A randomized, placebo-controlled, phase I/II study of tivantinib (ARQ 197) in combination with cetuximab and irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (CRC) who had received previous front-line systemic therapy.

Abstract

3508 Background: Tivantinib (ARQ 197) selectively inhibits the MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, and metastasis. Resistance to EGFR inhibitors has been associated with activation of alternative pathways including MET. Methods: Pts with advanced KRAS WT CRC that progressed on or after 1 prior line of chemotherapy and no previous treatment with an EGFR inhibitor were eligible. Pts were randomized 1:1 to receive cetuximab (500 mg/m2) and irinotecan (180 mg/m2) on days 1 and 15 every 28 days, plus oral tivantinib (360 mg twice daily [BID]) or placebo. The primary endpoint was progression-free survival (PFS); additional endpoints include safety, objective response rate, overall survival (OS) and exploratory biomarker analyses. Results: Between Jul 2010 and Feb 2012, 122 pts were randomized; 117 pts were eligible for analysis (60 tivantinib, 57 placebo). Mean age was 57 years (range, 27-79 years); ECOG PS 0/1 55%/45%; and 81% received prior oxaliplatin. Median PFS was 8.3 months in the tivantinib arm vs 7.3 months in the placebo arm (hazard ratio [HR] = 0.85; 95% CI, 0.55-1.33; P = 0.38). Objective response rate (95% CI) was 45% (33%-58%) in the tivantinib arm and 33% (23%-46%) in the placebo arm. Median OS has not yet been reached but is trending in favor of tivantinib vs placebo (HR = 0.67). Among pts with prior oxaliplatin therapy, median PFS was 8.4 months for tivantinib and 7.2 months for placebo (HR = 0.67; 95% CI, 0.44-1.00; P= 0.1). The most common grade 3/4 adverse events (≥ 10%) were neutropenia, diarrhea, and nausea. Correlation of clinical outcomes with additional factors including mutation status and immunohistochemical analysis of tumor MET expression will be presented. Conclusions: Outcomes in this trial trended towards improvement with tivantinib (360 mg BID) plus cetuximab and irinotecan, particularly in the subgroup who had previous oxaliplatin. Further studies are needed to identify the CRC population most likely to benefit from addition of tivantinib to standard therapy. Clinical trial information: NCT01075048.

A Phase II Randomized Trial (GO27827) of First-Line FOLFOX Plus Bevacizumab with or Without the MET Inhibitor Onartuzumab in Patients with Metastatic Colorectal Cancer

“…Although this finding could be due to chance, it is in line with an exploratory analysis of the monoclonal antibody ficlatuzumab in NSCLC, which demonstrated that the addition of ficlatuzumab to gefitinib appeared to benefit patients with low tumoral MET expression . In addition, a subgroup analysis of a phase Ib study in colorectal cancer showed that patients with low MET expression tumors derived a statistically significant improvement in PFS with the possible anti‐MET TK inhibitor tivantinib . These results indicate a complex and as yet not understood relationship between MET expression and tumor response to anti‐MET agents.…”

Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1

“…After describing Bcl-xl, Mcl-1 and Cyclin B1 as functional targets of tivantinib in determining apoptosis and cell cycle arrest, we assessed whether the influence of tivantinib on these molecules is dependent on its efficacy as inhibitor of c-MET, as the predictive significance of this receptor in clinical trials seems to suggest [ 2 , 16 ]. To this aim, we assessed the effects of c-MET silencing by siRNA transfection in Huh7 cells; additionally, we compared the effect of tivantinib on DLD1 cells, which express the native form of c-MET vs. that on syngenic DLD1 c-MET exon 16 KO cell lines, which express a genetically modified variant of c-MET lacking the binding site of tivantinib.…”

Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors

“…As a result of promising signals of activity of the anti-MET TKI tivantinib in a Phase IB study in colorectal cancer where four of nine patients had an objective response, a combination study of irinotecan–cetuximab (Erbitux, Merk-Serono) with or without this drug was investigated in a randomized, Phase II trial in a population of KRAS wild-type metastatic colorectal cancer patients (n=122) who had progressed on or after one line of systemic therapy. 76 , 77 Tivantinib in combination with standard treatment was associated with a higher response rate (45% versus 33.3%) and a slight improvement in PFS (8.3 versus 7.3 months, respectively); however this was not statistically significant (PFS HR 0.85, P =0.38). Surprisingly, but in line with what has been observed with ficlatuzumab in NSCLC, a subgroup analysis conducted in a small number of study patients showed a statistically significant improvement in PFS with tivantinib in patients with low-MET-expressing tumors; however this subgroup contained only 23 patients and requires validation in a larger patient cohort.…”