MET INHIBITORS FOR PAPILLARY RENAL CANCER  

Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma

Choueiri TK, Vaishampayan U, Rosenberg JE, et al

J Clin Oncol. 2013;31:181-186

Summary

In this multicenter phase 2 trial, 74 patients with papillary renal cell carcinoma were treated with the novel oral antineoplastic agent foretinib, which was developed to favorably affect multiple cancer-relevant receptors (MET, VEGF, RON, AXL, and TIE-2). Molecular abnormalities (activating mutations and amplifications) within the MET pathway have previously been shown to be present in this relatively uncommon tumor.^[1]

The toxicities seen with this agent were similar to those seen with other anti-vascular endothelial growth factor receptor agents (eg, fatigue, hypertension, gastrointestinal side effects), but the overall response rate was a relatively unimpressive 13.5%. Median progression-free survival was 9.3 months, and the 1-year survival rate was 70%; median overall survival was not reached.

However, of considerable interest was the difference in response rates among patients with and withoutgermline MET mutations, not somatic mutations that develop within the tumor tissue. In the patient population without a germline MET mutation, the objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) criteria was only 9% (5 of 57 patients). By contrast, 50% (5 of 10) of those with documented germline MET abnormalitiesshowed partial response, and the remaining patients in this cohort showed stable disease. Among the latter, 4 of 5 showed some measure of tumor reduction, but it was insufficient for RECIST criteria.

Viewpoint

Over the past decade, a rather impressive number of novel antineoplastic agents have been successfully developed and introduced into routine clinical practice for the management of renal cell carcinoma.^[2] However, the focus of this effort has been on clear cell carcinomas, which are responsible for the majority of malignancies in the kidney. Papillary renal cell carcinomas, which comprise only 10%-15% of renal cancers, are, from a molecular perspective, a rather heterogeneous group of conditions that share a papillary architecture on pathology.^[3]

Thus, the relatively low objective response rate seen in this heterogeneous population is not surprising. What is surprising, and quite provocative, is that of the 10 patients with a germline mutation in MET, 5 achieved a documented response by RECIST criteria, and the cancers in 4 additional patients had at least a biological effect, if not a RECIST-measurable one.

These data, if confirmed through additional investigation, suggest that the presence of a germline molecular abnormality could strongly predict for the biological and clinical activity of a targeted therapeutic. Further, the data raise the question of whether such germline mutations may be relevant in defining the effectiveness of therapy in other clinical settings.

Ultimately, however, one critical issue to be addressed is how an agent that targets a germline MET mutation might receive regulatory approval considering that only a small subset (< 20%) of patients with an uncommon cancer (only 10%-15% of renal cell cancers) benefit from the delivery of this unique targeted therapy.