Adjuvant Therapy of Resected Non-small Cell Lung Cancer: can We Move Forward?

Abstract

Twenty years ago, an individual patient data meta-analysis of eight cisplatin-based adjuvant chemotherapy (AC) studies in completely resected early stage non-small cell lung cancer (NSCLC) demonstrated a 13 % reduction of the risk of death favoring chemotherapy that was of borderline statistical significance (p = 0.08). This marginal benefit boosted a new generation of randomized trials to evaluate the role of modern platinum-based regimens in resectable stages of NSCLC and, although individual studies generated conflicting results, overall they contributed to confirm the role of AC which is now recommended for completely resected stage II and III NSCLC, mostly 4 cycles, while subset analyses suggested a benefit in patients with large IB tumors. Cisplatin-based therapy was the core regimen of those adjuvant clinical trials and even if a substitution with other platinum-derived was also suggested, mainly based on extrapolated data from studies in advanced disease, cisplatin was confirmed to be slightly superior to carboplatin and is still the drug of choice in the adjuvant setting. Currently, any attempt to improve efficacy of cisplatin-based chemotherapy through antiangiogenic drugs association or pharmacogenomics approaches have failed, while results of additional studies are eagerly awaited. In the context of promising targeted therapies, even if several randomized trials in the advanced setting evaluated tyrosine kinase inhibitors (TKis) versus platinum-based chemotherapy and showed impressive results, clinical experience with TKIs in the adjuvant setting is still limited and most of the trials have not required patients to be molecularly tested for the drug-specific molecular predictive factor. At the present time, the role of targeted agents as adjuvant approaches remains largely not investigated. Finally, with the negative experience of the use of vaccines in this setting, the integration of immunotherapy (mainly immunocheckpoint inhibitors) in platinum-based schedules has just started to be evaluated, representing a potential future clinical option, but still far from clinical practice.

Keywords: Adjuvant treatment; Afatinib; Anti-angiogenic drugs; Atezolizumab; BRCA1; Bevacizumab; Crizotinib; Durvalumab; ERCC1; Early stage; Erlotinib; Gefitinib; ITACA trial; Immunotherapy; MAGE-A3; NSCLC; Nivolumab; Non-small cell lung cancer; Pembrolizumab; Predictive biomarkers; RRM1; TKIs; TS; Tyrosine kinase inhibitors.