Abstract
SummaryBackground Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.
Highlights
Metastatic castration resistant prostate cancer is the lethal version of this common disease
The overall survival of men with Metastatic castration resistant prostate cancer (mCRPC) has improved over the past few years with the introduction of several different agents with non-overlapping mechanisms of action. [1,2,3,4,5] Despite this progress, further improvement is needed as men with mCRPC still invariably succumb to this disease
Hepatocyte growth factor (HGF) and its receptor N-methyl-N ′-nitrosoguanidine human osteosarcoma transforming gene (MET) seem to play important roles in the metastatic process [6, 7] and its signaling is abnormal in a variety of malignancies [8]
Summary
Metastatic castration resistant prostate cancer (mCRPC) is the lethal version of this common disease. Prostate cancer reaches this point through the combined events of metastasis and adaptation by the tumor to a low testosterone environment. [1,2,3,4,5] Despite this progress, further improvement is needed as men with mCRPC still invariably succumb to this disease. [13] [14, 15] Tivantinib has been found to have additional properties and in some preclinical studies its anti-cancer properties were independent of the c-MET inhibition. We performed a phase II randomized placebo controlled trial of tivantinib in men with asymptomatic or minimally symptomatic mCRPC
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