Abstract 22: A novel, inflamed small cell lung cancer transcriptional subtype, SCLC-I, defines a subset of patients with distinct immunotherapy vulnerability
Authors: Gay Carl M. , Stewart C. Allison , Diao Lixia , Nabet Barzin Y. , Fujimoto Junya , Solis Luisa M. , Lu Wei , Xi Yuanxin , Cardnell Robert J. , Vokes Natalie I. , Ramkumar Kavya , Swisher Stephen G. , Roth Jack A. , Glisson Bonnie S. , Shames David S. , Wistuba Ignacio I. , Wang Jing , Minna John , Heymach John V. , Byers Lauren A. 
Published: July 2021

Abstract
Background
Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with dismal survival outcomes and no established predictive biomarkers. The landmark randomized, phase III IMpower133 trial established the new frontline standard of care for extensive-stage SCLC (ES-SCLC) as etoposide/platinum (EP) plus immune checkpoint blockade (ICB) [anti-PD-L1; atezolizumab (atezo)] based on an overall survival (OS) benefit compared to EP plus placebo. However, this survival benefit is limited in unselected populations, emphasizing the need for predictive biomarkers. Preclinically, there is emerging evidence of transcriptional heterogeneity among SCLC tumors, but the impact on therapeutic benefit remains undefined. Using non-negative matrix factorization (NMF) analysis of gene expression data from 81 SCLC tumors samples, we previously identified four subtypes, including three defined largely by differential expression of the transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P), and a novel, fourth subtype with low expression of all three transcription factor signatures.
Method and Results
Using transcriptional and proteomic data from patient tumors and tumor-derived models, we molecularly characterized each of the four identified subtypes. The previously undescribed fourth subtype, dubbed SCLC-Inflamed (SCLC-I) showed high expression of non-neuroendocrine transcription factors (e.g. REST) and markers of EMT. Most distinctly, relative to the “cold” immune microenvironment typical of SCLC tumors, SCLC-I tumors possess markedly higher expression of interferon-γ signatures and immune checkpoints, including CD274 (PD-L1). Furthermore, cell type deconvolution using CIBERSORTx identified significantly higher infiltration into SCLC-I tumors by multiple immune cell types including T-cells, NK cells, macrophages, and dendritic cells. We predicted SCLC-I might derive disproportionate benefit from ICB due to its inflamed features. To test this, we applied our NMF-derived gene signature to 276 treatment-naïve, ES-SCLC patient tumors from the IMpower133 trial to assign patient subtype. The distribution of subtypes was as follows: SCLC-A 51%, SCLC-N 23%, SCLC-I 18% and SCLC-P 7%. While there was a trend toward OS benefit with the addition of atezo in each subtype, the benefit was numerically greater in SCLC-I. Specifically, median OS (atezo vs placebo arm) in months (mo) was 18.2 mo vs 10.4 mo for SCLC-I tumors, while median OS for the other three subtypes ranged from 9.6-10.9 mo (atezo arm) and 6.0-10.6 mo (placebo arm).
Conclusion
Unbiased transcriptional analyses identify four subtypes with distinct tumor and immune features. While all subtypes experienced improved OS with addition of anti-PD-L1 to frontline EP, SCLC-I patients appear to experience the most durable benefit.
Citation Format: Carl M. Gay, C. Allison Stewart, Lixia Diao, Barzin Y. Nabet, Junya Fujimoto, Luisa M. Solis, Wei Lu, Yuanxin Xi, Robert J. Cardnell, Natalie I. Vokes, Kavya Ramkumar, Stephen G. Swisher, Jack A. Roth, Bonnie S. Glisson, David S. Shames, Ignacio I. Wistuba, Jing Wang, John Minna, John V. Heymach, Lauren A. Byers. A novel, inflamed small cell lung cancer transcriptional subtype, SCLC-I, defines a subset of patients with distinct immunotherapy vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 22.