Biomarkers Are Here to Stay for Clinical Research and Standard Care

Abstract

Subramanian et al.1 reviewed the status of lung cancer clinical trials active in 2009 by searching the ClinicalTrials.gov website. This website does not include every trial enrolling lung cancer patients, but the results are quite sobering. The data suggest that there are at least 500 ongoing therapeutic trials for non-small cell lung cancer (NSCLC) worldwide. Of these, about 240 were phase II trials and about 77 were phase III. Enrollment averaged 66 patients in phase II trails and 600 patients in phase III. Phase II trials were open about 2 years and phase III trials about 3 years. These data suggest that approximately 31,000 lung cancer patients are enrolled onto a clinical trial each year. These data focus on trials in the US, but half of the studies enrolled patients outside the US. There are more than 220,000 new lung cancer cases in the US each year and more than 1.2 million worldwide.2,3 Thus, the fraction of patients who are enrolled on a therapeutic clinical trial remains small. These data are consistent with data from US cooperative groups, suggesting that less than 5% of patients diagnosed with lung cancer are enrolled on a therapeutic trial.4 These numbers are even smaller for early-stage lung cancer. The data regarding biomarkers were also striking. A biomarker analysis was included as a study objective in only about one-third of the trials. Biomarker-based patient selection was used in only 7% of the trials! We know that the majority of phase III trials fail to meet their primary objective. We need to improve our strategies. Why does all this matter? Now is the time for paradigm shifts in the way we conduct clinical trial research and the way we treat patients. In the new era of personalized medicine—more than ever—tissue is the issue. Activating mutations in the epidermal growth factor receptor (EGFR) were shown to be associated with benefit from the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib in 2004.5,6 Since that time, several randomized trials have shown that these EGFR TKIs provide higher response rates ( 70%), longer progression-free survival, better quality of life, and less severe toxicity compared with platinum doublet chemotherapy in chemonaive patients with advanced NSCLC whose tumors harbor activating EGFR mutations.7–11 In contrast, chemotherapy provided higher response rates and longer progression-free survival in patients with EGFR wild-type tumors. Activation of the ALK tyrosine kinase oncogene in lung cancer by fusion to the EML4 gene or other partners was first reported in 2007.12 Early studies of the ALK tyrosine kinase inhibitor termed crizotinib (PF-02341066) showed tumor regression in 39 of 41 patients and objective response by RECIST criteria in 63% in patients whose tumors harbor ALK gene rearrangements.13 Thus, selection by analysis of molecular features improved outcome. In patients with EGFR wild-type tumors, EGFR TKIs improved survival in the maintenance and second-line and third-line settings compared with best supportive care, but the hazard rate reductions were less than in EGFR-mutant tumors.14,15 Whether this represents genuine benefit in the wild-type population or a false-negative rate associated