Benefit of Alpelisib When Combined with Fulvestrant as Demonstrated Through Biomarker Subanalysis from the SOLAR-1 Study

In a range of groups with PIK3CA alterations, recent findings demonstrate a clear and consistent clinical benefit of alpelisib when combined with fulvestrant, which was detected in circulating tumor DNA by next-generation sequencing.

Tumors with mutations in PIK3CA occur in approximately 40% of patients with hormone receptor–positive, HER2-negative advanced breast cancer. Contributing to cell proliferation, drug resistance, and poor prognoses, these types of mutations encode the alpha-isoform of PI3K, p110-alpha, and are a known cause of hyperactivation of the PI3K pathway.

In the phase 3 SOLAR-1 clinical trial, in patients with hormone receptor–positive, HER2-negative, PIK3CA mutant–positive advanced breast cancer following progression on or after previous aromatase inhibitor use, an alpha-selective PI3K inhibitor, alpelisib, was administered in combination with fulvestrant. The study demonstrated positive outcomes, as measured by prolonged median progression-free survival (PFS).

The study design was a phase 3 double-blind, placebo-controlled trial. Patients were randomized to receive daily placebo or alpelisib 300 mg with fulvestrant 500 mg every 28 days plus cycle 1 day 15. The study included postmenopausal women and men with hormone receptor–positive, HER2-negative advanced breast cancer. In this study, PIK3CA mutation testing was performed on tumor tissue using polymerase chain reaction (PCR)-based assays.

Clinical outcomes of patients with alterations in PIK3CA, detected by next-generation sequencing in circulating tumor (ct)DNA, were assessed in this exploratory biomarker analysis. Retrospectively, using plasma ctDNA collected at baseline, sequencing of the entire exonic region of the PIK3CA gene was conducted. Using Kaplan-Meier methodology per investigator assessment, median PFS was evaluated.

Of the total patients (N = 572) in SOLAR-1, valid plasma ctDNA data were gathered in 381 (66.6%) patients across PIK3CA mutation–positive and nonmutant cohorts. Detailed examination revealed that of these patients, 50.7% (N = 193) had a PIK3CA alteration; 87% (N = 168) had PCR-detectable mutations; and 76% (N = 147) had a single alteration. Alterations in exons 9 and 20 occurred correspondingly in a total of 36% (N = 70) and 53% (N = 102) of patients.

Patients (N = 101) who had PIK3CA alterations detected in plasma ctDNA by next-generation sequencing, median PFS was prolonged with treatment consisting of alpelisib combined with fulvestrant.

Observed clinical benefit was documented in 88 patients with PCR-detectable mutations, 83 patients with single mutations, 34 patients with mutations in exon 9, and 54 patients with exon 20.

There was a small number of patients (N = 13) with alterations not detectable by PCR, and in patients with multiple alterations, there was an observation of wide 95% confidence intervals. The investigators noted that limitations of the retrospective study were caused by this being a subgroup analysis, consisting of roughly two-thirds of the overall SOLAR-1 patient population. Furthermore, patients with a PIK3CA mutation in their tumor tissue were included in the subgroup of patients with nonaltered PIK3CA.

In patients with PIK3CA mutations detected in plasma ctDNA by next-generation sequencing, alpelisib combined with fulvestrant demonstrated clinical benefit in patients with single alterations as well as in those patients with alterations in exons 9 and 20. Across patient groups, findings were consistent, excluding alterations undetectable by PCR. In a range of groups with PIK3CA alterations, these findings show a clear clinical benefit of alpelisib combined with fulvestrant that was consistently detected in ctDNA by next-generation sequencing.

Source: Ciruelos EM, Loibl S, Mayer IA, et al. Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: biomarker analysis from the SOLAR-1 study. Presented at: 2020 San Antonio Breast Cancer Symposium, December 8-11, 2020. Abstract PD2-06.