The application of translational science in non-small cell lung cancer (NSCLC): Successes, failures and pitfalls


Session type:

Frances A Shepherd1
1Princess Margaret Hospital and University of Toronto, Toronto, Canada


The identification of key genetic pathways and mutations in NSCLC will be critical to furthering our understanding of this malignancy and to developing new molecularly targeted therapies. This presentation will focus on the complexity of genetic mutations in lung cancer using select mutations as examples.

KRAS frequently is mutated in NSCLC. The LACE-Bio meta-analysis involving 1721 patients reported modestly worse outcome (HR 1.09, p=0.39; adenocarcinoma HR 1.03, p=0.93). However, overall, KRAS mutation was not predictive of differential benefit from chemotherapy with the exception of Codon-13 mutations. Data also are conflicting with respect to the ability of KRAS mutation to predict outcome in patients treated with EGFR TKIs and no study has shown that KRAS is predictive for EGFR monoclonal antibody therapy.

Biomarker studies of EGFR mutation are complex, and results vary depending on whether the EGFR TKI is compared to placebo, added to other treatments or compared to other treatments. Clearly EGFR driver mutations on exons 19 and 21 predict for very high response rates to TKIs, but despite initially dramatic responses, all patients with NSCLC relapse and die of disease. Examination of the downstream pathway markers has led to strategies to delay or overcome resistance through combination of agents or new agents in the same class designed to overcome or bypass resistance. MET inhibitors, angiogenesis inhibitors are under study, and second and third-generation EGFR inhibitors are being tested and even approved.

The identification of EML4-ALK mutations led to the rapid approval of crizotinib based on Phase II trials alone, and now Phase III post-commitment studies have confirmed this activity in trials comparing crizotinib to chemotherapy. Despite approval <2 years ago, several second generation ALK inhibitors are in development, and have demonstrated activity. The addition of HSP90 targeting agents also may be particularly useful in the setting of ALK mutations resistant to crizotinib.