Abstract LB523: Biomarker assessment of PTEN protein expression and gene expression profiling (GEP) in a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL)

Introduction: The combination of the PI3K inhibitor copanlisib (C) plus the anti-CD20 antibody rituximab (R) has been shown to be superior to R plus placebo (P) in patients with relapsed iNHL (Matasar et al. Lancet Oncol 2021). We report here the biomarker analysis to assess correlation with response of baseline samples for PTEN expression and GEP signatures. Methods: Adult patients with relapsed B-cell iNHL were randomly assigned 2:1 to either C + R or P + R; standard dosing on a 28-day cycle applied. Either fresh or archival tumor tissues were collected for central pathology review and biomarker analysis. Extraction of the formalin-fixed, paraffin-embedded (FFPE) tissue slides was performed using the Qiagen AllPrep DNA/RNA FFPE Kit, where quality was assessed using a combination of Agilent TapeStation for integrity and ThermoFisher NanoDrop for quantity and purity. Immunohistochemistry (IHC) for PTEN expression was performed by Mosaic Laboratories (Lake Forest, CA, USA) and RNA sequencing analysis was performed by Almac Diagnostics (Durham, NC, USA). GEP was also conducted using claraT pathway signatures provided by Almac. Results: Patients with complete, very good partial, and partial objective responses were combined in a “responders” group and compared against all other patients (“non-responders” group). Data from PTEN IHC were available for 222 patients (149 for C + R; 73 for P + R). There was no statistically significant difference in response with PTEN presence or absence for the 3 subgroups - total iNHL, follicular lymphoma (FL), and non-FL. Also, baseline PTEN expression did not show significant correlation with best overall response. C + R treatment improved median progression-free survival (PFS) for all patients, with a statistically significant benefit to those with PTEN presence in all 3 subgroups. For patients treated with P + R, Kaplan-Meier plots and log-rank tests showed statistically improved median PFS in patients with PTEN absence vs PTEN presence in overall iNHL (p=0.031) and FL (p=0.0021). Data from GEP were available for 202 patients (133 for C + R; 69 for P + R). The association with best overall response and PFS was analyzed using specific biomarker gene sets and/or 23 preselected clinical parameters. Association of GEP analysis based on hypothesis-based modeling, single-gene hypothesis-free modeling, and claraT pathway signatures showed no predicted responsiveness or PFS that was statistically significant. Conclusions: C + R improved median PFS in the overall iNHL, FL, and non-FL groups, with a statistically significant improvement in the PTEN-positive population. In the P + R group, PTEN-positive patients had worse PFS in all 3 subgroups. Data from GEP and pathway analysis did not show correlation with overall response or PFS. Citation Format: Shalini Chaturvedi, Anke Schulz, Lidia Mongay Soler, Barrett H. Childs, Matthew Matasar, Pier Luigi Zinzani. Biomarker assessment of PTEN protein expression and gene expression profiling (GEP) in a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB523.