Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Biomarker (BM) analyses by next-generation sequencing (NGS) from the SOLAR-1 study.

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1006 Background: PIK3CA mutations (mut; ~40% of HR+, HER2– ABC) are linked to poor prognosis. In SOLAR-1, ALP (PI3Kα-selective inhibitor and degrader) + FUL improved progression-free survival (PFS) vs placebo (PBO) + FUL in pts with PIK3CA-mutated HR+, HER2– ABC. Here, we focus on efficacy data by gene alterations in SOLAR-1 PIK3CA-altered (alt) cohort. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or PBO) + FUL in HR+, HER2– ABC progressing on/after an aromatase inhibitor. Baseline tissue samples with enough quantity/quality (N = 398) were retrospectively tested by NGS (FoundationOne CDx 324-gene panel) and pts grouped by PIK3CA-alteration status. Clinical benefit was assessed using PFS and hazard ratio (HR) based on tumor mutational burden (TMB) and gene alteration status in the PIK3CA-alt cohort. No multiplicity adjustment was made. Results: PIK3CA-alt (ALP, n = 120; PBO, n = 117) and PI3KCA-non-alt (ALP, n = 81; PBO, n = 80) cohorts had differential gene alteration landscapes. In the PIK3CA-alt cohort, ALP + FUL clinical benefit was seen across TMB quartiles (Q1: 0 -<2.52, Q2: 2.52 -<3.78, Q3: 3.78 -<5.04, Q4: ≥ 5.04 mut/megabase). ALP + FUL had greater benefit in pts with alt vs non-alt FGFR1/ 2 (Table). ALP + FUL benefit was independent of alterations in TP53, ESR1, CCND1, MAP3K1, and ARID1A and limited in MYC- and RAD21-alt cohorts . ALP + FUL benefit was seen in pts with alt genes in the MAPK (HR [95% CI] vs PBO: alt 0.43 [0.23 - 0.80]; non-alt 0.56 [0.40 - 0.79]) and PI3K (in addition to PIK3CA; alt 0.68 [0.38 - 1.23]; non-alt 0.48 [0.34 - 0.68]) pathways, and implicated in CDK4/6i resistance (alt 0.52 [0.30 - 0.89]; non-alt 0.53 [0.37 - 0.76]). Conclusions: The unique mut profile of PIK3CA-alt tumors did not affect ALP + FUL benefit in pts with HR+, HER2– ABC. Clinical benefit was maintained regardless of alterations in most BMs, including ESR1 and genes implicated in CDK4/6i resistance, consistent with ALP targeting the PIK3CA driver oncogene. Clinical trial information: NCT#02437318; EUDRA CT#2015-000340-42. [Table: see text]