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Last Updated: 03/13/18

Information below provided by the Pharmaceutical Company.

Vistusertib (AZD2014)

Agent Description

Selective inhibitor of the kinase activity of mammalian Target of Rapamycin (mTOR) serine threonine kinase, which plays a critical role in regulating cellular energy, sensing, growth and metabolism. Vistusertib delivers efficacy in several different tumor types, particularly breast cancer models which are sensitive or resistant to endocrine therapy.

Mechanism of Action

Dual mTORC1 and mTORC2 inhibition

Classification

mTOR kinase inhibitor

Molecular Targets

mTOR kinase

Monograph

Vistusertib is being developed in a range of solid tumor and hematological malignancies, both as a single agent and in combination. The core focus of the AstraZeneca sponsored clinical program is breast cancer and DLBCL. In ER+, HER2- advanced breast cancer that is resistant to prior endocrine therapy, AstraZeneca is exploring a combination trial with fulvestrant (MANTA) and a triplet combination trial of vistusertib, palbociclib and fulvestrant (PASTOR). In addition, two doses and schedules are being explored: a continuous schedule (50mg BID) and an intermittent schedule (125mg BID 2 days on, 5 days off). These clinical studies are ongoing and the efficacy of vistusertib in breast cancer is not yet known. In DLBCL a combination trial with the BTK inhibitor, acalabrutinib is planned for 2017.

In May, 2017, a combination trial of vistusertib and durvalumab in bladder cancer (BISCAY) was initiated.

The remainder of the clinical portfolio is largely made up of externally sponsored research studies that are assessing the clinical activity of vistusertib in a range of solid tumors and hematological malignancies. A combination based approach is favored and the ongoing studies include:

  • Vistusertib + selumetinib: advanced cancers, NF1 MPNST and other pediatric; NSCLC (WT and KRASm); TNBC; CRC (RASm); LGSOv (RASm); uveal melanoma expansion cohorts. RP2D established.
  • Vistusertib + olaparib: TNBC, ovarian, endometrial expansion cohorts. RP2D established.
  • Vistusertib + navitoclax: SCLC. RP2D not established.
  • Vistusertib + AZD8186: Prostate cancer and TNBC
  • Vistusertib + durvalumab + tremelimumab: HNSCC
  • Vistusertib + paclitaxel: solid tumors; high grade serous ovarian; squamous NSCLC; gastric cancer
  • Vistusertib + rituximab: DLBCL
  • Vistusertib + temozolomide + topotecan: Pediatric Phase 1
  • Vistusertib + temozolomide: GBM

No clinical data suggests vistusertib crosses the BBB but all the preclinical evidence suggests that it is a poor BBB penetrator.

Clinical activity of vistusertib in tumors with genetic alterations that might result in hyperactivation of the mTORC complexes, e.g., TSC1/2 mutation (mTORC1 activation) and RICTOR amplification (mTORC2 activation) are being explored. Several basket/umbrella studies are either recruiting or in set-up across tumor types including lung cancer, breast cancer, gastric cancer and sarcomas.

Studies of Interest

Only non-clinical proposals are being accepted for this agent.

Information collaborator would like included in investigator proposals

N/A