Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with hepatocellular carcinoma (HCC) from a phase I study.

Authors

null

Robert E. Martell

Tufts Medical Center Cancer Center, Boston, MA

Robert E. Martell , Igor Puzanov , Wen Wee Ma , Armando Santoro , Grace K. Dy , Laura Williams Goff , Gerald J. Fetterly , Shaunita A. Michael , Julie Ann Means-Powell , Feng Chai , Maria Lamar , Matteo Simonelli , Wendy M. Chiang , Jamie Jarboe , Brian E. Schwartz , Alex A. Adjei

Organizations

Tufts Medical Center Cancer Center, Boston, MA, Vanderbilt University Medical Center, Nashville, TN, Roswell Park Cancer Institute, Buffalo, NY, Istituto Clinico Humanitas, Milan, Italy, ArQule, Inc., Woburn, MA

Research Funding

Pharmaceutical/Biotech Company
Background: The multikinase inhibitor sorafenib is standard of care for pts with advanced HCC. Tivantinib, an oral, selective MET inhibitor, demonstrated synergistic antitumor activity when combined with sorafenib in several tumor models. The phase 1 dose-escalation study assessed the safety profile of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase 2 dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with HCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. After a safety review in HCC pts in other studies and a report of febrile neutropenia in this study, the tivantinib dose for newly enrolled pts was reduced to 240 mg BID. Results: 20 pts with HCC (mean age, 62 yr; Child-Pugh [CP] A [n = 14], or CP B [n = 6]) were treated at the RP2D (n = 10) or at the reduced tivantinib dose plus sorafenib (n = 10). 10 pts received ≥ 1 previous systemic anticancer treatment (median, 0.5; range, 0-3). The most common adverse events (≥ 25%) were rash (40%), palmar-plantar erythrodysesthesia syndrome (35%), fatigue and diarrhea (30% each), and nausea and anorexia (25% each). Neutropenia was reported in 2 pts. Best response was 1 complete response (CR), 1 partial response (PR), and 12 stable disease (SD). Overall response rate and disease control rate were 10% and 70%, respectively. Median progression-free survival (mPFS) was 3.5 mo (95% CI, 2.8-11.1 mo). Among 8 pts previously treated with vascular endothelial growth factor (VEGF) inhibitors (6 sorafenib; 1 sunitinib; 1 sorafenib plus sunitinib), best response was 1 CR, 1 PR, and 3 SD, and mPFS was 15.9 mo (95% CI, 1.6-15.9 mo). 2 pts are still on study. Conclusions: The combination of tivantinib (360 mg BID) plus sorafenib (240 mg BID) was well tolerated. Preliminary evidence of antitumor activity indicates that combined inhibition of MET and angiogenic signals may have therapeutic potential in this setting, including pts pretreated with VEGF inhibitors.

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Abstract Details

Meeting

2012 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Gastrointestinal (Noncolorectal) Cancer

Track

Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

Sub Track

Other GI Cancer

Clinical Trial Registration Number

NCT00827177

Citation

J Clin Oncol 30, 2012 (suppl; abstr 4117)

DOI

10.1200/jco.2012.30.15_suppl.4117

Abstract #

4117

Poster Bd #

50D

Abstract Disclosures