Small Cell Lung Cancer

SCLC at a glance

Small cell lung cancer (SCLC) is a highly proliferative type of cancer with a strong predisposition for early metastasis.¹ Globally, it accounts for 14%-15% of all lung cancers and is strongly associated with exposure to tobacco carcinogens.^1-3

Overall, the 5-year survival rate for SCLC is <10%.⁴ Survival depends on stage at diagnosis, and only one-third of patients are diagnosed with localized, earlier-stage disease that is amenable to potentially curative therapy.^1,5

Small cell lung cancer (SCLC) can generally be split into two stages, limited and extensive, with extensive stage referring to metastatic disease which has spread beyond the ipsilateral lung and regional lymph nodes and is not possible to include in a single radiation field.^2,3,6 Most patients (60‒70%) have extensive-stage disease at the time of diagnosis.⁶ Although SCLC is highly sensitive to initial chemotherapy and radiotherapy, most patients relapse within a year and eventually die of recurrent disease.^2,3,5

Developments in extensive-stage SCLC treatment

Treatment of extensive-stage SCLC

Systemic therapy can palliate symptoms and prolong survival in most patients with extensive disease, but long-term survival is rare.² Radiotherapy might be used in certain patients for palliation of symptoms.²

Comparative trials in the first-line setting for SCLC are challenging due to the high response rate with initial chemotherapy⁷, and complexity of this disease.⁸ Nevertheless, following regulatory approvals, treatment guidelines have recommended certain combination regimens with immune checkpoint inhibitor (ICI) therapy as preferred first-line options for extensive-stage SCLC.² SCLC is associated with a high tumour mutation burden, and the use of ICIs is a valuable component of SCLC treatment⁸, setting a new benchmark, however the magnitude of benefit gained with immunotherapy in SCLC is more modest than seen in other malignancies.⁹

Identification of predictive biomarkers for patient subgroup selection is a key research interest in scientific community for the future development of ICIs.^8,10

Potential for future therapies

Beyond ICIs, future potential immune-based treatment strategies include chimeric antigen receptor (CAR)-T cells, bispecific T cell engagers, oncolytic viruses, vaccine-based approaches, and immune-activating agents such as PD-1/TIM-1 small molecule agents.^6,7,10,11

Unlike non-small cell lung cancer, in which major advances have been made using oral targeted therapies, to date, none have been approved for use in SCLC.⁹

The inhibitory Notch ligand DLL3 represents an interesting target since it is highly expressed in SCLC but not in normal lung tissue.^7,12 Studies in an SCLC model indicate that DLL3 promotes tumour growth, migration and invasion.¹²

Poly (ADP-ribose) polymerase (PARP) 1 is highly expressed in SCLC and so its inhibition with PARP inhibitors is another approach being explored for SCLC treatment to augment the activity of ICIs, in an attempt to modulate the DNA damage response.^13,14

A 2021 study on patterns of transcription factor programs and immune pathway activation classified SCLC tumours into 4 molecular subtypes and identified potential therapeutic approaches.¹⁵ Further confirmation of the validity of these subtypes in clinical trials could represent a molecular biomarker selection approach for SCLC.

CAR, chimeric antigen receptor; DLL3, delta-like canonical Notch ligand 3; ICI, immune checkpoint inhibitor; PARP, poly (ADP-ribose) polymerase; PD-1, programmed cell death protein-1; SCLC, small cell lung cancer; TIM-1, T-cell immunoglobulin and mucin domain 1.