On May 24, 2019, the United States Food and Drug Administration (FDA) granted approval to the phosphoinositide 3-kinase (PI3K) inhibitor alpelisib for use in combination with fulvestrant for treatment of women and men with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer who carry PIK3CA mutations and have progressed on or after endocrine therapy. The therascreen® PIK3CA RGQ PCR Kit, a companion diagnostic, was approved simultaneously for use with alpelisib. This approval was based on results from the randomized, phase III SOLAR-1 trial, which compared alpelisib plus fulvestrant to fulvestrant plus placebo in 572 patients with HER2–, HR+ breast cancer who had progressed following treatment with an aromatase inhibitor. In the subgroup of patients with PIK3CA-mutated tumors, addition of alpelisib to fulvestrant significantly improved progression-free survival (PFS) compared with fulvestrant plus placebo (11.0 months vs 5.7 months; hazard ratio 0.65; P <.001). Importantly, unlike previous PI3K inhibitors tested in breast cancer, which were pan-PI3K inhibitors and associated with high rates of adverse events (AEs), alpelisib is specific for the PI3K alpha isoform, and the rate of AEs in the SOLAR-1 trial compared favorably with that reported in other PI3K inhibitor studies. In SOLAR-1, serious AEs occurred in 34.9% of patients receiving the combination of alpelisib and fulvestrant, compared with 16.7% of patients receiving fulvestrant alone.
High Altitude: PI3K inhibitors in breast cancer have historically been disappointing, with low clinical benefit and high toxicity. Identification of genetic subtypes in which a targeted therapy is more active can allow for more-effective patient selection. Given this, the success of alpelisib highlights the importance of precise molecular targeting and genetic screening in improving the clinical utility of targeted therapy. Overall survival data from the SOLAR-1 trial are still awaited and will likely inform future directions for this agent in advanced breast cancer.
Ground Level: This approval is a major advance in the treatment of HER2–, HR+ advanced breast cancer. While first-line therapy in this population is very effective, most patients eventually relapse or develop resistance, and there is a need for improved treatment options. Given the significant improvement in PFS seen with the addition of alpelisib to fulvestrant, it is likely that this agent will become a valuable treatment option in second-line HER2–, HR+ advanced breast cancer patients. Testing for PIK3CA mutations may become part of routine clinical practice for patients with HER2–, HR+ advanced breast cancer with progression on endocrine therapy, to enable identification of patients who can benefit from this new therapeutic option.