New research has found that combination therapy with alpelisib (Piqray; Novartis) and fulvestrant (Faslodex; AstraZeneca) results in clinically meaningful efficacy and manageable toxicity among patients with PIK3CA-mutated HR+/HER2- advanced breast cancer previously treated with a cyclin-dependent kinase 4/6 (CDK) inhibitor plus an aromatase inhibitor.

Although follow-up of the international, multi-center BYLieve trial is ongoing, the authors said the results further support the use of alpelisib plus fulvestrant for HR+/HER2-/PIK3CA-mutated advanced breast cancer. 

Reporting in an abstract published online as part of the 2020 virtual meeting of the American Society of Clinical Oncology (abstract 1006), the authors explained that PIK3CA mutations affect some 40% of patients with HR+/HER2- advanced breast cancer and are associated with poor prognosis and treatment resistance. Surprisingly, however, there is little clinical information and few prospective studies regarding treatment options for patients with HR+/ HER2-/PIK3CA-mutated advanced breast cancer following treatment with a CDK inhibitor. 

Enter the BYLieve study (NCT03056755), the first of its kind to evaluate alpelisib plus endocrine therapy with either fulvestrant or letrozole in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer who progressed on or after prior treatment, including CDK inhibitors. 

Patients with centrally confirmed PIK3CA mutations in tumor tissue were included in the phase-II, open-label, non-comparative study. These individuals had all undergone prior therapy with one of four possible regimens: CDK inhibitor plus an aromatase inhibitor; CDK inhibitor plus fulvestrant; systemic chemotherapy; or endocrine therapy. 

In the current analysis, the researchers reported on the cohort of 127 patients who had undergone immediate prior therapy with a CDK inhibitor plus an aromatase inhibitor. Each patient had received 300 mg daily alpelisib plus 500 mg fulvestrant every 28 days, plus cycle 1/day 15 therapy.

The trial’s primary endpoint was the proportion of patients alive without disease progression at six months with local assessment. 

The investigators reported that 121 of the 127 participants had centrally confirmed PIK3CA mutations. Median follow-up among these individuals was 11.7 months. 

As reported by lead author Hope S. Rugo, MD, of the University of California San Francisco, 50.4% of patients (95% confidence interval: 41.2-59.6%) were without disease progression at six months. As such, the authors noted that the study’s primary efficacy endpoint had been met. 

With respect to tolerability, it was found that the most common all-grade adverse events were diarrhea (in 60% of patients), hyperglycemia (58%), nausea (46%), fatigue (29%), decreased appetite (28%), and rash (28%). The most frequent adverse events of at least grade three included hyperglycemia (28%), rash (9%), and rash maculopapular (9%). 

Despite this, however, they noted that the incidence of adverse events leading to treatment discontinuation was low. Rash was the most common of these, affecting five patients (3.9%). This was followed by colitis, hyperglycemia, urticaria, and vomiting, each of which led to treatment discontinuation in two patients (1.6% each).

The authors concluded that these findings bolster the potential for alpelisib-fulvestrant combination therapy in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer. 

The investigation was funded by Novartis.