Unfortunately, there has been a notable lack of activating mutations in driver oncogenes in SCLC, and molecularly targeted agents have yet to find a place in the treatment of SCLC. Studies have shown high somatic mutation rates and copy number alterations in the tumor tissues with a near-universal bi-allelic inactivation of TP53 and RB1. Several groups have pursued comprehensive genomic profiling of SCLC with hopes of identifying actionable genomic targets. As outcomes are poor, therapeutic options after relapse are limited. Despite a typically dramatic initial response to therapy, most patients with SCLC experience relapse within 6 months despite chemotherapy and radiation and the 5-year survival rates for patients with ES disease remain low (5%). Radiotherapy is traditionally reserved for the palliation of symptoms in patients with ES disease, and PCI remains controversial. For ES disease, the first-line chemotherapy for newly diagnosed metastatic SCLC consisted of a platinum agent (cisplatin or carboplatin) with etoposide. In patients who respond to initial treatment, prophylactic cranial irradiation (PCI) is also part of the standard management with non-metastatic disease. The standard chemotherapy regimen in this setting is cisplatin–etoposide. Chemotherapy can both augment the local efficacy of radiation and potentially treat micrometastatic disease. Local treatment options include surgery and radiotherapy. In non-metastatic SCLC, the therapeutic goals are to achieve durable control of thoracic disease and reduce the risk of metastatic dissemination. The initial approach to SCLC treatment varies substantially by stage. Although the tumor–node–metastasis (TNM) classification is preferred to the staging system of the Veterans Administration Lung Study Group (VALSG), which separates limited-stage (LS) disease (tumor confined to one hemi-thorax and one radiation port no malignant pleural or pericardial effusion) from extensive-stage (ES) disease (not meeting criteria for LS), the latest staging system is still widely used in both designing clinical trials and presenting data from them, as it effectively distinguishes patients treated primarily with chemotherapy (LS disease) from those treated with systemic chemotherapy or chemoimmunotherapy (ES disease). In these patients, systemic chemotherapy is typically the primary therapeutic modality, with some patients also drawing benefit from radiation therapy. Most patients have advanced disease and present with distant metastases, malignant effusions, and/or contralateral supraclavicular or hilar lymph node involvement. These two properties contribute to a particularly high mortality rate. In general, SCLC grows rapidly and has high metastatic potential. Small-cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 13% of all lung cancers and occurs predominantly in smokers. With the therapeutic landscape for SCLC rapidly evolving, we review prior experience and future directions of pembrolizumab in ES-SCLC. In a recent clinical trial that included patients with previously untreated ES-SCLC, pembrolizumab in combination with platinum/etoposide met its progression-free survival endpoint, but overall survival (OS) did not cross the threshold for superiority. ![]() Food and Drug Administration (FDA) granting pembrolizumab accelerated approval as second- or third-line monotherapy for patients with extensive-stage (ES) SCLC. Prospective trials of pembrolizumab in patients with previously treated SCLC showed significant durability of responses. Pembrolizumab, a humanized IgG4 isotype antibody, targets the programmed cell death protein 1 (PD-1) pathway to restore anti-tumor immunity. The management of SCLC significantly changed for the first time in decades with the introduction of immune checkpoint inhibitors. Small-cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by a rapid initial response and early development of resistance to systemic therapy and radiation.
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