Genomic determinants of response to alpelisib plus fulvestrant in the SOLAR-1 trial.

BACKGROUND

Approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of PIK3CA-mutated, HR-positive, HER2-negative ABC, based on the results of the SOLAR-1 trial (NCT02437318). Aside from PIK3CA, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population.

PATIENTS AND

METHODS

In this retrospective analysis, we carried out tissue-based next-generation sequencing of 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was carried out in the PIK3CA-altered cohort.

RESULTS

PIK3CA-altered and PIK3CA-wild type tumors had distinct genomic profiles. In the PIK3CA-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (P = 0.0004). Patients in the lowest tumor mutational burden quartile as well as those with FGFR1 or FGFR2 alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant [18.5 versus 3.22 months: hazard ratio (HR) 0.38, 95% confidence interval (CI) 0.21-0.68; FGFR1 12.71 versus 3.75 months: HR 0.38, 95% CI 0.17-0.81, P = 0.32; FGFR2 9.63 versus 2.78 months: HR 0.31, 95% CI 0.1-0.94, P = 0.29]; patients with MYC or RAD21 alterations derived limited PFS benefit. Cox and multitask machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and PTEN or TP53 alterations among the most deleterious factors for PFS in the PIK3CA-altered cohort.

CONCLUSIONS

Alpelisib plus fulvestrant provides clinical benefit for patients with PIK3CA-altered, HR-positive, HER2-negative ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models can identify factors including gene mutations that influenced PFS.