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

backgroundKRAS mutations 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 KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND

methodsPreviously treated patients with advanced KRAS mutant 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.

resultsNinety-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.

conclusionIn previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.