MET Immunohistochemistry Expression Is Best Predictor of Benefit From Addition of Onartuzumab to Erlotinib in Advanced NSCLC
A recent phase II study showed progression-free survival and overall survival benefits with the addition of onartuzumab (an antibody directed against MET, a receptor kinase that binds hepatocyte growth factor [HGF]) to erlotinib (Tarceva) in the subset of patients with advanced non–small cell lung cancer (NSCLC) who were MET-positive on immunohistochemistry analysis. In a study reported in Clinical Cancer Research, Koeppen et al found that a standardized MET immunohistochemistry assay performed better than other biomarkers in predicting patient benefit from onartuzumab in the phase II study population.
Study Details
The phase II study assessed the addition of onartuzumab to erlotinib in 137 patients with stage IIIB/IV NSCLC as second- or third-line therapy. In the current study, the investigators compared the predictive ability of a standardized MET immunohistochemistry assay with other retrospectively assessed biomarkers related to MET or EGFR signaling as measured by Western blot (MET), fluorescence in situ hybridization (FISH; MET and EGFR copy number), quantitative reverse transcription polymerase chain reaction (MET, HGF, EGFR, amphiregulin, and epiregulin mRNA transcripts), mutation detection techniques (EGFR, KRAS, and MET mutations), and ELISA (plasma HGF).
MET Immunohistochemistry
An immunohistochemistry scoring system of MET expression taking both proportional and intensity-based thresholds into account, in which tumors expressing moderate or strong levels of MET in ≥ 50% of cells (clinical immunohistochemistry score 2+ or 3+) were classified as MET-positive, resulted in the best differentiation of outcomes in the phase II study. In the study, the addition of onartuzumab was associated with improved progression-free survival (hazard ratio [HR] = 0.53, P = .04) and overall survival (HR = 0.37, P = .002) on these criteria.
Other Biomarkers
Other analyses indicated a nonsignificant overall survival improvement with the addition of onartuzumab in patients with high MET copy number (mean ≥ 5 copies/cell on FISH), although a significant benefit was maintained in patients who were MET immunohistochemistry-positive/MET FISH-negative (HR = 0.37, P = .01). MET, EGFR, amphiregulin, epiregulin, and HGF mRNA expression were not associated with significant benefits for onartuzumab/erlotinib vs erlotinib. A nonsignificant overall survival improvement was observed in patients with high tumor MET mRNA levels (HR = 0.59, P = .23). The addition of onartuzumab was associated with a trend toward improved overall survival in patients with low baseline plasma HGF (HR = 0.519, P = .09).
The investigators concluded, “MET [immunohistochemistry] remains the most robust predictor of [overall survival] and [progression-free survival] benefit from [onartuzumab plus erlotinib] relative to all examined exploratory markers.”
Robert L. Yauch, PhD, of Genentech, Inc, is the corresponding author for the Clinical Cancer Research article.
The study was supported by grants from University of Texas Lung Specialized Programs of Research Excellence and MD Anderson Cancer Center, F. Hoffmann-La Roche Ltd, and Genentech, Inc. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
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