MILAN – Adding the targeted investigational agent MetMAb to erlotinib improved survival in a select group of patients who were being treated for advanced non–small cell lung cancer in a phase II trial.
The risk of disease progression and death was nearly halved when patients with high expression of the Met receptor targeted by MetMAb received the novel agent plus erlotinib (Tarceva). High Met expression was associated with a worse outcome in patients who were treated with erlotinib alone.
Dr. David Spigel
“These results support further testing of MetMAb in lung cancer, and highlight the importance of diagnostic development,” said lead author Dr. David Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
MetMAb is a selective monovalent monoclonal antibody that blocks hepatocyte growth factor (HGF) from activating the Met signaling pathway. Met is amplified, mutated, and overexpressed in many tumors. Its expression is associated with worse prognosis in many cancers, including non–small cell lung cancer (NSCLC), Dr. Spigel explained. Met activation is also implicated in resistance to tyrosine kinase inhibitors such as erlotinib and gefitinib (Iressa) in patients with activating epidermal growth factor receptor (EGFR) mutations.
There is a strong rationale for combining MetMAb with erlotinib, Dr. Spigel said. Met activation by HGF decreases the sensitivity to erlotinib. “When you add MetMAb, that sensitivity to erlotinib is restored,” he said.
The phase II, double-blind trial evenly randomized 128 patients who required second- or third-line therapy for NSCLC of all histologies to MetMAb 15 mg/kg intravenously every 3 weeks plus daily oral erlotinib 150 mg or daily erlotinib plus IV placebo. In all, 23 patients in the placebo group crossed over at progression to MetMAb.
Adequate tissue for Met evaluation by immunohistochemistry was available from 121 patients. Of these, 51% in the control arm and 56.5% in the experimental arm were “Met high,” defined as at least 50% tumor cells with a staining intensity of 2+ or 3+ on a 0-3 scale, Dr. Spigel said. “Met low” was defined as no expression or 1+ expression. Of 112 evaluable patients, a KRAS mutation was present in 23% of patients in both arms, and an EGFR mutation in 11% of the control arm and in 12.5% of the experimental arm.
In the overall intent-to-treat population, the primary end point of median progression-free survival reached 11.1 weeks for erlotinib and placebo and 9.6 weeks for MetMAb and erlotinib (hazard ratio, 1.09; log-rank P = .69,), suggesting no advantage with MetMAb, Dr. Spigel said. This also was true for median overall survival at 8.2 months and 7.1 months, respectively (HR, 1.09; log-rank P = .76).
When the researchers looked only at the Met-high group, however, median progression-free survival increased from 6.4 weeks with erlotinib and placebo to 12.4 weeks with combination therapy (HR, 0.56; log-rank P = .054). What is also impressive, he added, is that this translated into an overall survival hazard ratio of 0.55 (7.4 months vs. 7.7 months; log rank P = .11).
The Met-low group, however, did worse with the combination of MetMAb and erlotinib, even though patients with low Met expression in general do better, Dr. Spigel said. Progression-free survival was 6.0 weeks with MetMAb vs. 11.4 weeks with placebo (HR, 2.01; log-rank P = .03) and overall survival 5.5 months vs. 9.2 months (HR, 3.02; log-rank P = .02).
The reason for this negative outcome is unclear, but the obvious speculation is that MetMAb must be interfering with erlotinib’s effectiveness, Dr. Spigel said during a discussion of the paper. “We know that there is a lot of crosstalk between these pathways, the EGFR and Met pathway[s], but I think at this point, it’s just speculation,” he said.
The worse outcome in Met-low patients who were treated with MetMAb and erlotinib could not be explained by adverse safety events. With the exception of peripheral edema, the overall toxicity for MetMAb appeared to be similar to that of erlotinib and placebo, Dr. Spigel said. The incidence of grade 3 and 4 rash, diarrhea, and fatigue were higher in the Met-high subgroup group who was treated with MetMAb, whereas the incidence of pneumonia was higher in the Met-low group receiving MetMAb. No grade 5 events occurred.
In additional analyses, the selective benefit of MetMAb and erlotinib was not observed in other subgroups including nonsquamous histology and EGFR or KRAS mutations.
Dr. Luis Paz-Ares, who was invited to discuss the paper, said that it was strange to see the negative response in patients with low Met expression, but that this has been seen in other trials with targeted agents.