When combined with fulvestrant, alpelisib produced clinically and statistically relevant progression-free survival despite the baseline poorer prognosis in patients with hormone receptor–positive, HER2-negative, PIK3CA mutation–positive advanced breast cancer.
In 2012, the US Food and Drug Administration approved the combination of everolimus plus exemestane, and in 2015, the first CDK4/6 inhibitor, palbociclib, was approved in combination with endocrine treatment. Recently, the PI3K inhibitors, a third class of therapeutic compounds, have been introduced to the treatment armamentarium to target endocrine-resistant hormone receptor–positive metastatic breast cancer.1
Occurring in approximately 40% of patients with hormone receptor–positive, HER2-negative breast cancer, PIK3CA mutations have been considered factors impacting poor survival. Early studies revealed that alpelisib, a PI3K-alpha–specific inhibitor, had antitumor activity.2
In the phase 3 SOLAR-1 clinical trial, patients considered to have a poor prognosis (ie, who had progression on or after therapy with an aromatase inhibitor) were treated with the PI3K-alpha–specific inhibitor combined with fulvestrant; the study showed significantly improved progression-free survival in the PIK3CA mutation–positive cohort (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.50-0.85; P <.001; median progression-free survival of 11.0 months with alpelisib plus fulvestrant vs 5.7 months with placebo plus fulvestrant). At final progression-free survival analysis, the time of first interim overall survival (OS) results was considered immature.
In this latest investigation presented at the European Society for Medical Oncology Virtual Congress 2020, 572 postmenopausal women and men with hormone receptor–positive, HER2-negative advanced breast cancer with no history of previous chemotherapy treatment and who experienced disease progression on or after aromatase inhibitor treatment were randomized 1:1 to receive alpelisib 300 mg orally daily or placebo, in addition to fulvestrant at a dose of 500 mg intramuscularly. OS was a key secondary end point.
With median OS follow-up of 30.8 months, there was a clinically relevant improvement of approximately 8 months in the alpelisib plus fulvestrant treatment arm; specifically, the study showed that median OS of the alpelisib plus fulvestrant group was 39.3 months (95% CI, 34.1-44.9) compared with 31.4 months (95% CI, 26.8-41.3) for treatment with fulvestrant plus placebo (HR, 0.86; 95% CI, 0.64-1.15; P = .15). While OS did not cross the prespecified boundary and was not considered statistically significant, it was considered clinically significant. Median time to chemotherapy was 14.8 months (95% CI, 10.5-22.6) with fulvestrant plus placebo (HR, 0.72; 95% CI, 0.54-0.95) compared with 23.3 months (95% CI, 15.2-28.4) with alpelisib plus fulvestrant.
Patients who had metastases of the lung and/or liver and were treated with alpelisib plus fulvestrant had a median OS of 37.2 months (95% CI, 28.7-43.6) compared with those who were treated with placebo plus fulvestrant who had a median OS of 22.8 months (95% CI, 19.0-26.8; overall: HR, 0.68; 95% CI, 0.46-1.00). With longer follow-up, no new safety signals were observed.
Based on the clinically and statistically significant progression-free survival, this study added to the body of evidence suggesting that for patients with PIK3CA mutation–positive advanced breast cancer, treatment with alpelisib plus fulvestrant may be beneficial, despite the poor prognosis of this population at baseline.
Source: Andre F, Ciruelos EM, Juric D, et al. Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Ann Oncol. 2020;31(4_suppl). Abstract LBA18.
References
1. Mavratzas A, Marmé F. Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. Future Oncol. 2020 Sep 23. Epub ahead of print.
2. André F, Ciruelos E, Rubovszky G, et al; for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940.