523 Small cell lung cancer molecular subtypes and vulnerability to immune checkpoint blockade (2022)

<h3>Background</h3> Extensive-stage (ES) small cell lung cancer (SCLC) disproportionately contributes to annual lung cancer-related deaths.<sup>1,2,3</sup> Following the pivotal Phase III IMpower133 study, the PD-L1 inhibitor atezolizumab, combined with carboplatin and etoposide (CE), was the first immune checkpoint inhibitor approved for first-line treatment of ES-SCLC and is now a standard-of-care.<sup>4</sup> In general, SCLC tumors are immunological deserts with limited tumor cell PD-L1 expression.<sup>5,6</sup> Previous subtyping define SCLC tumors as neuroendocrine (NE) (ASCL1 or NEUROD1-driven) and non-neuroendocrine (nonNE) (POU2F3 or an Inflamed subtype). <sup>5,7,8,9</sup> Subtyping approaches have been limited to small cohorts and cell lines, with associated clinical outcomes suggesting improved benefit of the inflamed subtype with immunotherapy.<sup>5</sup> <h3>Methods</h3> We analyzed pre-treatment RNA-sequencing (RNA-seq) from 271 patient tumors from IMpower133. We applied nonnegative matrix factorization (NMF) to define SCLC classes within this dataset and correlated these new subtypes with clinical outcomes to atezolizumab+CE versus placebo+CE. We defined cell-intrinsic and –extrinsic hallmarks of each subtype with differential gene expression analyses. <h3>Results</h3> We identify four subtypes that can be characterized by both cell-intrinsic and tumor microenvironmental features. The subtypes include NEUROD1-driven (NE-N, 31%), ASCL1-driven (NE-A, 33%), NE inflamed (NE-I, 14%), and nonNE inflamed (nonNE-I, 22%). Prior classification schema had one inflamed subgroup, whereas we identify two clusters with inflamed hallmarks. We observe both a NE-I and nonNE-I group with enrichment for T cells, B/plasma cells, antigen presentation machinery, and immune cell PD-L1 expression. We find that while the NE-A and NE-N subtypes show similar atezolizumab+CE benefit compared to placebo, the inflamed subtypes have markedly distinct outcomes. The NE-I subtype shows a near doubling of median overall survival (OS) with atezolizumab+CE compared to placebo+CE (OS HR, 0.45 [0.22-0.89]), while the nonNE-I subtype shows no benefit despite hallmarks of lymphocyte inflammation and PD-L1 expression (OS HR, 1.02 [0.55-1.91]). The balance of T-effector to tumor-associated macrophage (TAM) signals distinguish these two inflamed subtypes (NE-I and nonNE-I). Tumors with high T-effector and high TAM signals have similar OS with atezolizumab+CE and placebo+CE (OS HR, 0.85 [0.53-1.37]), while tumors with high T-effector, but low TAM signals demonstrate markedly longer OS with atezolizumab+CE compared to placebo+CE (OS HR, 0.26 [0.12-0.57]). <h3>Conclusions</h3> We further refine SCLC subtypes and describe a spectrum of heterogeneity. We identify two inflamed subtypes with distinct clinical outcomes to atezolizumab+CE therapy dependent on the balance of T-effector to TAM infiltration. These results demonstrate the potential for personalization of therapy for SCLC patients based on molecular subtypes. <h3>Acknowledgements</h3> We thank the patients and their families. Medical writing assistance for this manuscript was provided by Michael J. Williams, PhD of Health Interactions and funded by F. Hoffmann-La Roche Ltd. <h3>References</h3> Fruh M, De Ruysscher D, Popat S, Crino L, Peters S, Felip E, and Group EGW. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. <i>Ann Oncol</i> 2013 <b>24(</b>Suppl 6), vi99–105. 10.1093/annonc/mdt178. Gazdar AF, Bunn PA, and Minna, JD. Small-cell lung cancer: what we know, what we need to know and the path forward. <i>Nat Rev Cancer</i>. 2017 <b>17</b>, 765. 10.1038/nrc.2017.106. van Meerbeeck JP, FenonNEll DA, and De Ruysscher DK. Small-cell lung cancer. <i>Lancet</i> 2011 <b>378</b>, 1741–1755. 10.1016/S0140-6736(11)60165-7. 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