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Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor

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Abstract

This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer.

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Acknowledgments

This study was funded by Sanofi. The authors received editorial support from Simone Blagg of MediTech Media, funded by Sanofi.

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Authors and Affiliations

  1. Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27710, USA

    Kimberly Blackwell

  2. Sarah Cannon Research Institute, Nashville, TN, USA

    Howard Burris

  3. Vall d’Hebron, Barcelona, Spain

    Patricia Gomez

  4. University of Michigan Medical School, Ann Arbor, MI, USA

    N. Lynn Henry

  5. Massachusetts General Hospital, Boston, MA, USA

    Steven Isakoff

  6. Sanofi, Cambridge, MA, USA

    Frank Campana & Lei Gao

  7. Sanofi, Bridgewater, NJ, USA

    Jason Jiang

  8. Sanofi, Vitry sur Seine, France

    Sandrine Macé

  9. Dana-Farber Cancer Institute, Boston, MA, USA

    Sara M. Tolaney

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  1. Kimberly Blackwell
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Correspondence to Kimberly Blackwell.

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Conflict of interest

Frank Campana, Lei Gao, Jason Jiang, and Sandrine Macé are employees of Sanofi. Jason Jiang has stock ownership in Sanofi. Sara Tolaney has received research funding from Genentech. The other authors have no conflicts to declare.

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These experiments comply with the current laws of the countries in which they were performed.

Electronic supplementary material

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10549_2015_3615_MOESM1_ESM.pdf

Supplementary Fig. S1 Mutational profiling in tumor samples from patients enrolled in phase I and phase II. Each of the 67 cancer genes in which a somatic mutation or copy number change has been identified is listed. The number of mutations in each gene (rows) and in each of 38 tumor samples (columns) is shown (PDF 442 kb)

10549_2015_3615_MOESM2_ESM.pdf

Supplementary Fig. S2. C-peptide levels over time with (a) pilaralisib 200 mg, (b) pilaralisib 400 mg, (c) voxtalisib 30 mg or (d) voxtalisib 50 mg in samples from patients enrolled in phase I and phase II. Each line represents a single patient. Samples were analyzed before drug dosing on days 1, 29 (week 5), 57 (week 9) and 85. Lower (0.27) and upper (1.28) normal limits for C-peptide levels are indicated (PDF 911 kb)

10549_2015_3615_MOESM3_ESM.pdf

Supplementary Fig. S3 Percentage change in C-peptide in patients treated with (a) pilaralisib 400 mg QD or (b) voxtalisib 50 mg BID in samples from patients enrolled in phase I and phase II. Serum samples were analyzed at baseline and before drug dosing on days 1, 29 (week 5), 57 (week 9) and 85. Boxes represent interquartile ranges, diamonds represent means, and horizontal bars represent median, Q25 and Q75 (PDF 899 kb)

Supplementary material 4 (DOCX 17 kb)

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Blackwell, K., Burris, H., Gomez, P. et al. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor. Breast Cancer Res Treat 154, 287–297 (2015). https://doi.org/10.1007/s10549-015-3615-9

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