Based on results in a phase II study with 137 patients, participation in the phase III trial is restricted to patients whose tumors are characterized as either MET diagnostic-positive or expressing high levels of the MET receptor protein on the cell surface. Patients will be classified as MET diagnostic-positive (high MET) or MET diagnostic-negative (low MET) based on the results of tissue studies from a companion diagnostic test that is also part of the phase III study.
In the phase II study, the addition of MetMAb to erlotinib tripled the amount of time people with high-MET tumors lived compared with participants who received erlotinib alone. Median overall survival was 12.6 months for the group receiving MetMAb, compared to 3.8 months for erlotinib alone. With MetMAb, the high-MET population also lived twice as long without their cancer progressing or dying from any cause (2.9 months) compared with the control group (1.5 months). Patients with low-MET tumors, however, had worse outcomes when given MetMAb and erlotinib than when they were given erlotinib alone.
In general, patients with low-MET tumors have a better prognosis, Spigel said, adding that in the MetMAb/erlotinib trial, survival outcomes for patients with high-MET tumors (and a poor prognosis) were raised to the level of the low-MET group treated with erlotinib alone.
Tivantinib is being tested in a randomized, double-blind, phase III study that assigns nearly 1000 patients with advanced or metastatic nonsquamous lung cancer who have been treated with one or two systemic therapies to one of two groups. One group will take tivantinib with erlotinib; the other will take erlotinib with a placebo. The study began in November 2010 and should be completed in July 2013. The primary outcome measure is overall survival.
“Earlier clinical trials established the role of tyrosine kinase small-molecule inhibitors on the EGFR pathway, and now we’re evaluating the impact of inhibiting two pathways on patients with previously treated nonsquamous NSCLC,” Sandler said. “We know that the oncogene c-Met
makes the cancer more likely to be metastatic, to grow and divide, and to be more invasive. What we’re hoping for is that by impacting and inhibiting the c-Met and EGFR pathway, patients will live longer and have a better quality of life.”
Secondary and exploratory objectives of the trial include a measure of progression-free survival and overall survival in molecular subgroups, including patients whose tumors show mutations to EGFR or to KRAS (a gene that plays a role in tissue signaling), overexpression of MET, and overexpression of serum hepatocyte growth factor. All participants will be tested for biomarkers. Tivantinib is also being evaluated for safety.
Based on the results of a smaller phase II study with 167 participants, the current trial is restricted to patients with nonsquamous cell tumors.
“When we looked at the data [in the phase II study] on progression-free survival, the tivantinib arm did better than the control arm, at 3.7 months compared with 2.2 months, which is more than a 50% improvement. But when we looked at the nonsquamous patients compared with the control, the results were even more dramatic—4.4 months compared to 2.3 months,” Sandler said. “We are trying to define the population that will respond best to this combination, and histology may be a way to determine that.”
The Need for New Therapies
Both studies are being watched closely because few therapies are available for late-stage lung cancer patients. “Half of patients who have already received one or even two therapies don’t make it to another therapy, and the remaining half have the option of chemotherapy or Tarceva. At that point, with single-agent chemotherapy there is a 10% response rate, and with Tarceva alone, approximately a 5% response rate in unselected patients,” Spigel said.
Chris Bowden, MD
The hope for both drugs is that they will be relevant for large populations of patients with NSCLC, the most common type of lung cancer. “Non–small cell lung cancer represents approximately 85% of all lung cancers and of those, nonsquamous tumors comprise 75%,” Sandler said.
Approximately half of all people with NSCLC have high levels of the MET protein on the surface of their cancer cells, said Chris Bowden, MD, vice president for Product Development in Clinical Oncology at Genentech, a sponsor of the MetMAb trial with Hoffman- LaRoche. He added that overexpression of MET correlates with poor prognosis, making the tumor type “a good candidate” for MET-targeted medicines.
“A lot of great advances recently have affected select groups of patients, as few as 2% to 4% in some cases. The potential here is as high as 50%, and so that would be a big step forward,” Spigel said.