Navigating Through New, First-Line Treatment Options for Lung Cancer

Until the advent of immunotherapy using checkpoint inhibitors directed at programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1), progress for patients with non–small-cell lung cancer (NSCLC) without actionable gene alterations, such as EGFR mutations or ALK rearrangements, had been limited. The PD-1 inhibitors nivolumab and pembrolizumab together with the PD-L1 inhibitor atezolizumab were approved for patients with NSCLC who received prior chemotherapy, and the PD-L1 inhibitor durvalumab has recently been approved for patients with locally advanced NSCLC after chemoradiation. Results from phase III clinical trials that investigated the role of these agents in patients with previously untreated NSCLC have been recently reported, creating new and rapidly evolving standards of care for these patients. The article by Bodor et al1 that accompanies this commentary provides an excellent overview of the data from these trials and a strategy to navigate through the range of new, first-line immunotherapy options, focusing on the population of patients with adenocarcinoma without actionable mutations, which represents the largest subgroup of patients in Western populations. Central to navigating through the range of new immunotherapy options for first-line therapy is the use of biomarkers that are predictive of clinical benefit from checkpoint inhibitors. Bodor et al1 propose an algorithm built around the tissue-based assessment of PD-L1 to guide treatment selection. Whereas there were many issues related to methodology and choice of cutoff, guidance from such efforts as the International Association for the Study of Lung Cancer Blueprint project has led to the standardization of PD-L1 testing, which, alongside histology and detection of driver mutations, such as EGFR, ALK, ROS1, and BRAF, has become mandatory in the management of lung adenocarcinoma. For patients with tumors with high PD-L1 scores (≥ 50%), treatment with single-agent pembrolizumab is an effective option that has been demonstrated to be superior to chemotherapy alone in the KEYNOTE–24 trial.2 Treatment with pembrolizumab, administered in combination with carboplatin and pemetrexed, is also an option for this group of patients on the basis of the KEYNOTE-189 trial.3 The combination regimen is associated with higher response rates—at the expense of more toxicity—and may be particularly useful for patients with higher disease burdens or for those in whom a rapid response is required. For patients with PD-L1 scores of < 50%, pembrolizumab in combination with chemotherapy is the preferred