Challenging the recalcitrant disease—developing molecularly driven treatments for small cell lung cancer

Abstract Small cell lung cancer (SCLC) has been described as a ‘recalcitrant’ disease characterised by poor survival and with little progress made in developing novel treatments in the last decades. However, recent drug developments have opened some potential therapeutic avenues. In this review, the genomic landscape of SCLC is explored, in particular the Notch pathway and attempts to target the key node DLL3. The likely primary importance of MYC to SCLC subtype transformation and recent attempts to drug MYC are discussed. Bcl-2 is a druggable protein, highly expressed in SCLC, and relevant Bcl-2 targeting drugs are reviewed. None of these drug targets are, however, as advanced their development as the field of immunotherapy for SCLC. The key developments in single agent PD-L1 and PD-1 inhibitors and in combination with chemotherapy have led to the only recent licencing approvals for SCLC in recent years and will likely pave the way for future rational drug combinations. Drug development in SCLC poses its own challenges with rapid clinical deterioration often precluding trial entry. Effective drug development in a biomarker-driven approach depends on early patient screening and use of circulating biomarkers. Given recent developments, we may hope to be at the start of an era of greater progress in the treatment of SCLC.