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Ref Type Journal Article
PMID (27126994)
Authors Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL
Title A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 1
Date 2017 Jan 01
URL
Abstract Text 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.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.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. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PIK3CA E78K missense unknown PIK3CA E78K lies within the PI3K-ABD domain of the Pik3ca protein (UniProt.org). E78K has been identified in the scientific literature (PMID: 27126994), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Feb 2020).
PIK3CA I273V missense unknown PIK3CA I273V lies within the PI3K-RBD domain of the Pik3ca protein (UniProt.org). I273V has been identified in the scientific literature (PMID: 27126994), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Feb 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 over exp PIK3CA mut estrogen-receptor positive breast cancer sensitive Alpelisib + Lucitanib Preclinical - Cell culture Actionable In a preclinical study, an estrogen-receptor positive breast cancer cell line over expressing FGFR1 and expressing a PIK3CA mutation demonstrated sensitivity to the combination of Alpelisib (BYL719) and Lucitanib (E-3810) in culture (PMID: 27126994). 27126994
FGFR1 amp estrogen-receptor positive breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, an estrogen-receptor positive breast cancer cell line harboring an FGFR1 amplification demonstrated resistance to Alpelisib (BYL719) in culture (PMID: 27126994). 27126994
FGFR1 amp estrogen-receptor positive breast cancer sensitive Lucitanib Preclinical - Cell culture Actionable In a preclinical study, an estrogen-receptor positive breast cancer cell line harboring FGFR1 amplification demonstrated sensitivity to treatment with Lucitanib (E-3810) in culture (PMID: 27126994). 27126994
PIK3CA E78K PIK3CA E726K PIK3CA D939G estrogen-receptor positive breast cancer no benefit Alpelisib + Letrozole Phase Ib/II Actionable In a Phase Ib trial, an estrogen-receptor positive breast cancer patient harboring PIK3CA mutations, E78K, D939G, and E726K, demonstrated progressive disease when treated with a combination of Femara (letrozole) and Alpelisib (BYL719) (PMID: 27126994). 27126994