Abstract
Small cell lung cancer (SCLC) is a particularly lethal subtype of lung cancer whose treatment landscape has been relatively devoid of advance. The recent integration of immunotherapy in the first-line treatment of SCLC has improved overall survival (OS), prompting the first major paradigm shift for this disease in decades. Despite this improvement in outcomes, most patients with SCLC will relapse after initial response. Standard salvage systemic therapy for SCLC remains disappointing, with few approved agents and consistently poor outcomes. The need for novel agents to combat this disease remains pressing. Fortunately, there are several agents in various stages of development that hold potential as novel treatments for advanced SCLC. Lurbinectedin, which targets active transcription, has shown activity in platinum-sensitive and platinum-resistant SCLC as monotherapy and in combination with doxorubicin. Aurora A kinase (AAK) inhibitors showed initial activity when given with paclitaxel but in randomized studies, failed to improve outcomes over paclitaxel plus placebo. However, in the subset of patients with MYC expression, targeting AAK was effective. Similarly, agents targeting poly-ADP ribose (PARP) pair well with other DNA damaging drugs but in the subset of patients whose tumors express Schlafen-11 (SLFN-11), efficacy appeared greater. CDK 4/6 inhibition is being explored, primarily as a means to protect myeloid cells during cytotoxic chemotherapy in a strategy expected to be uniquely effective in SCLC. Ongoing trials are also studying are novel formulations of established cytotoxic agents. Delta-like protein 3 (DLL3) is an appealing therapeutic target given its selective expression on SCLC cells, but after initial exciting results, the antibody-drug conjugate (ADC) Rovalpituzumab tesirine (Rova-T) did not have a favorable efficacy to toxicity profile in randomized trials. Other agents targeting DLL3 are under study. Targeting angiogenesis has yielded modest improvements in the past but newer agents such as anlotinib are renewing interest. While the current therapeutic landscape beyond chemo-immunotherapy remains the same as it was decades ago, drug development for SCLC is rapidly moving forward and promises to deliver the needed novel agents in the very near future.