A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ERþ/HER2 Metastatic Breast Cancer

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

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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.

Original languageEnglish (US)
Pages (from-to)26-34
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2017

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letrozole
Breast Neoplasms
Neoplasms
Mutation
Maximum Tolerated Dose
Therapeutics
Exanthema
Drug-Related Side Effects and Adverse Reactions
Phosphatidylinositol 3-Kinases
Hyperglycemia
Nausea
Fatigue
NVP-BYL719
Diarrhea
Catalytic Domain
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ERþ/HER2 Metastatic Breast Cancer. / Mayer, Ingrid A.; Abramson, Vandana G.; Formisano, Luigi; Balko, Justin M.; Estrada, Mónica V.; Sanders, Melinda E.; Juric, Dejan; Solit, David; Berger, Michael F.; Won, Helen H.; Li, Yisheng; Cantley, Lewis C.; Winer, Eric; Arteaga, Carlos L.

In: Clinical Cancer Research, Vol. 23, No. 1, 01.01.2017, p. 26-34.

Research output: Contribution to journalArticle

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 2017, 'A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ERþ/HER2 Metastatic Breast Cancer', Clinical Cancer Research, vol. 23, no. 1, pp. 26-34. https://doi.org/10.1158/1078-0432.CCR-16-0134
Mayer, Ingrid A. ; Abramson, Vandana G. ; Formisano, Luigi ; Balko, Justin M. ; Estrada, Mónica V. ; Sanders, Melinda E. ; Juric, Dejan ; Solit, David ; Berger, Michael F. ; Won, Helen H. ; Li, Yisheng ; Cantley, Lewis C. ; Winer, Eric ; Arteaga, Carlos L. / A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ERþ/HER2 Metastatic Breast Cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 1. pp. 26-34.
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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.",
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T1 - A Phase Ib Study of Alpelisib (BYL719), a PI3Ka-Specific Inhibitor, with Letrozole in ERþ/HER2 Metastatic Breast Cancer

AU - Mayer, Ingrid A.

AU - Abramson, Vandana G.

AU - Formisano, Luigi

AU - Balko, Justin M.

AU - Estrada, Mónica V.

AU - Sanders, Melinda E.

AU - Juric, Dejan

AU - Solit, David

AU - Berger, Michael F.

AU - Won, Helen H.

AU - Li, Yisheng

AU - Cantley, Lewis C.

AU - Winer, Eric

AU - Arteaga, Carlos L.

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N2 - 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.

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