State of the art in treatment of small cell lung cancer.

Abstract

Small cell lung cancer (SCLC) is an aggressive cancer, with most cases diagnosed as extensive-stage (ES-SCLC). Platinum and etoposide chemotherapy is the mainstay of first-line treatment, achieving high initial response rates. However, treatment resistance develops quickly, leading to poor overall survival and limited efficacy of subsequent therapies, especially for platinum-resistant disease. The addition of immune checkpoint inhibitors (ICIs) to first-line chemotherapy for ES-SCLC has resulted in modest improvements in survival. For limited-stage SCLC (LS-SCLC) treated with radical chemo-radiotherapy, the ICI durvalumab is now approved as a consolidation therapy to reduce relapse risk. Further trials are investigating ICIs concurrently with chemo-radiotherapy and/or as consolidation or maintenance therapy. For relapsed SCLC, treatment options include chemotherapies such as topotecan or lurbinectedin and carboplatin/etoposide rechallenge. The delta-like ligand 3-targeting bispecific T-cell engager (BiTE), tarlatamab, has been approved by the FDA for ES-SCLC with disease progression on or after platinum-based chemotherapy and is being evaluated in earlier lines of treatment. Other BiTEs are also in early-phase development, with promising early activity. Several antibody-drug conjugates, including sacituzumab govitecan, are being tested in clinical trials and have demonstrated encouraging efficacy. Novel targeted therapies aimed at overcoming resistance to chemotherapy and immunotherapy are also in preclinical development. Despite these advancements, progress remains hindered by the absence of validated biomarkers for predicting treatment outcomes. The identification of SCLC transcriptional subtypes with distinct therapeutic vulnerabilities offers hope for better treatment stratification. The SCLC-I transcriptional subtype, tumour mutational burden and tumour immune cell signatures are promising biomarkers for longer-term survival benefit from ICIs. Circulating tumour DNA and circulating tumour cells have demonstrated potential for prognostication, molecular subtyping and tumour monitoring. Further research remains essential to support treatment stratification, prolong treatment responses, overcome resistance and ultimately improve outcomes for this devastating disease.