Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer

Abstract Background KRASmutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRASmutant cancers in an earlier phase 2 study of erlotinibplus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinibalone (progression-free survival [PFS] HR 0.18; P  KRASmutant non-small cell lung cancer (NSCLC). Materials and methods Previously treated patients with advanced KRASmutant NSCLC were randomized to receive either oral tivantinib(360 mg twice daily) plus erlotinib(150 mg daily) (ET) or single-agent chemotherapy (investigator’s choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. Results Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P  = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P  = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. Conclusion In previously treated patients with advanced KRASmutant NSCLC, the combination of the MET inhibitor tivantiniband erlotinibis not superior to conventional single-agent chemotherapy.