The majority of non-small cell lung cancer (NSCLC) tumours do not present targetable driver mutations, and less than 25% of NSCLC patients derive benefit from immunotherapy. Therefore, conventional cytotoxic chemotherapy (CCC) remains the cornerstone treatment for NSCLC patients. Predictive biomarkers of CCC able to identify chemosensitive patients and select appropriate drug combinations are crucially lacking. Such biomarkers would also be helpful to limit toxicities, decrease overall costs, and hopefully improve patient outcome. A variety of biomarkers have been evaluated either in the pre-clinical or clinical setting and the most promising of them will be discussed in detail. However, despite all efforts to identify predictive biomarkers of sensitivity to CCC in NSCLC, results have been disappointing and a strikingly high attrition rate between promising pre-clinical data and negative clinical results has been observed. Not even a handful of biomarkers are still in the race, and none are ready yet for clinical practice implementation. The causes of failure (lack of standardisation along with clinical, biological, and technical challenges) will be discussed in this review. Nevertheless, recent technological developments open encouraging perspectives for performing analytical validation of candidate biomarkers of CCC efficacy. Technological innovation also drives the development of alternative types of predictive biomarkers such as DNA signatures.
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