SCLC at a glance

Small cell lung cancer (SCLC) is a highly proliferative type of cancer with a strong predilection for early metastasis.¹ It accounts for 14–15% of all lung cancers and is strongly associated with exposure to tobacco carcinogens.^1–3 Overall, the five-year survival rate for SCLC (all stages) is 9%.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 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.^2,3,6
 

SCLC five-year relative survival rate (US)*⁴

*Values are based on people diagnosed with SCLC between 2012 and 2018.

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 chemotherapy.⁷ Nevertheless, following regulatory approvals, treatment guidelines have recommended regimens with immune checkpoint inhibitor (ICI) therapy as preferred first-line options for extensive-stage SCLC.² The use of ICIs, such as atezolizumab or durvalumab, in SCLC still presents challenges due to their relatively limited survival benefit of approximately two additional months compared with the previous standard chemotherapy regimen.^8,9 Response rates in the first-line setting remain consistent at 60─64% with or without ICIs.⁸ 

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

Potential for targeted therapies in SCLC

Unlike non-small cell lung cancer, in which major advances have been made using targeted therapies, there are few approved targeted drugs for SCLC. The tyrosine multikinase inhibitor anlotinib achieved an increase in progression-free survival and overall survival in heavily pretreated patients in Phase II studies. Currently, anlotinib is only approved for third-line and further line treatment of SCLC in China; further validation will be required before any potential approval in Europe or the US.^11,12 

The inhibitory Notch ligand DLL3 represents an interesting target since it is highly expressed in SCLC but not in normal lung tissue.^7,13 Studies in an SCLC model indicate that DLL3 promotes tumor growth, migration and invasion.¹³ Studies evaluating T-cell engagers that bind both DLL3 on cancer cells and CD3 on T cells are ongoing.^14–16

Poly (ADP-ribose) polymerase (PARP) 1 inhibition is another approach being explored for SCLC treatment. Phase II trial results of a PARP inhibitor (olaparib) did not meet the preset bar for efficacy, but examination of pretreatment and during-treatment biopsy specimens provided important insights into selection of patients with SCLC for ICI-based treatment. Further study on the predictive value of pre-existing CD8-positive T-cell infiltrates was suggested.¹⁷ 

A 2021 study on patterns of transcription factor programs and immune pathway activation classified SCLC tumors into 4 molecular subtypes and identified potential therapeutic approaches. Further confirmation of the validity of these subtypes in clinical trials could represent a molecular biomarker selection approach for SCLC and might open the door to personalized therapies.¹⁸

CAR, chimeric antigen receptor; CD3/8, cluster of differentiation 3/8; 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; SEER, Surveillance, Epidemiology, and End Results; TIM-1, T-cell immunoglobulin and mucin domain 1; US, United States of America.