Abstract 3410: MARQUEE: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tivantinib (ARQ 197) Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Patients With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer (NSCLC)
Background: The CMet pathway is felt to be one mechanism by which resistance develops to EGFR inhibitors. It thus may be desirable to inhibit both EGFR and CMET.
One of the first trials to look at this dual inhibition in NSCLC was a phase 2 trial OAM4558g. The monoclonal antibody MetMab added to erlotinib was compared to erlotinib alone. Met high was defined as > 50% staining of the MET protein by IHC. In Met high tumors, progression-free survival (PFS) was doubled (1.5 to 2.9 months HR = 0.53, p = 0.04). More interesting, overall survival (OS) was tripled (3.8 to 12.6 months (HR 0.37, p = 0.002). The phase 3 results are to be presented ASCO 2014 and are anticipated to be pos.
The MARQUEE phase 3 trial was presented at ESMO 2013. Tivantinb (ARQ 197) is an oral tyrosine kinase inhibitor of Cmet. 1048 patients with nonsquamous NSCLC in the second or third line setting were randomized to the combination of tivantinib (ARQ 197) and erlotinib versus erlotinib alone. Although the PFS was increased (3.6 vs. 1.9 months HR 0.74 p < 0.001), the primary endpoint of OS was not met (8.7 vs. 7.8 months HR .98 p = 0.81). A negative trial was reported to the media.
This trial’s importance lies in the biomarker of Met high by IHC. Staining for Met IHC was available in only 40% of the patients so far. In the Met high patients, the PFS paralleled the ITT group. However the overall survival was impressively positive. Erlotinib alone in this patient population had an overall survival of 5.9 months. When tivantinib was combined with erlotinib in the Met high patients, overall survival was increased to 9.3 months. HR .70 p = 0.81.
When the trial was designed, the biomarker as defined by the OAM4558g trial was not known. Although this biomarker was not prospectively defined in MARQUEE, the results are intriguing and confirm initial findings of the Metmab trial. Completion of IHC staining for Met are ongoing and results will be presented at World Lung in Australia end of October 2013. We await them eagerly. A new biomarker has arrived!