期刊
CLINICAL CANCER RESEARCH
卷 23, 期 1, 页码 26-34出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-0134
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资金
- Stand Up to Cancer Dream Team Translational Research Grant - Stand Up To Cancer is a program of the Entertainment Industry Foundation [SU2CAACR-DT0209]
- Breast SPORE [P50 CA098131]
- VICC [P30 CA68485]
- Breast Cancer Research Foundation
- Susan G. Komen for the Cure Foundation SAC grant [SAC100013]
- Novartis Pharmaceuticals
- [K23 CA127469-01A2]
- [R01 GM041890]
- NATIONAL CANCER INSTITUTE [P30CA068485, P30CA008748, P30CA016672, P50CA098131, K23CA127469] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM041890] Funding Source: NIH RePORTER
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. (C) 2016 AACR.
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