The researchers found that squamous cell carcinoma (SCC) of the lung is a subtype of non-small cell lung cancer (NSCLC) with a distinct molecular profile distinguishing it from adenocarcinoma of the lung. There was a critical unmet need for efficient second-line options following immunotherapy, especially as immune checkpoint inhibitors are being rapidly elevated from second to first-line status in NSCLC. A lack of prospective clinical data exacerbated current difficulties in making effective treatment decisions. The combination of ramucirumab and docetaxel has not been formally studied in this setting, but the available real-world data suggested it merits prospective evaluation. Additionally, afatinib is an approved second-line treatment for patients whose SCC has progressed despite first-line platinum-based chemotherapy, and it may be an option for patients whose cancer has not responded to immunochemotherapy. Afatinib’s oral administration and well-defined tolerability profile are 2 of its many benefits. Some patients may be candidates for second-line treatment after immunotherapy, which includes docetaxel, gemcitabine, and platinum-based chemotherapy. To better match patients with appropriate targeted therapies and to elucidate additional genomic targets, efforts have been made to better define the molecular profile of lung SCC. Genomic testing is required to identify patients with lung SCC who could benefit from targeted agents or clinical trials, and additional prospective data were urgently needed to evaluate potential second-line regimens after immunotherapy so that these patients receive the best care possible.