Assessing the Additive Benefit of Alpelisib to Fulvestrant in Advanced Breast Cancer Across the Gene Mutation Landscape: Findings from a Post Hoc Analysis of the SOLAR-1 Trial

The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) is mutated in approximately 40% of patients with HR-positive/HER2-negative advanced breast cancer, with some of these mutations leading to PI3K pathway hyperactivation; these mutations are associated with resistance to endocrine therapy and poor prognosis in advanced disease. Alpelisib, an alpha-selective PI3K inhibitor, demonstrated clinical benefit in combination with fulvestrant in the SOLAR-1 study in patients with PIK3CA aberrations; SOLAR-1 (NCT02437318) was a double-blind, placebo-controlled, stratified, randomized, phase 3 study of alpelisib plus fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer who progressed on or after treatment with aromatase inhibitors. This study aimed to compare the gene alteration landscape in patients with altered and non-altered PIK3CA, as well as the efficacy of alpelisib plus fulvestrant in patients with alterations in both selected genes or cell signaling pathways, as well as PIK3CA alterations, as determined by next-generation sequencing.

The FoundationOne CDx 324-gene panel was performed on available tissue samples, with 324 patients categorized into 2 cohorts based on PIK3CA status. The cohort with PIK3CA alterations was comprised of 237 patients (alpelisib, n = 120; placebo, n = 117), and the cohort without PIK3CA alterations included 161 patients (alpelisib, n = 81; placebo, n = 80). Selected genes found to be altered in more than 20 patients were investigated further. Clinical benefit was assessed by progression-free survival (PFS) based on alteration status in the PIK3CA-altered and non-altered cohorts. Hazard ratios (HRs) for PFS were estimated using multivariate Cox proportional hazards model by adjusting clinical covariates, including age, ECOG performance status, bone lesion, prior CDK4/6 inhibitor therapy, and lung or liver metastasis.

Differential PFS benefit was observed among the genes analyzed, including ARID1A, EMSY, FGFR2, MAP3K1, MYC, RAD21, RAD51C, TP53, and a gene set associated with the MAPK pathway. In most patients with gene alterations, numerically longer PFS was observed with alpelisib versus placebo in the PIK3CA-altered cohort than in the non-altered cohort; this was particularly seen in patients with alterations in ARID1A (alpelisib vs placebo in PIK3CA-altered cohort: median PFS, 22.11 vs 12.42 months; HR, 0.48; in non-altered cohort: median PFS, 6.21 vs 22.31 months; HR, 1.33) and MAP3K1 (PIK3CA-altered cohort: median PFS, 17.25 vs 7.70 months; HR, 0.50; non-altered cohort: median PFS, 9.17 vs 5.26 months; HR, 1.32). Due to small patient samples in multiple subgroups, caution should be taken in interpreting these findings.

The authors concluded that a differential genomic landscape was observed in PIK3CA-altered vs non-altered populations. In patients with PIK3CA-altered disease who also had alterations in analyzed genes and/or genes associated with the MAPK pathway, clinical benefit of alpelisib vs placebo was observed. Investigators concluded that these data suggest, of the genes analyzed, only PIK3CA mutations can predict patient sensitivity to alpelisib.


Juric D, Rugo HS, Reising A, et al. Differential gene mutation landscape in patients with PIK3CA-altered and non-altered hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the SOLAR-1 clinical study. San Antonio Breast Cancer Symposium 2022. Abstract P5-02-32.

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