Buparlisib overcomes endocrine resistance in hormone receptor–positive breast cancer

SAN ANTONIO – Buparlisib, an oral investigational pan-phosphoinositide 3-kinase (pan-PI3) kinase inhibitor, appears to be efficacious for overcoming endocrine resistance in advanced breast cancer, according to first results of the BELLE-2 trialreported at the San Antonio Breast Cancer Symposium. But benefit is likely restricted to patients whose tumors have a mutation of the PI3 kinase alpha gene (PIK3CA) detectable in circulating tumor DNA.

Trial participants were 1,147 postmenopausal women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that had progressed on or after prior aromatase inhibitor therapy. They were randomized to treatment with buparlisib (formerly BKM120) or placebo, each added to the estrogen-receptor antagonist fulvestrant (Faslodex).

Results showed that buparlisib prolonged progression-free survival by about 2 months relative to placebo, meeting the trial’s primary endpoint, according to data reported in a session and related press briefing.

The presence of a PIK3CA mutation and/or loss of PTEN in archival tumor tissue was not helpful in identifying women who would benefit. But the presence of a PIK3CA mutation detected in circulating cell-free tumor DNA (a so-called liquid biopsy) was, with a progression-free survival advantage from buparlisib approaching 4 months in this subset.

“This is the first time that we showed that eliminating the PI3 kinase pathway may be a viable option for patients with hormone therapy–resistant breast cancer,” coinvestigator Dr. Mario Campone, Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, in Nantes, France, commented in the press briefing. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy.”

“The BELLE-2 study suggests that assessment of PIK3CA mutations in a liquid biopsy may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” he added. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations detected by liquid biopsy and tumor tissue, which we see in the SOLAR-1 clinical trial” testing the drug alpelisib (BYL719).

He speculated that the lack of predictive value of mutational status in the tumor vs. mutational status in the circulating tumor DNA was due in part to the timing of collection of these samples. In about 80% of cases, the tumor was the primary tumor, collected before any treatment, whereas the circulating tumor DNA was obtained at trial enrollment, after patients had been exposed to aromatase inhibitors.

Press briefing moderator Dr. C. Kent Osborne, a professor and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, commented that buparlisib “is not a home run, if you will, in terms of patients benefiting, probably because there are many other pathways that can contribute [to resistance] … And we just have to identify those and then determine which treatments we can combine together to have a better, more optimal effect.”

The 2-month benefit from buparlisib seen in the entire trial population was modest but based on median values, he cautioned. Looking at the progression-free survival curves at 2-3 years, the proportion of patients still free of events was about 20% with the drug, compared with 10% with placebo.

“It will take time to know whether we see an overall survival benefit. I wouldn’t be surprised if we didn’t,” given that patients in the control group will be given effective therapies at the time of progression, Dr. Osborne further commented. “A lot of studies in metastatic breast cancer show these sort of modest benefits, but then when you take the treatment earlier in the course of disease, such as in the adjuvant setting, for instance, you see a much more dramatic benefit. So this is the first time that a PI3 kinase inhibitor has shown this, and I would say that this is still an advance and tells us that this gives us more information about the importance of this pathway in endocrine-resistant disease.”

BELLE-2 was designed on the basis of data suggesting that activation of the PI3 kinase/mTOR pathway is a hallmark of hormone receptor–positive breast cancers that have become resistant to endocrine therapy, according to the investigators. Thus, a dual blockade of signaling through both the estrogen receptor pathway and the PI3 kinase pathway may circumvent resistance.

Trial results showed that the median duration of treatment was 4.2 months with buparlisib plus fulvestrant (1.9 months, specifically with buparlisib) and 5.0 months with placebo plus fulvestrant (4.0 months, specifically with placebo), reported Dr. Campone.

The drug was associated with a higher rate of grade 3 or 4 adverse events (77% vs. 32%), mainly driven by more cases of transaminitis, hyperglycemia, rash, and mood disorders.

In the entire trial population, median progression-free survival was 6.9 months with buparlisib and 5.0 months with placebo (hazard ratio, 0.78; P less than .001), meeting the trial’s primary endpoint.

In the subset of 372 patients with PI3K activation that was defined by presence of a PIK3CA mutation of any type (activating or not) and/or PTEN loss in archival tumor tissue, median progression-free survival was 6.8 months with buparlisib and 4.0 months with placebo (HR, 0.76), but the P value missed the threshold for significance in this analysis.

In a preplanned exploratory analysis, the investigators analyzed circulating tumor DNA in 587 patients for two PIK3CA mutations known to be activating mutations. Results here suggested that the progression-free survival benefit was limited to those who had a mutation – 7.0 months with buparlisib vs. 3.2 months with placebo (HR, 0.56; P less than .001) – with no significant benefit in patients having the wild-type (nonmutated) gene.

SAN ANTONIO – Buparlisib, an oral investigational pan-phosphoinositide 3-kinase (pan-PI3) kinase inhibitor, appears to be efficacious for overcoming endocrine resistance in advanced breast cancer, according to first results of the BELLE-2 trialreported at the San Antonio Breast Cancer Symposium. But benefit is likely restricted to patients whose tumors have a mutation of the PI3 kinase alpha gene (PIK3CA) detectable in circulating tumor DNA.

Trial participants were 1,147 postmenopausal women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that had progressed on or after prior aromatase inhibitor therapy. They were randomized to treatment with buparlisib (formerly BKM120) or placebo, each added to the estrogen-receptor antagonist fulvestrant (Faslodex).

Results showed that buparlisib prolonged progression-free survival by about 2 months relative to placebo, meeting the trial’s primary endpoint, according to data reported in a session and related press briefing.

The presence of a PIK3CA mutation and/or loss of PTEN in archival tumor tissue was not helpful in identifying women who would benefit. But the presence of a PIK3CA mutation detected in circulating cell-free tumor DNA (a so-called liquid biopsy) was, with a progression-free survival advantage from buparlisib approaching 4 months in this subset.

“This is the first time that we showed that eliminating the PI3 kinase pathway may be a viable option for patients with hormone therapy–resistant breast cancer,” coinvestigator Dr. Mario Campone, Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, in Nantes, France, commented in the press briefing. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy.”

“The BELLE-2 study suggests that assessment of PIK3CA mutations in a liquid biopsy may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” he added. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations detected by liquid biopsy and tumor tissue, which we see in the SOLAR-1 clinical trial” testing the drug alpelisib (BYL719).

He speculated that the lack of predictive value of mutational status in the tumor vs. mutational status in the circulating tumor DNA was due in part to the timing of collection of these samples. In about 80% of cases, the tumor was the primary tumor, collected before any treatment, whereas the circulating tumor DNA was obtained at trial enrollment, after patients had been exposed to aromatase inhibitors.

Press briefing moderator Dr. C. Kent Osborne, a professor and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, commented that buparlisib “is not a home run, if you will, in terms of patients benefiting, probably because there are many other pathways that can contribute [to resistance] … And we just have to identify those and then determine which treatments we can combine together to have a better, more optimal effect.”

The 2-month benefit from buparlisib seen in the entire trial population was modest but based on median values, he cautioned. Looking at the progression-free survival curves at 2-3 years, the proportion of patients still free of events was about 20% with the drug, compared with 10% with placebo.

“It will take time to know whether we see an overall survival benefit. I wouldn’t be surprised if we didn’t,” given that patients in the control group will be given effective therapies at the time of progression, Dr. Osborne further commented. “A lot of studies in metastatic breast cancer show these sort of modest benefits, but then when you take the treatment earlier in the course of disease, such as in the adjuvant setting, for instance, you see a much more dramatic benefit. So this is the first time that a PI3 kinase inhibitor has shown this, and I would say that this is still an advance and tells us that this gives us more information about the importance of this pathway in endocrine-resistant disease.”

BELLE-2 was designed on the basis of data suggesting that activation of the PI3 kinase/mTOR pathway is a hallmark of hormone receptor–positive breast cancers that have become resistant to endocrine therapy, according to the investigators. Thus, a dual blockade of signaling through both the estrogen receptor pathway and the PI3 kinase pathway may circumvent resistance.

Trial results showed that the median duration of treatment was 4.2 months with buparlisib plus fulvestrant (1.9 months, specifically with buparlisib) and 5.0 months with placebo plus fulvestrant (4.0 months, specifically with placebo), reported Dr. Campone.

The drug was associated with a higher rate of grade 3 or 4 adverse events (77% vs. 32%), mainly driven by more cases of transaminitis, hyperglycemia, rash, and mood disorders.

In the entire trial population, median progression-free survival was 6.9 months with buparlisib and 5.0 months with placebo (hazard ratio, 0.78; P less than .001), meeting the trial’s primary endpoint.

In the subset of 372 patients with PI3K activation that was defined by presence of a PIK3CA mutation of any type (activating or not) and/or PTEN loss in archival tumor tissue, median progression-free survival was 6.8 months with buparlisib and 4.0 months with placebo (HR, 0.76), but the P value missed the threshold for significance in this analysis.

In a preplanned exploratory analysis, the investigators analyzed circulating tumor DNA in 587 patients for two PIK3CA mutations known to be activating mutations. Results here suggested that the progression-free survival benefit was limited to those who had a mutation – 7.0 months with buparlisib vs. 3.2 months with placebo (HR, 0.56; P less than .001) – with no significant benefit in patients having the wild-type (nonmutated) gene.

SAN ANTONIO – Buparlisib, an oral investigational pan-phosphoinositide 3-kinase (pan-PI3) kinase inhibitor, appears to be efficacious for overcoming endocrine resistance in advanced breast cancer, according to first results of the BELLE-2 trialreported at the San Antonio Breast Cancer Symposium. But benefit is likely restricted to patients whose tumors have a mutation of the PI3 kinase alpha gene (PIK3CA) detectable in circulating tumor DNA.

Trial participants were 1,147 postmenopausal women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that had progressed on or after prior aromatase inhibitor therapy. They were randomized to treatment with buparlisib (formerly BKM120) or placebo, each added to the estrogen-receptor antagonist fulvestrant (Faslodex).

Results showed that buparlisib prolonged progression-free survival by about 2 months relative to placebo, meeting the trial’s primary endpoint, according to data reported in a session and related press briefing.

The presence of a PIK3CA mutation and/or loss of PTEN in archival tumor tissue was not helpful in identifying women who would benefit. But the presence of a PIK3CA mutation detected in circulating cell-free tumor DNA (a so-called liquid biopsy) was, with a progression-free survival advantage from buparlisib approaching 4 months in this subset.

“This is the first time that we showed that eliminating the PI3 kinase pathway may be a viable option for patients with hormone therapy–resistant breast cancer,” coinvestigator Dr. Mario Campone, Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, in Nantes, France, commented in the press briefing. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy.”

“The BELLE-2 study suggests that assessment of PIK3CA mutations in a liquid biopsy may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” he added. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations detected by liquid biopsy and tumor tissue, which we see in the SOLAR-1 clinical trial” testing the drug alpelisib (BYL719).

He speculated that the lack of predictive value of mutational status in the tumor vs. mutational status in the circulating tumor DNA was due in part to the timing of collection of these samples. In about 80% of cases, the tumor was the primary tumor, collected before any treatment, whereas the circulating tumor DNA was obtained at trial enrollment, after patients had been exposed to aromatase inhibitors.

Press briefing moderator Dr. C. Kent Osborne, a professor and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, commented that buparlisib “is not a home run, if you will, in terms of patients benefiting, probably because there are many other pathways that can contribute [to resistance] … And we just have to identify those and then determine which treatments we can combine together to have a better, more optimal effect.”

The 2-month benefit from buparlisib seen in the entire trial population was modest but based on median values, he cautioned. Looking at the progression-free survival curves at 2-3 years, the proportion of patients still free of events was about 20% with the drug, compared with 10% with placebo.

“It will take time to know whether we see an overall survival benefit. I wouldn’t be surprised if we didn’t,” given that patients in the control group will be given effective therapies at the time of progression, Dr. Osborne further commented. “A lot of studies in metastatic breast cancer show these sort of modest benefits, but then when you take the treatment earlier in the course of disease, such as in the adjuvant setting, for instance, you see a much more dramatic benefit. So this is the first time that a PI3 kinase inhibitor has shown this, and I would say that this is still an advance and tells us that this gives us more information about the importance of this pathway in endocrine-resistant disease.”

BELLE-2 was designed on the basis of data suggesting that activation of the PI3 kinase/mTOR pathway is a hallmark of hormone receptor–positive breast cancers that have become resistant to endocrine therapy, according to the investigators. Thus, a dual blockade of signaling through both the estrogen receptor pathway and the PI3 kinase pathway may circumvent resistance.

Trial results showed that the median duration of treatment was 4.2 months with buparlisib plus fulvestrant (1.9 months, specifically with buparlisib) and 5.0 months with placebo plus fulvestrant (4.0 months, specifically with placebo), reported Dr. Campone.

The drug was associated with a higher rate of grade 3 or 4 adverse events (77% vs. 32%), mainly driven by more cases of transaminitis, hyperglycemia, rash, and mood disorders.

In the entire trial population, median progression-free survival was 6.9 months with buparlisib and 5.0 months with placebo (hazard ratio, 0.78; P less than .001), meeting the trial’s primary endpoint.

In the subset of 372 patients with PI3K activation that was defined by presence of a PIK3CA mutation of any type (activating or not) and/or PTEN loss in archival tumor tissue, median progression-free survival was 6.8 months with buparlisib and 4.0 months with placebo (HR, 0.76), but the P value missed the threshold for significance in this analysis.

In a preplanned exploratory analysis, the investigators analyzed circulating tumor DNA in 587 patients for two PIK3CA mutations known to be activating mutations. Results here suggested that the progression-free survival benefit was limited to those who had a mutation – 7.0 months with buparlisib vs. 3.2 months with placebo (HR, 0.56; P less than .001) – with no significant benefit in patients having the wild-type (nonmutated) gene.