Systemic Therapy of Extensive Stage Small Cell Lung Cancer in the Era of Immunotherapy.

OPINION STATEMENT: In March 2019, the FDA approved the use of the anti-programmed death ligand 1 (PD-L1) antibody atezolizumab, as a first-line treatment option in combination with platinum-etoposide (PE) for patients with extensive stage small cell lung cancer (ED SCLC) based upon the results of the IMpower133 trial. More recently, the FDA approved the anti-PD-L1 antibody durvalumab in March 2020 , also in the frontline setting for SCLC based upon the results of the CASPIAN trial. Both these trials demonstrated a small, but significant overall survival (OS) benefit with the addition of a PD-L1 antibody to standard chemotherapy in the treatment of ED SCLC, thereby altering the treatment paradigm for this aggressive disease. Previously, the FDA had approved the anti-PD1 antibodies nivolumab and pembrolizumab as single-agent third-line treatment options based upon encouraging phase 1/2 data in patients with relapsed SCLC who had not received prior immunotherapy (IO). Despite these recent advances, the overall benefit of IO in SCLC remains somewhat disappointing in comparison with the results seen in non-small cell lung cancer (NSCLC). To date, no reliable biomarkers exist to predict responsiveness to IO in SCLC, and the utility of second- or third-line immunotherapy is questionable in patients who have received IO as part of first-line treatment. There has also been minimal success in identifying targetable mutations in SCLC. Novel approaches include combination approaches with IO, including PARP inhibitors and CDK inhibitors. Few ongoing trials, however, have enrolled patients who have received frontline immunotherapy given the only recent change in standard of care. Consequently, the results of current trials evaluating second- and third-line therapies need to be interpreted and translated into clinical practice with caution. The most significant challenge in SCLC remains the identification of molecular targets for which drugs can be developed that can improve survival over the current standard of care.