A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer Journal Article
| Authors: | Mayer, I. A.; Abramson, V. G.; Formisano, L.; Balko, J. M.; Estrada, M. V.; Sanders, M. E.; Juric, D.; Solit, D.; Berger, M. F.; Won, H. H.; Li, Y.; Cantley, L. C.; Winer, E.; Arteaga, C. L. |
| Article Title: | A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer |
| Abstract: | Purpose: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER+/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 solidtumor 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. © 2016 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 23 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-01-01 |
| Start Page: | 26 |
| End Page: | 34 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-16-0134 |
| PROVIDER: | scopus |
| PMCID: | PMC5085926 |
| PUBMED: | 27126994 |
| DOI/URL: | |
| Notes: | Article -- Presented in part at the 2015 Annual Meeting of the American Association for Cancer Research (AACR) in Philadelphia, PA -- Export Date: 2 March 2017 -- Source: Scopus |
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