. PI3 kinase is an oncogene commonly mutated in cancer. The PI3k/Akt/mTOR pathway regulates cell growth and survival. However, pictilisib is a nonselective pan-inhibitor of this pathway, so concern remains about side effects involving normal PI3k processes.

The FERGI study randomized 168 women (89 in the combination arm) with estrogen receptor–positive and/or progesterone receptor–positive tumors to either fulvestrant 500 mg plus placebo or fulvestrant 500 mg plus pictilisib 340 mg. All patients had failed prior treatment with an aromatase inhibitor, relapsing within 6 months of beginning or completing AI treatment, or by having disease progression while on AI treatment. They were stratified by both hormone receptor and PIK3CA tumor status. The study’s primary endpoint was progression-free survival duration in the entire group, and within both subgroups.

Fulvestrant was administered on day 1 of each 28-day cycle and pictilisib or placebo every day. Tumor assessments were performed every 8 weeks of the 24-week trial.

At a mean follow-up of 17 months, 120 patients had progressed – 59 in the combination group and 61 in the placebo group – a nonsignificant difference (P = .096). Time to progression was 6.6 months in the combination arm vs. 5.1 months in the placebo arm.

Combination therapy conferred a significant advantage, however, upon women whose tumors were both ER+ and PR+. Among this group of 116, there were 57 progression events. The median time to progression was significantly longer in the combination arm than in the placebo arm (7.4 months vs. 3.7 months), representing a 56% risk reduction (P = .002).

The combination conferred no survival benefit on women whose tumors were positive for the PIK3CA mutation. “This was a surprise because the PIK3CA gene is a central component of the PI3k signaling pathway. It may be that PIK3CA mutation is not the only way to activate PI3k signaling,” Dr. Winer said.

Adverse events were significantly more common among those taking combination therapy. (31% vs. 20%).

Among these were diarrhea (63% vs. 9%); nausea (48% vs. 19%); rash (43% vs. 6%); fatigue (27% vs. 20%); vomiting (20% vs. 4%); decreased appetite (19% vs. 6%); and hyperglycemia (17% vs. 5%). Dysgeusia occurred in 35% of those in the combination arm and in none of those in the placebo arm. There appeared to be no drug-drug interaction between fulvestrant and pictilisib; there were no treatment-related deaths.

“The bottom line is we had hoped for a somewhat more active improvement seen in progression-free survival, but the exploratory subgroup [of ER+ PR+ tumors] is worth looking into further,” Dr. Winer said.

In an interview, moderator Dr. Jennifer Litton of the University of Texas MD Anderson Cancer Center, Houston, questioned what the statistically significant progression-free survival differences would really mean clinically. By 21 months, the median overall survival difference had declined to 6.6 months vs. 5.1 months for the intention-to-treat group. “You have to wonder if it’s really worth it, considering the side effects.”

At any rate, Dr. Winer wondered aloud if pictilisib has much of a future. While Genentech continues to test the drug in phase III trials, several other PI3k inhibitors are in early studies. These look to be both more effective and more selectively targeted than pictilisib – a combination that would theoretically decrease side effects while improving survival.

“There are more data to be analyzed,” he said. “But I predict that in the wake of these newer drugs, pictilisib will not go forward after they are.”

The study was funded by Genentech. Dr. Winer had no financial disclosures. The principal investigator, Dr. Ian Krop of the Dana-Farber Cancer Institute, receives research funding from the company.

[email protected]

S3-01. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012)

Tutt A et al.

S3-08. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor–positive (HR+) early breast cancer (BC): Analysis of the SOFT trial

Francis PA et al.

S3-09. Patient-reported endocrine symptoms, sexual functioning and quality of life (QoL) in the IBCSG SOFT trial: Adjuvant treatment with tamoxifen (T) alone versus tamoxifen plus ovarian function suppression (OFS) in premenopausal women with hormone receptor–positive (HR+) breast cancer (BC)

Ribi K et al.

S6-01. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1

Hurvitz SA et al.

S1-09. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer

Nanda R et al.

Dr. Hope S. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

S3-01. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012)

Tutt A et al.

S3-08. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor–positive (HR+) early breast cancer (BC): Analysis of the SOFT trial

Francis PA et al.

S3-09. Patient-reported endocrine symptoms, sexual functioning and quality of life (QoL) in the IBCSG SOFT trial: Adjuvant treatment with tamoxifen (T) alone versus tamoxifen plus ovarian function suppression (OFS) in premenopausal women with hormone receptor–positive (HR+) breast cancer (BC)

Ribi K et al.

S6-01. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1

Hurvitz SA et al.

S1-09. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer

Nanda R et al.

Dr. Hope S. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

S3-01. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012)

Tutt A et al.

S3-08. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor–positive (HR+) early breast cancer (BC): Analysis of the SOFT trial

Francis PA et al.

S3-09. Patient-reported endocrine symptoms, sexual functioning and quality of life (QoL) in the IBCSG SOFT trial: Adjuvant treatment with tamoxifen (T) alone versus tamoxifen plus ovarian function suppression (OFS) in premenopausal women with hormone receptor–positive (HR+) breast cancer (BC)

Ribi K et al.

S6-01. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1

Hurvitz SA et al.

S1-09. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer

Nanda R et al.

Dr. Hope S. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.