6IN - From landmarks of cancer to targeted therapies: Lessons learnt and perspectives

Date 30 September 2012
Event ESMO Congress 2012
Session The hallmarks of cancer revisited
Topics Anticancer Agents
Cancer Biology
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological Therapy
Presenter Ahmad Awada
Authors A. Awada
  • Medical Oncology, Institute Jules Bordet, 1000 - Brussels/BE

Abstract

TKIs and antibodies (trastuzumab, imatinib,..) emerged as “revolutionary” drugs. Nevertheless, testing different agents in studies turned to be negative or “marginally” positive. Negative trials highlighted important issues: 1) The genetic complexity of carcinogenesis 2) Defining the implication of a target to oncogenesis is essential. 3) Due to the “plasticity” of signaling pathways, combination agents or multitargeted kinase may be needed but “cumulative” toxicities emerged. 4) A well performed early study is a prerequisite for the succes of a new agent. Marginally positive studies lead in limited circumstances to retrospective identification of subpopulations likely to benefit (e.g., WT KRAS and sensitivity to EGFR MoAbs in CRC). The sensibilisation towards tumor selection has demonstrated better results. NSCLC with ALK gene rearrangements are senstitive to ALK inhibitors. Melanoma with BRAF mutation responded to vemurafenib. A drawback would be the heterogeneity of the tumor. Moreover, modern techonologies allows the development of agents with a higher selectivity. Although advances have been achieved further, efforts are needed: Biomarkers of sensitivity have been evaluated but not optimaly validated. Mechanisms of resistance have been described, but a proper assessment is lacking. So it is fundamental to prioritize “powered” clinical trials. Prospective collection of biospecimens during disease evolution and therapies must become a standard approach. A comprehensive drug development plan (in advanced or neoadjuvant setting) has the potential to identify drugs to be tested in the adjuvant setting in subgroups where cure will be much higher. The lessons learnt so far should bring the concept of “personalized treatment” closer to the reality. A close collaboration of scientists, chemists, investigators and statisticians is needed to reach this goal.

Disclosure

The author has declared no conflicts of interest.