ANTII-MET THERAPY IS ON THE WAY FOR NSCLC

October 9, 2010 (Milan, Italy) — Combining the investigational agent MetMAb (Genentech) with erlotinib (Tarceva; Genentech) in patients with non–small cell lung cancer (NSCLC) with high MET expression improved both progression-free and overall survival, according to the results of a phase 2 trial.

In this subset of patients, the addition of MetMAb to erlotinib cut the risk for disease progression or death by nearly half compared with the erlotinib plus placebo group.

The findings of the industry-sponsored trial were presented here at the 35th European Society for Medical Oncology Congress.

"These findings are quite relevant," said lead author David Spigel, MD, director of lung cancer research for the Sarah Cannon Research Institute in Nashville, Tennessee. "Not only does it define an active antibody that is safe in patients with this receptor, but it emphasizes the importance of selecting patients for proper therapy.

"Even though this is a phase 2 study, and has all of the limitations of a phase 2 study," he added, "I think this certainly provides rationale for proceeding with randomized trials in a very select group of patients that have MET expression."

MET can be amplified, mutated, and overexpressed in many tumors, especially in lung cancer, Dr. Spigel explained. This expression is associated with a worse prognosis and has been associated with the development of resistance in tumors possessing activating epidermal growth factor receptor (EGFR).

MetMAb is a unique monovalent antibody that binds to the MET receptor and prevents hepatocyte growth factor from binding to MET receptors, which in turn blocks receptor stimulation, and thus inhibits the MET signaling pathway, which can be inappropriately activated in cancer.

Study Details

In this randomized, double-blind phase 2 study, Dr. Spigel and colleagues compared MetMAb (15 mg/kg intravenously) plus erlotinib to erlotinib plus placebo in 128 patients with advanced NSCLC. The study included patients with all histologies, and all patients had all received 1 or 2 prior therapies.

"An important part of the trial was that the patients in the control arm had the option of being unblinded and crossing over to receive MetMab," he explained. "We had 23 patients cross over."

The primary endpoint was progression-free survival, with overall survival and safety as additional endpoints. Archival tissue was evaluable for MET in 121 patients and for EGFR and KRAS mutations in 112 patients.

Among patients who received MetMab, 57% were MET-positive, 23% had a KRAS mutation, and 13% were positive for EGFR mutation. These characteristics were very similar to those in the erlotinib and placebo group — 51%, 23%, and 11%, respectively.

Dr. Spigel and colleagues evaluated the primary endpoint of progression-free survival in the overall intent-to-treat population, as well as in a specific predefined population of patients with high expression of MET.

MET High vs MET Low

After randomization, immunohistochemistry was performed for the presence of MET. Patients who had 2+ or 3+ stains were defined as "MET high," whereas those with either no expression or 1+ expression were defined as "MET low," Dr. Spigel explained.

For the entire intent-to-treat population, the hazard ratio (HR) for progression-free survival was 1.09 (95% confidence interval [CI], 0.71 - 1.67; P = .70), and it was 1.13 (95% CI, 0.64 1.97; P = .68) for overall survival.

"Progression-free survival in the overall intent-to-treat population for combination erlotinib and MetMab and erlotinib and placebo were nearly identical, indicating no advantage to MetMab," Dr. Spigel said. "This was true also for survival."

However, in the predefined population with MET overexpression, there was a dramatic finding in the treatment group, he noted. For the combination group, the progression-free survival was about 12.4 weeks.

"This was in comparison to the erlotinib plus placebo group, which was 6.4 weeks, and resulted in a dramatic hazard ratio of 0.56," said Dr. Spigel.

The authors observed both a progression-free survival benefit (HR, 0.56; 95% CI, 0.31 - 1.02; P = .05) and an overall survival benefit (HR, 0.55; 95% CI, 0.25 1.16; P = .11) for MET high patients who received the combination treatment.

These results indicate that in this select group of patients, combination therapy proved to be an advantage not only for progression-free survival but also for overall survival, Dr. Spigel noted.

However, these positive results were counterbalanced by patients with low expression. "Progression-free survival was worse in patients who received the combination therapy, and this carried over to overall survival," he said.

In the MET low group, worse progression-free survival (HR, 2.01; 95% CI, 1.04 3.91; P = .04) and worse overall survival (HR, 3.26; 95% CI, 1.20 8.80; P = .01) were observed for those who received MetMab.

"The reasons for this finding are unclear," said Dr. Spigel, who explained that in general, patients with low MET expression do better. "The obvious speculation is that MetMab is interfering with erlotinib's effectiveness."

It is also known that there is "crosstalk" between EGFR and MET pathways, he added, but whether this happened here is also speculation.

The benefit of the combination therapy was not observed in any other subgroup, including patients with nonsquamous cell cancer and those with EGFR or KRAS mutations.

Adverse events, including rash, diarrhea, and fatigue, were comparable between treatment groups in both Met-positive and Met-negative subpopulations. The incidence of grade 3 and higher events were similar in the MET-positive population in both treatment groups (54% vs 53%) but were considerably higher among MET-negative patients who received the combination therapy (52% vs 35%).

Further Exploration Warranted

The present results are interesting and warrant further exploration, said Luis Paz-Ares, MD, who served as a discussant for the paper.

"C-Met inhibition is a potentially valuable intervention in lung cancer," said Dr. Paz-Ares, from the Hospital Universitario Virgen del Rocío, in Seville, Spain.

The negative result seen for patients with low MET expression was "very strange," he said.

However, he pointed out, this has been seen in trials with other targeted agents such as IGFR inhibitors, gefitinib, and celecoxib.

For the future, phase 2 and phase 3 trials should be conducted, as well as combination trials with chemotherapy agents and other targeted therapies, Dr. Paz-Ares said.

He also pointed out that other diseases might benefit from targeting the MET receptor, such as small cell lung cancer.

Dr. Spigel is a nonpaid consultant at Genentech; coauthors W. Yu, P. Patel, and A. Peterson are Genentech employees. All other authors have disclosed no relevant financial relationships.

35th European Society for Medical Oncology Congress: Abstract LBA15. Presented October 9, 2010.