User login
CHICAGO – Is two months of progression-free survival worth it if those months mean living with serious side effects?
For women with advanced estrogen receptor-positive, HER2-negative breast cancer, the combination of the PI3K inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) bought two additional months of PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half the patients treated with the combination, results of the SANDPIPER trial show.
“These results are positive, but I think we all agree they are modest,” lead investigator José Baselga, MD, PhD from Memorial Sloan Kettering Cancer Center in New York, said at a briefing at the annual meeting of the American Society of Clinical Oncology.
The “challenging tolerability” of the combination led to frequent treatment discontinuations, and may have limited the clinical benefit of the combination, he said, but added that the study serves as proof of principle that PI3K may be a bona fide target in advanced breast cancer.
ASCO expert Harold Burstein, MD, from the Dana-Farber Cancer Institute in Boston agreed that PI3K “is a very appealing target. It’s a mutation that probably is the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”
He likened the study findings, however, to a key opening a locked door, only to find that there is a chain latch on the other side preventing entry.
In an interview, Dr. Burstein said that despite the best efforts of Dr. Baselga and others to find a suitable approach to targeting the PI3K pathway, the evidence to date suggests that it may not be an important driver of breast cancer.
Taselisib is the first agent in its class to specifically block the PI3K alpha isoform that is found to be mutated in approximately 40% of advanced ER-positive breast cancer. The agent has been shown to offer clinical benefits in early trials for patients with head and neck and some gynecologic cancers.
In the phase 3 SANDPIPER trial, 516 women with locally advanced or metastatic ER-positive, HER2-negative breast cancer that had progressed or recurred following aromatase inhibitor therapy were enrolled and randomly assigned on a 2:1 basis to receive fulvestrant plus taselisib (340 patients) or fulvestrant plus a placebo (176 patients).
As noted, the median progression-free survival was 7.4 months for women who received the combination, compared with 5.4 months for controls. The stratified hazard ratio was 0.70 favoring taselisib (P = .0037).
But also as noted, the addition of taselisib “clearly led to toxicity,” Dr. Baselga said.
Serious adverse events occurred in 32% of patients in the fulvestrant/taselisib group, compared with 8.9% of controls. Grade 3 or greater side effects occurred in 49.5% vs. 16.4%, respectively, and side effects leading to discontinuation of taselisib occurred in 16.8% of patients, vs. 2.3% of those on placebo.
The primary toxicities were gastrointestinal effects, especially diarrhea, which occurred in 60.1% vs. 19.7% of patients (all grades). Hyperglycemia occurred in 40.4% of patients on taselisib, vs. 9.4% on placebo.
Dr. Baselga noted that the secondary endpoints of overall response rate, clinical benefit rate, and duration of response all favored taselisib.
Asked whether taselisib was the right agent in this setting, given the commercial availability of at least two other PI3K inhibitors – idelalisib (Zydelig) and copanlisib (Aliqopa) – Dr. Baselga agreed that another, more specific agent may offer similar or better efficacy with fewer off-target effects. He noted that taselisib is highly active against the alpha isoforms of PI3K, but also hits the delta and gamma isoforms.
“The side effects that we see that are limiting patients staying on [taselisib] are mostly delta and gamma. So I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer,” he said.
During the oral abstracts session where Dr. Baselga presented the SANDPIPER results, Cynthia X Ma, MD, PhD, from Washington University School of Medicine in St. Louis, the invited discussant, agreed that the trial provides proof of concept that PI3K inhibition may be an effective therapeutic strategy in breast cancer.
“However, the modest progression-free survival improvement and significant toxicity profile does not support its clinical application,” she said.
SOURCE: : Baselga J et al. ASCO 2018 Abstract LBA1006 .
CHICAGO – Is two months of progression-free survival worth it if those months mean living with serious side effects?
For women with advanced estrogen receptor-positive, HER2-negative breast cancer, the combination of the PI3K inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) bought two additional months of PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half the patients treated with the combination, results of the SANDPIPER trial show.
“These results are positive, but I think we all agree they are modest,” lead investigator José Baselga, MD, PhD from Memorial Sloan Kettering Cancer Center in New York, said at a briefing at the annual meeting of the American Society of Clinical Oncology.
The “challenging tolerability” of the combination led to frequent treatment discontinuations, and may have limited the clinical benefit of the combination, he said, but added that the study serves as proof of principle that PI3K may be a bona fide target in advanced breast cancer.
ASCO expert Harold Burstein, MD, from the Dana-Farber Cancer Institute in Boston agreed that PI3K “is a very appealing target. It’s a mutation that probably is the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”
He likened the study findings, however, to a key opening a locked door, only to find that there is a chain latch on the other side preventing entry.
In an interview, Dr. Burstein said that despite the best efforts of Dr. Baselga and others to find a suitable approach to targeting the PI3K pathway, the evidence to date suggests that it may not be an important driver of breast cancer.
Taselisib is the first agent in its class to specifically block the PI3K alpha isoform that is found to be mutated in approximately 40% of advanced ER-positive breast cancer. The agent has been shown to offer clinical benefits in early trials for patients with head and neck and some gynecologic cancers.
In the phase 3 SANDPIPER trial, 516 women with locally advanced or metastatic ER-positive, HER2-negative breast cancer that had progressed or recurred following aromatase inhibitor therapy were enrolled and randomly assigned on a 2:1 basis to receive fulvestrant plus taselisib (340 patients) or fulvestrant plus a placebo (176 patients).
As noted, the median progression-free survival was 7.4 months for women who received the combination, compared with 5.4 months for controls. The stratified hazard ratio was 0.70 favoring taselisib (P = .0037).
But also as noted, the addition of taselisib “clearly led to toxicity,” Dr. Baselga said.
Serious adverse events occurred in 32% of patients in the fulvestrant/taselisib group, compared with 8.9% of controls. Grade 3 or greater side effects occurred in 49.5% vs. 16.4%, respectively, and side effects leading to discontinuation of taselisib occurred in 16.8% of patients, vs. 2.3% of those on placebo.
The primary toxicities were gastrointestinal effects, especially diarrhea, which occurred in 60.1% vs. 19.7% of patients (all grades). Hyperglycemia occurred in 40.4% of patients on taselisib, vs. 9.4% on placebo.
Dr. Baselga noted that the secondary endpoints of overall response rate, clinical benefit rate, and duration of response all favored taselisib.
Asked whether taselisib was the right agent in this setting, given the commercial availability of at least two other PI3K inhibitors – idelalisib (Zydelig) and copanlisib (Aliqopa) – Dr. Baselga agreed that another, more specific agent may offer similar or better efficacy with fewer off-target effects. He noted that taselisib is highly active against the alpha isoforms of PI3K, but also hits the delta and gamma isoforms.
“The side effects that we see that are limiting patients staying on [taselisib] are mostly delta and gamma. So I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer,” he said.
During the oral abstracts session where Dr. Baselga presented the SANDPIPER results, Cynthia X Ma, MD, PhD, from Washington University School of Medicine in St. Louis, the invited discussant, agreed that the trial provides proof of concept that PI3K inhibition may be an effective therapeutic strategy in breast cancer.
“However, the modest progression-free survival improvement and significant toxicity profile does not support its clinical application,” she said.
SOURCE: : Baselga J et al. ASCO 2018 Abstract LBA1006 .
CHICAGO – Is two months of progression-free survival worth it if those months mean living with serious side effects?
For women with advanced estrogen receptor-positive, HER2-negative breast cancer, the combination of the PI3K inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) bought two additional months of PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half the patients treated with the combination, results of the SANDPIPER trial show.
“These results are positive, but I think we all agree they are modest,” lead investigator José Baselga, MD, PhD from Memorial Sloan Kettering Cancer Center in New York, said at a briefing at the annual meeting of the American Society of Clinical Oncology.
The “challenging tolerability” of the combination led to frequent treatment discontinuations, and may have limited the clinical benefit of the combination, he said, but added that the study serves as proof of principle that PI3K may be a bona fide target in advanced breast cancer.
ASCO expert Harold Burstein, MD, from the Dana-Farber Cancer Institute in Boston agreed that PI3K “is a very appealing target. It’s a mutation that probably is the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”
He likened the study findings, however, to a key opening a locked door, only to find that there is a chain latch on the other side preventing entry.
In an interview, Dr. Burstein said that despite the best efforts of Dr. Baselga and others to find a suitable approach to targeting the PI3K pathway, the evidence to date suggests that it may not be an important driver of breast cancer.
Taselisib is the first agent in its class to specifically block the PI3K alpha isoform that is found to be mutated in approximately 40% of advanced ER-positive breast cancer. The agent has been shown to offer clinical benefits in early trials for patients with head and neck and some gynecologic cancers.
In the phase 3 SANDPIPER trial, 516 women with locally advanced or metastatic ER-positive, HER2-negative breast cancer that had progressed or recurred following aromatase inhibitor therapy were enrolled and randomly assigned on a 2:1 basis to receive fulvestrant plus taselisib (340 patients) or fulvestrant plus a placebo (176 patients).
As noted, the median progression-free survival was 7.4 months for women who received the combination, compared with 5.4 months for controls. The stratified hazard ratio was 0.70 favoring taselisib (P = .0037).
But also as noted, the addition of taselisib “clearly led to toxicity,” Dr. Baselga said.
Serious adverse events occurred in 32% of patients in the fulvestrant/taselisib group, compared with 8.9% of controls. Grade 3 or greater side effects occurred in 49.5% vs. 16.4%, respectively, and side effects leading to discontinuation of taselisib occurred in 16.8% of patients, vs. 2.3% of those on placebo.
The primary toxicities were gastrointestinal effects, especially diarrhea, which occurred in 60.1% vs. 19.7% of patients (all grades). Hyperglycemia occurred in 40.4% of patients on taselisib, vs. 9.4% on placebo.
Dr. Baselga noted that the secondary endpoints of overall response rate, clinical benefit rate, and duration of response all favored taselisib.
Asked whether taselisib was the right agent in this setting, given the commercial availability of at least two other PI3K inhibitors – idelalisib (Zydelig) and copanlisib (Aliqopa) – Dr. Baselga agreed that another, more specific agent may offer similar or better efficacy with fewer off-target effects. He noted that taselisib is highly active against the alpha isoforms of PI3K, but also hits the delta and gamma isoforms.
“The side effects that we see that are limiting patients staying on [taselisib] are mostly delta and gamma. So I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer,” he said.
During the oral abstracts session where Dr. Baselga presented the SANDPIPER results, Cynthia X Ma, MD, PhD, from Washington University School of Medicine in St. Louis, the invited discussant, agreed that the trial provides proof of concept that PI3K inhibition may be an effective therapeutic strategy in breast cancer.
“However, the modest progression-free survival improvement and significant toxicity profile does not support its clinical application,” she said.
SOURCE: : Baselga J et al. ASCO 2018 Abstract LBA1006 .
REPORTING FROM ASCO 2018
Key clinical point:
Major finding: The combination of taselisib/fulvestrant extend median progression-free survival by two months.
Study details: Phase 3 randomized trial in 516 women with locally advanced or metastatic ER+/HER2- breast cancer.
Disclosures: The study was funded by F. Hoffman La-Roche. Dr. Baselga had disclosures related to GRAIL, Lilly, and Novartis, Infinity Pharmaceuticals, and Varian Medical Systems, PMV Pharma, and Juno Therapeutics. Dr. Burstein disclosed institutional research funding and speaker’s bureau activities for Novartis. Dr. Ma reported no relevant disclosures.
Source: Baselga et al. ASCO Abstract LBA1006.