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Taselisib with fulvestrant modestly improves PFS in PIK3CA-mutated breast cancer
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CHICAGO — The addition of taselisib to fulvestrant conferred a statistically significant, yet modest, PFS benefit among postmenopausal women with ER-positive, HER-2-negative, PIK3CA-mutated breast cancer, according to results of the phase 3 SANDPIPER clinical trial presented at ASCO Annual Meeting.
However, the combination led to frequent treatment discontinuations and may have limited benefit among this patient population.
“This is the first placebo-controlled and randomized study that evaluated efficacy and safety of taselisib in patients with advanced disease,” José Baselga, MD, PhD, FASCO, physician in chief of Memorial Sloan Kettering Cancer Center, said during a press conference.
Taselisib (GDC0032/RG7604, Genentech/Roche) — an oral, selective inhibitor of class 1 PI3K alpha, delta and gamma isoforms — previously demonstrated positive activity in PIK3CA-mutated breast cancer and conferred partial responses as a single agent or in combination with fulvestrant (Faslodex, AstraZeneca), a selective ER degrader.
About 40% of all patients with advanced ER-positive breast cancer harbor PIK3CA mutations.
For this study, researchers assessed the safety and efficacy of the addition of taselisib to fulvestrant among 516 postmenopausal patients with locally advanced or metastatic ER-positive, HER-2-negative metastatic breast cancer that progressed or recurred despite hormone treatment with aromatase inhibitors.
Researchers randomly assigned patients 2:1 to receive 500 mg fulvestrant with 4 mg taselisib (n = 340) or placebo (n = 176) once daily based on visceral disease, endocrine sensitivity and geographic region. Patients with PIK3CA-mutated disease were randomly assigned separately from patients without mutated disease.
Investigator-assessed PFS among patients with PIK3CA-mutated disease served as the primary endpoint. Secondary endpoints included objective response rate, OS, clinical benefit rate, duration of objective response, PFS by blinded independent central review and safety.
Median PFS was 7.4 months among patients who received taselisib with fulvestrant compared with 5.4 months among patients who received placebo with fulvestrant. The taselisib and fulvestrant combination showed improved investigator-assessed PFS (HR = 0.7; 95% CI, 0.56-0.89). The benefit was confirmed by blinded independent review (HR = 0.66).
Secondary endpoints showed consistent improvement with the combination regimen, according to Baselga.
ORR appeared higher among patients who received taselisib compared with patients who received placebo (28% vs. 11.9%; P = .0002). The duration of objective response was 8.7 months in the taselisib group and 7.2 months in the placebo group.
Further, the taselisib and fulvestrant treatment group demonstrated a higher clinical benefit rate than the placebo group (51.5% vs. 37.3%).
Survival data were immature at the time of the analysis.
“Our findings are proof that that targeting this pathway in breast cancer is effective,” Baselga said in a press release. “However, the benefit to patients was more modest than we had hoped for, and there is a risk for considerable side effects with the addition of taselisib.”
More patients in the combination group experienced grade 3 or higher adverse events (32% vs. 8.9%) and serious adverse events (32% vs. 8.9%) than patients in the placebo group.
Adverse events led to more treatment discontinuations (16.8% vs. 2.3%) and dose reductions (37% vs. 2%) in the taselisib and fulvestrant group than in the placebo group.
Gastrointestinal toxicities more frequently observed in the taselisib group than placebo group included diarrhea (all grades, 60.1% vs. 19.7%) and hyperglycemia (all grades, 40.4% vs. 9.4%).
The safety profile appeared consistent with previous studies, Baselga said.
“This is a challenging combination, but I do think this establishes proof of principle that this is a bona fide target,” Baselga said during the press conference. – by Melinda Stevens
Reference:
Baselga J, et al. LBA1006. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: F. Hoffmann-La Roche funded the study. Baselga reports consultant/advisory roles with Eli Lilly, GRAIL, and Novartis; leadership roles with Infinity Pharmaceuticals and Varian Medical Systems; and stock and ownership interests with GRAIL, Infinity Pharmaceuticals, Juno Therapeutics, PMV Pharma and Varian Medical Systems. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Darcy V. Spicer, MD
Taselisib is a potent selective oral PI3K inhibitor; PI3KCA mutations are frequent in breast cancer. A prior phase 2 trial of the agent in combination with fulvestrant supported further study. The SANDPIPER phase 3 trial reported at ASCO provides important evidence that targeting the PI3K pathway has an impact in advanced breast cancer. Although there was toxicity, it is consistent with prior data with this agent and other agents targeting this pathway. This is an important step in the development and study of agents combating hormonal resistance.
Perspective
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Harold J. Burstein, MD, PhD, FASCO
This is a very impeding target, a mutation that is one of the most common in breast cancer. What’s interesting about this study is it shows we finally have a lock and a key that has begun to open the door. It is a modest step forward, but it is an important step forward because it does suggest we can effectively target the pathway. Hopefully this gives us something we can build on so we can use a targeted precision approach in this very common type of breast cancer subset.
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