Posted: Thursday, January 20, 2022
In a phase II study published in Clinical Cancer Research, adding the dual mTOR1/2 inhibitor sapanisertib to fulvestrant therapy seemed to demonstrate numerically longer duration of progression-free survival in postmenopausal women with estrogen receptor–positive, HER2-negative advanced or metastatic breast cancer. Although these findings support the principle of targeting the PI3K/AKT/mTOR pathway to restore endocrine sensitivity, Dennis Slamon, MD, PhD, of the David Geffen School of Medicine, Los Angeles, and colleagues do not recommend the use of this combination regimen due to the toxicity profile of sapanisertib.
“The efficacy and safety findings from this study do not suggest a favorable risk-benefit profile for this combination in the overall study population,” the investigators concluded. “Future research should focus on the role of mTOR inhibition in relation to other strategies, such as CDK4/6 inhibition, with a view to optimizing treatment benefits, since patients with a history of CDK4/6 inhibitor treatment appeared to derive the greatest benefit from mTOR inhibition with sapanisertib.”
A total of 141 patients with a history of resistance to aromatase inhibitor treatment were randomly assigned to receive 500 mg of single-agent fulvestrant (28-day treatment cycles), 4 mg of fulvestrant plus sapanisertib daily, or 30 mg of fulvestrant plus sapanisertib weekly. The median duration of progression-free survival was 3.5 months with single-agent fulvestrant, 7.2 months with daily fulvestrant plus sapanisertib (hazard ratio = 0.77), and 5.6 months with weekly fulvestrant plus sapanisertib (hazard ratio = 0.88). Patients who were previously administered CDK4/6 inhibitors seemed to experience the greatest progression-free survival benefit.
Nausea, vomiting, and hyperglycemia were the most commonly reported adverse events; these toxicities occurred more frequently with the combination therapy. The rates of treatment discontinuation due to adverse events were higher with daily and weekly administration of fulvestrant plus sapanisertib than with single-agent fulvestrant (32% and 36% vs. 4%, respectively).
Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.