Alpelisib Plus Letrozole Shows Promise After CDK 4/6 Inhibitor Therapy in PIK3CA‐Mutated HR+/HER2– Advanced Breast Cancer

Short abstract

Treatment with alpelisib and letrozole appears to be effective in patients with HR‐positive, HER2‐negative, PIK3CA‐mutated advanced breast cancer previously treated with a CDK 4/6 inhibitor, according to updated findings from the phase II BYLieve trial.

As new treatments become available for advanced breast cancer, the optimal sequencing of agents through multiple lines of therapy grows increasingly complex. Standard first‐line therapy for patients with (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer is endocrine therapy in combination with a cyclin‐dependent kinase (CDK) 4/6 inhibitor. However, resistance to endocrine therapy is common, leading to disease progression and the need for subsequent‐line therapy.

Alpelisib is an oral inhibitor of phosphatidylinositol‐3‐kinase (PI3K) that acts predominantly against the alpha isoform. Mutations in the PIK3 catalytic subunit alpha (PIK3CA) gene, which encodes the alpha isoform of PI3K, occur in approximately 40% of patients with HR‐positive, HER2‐negative breast cancer and predict worse survival outcomes. Alpelisib is currently approved in combination with fulvestrant for HR‐positive, HER2‐negative, PIK3CA‐mutated, advanced or metastatic breast cancer in patients who progressed on or after an endocrine‐based regimen.

The phase II BYLieve study is the first prospective trial to evaluate alpelisib in combination with endocrine therapy (fulvestrant or letrozole) in patients with HR‐positive, HER2‐negative, PIK3CA‐mutated advanced breast cancer who have progressed on or after prior treatment with a CDK 4/6 inhibitor.

Study Design

The BYLieve trial enrolled 336 premenopausal or postmenopausal women (or men) with HR‐positive, HER2‐negative advanced breast cancer and a PIK3CA mutation. All patients were most recently treated with a CDK 4/6 inhibitor plus endocrine therapy or chemotherapy. Patients were assigned to study cohorts (A–C) based on their most immediate prior treatment history (Table 1).

Table 1.

BYLieve patient cohorts and treatment assignments

Cohort	Immediate prior therapy	Study treatment
A (n = 112)	CDK 4/6 inhibitor and an AI	Alpelisib 300 mg once daily plus fulvestrant 500 mg
B (n = 112)	CDK 4/6 inhibitor and fulvestrant	Alpelisib 300 mg once daily plus letrozole 2.5 mg
C (n = 112)	Chemotherapy or ET	Alpelisib 300 mg once daily plus fulvestrant 500 mg

Abbreviations: AI, aromatase inhibitor; CDK, cyclin dependent kinase; ET, endocrine therapy.

All patients were treated with alpelisib in combination with fulvestrant (Cohorts A and C) or letrozole (Cohort B). Treatment continued until disease progression or unacceptable toxicity. Crossover between treatment arms was not permitted. The primary endpoint was the proportion of patients alive without disease progression at 6 months.

Hope Rugo, M.D., of the University of California at San Diego, presented updated findings from Cohort B of the BYLieve trial [1].

The median patient age in Cohort B was 61.0 years (range, 37–80 years). Most patients (82%) experienced progression on prior aromatase therapy, and nearly all (98%) had prior endocrine therapy in the metastatic setting. Endocrine status among patients at the time of enrollment was most commonly secondary endocrine resistance (58%), followed by primary endocrine resistance (9.5%) and endocrine sensitivity (40%). The median follow‐up in Cohort B was 15.0 months.

Key Findings

In total, 46.1% of patients reached the primary endpoint and were alive without disease progression at 6 months. Median progression‐free survival was 5.7 months.

The overall response rate was 15.7%, with no patients achieving a complete response and 15.7% achieving a partial response (Table 2). The clinical benefit rate, which includes patients who achieved responses or stable disease for at least 24 weeks, was 32.2%.

Table 2.

Responses to alpelisib plus letrozole following prior CDK 4/6 and fulvestrant treatment (n = 115)

Response	Percentage
Best overall response
Complete response	0%
Partial response	15.7%
Neither complete response nor progressive disease	7.0%
Stable disease	42.6%
Progressive disease	17.4%
Unknown	17.4%
Overall response rate (CR + PR)	15.7%
Clinical benefit rate (CR + PR + NCR/NPD + SD for ≥24 weeks)	32.2%

Abbreviations: CDK, cyclin dependent kinase; CR, complete response; NCR/NPD, neither complete response nor progressive disease; PR, partial response; SD, stable disease.

The most common grade ≥3 adverse events (AEs) were hyperglycemia (25.4%), rash (9.5%), rash maculopapular (7.9%), diarrhea (4.0%), fatigue (4.0%), and asthenia (4.0%). Overall, 54.8% of patients experienced a grade ≥3 AE that led to a dose adjustment or interruption, and 8.7% experienced grade ≥3 AEs leading to discontinuation.

Overall, interim findings from Cohort B of the BYLieve trial support the activity of alpelisib in combination with letrozole in patients with HR‐positive, HER2‐negative, PI3KCA‐mutated advanced breast cancer that progressed on prior treatment with a CDK 4/6 inhibitor plus fulvestrant.