Effect of Onartuzumab Added to Erlotinib on Metastasis in Patients With Lung Cancer

TO THE EDITOR: A randomized phase II trial suggests improved outcome with the addition of onartuzumab to erlotinib in patients with advanced non–small-cell lung cancer (NSCLC) expressing MET. Overall survival (OS) is improved disproportionately in the combination arm compared with progression-free survival (PFS). Median OS improvement of 8.8 months compares with a 1.4-month improvement for median PFS, and response rates in both groups were low and not significantly different. In considering the current understanding of MET biology, the authors suggest that the therapeutic benefit of onartuzumab may arise from inhibition of migration and invasion rather than direct inhibition of tumor growth. Upregulation of oncogenic MET signaling results in features of epithelial to mesenchymal transition, including increased protease production, cell dissociation, and increased motility. This can contribute to cellular invasion through extracellular matrix, enabling tumor invasion and metastasis. In mouse models, silencing of endogenous overexpressed MET gene in tumor cells suppresses tumor growth and metastasis. Onartuzumab may have had a similar effect in the patients on this trial. We suggest that clinical support for this mechanism of action may be available in the data collected by Spigel et al. Review of computed tomography scans documenting progression could categorize patients according to increase in size of target lesions identified at baseline, or detection of new metastatic sites. If, compared with erlotinib controls, MET-positive patients who experience disease progression in the combination arm are less likely to have new distant metastases, indirect clinical support for their hypothesis would be provided. In addition, if confirmed, this finding would provide a possible explanation for the observed impressive survival benefit with the addition of onartuzumab to erlotinib, despite a low response rate and the absence of significant PFS difference seen with the combination. In an era of individualized treatment with expensive targeted therapies, early prediction of clinical benefit is of great value. However, current radiological tools, including response, may not be sufficient to evaluate the complex biology that underlies the mode of action of these drugs. The results presented by Spigel et al offer an exciting new perspective for patients with MET-positive NSCLC, but further exploration of the mode of disease progression, as suggested above, is warranted.