Abstract 2047: Association of retinoblastoma function with response to immuno-oncology treatment in patients with small cell lung cancer
Authors: David Balli, Xuya Wang, Naiyer A. Rizvi, Timothy A. Chan, Afshin Dowlati, Parul Doshi, Han Chang
Journal: Cancer Research (2020)

Abstract Background: Anti–programmed death-1/programmed death ligand 1 inhibitors have been approved for the treatment of advanced small cell lung cancer (SCLC) as a single disease entity. However, efforts to detect and characterize biologically distinct subtypes of SCLC based on gene expression profiling (GEP) have identified multiple subtypes of SCLC, with potential therapeutic implications. These SCLC subtypes can be characterized as neuroendocrine (NE) or non-NE by GEP. Mutation in the retinoblastoma (Rb) transcriptional corepressor 1 (RB1) gene occurs in 65–85% of patients with SCLC, and RB1 mutation may be associated with improved survival with chemotherapy. In this retrospective, exploratory analysis, we investigated the association of genomic and transcriptional biomarkers, including RB1 mutation, with response to immuno-oncology (I-O) in patients with SCLC. Methods: Biomarker evaluation was performed in baseline samples from patients with SCLC who received second-line or later nivolumab ± ipilimumab (NIVO±IPI) in CheckMate 032 (NCT01928394). RB1 wild type (RB1WT) or mutant (RB1MUT) status and tumor mutational burden (TMB) were determined by whole exome sequencing (WES). Gene expression signatures for SCLC transcriptional subtype (6 genes), Rb protein loss of function (LOF; 87 genes), and inflammation (4 genes) were determined using RNA sequencing. Results: Of 460 total samples from patients with SCLC, WES and GEP data were available for 279 and 286 samples, respectively. 166 patients (59%) carried frameshift, in-frame insertions or deletions, truncations, or stop-gained mutations in RB1. No differences in RB1 mutation frequency were observed between treatment arms. Overall survival (OS) with NIVO was lower in RB1MUT patients compared with RB1WT (HR = 1.46 [1.02–2.1]). RB1 mutation status was not associated with OS in patients receiving NIVO+IPI. Similar trends were observed for objective response rates. Moreover, stratifying patients based on an Rb protein LOF gene expression signature showed an association between Rb protein loss and lower OS with NIVO (HR = 1.3 [1.05–1.65]) and NIVO+IPI (HR = 1.2 [0.95–1.49]). RB1 mutation status also associated with NE transcriptional subtype (P &amp;lt; 0.0001). Stratification of patients into NE/non-NE subtypes was not associated with OS. TMB and inflammation signatures did not differ between NE and non-NE SCLC subtype or RB1 mutation status. Conclusion: This analysis of SCLC samples suggests that transcriptionally subtyping SCLC has limited clinical utility. Rb protein function, inflammatory gene signatures, and TMB may represent independent biomarkers of response to I-O in patients with SCLC, warranting further investigation to determine the predictive value of these biomarkers, alone and in combination. Citation Format: David Balli, Xuya Wang, Naiyer A. Rizvi, Timothy A. Chan, Afshin Dowlati, Parul Doshi, Han Chang. Association of retinoblastoma function with response to immuno-oncology treatment in patients with small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2047.