Abstract CT082: Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints
Authors: Chaturvedi Shalini , Weispfenning Anke , Bauer David , Du Rong , Descamps Tine , Bellinvia Sara , Lunt Teresa , Soler Lidia Mongay , Childs Barrett H. , Zinzani Pier Luigi 
Published: April 2023

Introduction: The PI3K inhibitor copanlisib (C) plus the anti-CD20 antibody rituximab (R) was superior to R plus placebo (P) in patients (pts) with relapsed iNHL (Matasar et al. Lancet Oncol 2021). We previously reported that C+R improved median progression-free survival (PFS) in the iNHL, follicular lymphoma (FL), and non-FL groups, with a statistically significant improvement in the PTEN-positive population (Shalini et al., AACR 2022). Here we conducted NGS analysis from pts treated with either C+R or P+R for possible impact on PFS outcomes. We also determined if there was an association between plasma cytokine levels at baseline with survival.

Methods: Adult pts 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. NGS was conducted using the TSO500 platform for 476 genes. Analyses included EZH2 and BCL2 mutation status in FL subset, and other genes for FL subsets and overall iNHL, as prognostic and predictive markers. The effect of mutations on PFS and overall survival (OS) outcomes was assessed. Cytokines from baseline plasma were assessed using the multiplex MSD platform (71-plex). Association between cytokine levels and PFS and OS were explored.

Results: Baseline tumor samples were evaluable by NGS from 200 pts; 127 C+R and 73 P+R. Variant alleles with frequencies &gt;10% were analyzed. One quarter (25.7%) of FL pts were determined to have EZH2 mutations. C+R treatment significantly improved PFS for FL pts with in mutant EZH2 (p=0.0066) compared to P+R. FL pts with mutant BCL2 had a statistically improved PFS compared to WT BCL2 when receiving C+R treatment. Plasma samples were available for 71-plex assessment in 373 pts; 246 C+R and 127 P+R. Pts were assigned as high or low baseline cytokine groups based on the median values. For majority of cytokines, the low cytokine group correlated with better PFS for all pts, FL and Other iNHL pts in the C+R arm. For OS, there were too few events at the time of primary data cutoff to make any associations. However, with longer follow up (2 years from primary completion) there was a significant improvement in OS in iNHL pts with low IL2 values at baseline receiving C+R compared to pts receiving P+R; HR 0.495 (95%CI: 0.270,0.908), p=0.0230. This association was only seen for pts with low (or undetected) levels of IL2 at baseline.

Conclusions: Mutation status was associated with improvements in PFS in FL pts with mutant BCL2 or mutant EZH2 treated with C+R. iNHL pts with low plasma levels of IL2 levels treated with C+R showed a significant improvement in OS.

Citation Format: Shalini Chaturvedi, Anke Weispfenning, David Bauer, Rong Du, Tine Descamps, Sara Bellinvia, Teresa Lunt, Lidia Mongay Soler, Barrett H. Childs, Pier Luigi Zinzani. Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT082.