Evidence Builds for Immunotherapy Combos in SCLC

Ticiana A. Leal, MD

Assistant Professor, Medicine

Team Leader, Thoracic Oncology Disease

Division of Hematology and Oncology

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin

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

Notably, in the majority of patients, the development of SCLC is associated with tobacco exposure.^16,17 This characteristic, combined with frequent TP53 mutation (>75%-90% pf SCLCs),^18,19 results in an aggressive highly complex disease at the molecular level, with a large number of mutations present in each tumor.20 Results from several studies have suggested that TMB is associated with a benefit from immunotherapy.^21,22 Presumably, increased mutational burden results in increased tumor antigenicity, thereby priming the tumor for immune attack. SCLC carries one of the highest mutational burdens of any malignancy.

Given the rapid progression and high tumor burden associated with SCLC, combining chemotherapy with nivolumab is the favored approach. I am serving as study chair of the first trial that will investigate nivolumab in combination with carboplatin and etoposide in patients with extensive-stage SCLC in the frontline setting (Figure).

Figure. EA5161 Study of Frontline Therapy for Extensive-Stage SCLC

This novel strategy is a multidisciplinary effort through the ECOG/ACRIN Cancer Research Group. The primary endpoint of this study is PFS, and secondary endpoints include ORR, OS, and safety. Additionally, our group will also investigate TMB in tumor tissue and perform circulating-free DNA analyses to evaluate TMB in blood and markers of resistance. This study, currently in the planning stages, will be opening to accrual soon through ECOG/ACRIN (ecog-acrin.org/clinical-trials).