Novel Small Molecule Pictilisib May Benefit Women with Advanced Breast Cancer

CancerConnect News:  The addition of the investigational drug pictilisib to Faslodex® (fulvestrant) has been demonstrated to delay the time of cancer in women with advanced or metastatic breast cancer to be positive for both estrogen receptor (ER) and progesterone receptor (PR) who have previously failed treatment with an aromatase inhibitor.

Each year roughly 200,000 U.S. women are diagnosed with breast cancer. Many of these breast cancers will be hormone receptor-positive, meaning that they are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Treatment of hormone receptor-positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen.

Faslodex® —a type of hormonal therapy known as an estrogen receptor antagonist—blocks the actions of estrogen. It’s used for the treatment of metastatic, hormone receptor-positive breast cancer in postmenopausal women who experience cancer progression or recurrence after prior hormone therapy.

Aberrant activation of the PI3K pathway has been widely implicated in many types of cancer, including breast cancer and lung cancer. Additionally, increased activity of the PI3K pathway is often associated with resistance to cancer therapies.1,2   Pictilisib (GDC-0941) is a novel, oral, highly specific, small-molecule, ATP-competitive class I PI3K inhibitor.3  In preclinical studies in a range of cancer models, combinations of pictilisib with cytotoxic agents or other targeted agents achieved synergistic antitumor activity compared with the chemotherapy or anticancer agent alone.4,5

In this clinical study 168 postmenopausal patients with ER-positive, HER2-negative, advanced or metastatic breast cancer who had relapsed or progressed following or during treatment with an aromatase inhibitor were enrolled in a clinical study and treated with either Faslodex® and pictilisib or Faslodex®  alone and directly compared.6

After 17 months of follow-up, analysis of the overall study population of women with ER-positive breast cancer showed that those treated with pictilisib and Faslodex® were 26 percent less likely to have disease progression compared with women treated with Faslodex®  alone.  Analysis of progression-free survival among those women with both ER- and PR-positive disease also found that those treated with pictilisib and Faslodex® were 56 percent less likely to have disease progression compared with women treated with Faslodex®  alone.  However when the authors analyzed data for all women with ER-positive disease, the improvement in progression-free survival was not significant.

For ER and PR- positive patients, the addition of pictilisib resulted in a significant doubling of progression-free survival, from 3.7 months to 7.4 months.  No unexpected side effects were reported. The side effects of pictilisib and Faslodex® were similar to those observed in clinical trials testing pictilisib as a single treatment.

 

References:

 

  1. Myers AP, Cantley LC. Targeting a common collaborator in cancer development. Sci Transl Med. 2010;2:48ps45.
  2. McCubrey JA, Steelman LS, Franklin RA, et al. Targeting the RAF/MEK/ERK, PI3K/AKT and p53 pathways in hematopoietic drug resistance. Adv Enzyme Regul. 2007;47:64-103.
  3. Folkes AJ, Ahmadi K, Alderton WK, et al. The identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008;51:5522-5532.
  4. Sampath D, Belvin M, Guan J, et al. Combination of class I PI3K inhibitor, GDC-0941, with standard of care therapeutics results in enhanced anti-tumor responses in human cancer models in vitro and in vivo. Presented at: 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 21-24, 2008; Geneva, Switzerland. Poster 220.
  5. Wallin JJ, Guan J, Prior WW, et al. Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer. Sci Transl Med. 2010;2:48ra66.
  6. Krop IE, Johnston S, Mayer IA, et al. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results Abstract #S2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.

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