Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study

Savas, P; Lo, LL; Luen, SJ; Blackley, EF; Callahan, J; Moodie, K; van Geelen, CT; Ko, YA; Weng, CF; Wein, L; Silva, MJ; Bujak, AZ; Yeung, MM; Ftouni, S; Hicks, RJ; Francis, PA; Lee, CK; Dawson, SJ; Loi, S

Author(s): Savas, P; Lo, LL; Luen, SJ; Blackley, EF; Callahan, J; Moodie, K; van Geelen, CT; Ko, YA; Weng, CF; Wein, L; Silva, MJ; Bujak, AZ; Yeung, MM; Ftouni, S; Hicks, RJ; Francis, PA; Lee, CK; Dawson, SJ; Loi, S;
Details: Publication Year 2022-09,Volume 12,Issue #9,Page 2058-2073
Journal Title: Cancer Discovery
Publication Type: Research article
Abstract: There is limited knowledge on the benefit of the alpha-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003). SIGNIFICANCE: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007.
Keywords: *Breast Neoplasms/drug therapy/genetics/pathology; Class I Phosphatidylinositol 3-Kinases/genetics; Female; Humans; Mutation; Phosphatidylinositol 3-Kinases/genetics; Receptor, ErbB-2/genetics; Thiazoles; *Triple Negative Breast Neoplasms/drug therapy/genetics
Department(s): Laboratory Research; Medical Oncology; Cancer Imaging; Biostatistics and Clinical Trials
PubMed ID: 35771551
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-21-1696
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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