Nabet and Hamidi et al. applied non-negative matrix factorization on transcriptomic data from 271 pre-treatment SCLC tumor samples from the IMpower133 trial and identified four patient subgroups with distinct clinical outcomes based on cell-intrinsic and -extrinsic features. Immune-enriched SCLCs were further delineated into two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes and responses to atezolizumab plus CE therapy. Tumors with low TAM but high T-eff signals had an NE phenotype and demonstrated longer overall survival compared to tumors with a non-NE phenotype, which showed high TAM and high T-eff signals.
Contributed by Shishir Pant
ABSTRACT: Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses.
Author Info: (1) Genentech Inc., South San Francisco CA, USA. Electronic address: nabet.barzin@gene.com. (2) Genentech Inc., South San Francisco CA, USA. (3) Genentech Inc., South San Francisco
Author Info: (1) Genentech Inc., South San Francisco CA, USA. Electronic address: nabet.barzin@gene.com. (2) Genentech Inc., South San Francisco CA, USA. (3) Genentech Inc., South San Francisco CA, USA. (4) Genentech Inc., South San Francisco CA, USA. (5) F. Hoffmann-La Roche Ltd, Basel, Switzerland. (6) F. Hoffmann-La Roche Ltd, Basel, Switzerland. (7) Genentech Inc., South San Francisco CA, USA; Rancho Biosciences, San Diego, CA, US. (8) Genentech Inc., South San Francisco CA, USA. (9) Genentech Inc., South San Francisco CA, USA. (10) Genentech Inc., South San Francisco CA, USA. (11) Genentech Inc., South San Francisco CA, USA. (12) Genentech Inc., South San Francisco CA, USA. (13) Genentech Inc., South San Francisco CA, USA. (14) Genentech Inc., South San Francisco CA, USA. (15) Genentech Inc., South San Francisco CA, USA. (16) Genentech Inc., South San Francisco CA, USA. (17) Genentech Inc., South San Francisco CA, USA. (18) Genentech Inc., South San Francisco CA, USA. (19) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-8593, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Departments of Internal Medicine and Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA. (21) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA. (23) Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA; Weill Cornell Medical College, New York, NY 10065, USA. (24) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. (26) Lung Clinic Grosshansdorf, Airway Research Center North, German Center of Lung Research, Grosshansdorf, Germany. (27) Genentech Inc., South San Francisco CA, USA. Electronic address: shames.david@gene.com.
