As reported in The Lancet Oncology by Howell et al, the phase II FAKTION trial has shown improved overall survival with the addition of the AKT inhibitor capivasertib to fulvestrant in patients with estrogen receptor–positive, HER2-negative advanced breast cancer who experienced disease relapse or progression on aromatase inhibitor treatment. Updated genetic testing showed that outcome benefits were largely observed in patients with PI3K/AKT/PTEN pathway alterations.
As noted by the investigators, the primary analysis of the trial showed that the addition of capivasertib to fulvestrant improved progression-free survival, with benefit appearing to be independent of PI3K/AKT/PTEN pathway alterations according to assays available at the time.
Study Details
In the double-blind multicenter trial, 140 patients were randomly assigned between March 2015 and March 2018 to receive intramuscular fulvestrant at 500 mg on day 1 every 28 days with a 500 mg loading dose on day 15 of cycle 1, with either capivasertib at 400 mg (n = 69) or placebo (n = 71) twice daily on a weekly schedule of 4 days on and 3 days off starting on cycle 1, day 15. The current report includes an examination of the effect on outcomes of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel.
Key Findings
Median follow-up was 58.5 months in the fulvestrant/capivasertib group and 62.3 months in the control group. Median overall survival was 29.3 months (95% confidence interval [CI] = 23.7–39.0 months) in the fulvestrant/capivasertib group vs 23.4 months (95% CI = 18.7–32.7 months) in the control group (adjusted hazard ratio [HR] = 0.66, 95% CI = 0.45–0.97, P = .035). Updated median progression-free survival was 10.3 months (95% CI = 5.0–13.4 months) vs 4.8 months (95% CI = 3.1–7.9 months; adjusted HR = 0.56, 95% CI = 0.38–0.81, P = .0023).
The expanded genetic testing panel showed that 39 patients in the fulvestrant/capivasertib group and 37 in the control group had PI3K/AKT/PTEN pathway alterations. Among these patients, median progression-free survival was 12.8 months (95% CI = 6.6–18.8 months) vs 4.6 months (95% CI = 2.8–7.9 months; adjusted HR = 0.44, 95% CI = 0.26–0.72, P = .0014) and median overall survival was 38.9 months (95% CI = 23.3–50.7 months) vs 20.0 months (95% CI = 14.8–31.4 months; adjusted HR = 0.46, 95% CI = 0.27–0.79, P = .0047). Among patients without pathway alterations, there were no significant differences in progression-free survival (median = 7.7 vs 4.9 months, adjusted HR = 0.70, P = .23) or overall survival (median = 26.0 vs 25.2 moths, adjusted HR = 0.86, P = .60).
The investigators concluded, “Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor–resistant, estrogen receptor–positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumors. Phase III data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial.”
Robert H. Jones, FRCP, of Cardiff University and Velindre Cancer Centre, Cardiff, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by AstraZeneca and Cancer Research UK. For full disclosures of the study authors, visit thelancet.com.
