Outcome Improved in MET-Positive and Worsened in MET-Negative NSCLC With Addition of Onartuzumab to Erlotinib in Phase II Trial
In patients with non–small cell lung cancer (NSCLC), increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to EGFR-targeted treatment. In a phase II study reported in the Journal of Clinical Oncology, David R. Spigel, MD, of Sarah Cannon Research Institute, and colleagues examined whether dual inhibition of MET/EGFR with the anti-MET monoclonal antibody onartuzumab and erlotinib (Tarceva) could provide clinical benefit in patients with advanced NSCLC. They found that the combination improved progression-free survival and overall survival among MET-positive patients but not among MET-negative patients.
Study Details
In the double-blind study, 137 patients with recurrent NSCLC were randomly assigned to receive onartuzumab at 15 mg/kg every 3 weeks plus erlotinib at 150 mg/d (n = 69) or erlotinib plus placebo (n = 68). MET status was assessed by immunohistochemistry. Crossover was allowed at progression. The primary endpoints were progression-free survival in the intent-to-treat population and MET-positive population.
Thirty-one patients in both the combination group and erlotinib group were MET-negative, and 31 and 35, respectively were MET-positive. Baseline characteristics were well balanced between the treatment groups in the intent-to-treat population and according to MET status, with the exception of EGFR mutation status; wild-type EGFR was present in 81% of the combination group MET-negative patients and 69% of the combination group MET-positive patients, and mutant EGFR was present in 13% and 7% of the erlotinib group MET-negative and MET-positive patients, respectively, and in 0% and 20% of the combination group MET-negative and MET-positive patients, respectively. Squamous cell carcinoma was more common (42% vs 15%) and never-smokers were less common (5% vs 20%) among MET-negative patients.
In total, 27 patients (12 MET-positive, 13 MET-negative, and two with nonevaluable MET status) in the erlotinib group (40%) had onartuzumab added to continued erlotinib treatment at the time of disease progression.
Progression-Free and Overall Survival Outcomes
Progression-free survival did not differ between the combination group and the erlotinib group (median, 2.2 vs 2.6 months, hazard ratio [HR] = 1.09, P = .69) in the intent-to-treat population. Progression-free survival was significantly prolonged in the combination group vs the erlotinib group among MET-positive patients (median, 2.9 vs 1.5 months, HR = 0.53, P = .04) and reduced among MET-negative patients (median, 1.4 vs 2.7 months, HR = 1.82, P =.05).
Overall survival did not differ significantly between the combination and erlotinib groups (median, 8.9 vs 7.4 months, HR = 0.80, P =.34) in the intent-to-treat population. However, the addition of onartuzumab nearly tripled survival in MET-positive patients (median, 12.6 vs 3.8 months, HR = 0.37, P = .002) and was associated with reduced overall survival in MET-negative patients (median, 8.1 vs 15.3, HR = 1.78, P = .16).
Analysis excluding patients with EFGR mutation yielded similar results for progression-free survival and overall survival. In the erlotinib group, progression-free survival (HR = 1.71, P = .06) and overall survival (HR = 2.61, P = .004) were worse in MET-positive patients vs MET-negative patients. Objective response rates in the combination vs erlotinib groups were 5.8% vs 4.4% in the intent-to-treat population, 8.6% vs 3.2% in MET-positive patients, and 3.2% vs 6.5% in MET-negative patients.
Adverse Events
Adverse events more frequently observed with onartuzumab were peripheral edema (23% vs 7.5%), pyrexia, asthenia, insomnia, and pneumonia, with most being grade 1 or 2 in severity. Although no specific pattern was observed, grade 3 or higher adverse events were more common in the combination group, including rash (10% vs 3%), fatigue (9% vs 3%), and pneumonia (7% vs 3%). Serious adverse events were reported in 42% of combination group patients and in 33% of erlotinib patients.
The investigators concluded, “Onartuzumab plus erlotinib was associated with improved [progression-free survival] and [overall survival] in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.”
The study was supported by Genentech and support for third-party writing assistance was provided by F. Hoffmann-La Roche and Genentech.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
