Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer

Abstract

Purpose: Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC.

Patients and methods: Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety.

Results: There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients.

Conclusion: Onartuzumab plus erlotinib was associated with improved PFS and 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.

Fig 1.

CONSORT diagram. IHC, immunohistochemistry.

Fig 2.

Kaplan-Meier estimates of (A, B, C) progression-free and (D, E, F) overall survival outcomes in (A, D) intent-to-treat, (B, E) MET-positive, and (C, F) MET-negative populations. HR, hazard ratio.

Fig 3.

Forest plots of overall survival outcomes in (A) MET-positive and (B) intent-to-treat populations. Dx, diagnosis; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IHC, immunohistochemistry.

Fig 4.

Kaplan-Meier estimates of (A, B) progression-free and (C, D) overall survival in (A, C) MET-positive and (B, D) MET-negative populations, excluding known EGFR mutation–positive patients. HR, hazard ratio.

Fig A1.

(A) Overall and (B) progression-free survival by MET status in patients receiving erlotinib plus placebo. HR, hazard ratio.

Fig A2.

Forest plots of (A) progression-free and (B) overall survival by MET immunohistochemistry (IHC) cutoff (≥ 10%, ≥ 50%, and ≥ 90%) and MET IHC score (0, 1+, 2+, and 3+). HR, hazard ratio.