SCLC IN FOCUS

Epidemiology, risk factors and survival

Epidemiology

An estimated 2.2 million new lung cancers are diagnosed globally each year,¹ with SCLC accounting for approximately 14% of these.² Although the incidence of SCLC has been decreasing in the US, the incidence in women is increasing.²

Risk factors

SCLC is strongly associated with cigarette smoking: almost all patients who develop SCLC have a history of heavy tobacco exposure.³ As well as reducing the risk of developing SCLC, smoking cessation has been shown to increase the 5-year survival rate by 34% in patients with localized SCLC.⁴ The incidence of SCLC varies geographically and is closely linked to smoking habits.⁵ The incidence of SCLC is decreasing with the decline of smoking rates and changes in smoking habits in certain Western countries.³ Other risk factors for SCLC include exposure to radon, halogenated ethers, arsenic, asbestos, chromium, polyaromatic hydrocarbons, and vinyl chloride.³

Survival

Overall, the 5-year survival rate for SCLCs (all stages) is 7%.⁶ Survival depends on stage at diagnosis, and only one-third of patients are diagnosed with localized disease, where cure is the treatment goal.⁵

Due to the aggressive course of the disease, screening programs are unlikely to reduce disease mortality, and smoking prevention, therefore, remains the most important intervention to decrease mortality.⁵

Presentation and diagnosis

Presentation

Symptoms of SCLC include:³

• Cough
• Wheezing
• Dyspnea
• Post-obstructive pneumonia

Patients with regional extension of disease may experience vocal hoarseness, chest or throat pain, dysphagia, or superior vena cava syndrome. Patients with metastatic disease may present with abdominal pain, bone pain, nausea, vomiting, anorexia, weight loss, or focal neurologic deficits. Finally, patients of any stage may present with paraneoplastic syndromes.³

Diagnosis

Diagnosis of SCLC is based on morphology: uniform, round to spindle-shaped small cells, sparse cytoplasm, high mitotic index, and necrotic areas.⁵ Immunohistochemistry can be used to confirm the diagnosis with the following markers: synaptophysin, chromogranin A, CD56, thyroid transcription factor 1, and MIB-1.⁵

Biopsies may be obtained by bronchoscopy, mediastinoscopy, endobronchial ultrasound, endoscopic ultrasound, transthoracic needle aspiration, or thoracoscopy.⁵ A biopsy from a metastatic lesion also allows pathologic staging.

Staging

Full staging of SCLC includes:²

• Medical history and physical examination
• CT scan (with intravenous contrast) of the chest/abdomen
• Brain imaging by MRI/ contrast CT scan

The Veterans Administration (VA) scheme has historically been used to define the extent of disease. In this scheme, limited-stage disease is defined as disease that is confined to a radiation field within the ipsilateral hemithorax, whereas extensive-stage disease extends beyond the ipsilateral hemithorax (including malignant pleural or pericardial effusion or hematogenous metastases). NCCN guidelines currently adopt a combined approach using the VA scheme together with the newer American Joint Committee on Cancer TNM staging system.²

Clinical management

Although SCLC is highly sensitive to initial chemotherapy and radiotherapy (the initial response rate to chemotherapy is 60─70%), most patients relapse within a year and eventually die of recurrent disease.^2,3,7 Patients with SCLC who continue to smoke have increased toxicity during treatment and shorter survival.²

Unlike in lung cancer overall, screening high-risk patients may not reduce the number of patients diagnosed with extensive-stage SCLC due to its early hematogenous spread.⁶

Treatment of limited-stage SCLC

In patients with limited-stage SCLC, the goal of treatment is tumor eradication using chemotherapy plus thoracic radiotherapy.² Etoposide plus cisplatin is the most commonly used initial combination chemotherapy regimen. Surgery is only recommended for certain patients with surgically resectable stage I to IIa SCLC, and stereotactic ablative radiotherapy (SABR) may be an option for certain patients with medically inoperable stage I to IIa SCLC.² Adjuvant chemotherapy is used for patients who have undergone surgical resection or SABR for early-stage disease.²

Treatment of extensive-stage disease

Most patients (60‒70%) have extensive-stage disease at the time of diagnosis.⁷ 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

Platinum-based chemotherapy in combination with etoposide has been the standard of care for nearly 30 years for extensive disease, with survival rates remaining fairly consistent across studies (median of 9–11 months), even in recent first-line trials.^2,8 There is a preference for carboplatin over cisplatin due to its equivalent efficacy and more tolerable toxicity profile.² Recently, this standard has changed as two trials have reported an overall survival (OS) advantage of 2–3 months with anti-PD-L1 therapy in combination with platinum-based chemotherapy plus etoposide.² The addition of atezolizumab to chemotherapy improved survival in the IMpower133 trial (median OS: 12.3 vs 10.3 months; p=0.0154),⁹ and the addition of durvalumab to chemotherapy improved survival in the CASPIAN trial (median OS: 12.9 vs 10.5 months; p=0.0032).¹⁰

Intracranial metastases occur in >50% of patients with SCLC. Prophylactic cranial irradiation or close brain surveillance imaging are options for patients with extensive-stage disease and a good response to initial systemic therapy.²

Subsequent systemic therapy

Treatment options for patients who have relapsed within the first 6 months after primary therapy include a variety of chemotherapy agents, lurbinectedin (an inhibitor of RNA polymerase II – hyperactivated in SCLC) and immunotherapy with a PD-1 inhibitor.² Entry into clinical trials might be another option in this setting.² Relapsed patients treated with subsequent systemic therapy have a median survival of 4–5 months.² Patients who relapse more than 6 months after first-line treatment should be treated with their original regimen or lurbinectedin.²

Hot topics in SCLC

Immunotherapy in SCLC

Given the high unmet need in improving survival of patients with SCLC, there has been a great deal of interest in immunotherapy. Comparative trials in the first-line setting are challenging due to the high response rate with initial chemotherapy.¹¹ Nevertheless, following FDA approvals, NCCN guidelines have recommended the following regimens as preferred first-line therapy options for extensize-stage SCLC:²

• Atezolizumab plus carboplatin and etoposide
• Durvalumab plus carboplatin and etoposide
• Durvalumab plus cisplatin and etoposide

NCCN guidelines also include the immune checkpoint inhibitor (ICI) nivolumab as a subsequent therapy option.² A recent Phase III clinical trial found that first-line pembrolizumab plus platinum-based chemotherapy and etoposide significantly improved progression-free survival of SCLC patients; however, this combination is not approved and is still not considered in treatment guidelines.¹²
The use of ICIs, such as atezolizumab or durvalumab, in SCLC still presents challenges due to their relatively limited survival benefit of approximately 2 additional months compared with the previous standard chemotherapy regimen.^9,10 Response rates in the first-line setting remain consistent at 60─64% with or without ICIs.⁹
Furthermore, no consistent predictive biomarkers of response to ICIs have been identified in SCLC. In many solid tumors, a high tumor mutational burden (TMB) is associated with improved efficacy of ICIs. TMB was found to also be higher in SCLC patients that achieved a better response to nivolumab (with or without ipilimumab), highlighting its usefulness as a predictor in SCLC.¹³ However, PD-L1 expression in SCLC is typically low or absent, and no association has been found between PD-L1 expression and TMB.¹³

Ongoing and future clinical trials will evaluate treatment scenarios that have not yet been tested with ICIs, such as the maintenance setting in patients with limited-stage disease, and test combinations of ICIs with novel targeted therapies.¹⁴ 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.^7,11,14,15

Potential for targeted therapy in SCLC

SCLC is characterized by the loss of tumor suppressors TP53 (75─90% of patients) and RB1 (approaching 100%) and by frequent 3p deletion.⁷ Increased expression of c-KIT, amplification of MYC family genes and loss of PTEN have also been described.⁷ Additionally, overexpression of the DNA repair proteins poly(ADP-ribose) polymerase 1 (PARP1), checkpoint kinase 1 (Chk1) and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) seems to occur independently of alterations in the corresponding genes.⁷

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 OS in heavily pretreated patients in a Phase II studies. Currently, anlotinib is only approved for SCLC in China; further validation will be required before any potential future approval in Europe or the US.^15,16

Characterization of potential drug targets and activated pathways is needed to improve outcomes for patients with SCLC, which can then translate the most promising drug targets into treatments for the clinic. There is also a need to better understand what drives therapeutic resistance in recurrent SCLC.⁷

However, SCLC is difficult to study due to the limited availability of sufficiently substantial tumor specimens for molecular profiling. This is a result of surgical resection rarely being a therapeutic option, leading to a reliance on diagnostic biopsy samples, which are often small and necrotic.¹⁴ Other barriers to progress in SCLC include a lack of early detection modalities, the molecular complexity of SCLC, and the rapid pace of disease progression.⁷

Potential novel targeted therapeutic approaches in SCLC include PARP inhibitors, and drugs targeting MYC-amplified or -driven tumors, such as aurora kinase or bromodomain inhibitors.⁷ The inhibitory Notch ligand DLL3 also represents an interesting target as a result of its high expression in SCLC.¹¹

A recent study classified SCLC tumors into 4 molecular subtypes and identified potential therapeutic approaches.¹⁷ All subtypes responded to ICIs, but one in particular, SCLC-I, experienced a greater benefit. SCLC-I tumors had an inflamed gene signature with high expression of immune-related genes. SCLC-I tumors also had the highest total immune infiltrates, which included T cells, NK cells and macrophages. Further confirmation of the validity of these subtypes in clinical trials could represent the first molecular biomarker selection for SCLC and might open the door to personalized therapies.