Home > Oncology > ASCO 2020 > Breast & Ovarian Cancer > BYLieve demonstrates efficacy of PIK3CA-directed treatment post CDK4/6-ihibition

BYLieve demonstrates efficacy of PIK3CA-directed treatment post CDK4/6-ihibition

Presented by
Prof. Hope S. Rugo, University of California San Francisco, CA, USA
ASCO 2020
Phase 2, BYLieve
The phase 2 BYLieve trial demonstrated that the combination of alpelisib and fulvestrant has a clinically meaningful efficacy in patients with PIK3CA-mutated hormone receptor (HR)-positive advanced breast cancer who progressed on treatment with CDK4/6 inhibitors plus an aromatase inhibitor, with manageable side effects.

PIK3CA is one of the most frequently mutated genes in breast cancer and a negative prognostic factor in HR-positive, HER2-negative advanced breast cancer. Approximately 40% of patients with this disease have a mutation of the PIK3CA gene in their tumour [1]. Alpelisib – an alpha-selective PI3 kinase inhibitor – plus fulvestrant recently demonstrated efficacy in the phase 3 SOLAR-1 trial in patients with HR-positive PIK3CA-mutant advanced breast cancer progressing on an aromatase inhibitor, nearly doubling the median progression-free survival (PFS) from 5.7 months in the placebo arm to 11 months in the alpelisib arm (HR 0.65; 95% CI 0.50-0.85; P<0.001) [2].

The current standard-of-care in first-line setting for patients with HR-positive advanced breast cancer is (in many countries) endocrine therapy with a CDK4/6 inhibitor. However, resistance develops over time in almost all patients. In SOLAR-1, 20 patients had previously progressed on CDK4/6 inhibitors. In this small cohort, median PFS in the alpelisib plus fulvestrant-treated arm was also prolonged compared with the placebo arm (5.5 vs 1.8 months; HR 0.48; 95% CI 0.17-1.36) [2].

The phase 2, open-label, non-comparative BYLieve trial is the first prospective trial that evaluated alpelisib and endocrine therapy with either fulvestrant or letrozole in 3 cohorts of patients with PIK3CA-mutated HR-positive advanced disease who had progressed on or after therapy with a CDK4/6 inhibitor [3]. Primary endpoint of the study was the proportion of patients alive without progression of disease at 6 months (RECIST v1.1). Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR), and safety. In cohort A, 127 patients with prior CDK4/6 and aromatase inhibition were enrolled and subsequently treated with alpelisib (300 mg once daily) and fulvestrant (500 mg).

After 6 months of follow-up, 50.4% of patients were alive without disease progression, median PFS was 7.3 months. For comparison, in SOLAR-1, PFS at 6 months was 44.4%. ORR was 17.4%, all responses were partial. Treatment-related adverse events grade ≥3 were observed in 66.9% of patients; adverse events leading to dose reduction or interruption in 53.5% and adverse events leading to discontinuation of treatment in 11.8%. The most frequent all-grade adverse events reported were diarrhoea and hyperglycaemia. Rash was reported in 28% of patients; 10 of 127 patients received antihistamines before developing a rash or had no rash events.

  1. Mosele F, et al. Ann Oncol. 2020; 31: 377-386.
  2. André F, et al. N Engl J Med 2019; 380:1929-1940.
  3. Rugo HS, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 1006.


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