Predictive Signatures for Responses to Checkpoint Blockade in Small-Cell Lung Cancer in Second-Line Therapy Do Not
Jeffrey C Thompson1,2, Caitlin Tilsed1, Christiana Davis2,3
1Division of Pulmonary, Allergy and Critical Care Medicine, Thoracic Oncology Group, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 228 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104, USA.
Abstract:
Although immune checkpoint blockade (ICB) is currently approved for the treatment of extensive-stage small-cell lung cancer (SCLC) in combination with chemotherapy, relatively few patients have demonstrated durable clinical benefit (DCB) to these therapies. Biomarkers predicting responses are needed. Biopsies from 35 SCLC patients treated with ICB were subjected to transcriptomic analysis; gene signatures were assessed for associations with responses. Twenty-one patients were treated with ICB in the first-line setting in combination with platinum-based chemotherapy; fourteen patients were treated in the second-line setting with ICB alone. DCB after ICB in SCLC in the second-line setting (3 of 14 patients) was associated with statistically higher transcriptomic levels of genes associated with inflammation (p = 0.003), antigen presentation machinery (p = 0.03), interferon responses (p < 0.05), and increased CD8 T cells (p = 0.02). In contrast, these gene signatures were not significantly different in the first-line setting. Our data suggest that responses to ICB in SCLC in the second-line setting can be predicted by the baseline inflammatory state of the tumor; however, this strong association with inflammation was not seen in the first-line setting. We postulate that chemotherapy alters the immune milieu allowing a response to ICB. Other biomarkers will be needed to predict responses in first-line therapy patients.
Insights
Durable clinical benefit from immune checkpoint blockade (ICB) in extensive-stage small-cell lung cancer (SCLC) is limited. Baseline tumor inflammation predicts ICB response in the second-line setting, suggesting chemotherapy may alter the immune microenvironment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint blockade (ICB) offers limited durable clinical benefit (DCB) in extensive-stage small-cell lung cancer (SCLC).
- Predictive biomarkers for ICB response in SCLC are urgently needed.
Purpose of the Study:
- To identify transcriptomic biomarkers associated with DCB in SCLC patients treated with ICB.
- To investigate differences in biomarker associations between first-line (ICB + chemotherapy) and second-line (ICB alone) settings.
Main Methods:
- Transcriptomic analysis of tumor biopsies from 35 SCLC patients treated with ICB.
- Assessment of gene signatures for association with durable clinical benefit (DCB).
- Comparison of gene signatures between first-line and second-line treatment groups.
Main Results:
- In the second-line setting, DCB was associated with higher transcriptomic levels of inflammation, antigen presentation machinery, interferon responses, and CD8 T cells (p < 0.05).
- These associations were not significant in the first-line setting (ICB + chemotherapy).
- Only 3 of 14 second-line patients achieved DCB.
Conclusions:
- Baseline tumor inflammation may predict ICB response in SCLC patients receiving second-line therapy.
- Chemotherapy may alter the tumor immune microenvironment, influencing ICB efficacy in the first-line setting.
- Novel biomarkers are required to predict responses to first-line ICB therapy in SCLC.
