Options for Systemic Therapy of Advanced Stage Small Cell Lung Cancer
Small cell lung cancer (SCLC) is the most aggressive type of lung tumor. Although it responds well to chemotherapy and radiotherapy, due to the early onset of treatment resistance, the 5-year survival rate is less than 10%. After more than 30 years of very limited progress in treating advanced SCLC patients, immune checkpoint inhibitors (checkpoints) have been introduced to the market, significantly prolonging survival. What are the current recommendations for treating patients with advanced SCLC?
Chemotherapy in the 1st Line of Treatment
The combination of platinum derivatives with etoposide has been the preferred regimen for advanced SCLC for decades. The median overall survival (OS) on this therapy is 9-10 months, the median progression-free survival (PFS) is 5-6 months, and the one-year OS is approximately 35%. No significant differences in OS were observed between the use of cisplatin and carboplatin, so the decision on which derivative to use should consider toxicity profiles and the patient's individual situation. Carboplatin use is associated with myelosuppression, while cisplatin brings more non-hematological side effects (nausea, vomiting, renal toxicity).
Systemic Treatment in the 1st Line
Immunotherapy brought significant changes to the treatment of various cancers, and SCLC is no exception. The new standard of therapy for patients with advanced SCLC was established based on two large phase III clinical trials that assessed the addition of programmed death-ligand 1 (PD-L1) inhibitors to chemotherapy with a platinum derivative and etoposide. The IMpower133 study investigated the efficacy of atezolizumab, while the CASPIAN study evaluated durvalumab (optionally in combination with tremelimumab). Both immunotherapeutic regimens showed statistically significant increases in OS of about 2 months compared to standard chemotherapy.
Based on the results of these studies, the European Society for Medical Oncology (ESMO) issued recommendations in 2021 to use atezolizumab or durvalumab in combination with a platinum derivative and etoposide for all previously untreated patients with stage III or IV small cell lung cancer, whose performance status (PS) is within the 0-1 range according to ECOG criteria.
Long-Term Survival with Durvalumab
A recent analysis of 3-year survival outcomes in the CASPIAN study was published. In this clinical evaluation, 805 patients were randomized into three arms - standard chemotherapy with etoposide and platinum derivative (EP, control arm, 4-6 cycles) and EP (4 cycles) combined with durvalumab (until progression or unacceptable toxicity) or with a combination of durvalumab and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor tremelimumab (also until progression or unacceptable toxicity). Patients in the immunotherapy arms received maintenance treatment with durvalumab after chemotherapy until disease progression (continuation of immunotherapy after progression was permitted in cases of demonstrable clinical benefit). The primary endpoint of the study was overall survival.
The latest data analysis, conducted in March 2021 with a median follow-up of 39.4 months, shows an OS of 12.9 months for patients on the durvalumab + EP combination vs. 10.5 months in the control arm (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.60-0.86; nominal p = 0.0003). The OS for patients treated with durvalumab + tremelimumab + EP was 10.4 months (HR 0.81; 95% CI 0.67-0.97; nominal p = 0.02). The 3-year survival rate for patients with durvalumab + EP was 17.6%, in the arm with durvalumab + tremelimumab + EP it was 15.3%, and in the control arm it was 5.8%.
Conclusion
Three years after the start of treatment, three times as many patients treated with durvalumab in combination with chemotherapy with a platinum derivative and etoposide were alive compared to the group treated with chemotherapy alone. Most patients were still taking durvalumab at the end of data collection, further supporting its role as the standard treatment for advanced SCLC in the 1st line.
In the Czech Republic, durvalumab is reimbursed in combination with etoposide and platinum in the 1st line of treatment for adult patients with advanced stage small cell lung cancer.
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Sources:
1. Dingemans A.-M. C., Früh M., Ardizzoni A. et al. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021; 32 (7): 839-853, doi: 10.1016/j.annonc.2021.03.207.
2. Paz-Ares L., Chen Y., Reinmuth N. et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open 2022; 7 (2): 100408, doi: 10.1016/j.esmoop.2022.100408.
3. SPC Imfinzi. Available at: www.ema.europa.eu/cs/documents/product-information/imfinzi-epar-product-information_cs.pdf
4. Data SÚKL. Available at: www.sukl.cz
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