Alpelisib Deemed Effective in Advanced Breast Cancer After Treatment With CDK4/6 Inhibitor

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The phase II BYLieve trial indicates the effectiveness of the PIK3CA inhibitor alpelisib in patients with PIK3CA-positive, hormone receptor–positive/HER2-negative advanced breast cancer previously treated with a cyclin-dependent kinase (CDK) 4/6 inhibitor plus an aromatase inhibitor. These results were announced at the ASCO20 Virtual Scientific Program.1

More than 50% of the 121 patients were alive without disease progression at 6 months, and the median progression-free survival was 7.3 months, according to Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

BYLieve is the first prospective trial to evaluate alpelisib and endocrine therapy with either fulvestrant or letrozole in patients with PIK3CA-mutated hormone receptor–positive advanced disease who have experienced disease progression on or after therapy with an inhibitor of CDK4/6. BYLieve met its primary endpoint, having exceeded the study-defined clinically relevant threshold of 30%, Dr. Rugo said.

“The combination of alpelisib and fulvestrant has demonstrated clinically meaningful efficacy” in this patient population, Dr. Rugo announced.

Rationale for Study

Alpelisib is approved for use in combination with fulvestrant for hormone receptor–positive, HER2-negative, ­PIK3CA-mutated, advanced or metastatic breast cancer, following disease progression on or after an endocrine-based regimen, based on a 35% improvement in progression-free survival in the phase III SOLAR-1 trial.2 For the small subset of 20 patients previously exposed to a CDK4/6 inhibitor in SOLAR-1, the median progression-free survival was 5.5 months vs 1.8 months in the control arm; 44.4% of patients were free of disease progression at 6 months.

As Dr. Rugo noted, the current standard of care in the first-line setting is endocrine therapy plus a CDK4/6 inhibitor, but resistance to these regimens typically develops. For patients with PIK3CA-mutated tumors, alpelisib plus fulvestrant could be a treatment option, though supportive clinical data were lacking.

BYLieve Details

The ongoing, open-label, phase II noncomparative BYLieve trial enrolled premenopausal or postmenopausal women (or men) with hormone receptor–positive, HER2-negative advanced breast cancer and a PIK3CA mutation. Patients’ last line of prior therapy was a CDK4/6 inhibitor plus an endocrine agent, systemic chemotherapy, or endocrine therapy. This population was allocated into one of three cohorts:

Cohort A: Patients who received a CDK4/6 inhibitor plus an aromatase inhibitor as immediate prior therapy (results presented here)

Cohort B: Patients who received a CDK4/6 inhibitor plus fulvestrant as immediate prior therapy (data pending)

Cohort C: Patients who experienced disease progression on or after an aromatase inhibitor and received chemotherapy or endocrine therapy as immediate prior treatment (enrolled later).

Of the 127 patients in cohort A, 121 had centrally confirmed PIK3CA mutations. Seventy percent had received one prior metastatic regimen; the remainder had received at least two prior therapies or none in the metastatic setting. No patients had fulvestrant as a first-line metastatic agent. Most patients (60%) had secondary endocrine resistance.

Patients received oral alpelisib at 300 mg once daily plus 500 mg of fulvestrant on days 1 and 15 on cycle 1, followed by day 1 of each cycle thereafter. The primary endpoint was 6-month progression-free survival.

Response and Stable Disease Rates

Among the 121 patients in cohort A with a confirmed PIK3CA mutation, the response rate was 17.4% (all partial responses). Almost half (45.5%) achieved stable disease, and 11.6% (n = 14) of patients had progressive disease as the best response. Among the 100 patients with measurable disease at baseline, the response rate was 21%, and the stable disease rate was 55.5%, Dr. Rugo reported.


  • The phase II BYLieve study evaluated the PIK3CA inhibitor alpelisib in patients with PIK3CA-mutated advanced breast cancer previously treated with a CDK4/6 inhibitor.
  • The primary endpoint, 6-month progression-free survival, was met, with more than 50% of the 121 patients alive without disease progression at 6 months, and a median progression-free survival of 7.3 months.
  • A real-world cohort of similar patients in the Flatiron database showed the median progression-free survival to be just 3.5 months.

Although BYLieve had no control arm, Dr. Rugo put the results in context with conventional treatment of patients with PIK3CA-mutated advanced breast cancer and previous treatment with a CDK4/6 inhibitor by comparing the data from BYLieve to data from 95 patients in the U.S. Flatiron Health–Foundation Medicine database. Patients had received a range of regimens, most frequently capecitabine monotherapy, fulvestrant monotherapy, fulvestrant plus palbociclib, everolimus plus exemestane, and fulvestrant plus letrozole and palbociclib.

Unadjusted results showed a median progression-free survival of 7.3 months in BYLieve cohort A vs 3.6 months in the real-world cohort. Similar outcomes were shown when data were weighted by odds, propensity score matching, and exact matching. “Matched analysis comparing BYLieve with real-world [data of] standard treatment in the post–CDK4/6 inhibitor setting further supports the use of alpelisib plus fulvestrant,” Dr. Rugo concluded.

Safety Profile

The most common adverse events of all grades were diarrhea, hyperglycemia, and nausea. Grade ≥ 3 adverse events occurred in 66.9% of patients; they were primarily hyperglycemia (28.3%), rash (9.4%), diarrhea (5.5%), dyspnea (2.4%), stomatitis (1.6%), vomiting (1.6%), and pruritus (1.6%). Treatment- related grade ≥ 3 serious adverse events occurred in 14.2% of patients. Eighteen percent of patients discontinued treatment due to treatment-related toxicity, and 65% had doses reduced or interrupted.

Dr. Rugo said that generally, the adverse events were consistent with previous studies of alpelisib. Based on a small number of patients, it appears that prophylactic antihistamines may ameliorate the occurrence and severity of rash associated with the drug. 

DISCLOSURE: Dr. Rugo has served as a consultant or advisor to Samsung and Puma and has received travel funding from Daiichi Sankyo, MacroGenics, Merck, Novartis, and Pfizer.


1. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib + fulvestrant in patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer previously treated with cyclin-dependent kinase 4/6 inhibitor + aromatase inhibitor: BYLieve study results. ASCO20 Virtual Scientific Program. Abstract 1006.

2. André F, Ciruelos EM, Rubovszky G, et al: Alpelisib + fulvestrant for advanced breast cancer: Results of the phase 3 SOLAR-1 trial. 2018 ESMO Congress. Abstract LBA3.