SCLC is an aggressive disease that accounts for approximately 15% of all lung cancer cases. Despite significant advancements in the treatment of other lung cancer types over the last few decades, the survival rate for extensive-stage SCLC remains alarmingly low: recent statistics show that 5-year survival rate for extensive-stage SCLC is only 4% for women and 2% for men (Siegel et al., 2023).

The field has seen recent advances for most patients diagnosed with extensive-stage disease with the addition of immunotherapy to chemotherapy. Prior to this, systemic options used as first-line remained unchanged for decades, with regimes based on platinum-etoposide as standard practice (Roth et al., 1992). Outcomes for these patients, however, remain short with a median OS of 12.3–15.4 months (Wang et al., 2022, Cheng et al., 2022a, Paz-Ares et al., 2019, Liu et al., 2021). While in the frontline setting there has been modest improvement after the introduction of immunotherapy, therapeutic options for the management of patients with a relapse are limited, and prognosis of these patients is poor.

One of the main prognostic factors and determinant for subsequent lines of treatment continues to be the progression-free interval (PFI) from completion of first-line platinum-etoposide: disease with a PFI longer than 90 days is considered ‘platinum-sensitive’, disease with initial benefit from chemotherapy but PFI < 90 days is considered ‘platinum resistant’, and disease who progresses through chemotherapy is considered ‘platinum refractory’ (Owonikoko et al., 2012). This paradigm may need revisiting after addition of immunotherapy to the frontline setting for most patients, as data on efficacy of systemic treatments and potential impact of immunotherapy in further lines remain scarce.

Standard options for relapsed SCLC persist almost unchanged in the last decades: re-challenging with platinum-etoposide doublets is a preferred option in patients with platinum-sensitive relapses, prolonging progression-free survival (PFS, 4.7 vs 2.7 months, HR 0.57; P = 0.0041) in a phase III randomized clinical trial compared with topotecan, but obtaining similar overall survival (OS) (HR 1.03; P = 0.94) (Baize et al., 2020). Initial data about oral topotecan compared it with best-supportive care, showing an increase in survival and better control of symptoms, (O’Brien et al., 2006) while intravenous topotecan showed similar effectivity than the combination of cyclophosphamide, doxorubicin and vincristine (CAV) (von Pawel et al., 1999). Lurbinectedin's FDA approval and EMA orphan drug designation in this indication, both based on a phase II clinical trial, mark the latest development in this setting. (Trigo et al., 2020). Over the last 15 years, multiple attempts to improve OS in the pretreated population have failed. However, several promising new treatments are currently being tested, with the hope of achieving improved outcomes in this challenging setting.

Due to its aggressive nature and the challenges associated with its treatment, there is an urgent need for a better understanding of this disease, along with the development of more effective treatment options. This is especially critical in cases of relapsed disease, where outcomes are particularly poor, and treatment options are limited. In this review, we focus on recent developments in the pre-treated setting and potential strategies to improve clinical outcomes of these patients.