Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer

SUMMARY: EML4-ALK (Echinoderm Microtubule associated protein Like 4) – ALK (Anaplastic Lymphoma Kinase) is an aberrant fusion-type oncoprotein and is a tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma, who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplification of the respective genes, the associated tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). Crizotinib (XALKORI®) is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In this open label phase III trial, 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum based regimen, were randomly assigned to receive XALKORI® 250 mg PO twice daily (N=173) or intravenous chemotherapy with either Pemetrexed (ALIMTA®) 500 mg/m2 or Docetaxel (TAXOTERE®) 75 mg/m2, every 3 weeks (N=174). The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and safety. The median PFS was 7.7 months in the XALKORI® group as compared to 3 months in the chemotherapy group (HR=0.49; P<0.001). The Response Rates for XALKORI® and chemotherapy were 65% and 20% respectively (P<0.001). At the time of interim analysis, there was no significant difference in the OS between the XALKORI® and chemotherapy groups. The authors pointed out that this lack of OS benefit was due to the high cross over rate to the XALKORI® group from the chemotherapy group. Patients in the XALKORI® group had better quality of life, greater reduction in lung cancer symptoms and were on the study treatment longer, than with chemotherapy. The authors concluded that XALKORI® improves PFS, Response Rates as well as Quality Of Life in patients with previously treated, ALK positive advanced Non Small Cell Lung Cancer. This is remarkable, considering that the response rates in this patient population treated with second line chemotherapy is around 10-15%. As we move forward, it is very likely that tailored therapy based on molecular genotyping will become standard practice. Shaw AT, Kim D, Nakagawa K, et al. N Engl J Med 2013; 368:2385-2394