Tivantinib (ARQ 197) is an investigational small molecule developed for cancer treatment. It was designed to target specific pathways involved in cancer growth and spread, explored for its potential to inhibit tumor progression.
The Intended Mechanism of Action
Tivantinib was initially conceived as an inhibitor of c-MET, a protein that acts as a receptor tyrosine kinase. In healthy cells, c-MET helps regulate normal cellular functions, but in cancer, it can become overactive, contributing to uncontrolled cell growth, survival, and the spread of tumors. The binding of hepatocyte growth factor (HGF) to c-MET activates signaling pathways that promote these cancerous behaviors, including increased cell growth, invasion, and resistance to cell death.
The drug was designed to block the HGF/c-MET pathway by stabilizing the inactive form of the c-MET kinase, thus preventing its activation and the subsequent signaling cascade. This mechanism was intended to suppress downstream pathways like PI3K-AKT, STAT3, and MEK-ERK, which are frequently dysregulated in various cancers. However, the precise way tivantinib works became a subject of debate as its development progressed.
Some research suggested that tivantinib might also affect microtubules, which are structures inside cells that play a role in cell division. This alternative mechanism, involving microtubule depolymerization, could lead to cell cycle arrest and programmed cell death, or apoptosis, regardless of c-MET activation. The ambiguous nature of its mechanism added complexity to understanding its therapeutic effects.
Cancers Investigated with Tivantinib
Tivantinib was investigated across several cancer types, particularly those where the c-MET pathway is overactive. Hepatocellular carcinoma (HCC), the most common type of liver cancer, was a primary focus of tivantinib’s clinical development. High c-MET activity is often observed in HCC tumors and is linked to aggressive disease and a poor outlook.
Non-small cell lung cancer (NSCLC) was another area of investigation for tivantinib, as c-MET mutations and overexpression are also found in this disease. The drug was also explored in trials for other solid tumors, including colorectal cancer, gastric cancer, pancreatic cancer, soft tissue sarcoma, and germ cell/embryonal neoplasms. The rationale for its use in these cancers was based on the observed dysregulation of the c-MET pathway, which suggested a potential therapeutic window for a c-MET inhibitor.
Key Clinical Trial Findings and Hurdles
Early clinical trials for tivantinib showed promising results, particularly in a subgroup of patients with high c-MET expression. A phase 2 study in advanced hepatocellular carcinoma (HCC) patients who had previously received sorafenib therapy indicated a statistically significant improvement in time to progression with tivantinib compared to placebo. This benefit was more pronounced in patients whose tumors showed high levels of MET expression, with median overall survival reaching 7.2 months in the tivantinib arm compared to 3.8 months in the placebo arm for this subgroup.
Despite these positive early signals, tivantinib faced significant challenges in larger, later-stage trials. Two major phase 3 studies in HCC, METIV-HCC and JET-HCC, failed to meet their primary endpoints of prolonging overall survival or progression-free survival. These setbacks led to the discontinuation of the tivantinib program for HCC and other indications.
A hurdle in tivantinib’s development was the ongoing controversy and lack of clarity surrounding its precise mechanism of action. While initially described as a selective c-MET inhibitor, later research suggested that its cytotoxic activity might be independent of its ability to bind c-MET. Instead, some studies indicated that tivantinib’s effects on tumor cells could be related to its impact on microtubule dynamics, leading to cell cycle arrest and apoptosis, which complicated the interpretation of trial results and patient selection.
Current Status and Outlook
Tivantinib has not received approval for any indication in any country. Following the negative outcomes of its phase 3 clinical trials, especially in hepatocellular carcinoma, the development of tivantinib for cancer treatment has largely been discontinued. Its journey highlights the complexities of drug development, particularly when the precise mechanism of action becomes a point of contention.
While tivantinib is no longer actively pursued as a stand-alone therapy, its story contributes to the broader understanding of cancer biology and drug discovery. The challenges encountered with tivantinib underscore the importance of thoroughly understanding a drug’s mechanism and identifying reliable biomarkers for patient selection. This experience informs ongoing research into c-MET and other pathways, influencing the design of future targeted therapies in oncology.