Beyond EGFR and ALK Inhibition: New Promising Targeted Therapy for Lung Cancer

Abstract

The OPTIMAL trial conducted by the Chinese Thoracic Oncology Group (C-TONG0806) was the first randomization trial that showed erlotinib is superior to chemotherapy of gemcitabine and carboplatin in first line setting for advanced NSCLC. The median progression-free survival in the erlotinib arm was 13.1 months, compared to 4.6 months for the chemotherapy arm of the study with a hazard ratio gap of 0.16. Post OPTIMAl there were some new drugs developed in NSCLC. Afatinib is an irreversible dual inhibitor of EGFR and HER2. The LUX-Lung 3 and 6 are two phase 3 trials that compared afatinib with chemotherapy in first line treatment for advanced NSCLC. Both trials showed that afatinib was superior to cisplatin/pemetrexed or gemcitabin with HR 0.58 (LUX-Lung 3) and 0.28 (LUX-Lung 6). Onartuzumab (MetMAb) is a monoclonal antibody that inhibits cMET signaling activity and cellular response. A randomized double-blind phase II study, comparing MetMAb plus erlotinib to placebo plus erlotinib in second-/third-line NSCLC showed that in Met Dx+ NSCLC onartuzumab resulted in PFS improved with median OS 12.6 months versus 4.6 months (p = 0.002). A phase 3 trial is ongoing. Some small molecular inhibitors are developed. Crizotinib is a new targeted agent has shown benefit in a subgroup of patients with EML4-ALK fusion of NSCLC. A phase 3 open-label trial (PROFILE 1007) compared crizotinib with chemotherapy in 347 patients with ALK-positive lung cancer in second line setting of NSCLC. Median PFS was 7.7 months in the crizotinib arm and 3.0 months in the chemotherapy arm (HR = 0.49, P < 0.001). Two trials of first line therapy (PROFILE 1014 and 1029) are ongoing. LDK378 is a more potent ALK TKI. In a multicenter phase I study of 88 evaluable NSCLC patients the overall response rate was 70%, in 64 crizotinib-resistant patients the ORR was 73%. In all 123 NSCLC pts, median PFS was 8.6 months. CH5424802 is a highly selective second-generation ALK inhibitor. 58 pts have been treated with CH5424802 the overall response rate was 93.5% with 2 CRs and 41 PRs. With a median follow-up period of 12.6 months the median treatment duration has passed 10.3 months. No grade 4 or fatal AEs were observed. Based these new drugs the targeted therapies for advanced NSCLC have milder adverse effects and offer a better quality of life, better responses, and maybe better overall survival.