Necitumumab for first-line treatment of advanced, squamous, non-small-cell lung cancer: a relevant step forward?

Squamous-cell lung carcinoma accounts for approximately 30-40% of the non-small-cell lung cancer (NSCLC) cases in our setting (1). Unfortunately, most of the recent advances in the treatment of metastatic NSCLC have been confined mainly to non-squamous histology. On the one hand, drugs included in currently used combination regimens in the first line setting such as bevacizumab and pemetrexed are restricted, because of toxicity and efficacy concerns, to non-squamous tumors (2). On the other hand, the success of precision oncology initiatives is almost exclusive to lung adenocarcinomas, since driver aberrations in EGFR/ALK/ROS-1 are rarely found in squamous-cell tumors (1,3). Comprehensive genomic profiling of lung squamous carcinomas has also revealed potentially druggable genomic alterations (PIK3CA, FGFR or DDR2 among others) in a non-negligible fraction of these tumors, but their clinical validation as potential predictive targets is yet to be demonstrated (1,4). Therefore, having platinum-based chemotherapy as the only first-line treatment option, there is a clear need to improve treatment outcomes in these patients. In this sense, the look for new targets and therapeutic options has been challenging in lung squamous-cell subsets. Among these targets EGFR has been one of the main focuses in recent years. It should be noted that while EGFR activating mutations are extremely rare in squamous-cell histologic subtype, EGFR overexpression is a common feature of these tumors (60-80%), some of which (7-10%) also demonstrate EGFR gene copy number alterations (3,5). Thus, EGFR seems to be a reliable target in squamous-cell lung cancer. A number of monoclonal IgG1 antibodies targeting EGFR have undergone clinical development, of which cetuximab and necitumumab have been more exhaustively studied in lung cancer. Both drugs block the ligand-binding site of EGFR (domain III) competitively with EGF. In addition, steric interactions following antibody binding impede the adoption of the extended conformation required for receptor dimerization (6). Alternatively, these drugs could also induce antibody-dependent immune cytotoxicity. Both strategies ultimately result in EGFR down-regulation and EGFR signaling inhibition (5).