Onartuzumab in Combination with Erlotinib in Patients with Advanced NSCLC
Results of phase II study of dual inhibition of MET/EGFR
In a randomised, phase II study in patients with recurrent non-small cell lung cancer (NSCLC), onartuzumab plus erlotinib was associated with improved progression-free survival (PFS) and overall survival (OS) 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, according to conclusion of the article published in the Journal of Clinical Oncology by Dr David Spigel of the Sarah Cannon Research Institute, Nashville, USA and colleagues.
Although the epidermal growth factor receptor (EGFR) inhibitor erlotinib has improved survival in patients with NSCLC, resistance eventually develops. Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to EGFR–targeted drugs in patients with NSCLC. Data from preclinical models support at least additive effects when anti-MET and anti-EGFR therapies are combined. Therefore, the study team investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC.
The study team conducted a global, randomised, placebo-controlled phase II trial in patients with recurrent NSCLC to compare erlotinib and onartuzumab with erlotinib and placebo. As erlotinib is approved in the refractory setting in unselected patients with NSCLC, the goal of this trial was to find if the addition of a novel MET antibody could improve efficacy.
A crossover was allowed at progression. Tumour tissue was required to assess MET status by immunohistochemistry (IHC). Co-primary endpoints were PFS in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included OS, objective response rate, and safety.
No difference in PFS was found in the ITT population. However, when MET-positive patients were assessed, a significant reduction in the risk of disease progression was noted compared with patients who were MET-negative. In MET-positive patients, the combination resulted in OS improvement three times greater than in the placebo arm. Crucially, the exact opposite effect was observed in patients with MET-negative tumours. Patients assigned to onartuzumab had significantly shorter overall survival compared with patients receiving placebo (median 8.1 months versus 15.3 months).
Most adverse events were comparable between the arms, although peripheral oedema was increased in patients treated with onartuzumab.
The addition of onartuzumab in MET-positive patients resulted in a similar median survival as that observed in MET-negative patients receiving erlotinib alone, indicating that the combination in MET-positive patients abrogated the negative prognostic effect seen in MET-negative patients.
A phase III trial in MET-positive patients with this combination is ongoing.
Spigel D, Ervin T, Ramlau R, et al. Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancerJ Clin Oncol 2013; 31(32):4105-14. doi: 10.1200/JCO.2012.47.4189. Epub 2013 Oct 7.