Alpelisib Plus Endocrine Therapy Yields Similar PFS Benefits in Subgroup Analysis of PIK3CA-Mutated, HR+ Breast Cancer

Fatima Cardoso, MD

The combination of alpelisib (Piqray) plus endocrine therapy elicited a clinical benefit across all subgroups of patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer with PIK3CA mutations, according to data from a subgroup analysis of the phase 2 BYLieve trial (NCT03056755) presented in a poster at the European Society for Medical Oncology Breast Cancer Congress 2022.¹

Across 3 cohorts, progression-free survival (PFS) ranged from 5.1 to 16.6 months in subgroups classified by menopausal status, bone-only lesions, and visceral disease. Patients in cohorts A and C received alpelisib plus fulvestrant (Faslodex), and patients in cohort B were administered alpelisib plus letrozole (Femara).

In cohort A, premenopausal patients (n = 20) had a median PFS of 5.6 months (95% CI, 3.4-11.1), compared with 8.1 months (95% CI, 5.6-8.6) in postmenopausal patients (n = 101). Patients with bone-only lesions (n = 22) achieved a median PFS of 16.6 months (95% CI, 11.1–not evaluable [NE]), vs 5.6 months (95% CI, 5.3-8.2) in patients without bone-only lesions (n = 99). In patients with visceral disease (n = 82), the median PFS was 5.6 months (95% CI, 4.8-8.2), compared with 12.0 months (95% CI, 7.0-18.2) in patients with visceral disease (n = 39).

In cohort C, premenopausal patients (n = 6) had a median PFS of 5.1 months (95% CI, 0.9-NE), compared with 5.7 months (95% CI, 3.7-7.2) in postmenopausal patients (n = 109). Patients with bone-only lesions (n = 11) achieved a median PFS of 11.0 months (95% CI, 2.8-NE), vs 5.5 months (95% CI, 3.7-6.2) in patients without bone-only lesions (n = 104). In patients with visceral disease (n = 88), the median PFS was 5.5 months (95% CI, 3.6-6.2), compared with 10.8 months (95% CI, 5.1-14.8) in patients with visceral disease (n = 27).

In cohort C, premenopausal patients (n = 16) had a median PFS of 6.9 months (95% CI, 2.8-11.7), compared with 5.6 months (95% CI, 5.4-7.4) in postmenopausal patients (n = 98). Patients with bone-only lesions (n = 14) achieved a median PFS of 5.5 months (95% CI, 2.8-10.2), vs 5.6 months (95% CI, 5.4-8.1) in patients without bone-only lesions (n = 101). In patients with visceral disease (n = 85), the median PFS was 5.6 months (95% CI, 5.4-8.1), compared with 6.4 months (95% CI, 4.8-8.4) in patients with visceral disease (n = 30).

“This analysis further confirms the clinical relevance of targeting the PIK3CA driver mutation given that clinical benefit was observed in patients with PIK3CA-mutated tumors treated with alpelisib plus endocrine therapy who had diverse demographic and disease characteristics and varied prior treatments,” lead study author Fatima Cardoso, MD, director of the Breast Unit of the Champalimaud Clinical Center in Lisbon, Portugal, wrote in the poster.

Approximately 40% of patients with HR-positive/HER2-negative advanced breast cancer have a PIK3CA driver mutation.² The presence of PIK3CA mutations is associated with a poor prognosis and can contribute to endocrine therapy resistance.

In May 2019, the FDA approved alpelisib plus fulvestrant as a treatment for postmenopausal patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.³

The BYLieve trial assessed the utility of combining alpelisib with additional endocrine therapies in patients with HR-positive/HER2-negative PIK3CA-mutated aggressive breast cancer who progressed on a CDK4/6 inhibitor or an aromatase inhibitor, a CDK4/6 inhibitor plus fulvestrant, or an aromatase inhibitor followed by chemotherapy or endocrine therapy as immediate prior treatment, across 3 respective cohorts. These subgroup analysis of BYLieve aimed to evaluate patients based on menopausal status, bone-only lesion status, and visceral disease status.

All patients enrolled in the trial were required to have pretreated HR-positive, HER2-negative advanced breast cancer harboring a PIK3CA mutation in tumor tissue or blood. Prior lines of treatment were required to include a CDK4/6 inhibitor plus endocrine therapy, systemic chemotherapy, or endocrine therapy alone. Moreover, patients needed ECOG performance status no greater than 2, plus measurable disease per the RECIST v1.1 criteria, or at least 1 predominantly lytic bone lesion.

Cohort A featured patients who received a CDK4/6 inhibitor plus an aromatase inhibitor as immediate prior treatment (n = 127). This cohort received 300 mg of oral alpelisib per day plus 500 mg of fulvestrant on day 1 and day 15 of the first cycle, followed by day 1 only in subsequent cycles. Cohort B included patients who received a CDK4/6 inhibitor plus fulvestrant as immediate prior treatment (n = 126). These patients received 300 mg of oral alpelisib per day, plus 2.5 mg of oral letrozole per day. Cohort C evaluated patients whose disease progressed on or after treatment with an aromatase inhibitor and then received chemotherapy or endocrine therapy as immediate prior treatment (n = 126). These patients received the same dosing of alpelisib and fulvestrant as cohort A.

The primary end point of the trial was the proportion of patients alive with progressive disease at 6 months per RECIST v1.1 criteria in each cohort. Previous findings showed the primary end point was reached in all 3 cohorts. Secondary end points included PFS, secondary PFS, overall response rate, clinical benefit rate, duration of response, overall survival and safety. Biomarker analysis served as an exploratory end point.

Baseline characteristics were well-balanced among patients in cohorts A, B, and C. A majority of patients in each cohort had received 1 prior line of therapy, had stage IV disease, and had an ECOG performance status of 0. Most patients who were premenopausal under the age of 46 years (range, 32-56) and those who were postmenopausal were over the age of 61 years (range, 31-84).

References

1. Cardoso F, Juric D, Lerebours F, et al. Alpelisib (ALP) + endocrine therapy (ET) in patients with PIK3CA‐mutated, hormone receptor‐positive (HR+), human epidermal growth factor receptor 2‐negative (HER2–) advanced breast cancer (ABC): subgroup analyses from the BYLieve study. Presented at: 2022 ESMO Breast Cancer Congress; May 3-5, 2022; Berlin, Germany. Poster 175P.
2. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi:10.1038/nature11412
3. FDA approves alpelisib for metastatic breast cancer. News release. FDA. May 24, 2019. Accessed May 6, 2022. https://bit.ly/3vNjWfJ