CHICAGO — Adding the investigational AKT inhibitor capivasertib to fulvestrant (Faslodex) significantly extended time without disease progression for women with metastatic, estrogen receptor (ER)-positive breast cancer, a phase II study found.
In the FAKTION trial, median progression-free survival (PFS) improved from 4.8 months to 10.3 months with the addition of capivasertib to hormonal therapy (HR 0.57, 95% CI 0.39-0.84, P=0.004), reported Sacha Jon Howell, MD, PhD, of the Christie NHS Foundation Trust in Manchester, England.
“The addition of capivasertib to fulvestrant more than doubles the progression-free survival seen with fulvestrant alone in women with ER-positive/HER2-negative metastatic breast cancer,” said Howell during his presentation at the American Society of Clinical Oncology (ASCO) annual meeting. “Although a third of patients required a dose reduction.”
Objective response rates were significantly improved in the combination arm, at 41% versus 12% with fulvestrant alone (all partial responses in both arms), and clinical benefit was numerically better with capivasertib, at 55% versus 36%, respectively.
Howell said that adding capivasertib showed a “strong trend” toward an increase in overall survival (OS). At 37% data maturity, OS was 26 months with capivasertib versus 20 months with placebo (HR 0.59, 95% CI 0.34-1.05, P=0.071).
“Notably, the benefit was seen irrespective of PI3K activation status,” said ASCO invited discussant Cesar Augusto Santa-Maria, MD, MS, of Johns Hopkins Medicine in Baltimore.
Patients experienced a PFS benefit in both the “activated” group (HR 0.59, 95% CI 0.34-1.03, P=0.064), defined as those having activating PIK3CA mutations in exon 9 or 20, as well as the non-activated group (HR 0.56, 95% CI 0.33-0.96, P=0.035).
“I can’t explain it,” said Howell during a question and answer session following the presentation. “It’s not really what we were expecting. There’s preclinical data to show that there is a preferential benefit in cell lines, for example, with the altered pathway.”
The PI3K/AKT/PTEN pathway is activated in roughly half of ER-positive tumors (mostly PIK3CA mutations), said Howell, who added that there’s a strong rationale for targeting PI3K/AKT/PTEN and the ER pathways simultaneously.
Capivasertib, a selective inhibitor of AKT, previously showed no benefit for patients with PIK3CA-mutant ER-positive metastatic breast cancer when combined with paclitaxel in the BEECH trial, but this study did not allow co-treatment with endocrine therapy.
Santa-Maria noted the significant toxicities with addition of the AKT inhibitor (in particular diarrhea, rash, and hyperglycemia), which is in line with other drugs against this pathway.
Grade ≥3 adverse events were more frequent in the capivasertib group (58% vs 30% with placebo), with rash (20%), diarrhea (14%), and infections (6%) being the most common. In the combination arm, 39% of patients required at least one dose reduction, compared with 4% in the placebo group; and 12% discontinued therapy due to toxicity compared with none in the placebo group. One patient death occurred in the capivasertib arm because of toxicity.
“We now have two approved agents against this pathway for patients with metastatic ER-positive breast cancer refractory to endocrine-based therapy — everolimus [Afinitor], which has shown benefit regardless of PI3K mutations status — and alpelisib,” Santa-Maria said. “We don’t know how these agents will compare against each other.”
Last month, the FDA approved the PI3K inhibitor alpelisib (Piqray) in combination with fulvestrant for treating advanced, PIK3CA-mutated, ER-positive/HER2-negative breast cancer in postmenopausal women. Prior everolimus treatment was not permitted in FAKTION.
Santa-Maria said the use of biomarkers for patient selection will be critical, and of interest will be whether patients will benefit from these agents following CDK4/6 inhibition.
FAKTION was a phase II double-blind, placebo-controlled trial that randomized 140 postmenopausal, metastatic or locally advanced breast cancer patients to fulvestrant plus either capivasertib (n=69) or placebo (n=71) at 21 U.K. sites from 2015 to 2018. Patients (median age 62 and 61, respectively) were allowed to have received a maximum of one prior line of chemotherapy and three prior lines of endocrine therapy.
Intravenous fulvestrant (500 mg) was administered on days 1 and 15 for the first 28-day cycle and on day 1 of subsequent cycles, with 400 mg oral capivasertib or placebo given daily (4 days on, 3 days off) starting with the second fulvestrant infusion. Median time on fulvestrant was doubled in the investigational arm (interquartile range, 9.2 vs 4.6 months). Treatment was given until disease progression or unacceptable toxicity.
Howell disclosed no relevant relationships with industry. Co-authors disclosed relevant relationship with AstraZeneca, Bristol-Myers Squibb, Novartis, Tesaro, Daiichi Sankyo, Eisai, Pfizer, Merck, Genomic Health, and Roche.
Santa-Maria disclosed relevant relationships with Genomic Health, Polyphor, and Halozyme, and support from Pfizer, Medimmune, and Tesaro.