28IN - The role of tumor/molecular target selection in the success of a new agent

Date 01 October 2012
Event ESMO Congress 2012
Session A paradigm shift in early drug development: Individualizing to more patient benefit
Topics Drug Development
Pathology/Molecular Biology
Presenter Christian Dittrich
Authors C. Dittrich
  • 3rd Med.dept. - Center For Oncology And Hematology, LBI-ACR VIEnna & ACR-ITR VIEnna, A-1100 - Vienna/AT

Abstract

Rational drug discovery/development is targeted at structures and pathways, which cause, permit, or maintain malignancy. This let restrain from the histopathologically characterized organ entities and substitute them for merely molecularly characterized entities, such as EGFR, HER2, KRAS, BRAF driven entities. The presence of a target and its therapeutic consequence in one organ cannot be extrapolated to another. As an example, a BRAF mutation positive (m+) status in melanoma, which is highly predictive for response to the anti-BRAF directed TKI vemurafenib (Flathery 2010), cannot be extrapolated to the situation in BRAFm+ CRC (Kopetz 2010). A further difficulty in switching from tumor entity to target entity lies in the experience that clinical effectiveness does not only depend on whether a functional axis is hit by a drug or a class of drugs anyhow and anywhere, but moreover in a much more defined context; TKIs like erlotinib (Zhou 2011; Rosell 2012) yielded increased OS and PFS, respectively, in EGFRm+ tumors. But, the interference of the same axis at a different site and via the anti-EGFR MoAb cetuximab (in combination with standard therapy) led to an OS advantage independent of the EGFR mutational status of NSCLC (O'Byrne 2011). This touches upon the necessity to discover, identify, develop, and finally validate the most relevant biomarker(s) for the purpose of drug development, notably with high predictive accuracy early in the developmental process. In NSCLC, it took almost a decade of trial and error to better define the position/clinical usefulness of various biomarkers and methodologies, respectively, to characterize/measure the probability to benefit clinically in form of EGFR expression/gene amplification/copy number and mutations on the one side, and ORR, PFS, and OS, respectively, on the other side. A shortcoming derived from the earlier developmental process is the lack of fixing the right time point to preselect/enrich the relevant patient population. This is of utmost importance, especially if patient segments are small. In addition, it has to be found out whether a new targeting substance is not only reaching /modulating the target, but has also enough impact on the relevant biology of the tumor to gain clinical effectiveness.

Disclosure

C. Dittrich: Unrestricted research grants to the research institutes Honoraria for consulting services by several companies