108IN - Pi3K and/or mTOR inhibitors: Current status, future directions

Date 30 September 2012
Event ESMO Congress 2012
Session ESMO-EACR Joint symposium: Targeted therapies: Promises, successes and failures
Topics Anti-Cancer Agents & Biologic Therapy
Translational Research
Presenter Sherene Loi
Authors S. Loi
  • Breast International Group (big), Institute Jules Bordet, 1000 - Brussels/BE


The high incidence of molecular aberrations that target the phosphatidylinositol-3 kinase (PI3K) pathway in cancer, as well as the demonstration that many resistance mechanisms to drugs also involve this pathway, has unsurprisingly led to high interest in the development of agents to inhibit PI3K signaling. Currently, many PI3K targeted agents are in phase I/II testing, alone and in combination with agents that are usual standard of care as well as those that target potential resistance pathways such as MEK/ERK. Some agents are about to commence phase III evaluation. Thus far in phase I, there have been signs of activity in the advanced setting for multiple tumor types but surprisingly yet no strong association with PI3K pathway aberrations such as PIK3CA mutations have been seen. Toxicities have been reasonably predictable and on-target, including hyperglycaemia, diarrhea, skin rash, nausea, fatigue and transaminitis Issues that are currently critical for optimal development in this field are: 1. understanding of who will benefit- thus far the relationship between PIK3CA, AKT1 mutations, PTEN loss and response to PI3K inhibitors has been not as clear as other targets such as BRAF mutants, EML4-ALK rearrangements and HER2 amplification. Activity has also been observed in genetically unselected cancer populations, though toxicity may preclude its acceptance in unselected populations if large and meaningful benefit cannot be shown; 2. Understanding the role of dual versus single versus isotype specific compounds- this may also depend on the genetic aberration and clinical setting; 3. prospective upfront stratification and power to look at mutated (as well as wild-type) subsets, particularly in early phase clinical trials; 4. Determining rationale combinations with PI3K targeted therapy, which will undoubtedly depend on the setting and cancer type. Addressing these issues, along with adequate genotyping of the tumor, will ensure that we get a clear picture of the molecular background of which patients, tumor types and clinical setting benefits.


The author has declared no conflicts of interest.