The Era of Checkpoint Blockade in Lung Cancer: Taking the Brakes Off the Immune System

Despite recent advances with targeted kinase inhibitors and better-tolerated chemotherapy, the treatment of metastatic non-small-cell lung cancer remains suboptimal. One recent advance that holds great promise is immunotherapy-an approach that enhances a patient's immune system to better recognize and react to abnormal cells. The most successful immunotherapeutic strategy to date uses antibodies to block inhibitory receptors (also called "checkpoints") that are up-regulated on the T cells that infiltrate the tumor. Two examples of such molecules are programmed cell death-1 (PD1) and cytotoxic T lymphocyte-associated protein-4. With more than a dozen clinical trials in non-small-cell lung cancer completed, checkpoint blockade targeting PD1 has demonstrated durable responses and superior survival compared with traditional chemotherapy agents when used as first-line therapy in individuals with more than 50% PD1 ligand (PDL1) expression by immunohistochemical staining and as second-line therapy independent of PDL1 status. Antibodies to PDL1 have shown similar activity. Combinations of anti-PD1 and anti-PDL1 with anti-cytotoxic T lymphocyte-associated protein-4 and chemotherapy are being actively tested. These agents have generally tolerable safety profiles; pneumonitis, although rare, remains the most feared adverse effect. PDL1 expression on tumors has been identified as a biomarker predictive of response. Although PDL1 expression has traditionally been measured on resected tumor specimens, the pulmonologist has a growing role in obtaining samples for testing via minimally invasive means.