MET aberrations (deletions, point mutations, fusions, gene amplifications or c-Met protein overexpression) contribute to disease pathogenesis and are associated with a poor prognosis in NSCLC. c-Met protein overexpression is an emerging biomarker and is prevalent in NSCLC. Multiple antibody backbone therapeutics directed at c-Met are in clinical development, including antibody drug conjugates and bispecific antibodies. Here we explore testing considerations for c-Met protein overexpression and measures for incorporating expanded IHC testing into the biomarker workup in NSCLC.
c-Met detection and quantification – the challenges
c-Met expression is quantitated through IHC staining and is graded according to intensity. Results can be influenced by the following factors:
- Variability in the quality of the antibody, quality control of the staining process, or tissue block selection.
- Size of the tumor area evaluated, due to uneven distribution of positive cells defined by testing criteria.
- Strong background staining.
Addressing IHC performance
Measures to mitigate technical and performance challenges with MET IHC testing include: antibody validation, standardizing tissue processing, staining procedures, and scoring criteria, implementation of robust quality control measures, and education and training programs.
Novel therapeutics in development have applied various c-Met protein expression scoring systems using the Ventana anti–total c-Met (SP44) rabbit monoclonal primary antibody. Experience with PD-L1 testing has demonstrated drawbacks of having multiple scoring systems and assays.
As therapies targeting the c-Met protein become available, the validation of companion diagnostics and accompanying guidelines will be critical to ensuring optimal reproducibility across different laboratories. Harmonizing reporting practices for c-MET expression results, including the use of consistent terminology and cut-off values, is critical for result interpretation and subsequent patient treatment decisions. Establishing referral centres at the initial stage of implementation of a new test in the clinical setting is beneficial for ensuring testing access and quality control.
Table. c-Met overexpression is distinct from other MET gene aberrations (7)
Limited tissue samples – maximum information
Optimal tissue management should be implemented to ensure prioritization of key actionable biomarkers in NSCLC: EGFR, ALK, ROS1, BRAF, KRAS, MET, NTRK, PDL1. It will be important to apply multiplex IHC assays that allow comprehensive multibiomarker testing and molecular profiling from a single tissue sample.
When no tissue sample is available, liquid biopsy, such as circulating tumor DNA analysis, can provide information on genomic alterations and biomarker status from peripheral blood samples. This is particularly pertinent in advanced NSCLC, where obtaining a tissue biopsy could be challenging.
Finally, implementation of a reflex testing system for NSCLC will facilitate test prioritization and efficiency. This should be based on clinical needs, interdisciplinary coordination among the various healthcare professionals involved in the biomarker workup process, along with industry collaboration.
*Depending on methods and cut-offs
The views and opinions expressed in this article are those of the author and do not necessarily reflect those of AbbVie. AbbVie does not endorse the use of unregistered products or products outside of their registered indications.
AbbVie 2024 approval code(2024 AbbVie inc. CMTP-AA-00001-MC V1 5/2024)
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