Two novel therapies designed to improve survival outcomes in patients with advanced non–small cell lung cancer (NSCLC) are now being evaluated in multisetting, international phase III trials after showing promise in earlier trials by slowing disease progression in distinct subgroups of study participants.

Both MetMAb (onartuzumab; Genentech), a monoclonal antibody, and ARQ 197 (tivantinib; ArQule and Daiichi Sankyo), a small-molecule inhibitor, are targeted therapies that block signaling pathways in cancer cells. Specifically, they inhibit c-MET, a cell membrane receptor molecule implicated in both tumor progression and metastasis in several cancers, including NSCLC.

“It’s an oncogenic pathway that drives cancer growth. The goal is to shut this pathway down,” said David Spigel, MD, director of Lung Cancer Research at the Sarah Cannon Research Institute in Nashville, Tennessee, and the principal investigator for the MetMAb trial.

The drugs, which are being tested in late-stage patients who have already received one or two lines of standard therapy, represent a paradigm shift in lung cancer treatment. (Related: MET Inhibitors in Cancer Therapy)

“In addition to surgery and radiation, the historical approach to lung cancer is chemotherapy, a broad, nonspecific approach that damages DNA and has accompanying toxicities,” said Alan Sandler, MD, division chief of Hematology and Medical Oncology at Oregon Health & Science University and one of the principal investigators for the tivantinib trial, along with Giorgio Scagliotti, MD, PhD, of the University of Torino in Italy. “The concept of personalized medicine is to develop targeted therapies that inhibit specific pathways in specific tumors. These therapies generally don’t affect bone marrow, do not cause hair loss, and, in general, have more benign side effects.”

In each trial, the drugs are being tested in combination with another targeted cancer treatment, erlotinib (Tarceva; Genentech). Erlotinib is a receptor tyrosine kinase inhibitor that blocks the signaling pathway of the epidermal growth factor receptor (EGFR), a cell surface receptor implicated in cancer cell growth. MET has been implicated in part in erlotinib resistance.

“In these two trials, the combined therapies work to delay and overcome resistance in tumors that initially respond to the other drug but then develop a resistance to it. Synergistic effects can be strong drivers of efficacy and patient benefit,” said Reinhard von Roemeling, MD, vice president of Clinical Development Oncology at Daiichi Sankyo, Inc, which is sponsoring the tivantinib trial with ArQule, Inc.

“Each drug has anticancer properties, and when we combine them there may be at least additive activity. It’s not clear how additive, although there appears to be a benefit in preclinical models,” Spigel noted of the MetMAb/erlotinib combination.

MetMAb Trial

MetMAb is being tested in a randomized, double-blind, phase III study that will assign nearly 500 patients who have already been treated with standard chemotherapy for advanced or metastatic disease into two groups. One group will take MetMAb in combination with erlotinib. The other group will take erlotinib with a placebo.

The study, which began in January 2012, has an estimated completion date of December 2015. The primary outcome measure is overall survival, while secondary endpoints are progression-free survival, overall response rate, and safety.