A Phase Ib Study of Alpelisib (BYL719), a PI3K alpha-Specific Inhibitor, with Letrozole in ER+/HER2(-) Metastatic Breast Cancer

作者：Mayer, Ingrid A.^*; Abramson, Vandana G.; Formisano, Luigi; Balko, Justin M.; Estrada, Monica V.; Sanders, Melinda E.; Juric, Dejan; Solit, David; Berger, Michael F.; Won, Helen H.; Li, Yisheng; Cantley, Lewis C.; Winer, Eric; Arteaga, Carlos L.

来源：Clinical Cancer Research, 2017, 23(1): 26-34.

DOI：10.1158/1078-0432.CCR-16-0134

• PHOSPHATIDYLINOSITOL 3-KINASE
• PIK3CA MUTATIONS
• ESTROGEN DEPRIVATION
• RESISTANCE
• GROWTH
• PI3K
• ACTIVATION
• ALPHA
• NVP-BYL719
• TUMORS

Purpose: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110 alpha, has shown synergistic antitumor activity with endocrine therapy againstER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER- breast cancer refractory to endocrine therapy. @@@ Experimental Design: Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing. @@@ Results: Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression >= 6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment >= 12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro. @@@ Conclusions: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing.

• 出版日期2017-1-1