Ticiana A. Leal, MD
Assistant Professor, Medicine
Team Leader, Thoracic Oncology Disease
Division of Hematology and Oncology
University of Wisconsin Carbone Cancer Center
The most common systemic treatment for patients with small cell lung cancer (SCLC) in North America is a platinum/etoposide doublet chemotherapy. This regimen achieves a response rate of 50% to 70%, a median survival of 9 to 11 months, and a median 5-year survival rate of less than 5%.1,2
There has been no significant improvement in clinical outcomes for patients with extensive-stage SCLC, which represents about 70% of cases diagnosed in the United States, in the last 2 decades, making it one of the most fatal cancers.3
Previous strategies to improve outcomes with the use of high-intensity chemotherapy led to an improvement in the response rate but did not translate into a survival benefit due to the heightened toxicities of intensive chemotherapy and lack of efficacy.4-6
So, although SCLC remains very sensitive to frontline platinum-based doublet chemotherapy, the majority of the patients relapse and die of their disease.
Increasing evidence suggests that immune responses against SCLC cells make immunotherapy a rational approach. Preclinical data show that certain chemotherapeutic regimens may augment the immunotherapeutic response in lung cancer. In the M109 mouse model of lung cancer, treating animals with an anti–CTLA-4 monoclonal antibody plus chemotherapy, such as gemcitabine, etoposide, or ixabepilone, revealed synergistic antitumor effects. Furthermore, after combination treatment with CTLA-4 blockade and chemotherapy, animals rejected a subsequent tumor rechallenge, suggesting the development of a protective immune response.7,8
However, a recently completed phase III trial investigating the combination of carboplatin and etoposide with ipilimumab, an anti–CTLA-4 antibody, in a phased approach, did not show a survival benefit compared with standard chemotherapy.9
Although this was disappointing and cast doubt on the validity of adding ipilimumab to a combination regimen in this disease, it also demonstrated that the addition of a third agent targeting the immune checkpoint pathway did not result in any unexpected toxicities.
The combination of nivolumab with ipilimumab is being investigated in the CheckMate 032 trial, which includes pretreated patients with SCLC in the phase I/II setting.10 Encouraging results have been reported to date, with durable responses and manageable safety profile. Additionally, the 2-year survival is 26% in the nivolumab plus ipilimumab arm and 14% in the nivolumab monotherapy arm.10
These data have led to the inclusion of nivolumab with or without ipilimumab in the National Comprehensive Cancer Network guidelines for patients with previously treated SCLC.
Questions remain regarding optimal patient selection. In SCLC, the majority (80%) of tumors do not express PD-L1, which differs from what has been reported for patients with NSCLC. Additionally, patients with SCLC respond to checkpoint blockade immunotherapy independent of PD-L1 status. Therefore, PD-L1 expression has not been a predictive biomarker for patients receiving nivolumab with or without ipilimumab. Another potential biomarker currently under study is tumor mutation burden (TMB).11
In an exploratory analysis of CheckMate 032 findings, patients with high TMB had improved overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with patients with low/intermediate TMB. This is a promising biomarker that will require further validation for patient selection in SCLC.
The combination of immunotherapy agents, such as nivolumab, that target the PD-1/PD-L1 pathway with platinum doublet chemotherapy in NSCLC has also shed light on a promising strategy for improved efficacy and better clinical outcomes for patients with SCLC.12
Increasing evidence suggests that the antitumor activity of chemotherapy is mediated not only through cytotoxic effects, but also through immunological effects, including reducing T-regulatory cell activity and enhancing cross-presentation of tumor antigens.12-14
It has also been hypothesized that decreasing the tumor burden through chemotherapy reduces the immunosuppressive properties of the tumor and creates an environment better suited for T-cell activation.15