Noura Choudhury, MD
Memorial Sloan Kettering Cancer Center
New York
Small cell lung cancer (SCLC) is difficult to treat, and most patients diagnosed have a poor prognosis. Most patients with SCLC treated with first line chemoimmunotherapy progress within months of immune checkpoint inhibitor (ICI) maintenance therapy. Previous studies in mice have revealed that SCLC treated with iadademstat and maintenance ICI shows enhanced tumor response compared to ICI alone. Dr. Choudhury will conduct a phase II randomized trial investigating this combination in patients with SCLC versus standard of care ICI alone to evaluate progression free survival.
Research Summary
We will conduct a phase II randomized clinical trial investigating the efficacy of combining iadademstat with maintenance ICI versus standard of care ICI maintenance alone for patients with SCLC. We will analyze cell-free DNA in the blood to identify whether treatment with iadademstat and ICI drives conversion to neuroendocrine-low SCLC subtype, which has not been previously demonstrated in a prospective clinical trial. From on-treatment biopsies, we will perform transcriptomic and immunohistochemical analysis to determine whether treatment with iadademstat and ICI induces immunogenicity in SCLC with increased expression of genes in the antigen presentation pathway.
Technical Abstract
Extensive-stage small cell lung cancer (ES-SCLC) has exceptionally poor prognosis, with median survival of one year from diagnosis. Despite neoantigen abundance, SCLC is poorly immunogenic with low expression of major histocompatibility complex class I (MHC-I). As a result, most patients with SCLC treated with first line chemoimmunotherapy progress within months of immune checkpoint inhibitor (ICI) maintenance therapy. Characterization of SCLC by subtypes defined by expression of master transcription factors (TFs) have suggested that ICI-responsive SCLC tumors are composed of neuroendocrine-low (NE-low) subtype with relatively high expression of MHC-I without POU2F3 and with downregulation of ASCL1 and NEUROD1. The hypothesized transcriptional plasticity of SCLC, or subtype switching in response to therapeutic pressures, suggests that leveraging conversion to NE-low subtype with increased immunogenicity may enhance response to ICI. We have shown that inhibition of lysine-specific demethylase 1 (LSD1) with ICI therapy augments tumor regression in ICI-resistant genetically engineered SCLC mouse models, with subsequent upregulation of MHCI and the antigen presentation pathway and suppression of NE gene signatures. With these data supporting its clinical investigation, we propose a phase 2 randomized trial of iadademstat, an oral LSD1 inhibitor, with ICI maintenance in patients with ES-SCLC who have completed initial chemoimmunotherapy. We hypothesize that combination iadademstat and ICI maintenance therapy will improve progression-free survival and promote conversion to NE-low, immunogenic SCLC. We will trace key SCLC TF activity throughout treatment using a novel cell-free DNA (cfDNA) nucleosome profiling assay and utilize optional on-treatment biopsies to characterize differential gene expression with treatment.