Abstract 5222: Biomarkers associated with complete metabolic response (CMR) to nivolumab and brentuximab vedotin (nivo + BV) for the treatment of children, adolescents, and young adults (CAYA) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the CheckMate 744 study
Authors: Garnett-Benson Charlie , Ammar Ron , Crowe Russell , Francis Stephen , Ansari Sahar , Akyol Alev 
Published: June 2022

Introduction: CAYA with R/R cHL without CMR have suboptimal outcomes. Biomarkers associated with poor outcomes in cHL include PD-L1 overexpression and presence of tumor-associated macrophages (TAMs). In the phase 2 CheckMate 744 study (NCT02927769), CAYA with R/R cHL treated with a risk-adapted approach using nivo + BV induction showed a CMR rate per BICR of 59% (26/44) in the standard risk cohort;

41% of patients (pts) did not achieve CMR (non-CMR). Here we compared biomarker data from pts achieving CMR vs non-CMR.

Methods: Pts aged 5-30 y with R/R cHL received 4 cycles of nivo + BV induction. Tumor biopsy and peripheral blood samples were collected at baseline (BL) and 4 prespecified timepoints during induction. CD163+ CD68+ TAMs were quantified using multiplex immunohistochemistry. Cytokine expression in pts with CMR vs non-CMR was assessed by the limma workflow and a linear model based on changes from BL. Immune cells were analyzed by flow cytometry. Statistical testing was adjusted for repeated measures across visits; values are reported from 39/39 cytokines and 13/16 cell subsets tested. Cytokine ratios to BL were compared across all timepoints and between response groups by ANOVA.

Results: Pts with CMR (n = 24/26) after nivo + BV induction had more CD163+ CD68+ TAMs than pts with non-CMR (n = 17/18) in the BL tumor microenvironment (P = 0.018). Hierarchical clustering of cytokine fold changes from BL to the indicated timepoint, between pts with CMR vs non-CMR, showed reduced levels of haptoglobin, RANTES, CRP, PARC, EN-RAGE, and TARC/CCL17, and increased levels of MCP-2, IFN-γ, IP-10, and MIG. In all pts, median concentrations of TARC, IL-2Rα, CRP, and ICAM-1 decreased significantly (all P &lt; 0.05); a greater reduction in TARC and CRP was observed in early cycles in pts with CMR vs non-CMR. In contrast, IP-10 levels increased from BL in all pts (P = 0.0012). Four cytokines showed higher concentrations in pts with CMR vs non-CMR: TNFR2, MCP-2, vWF, and TIMP-1 (all P &lt; 0.05). Increased numbers of lymphocytes and monocytes and decreased numbers of granulocytes were observed after induction in all pts (all P &lt; 0.01). Pts with non-CMR had more naive (CCR7+ CD45RA+) CD4, and naive CD8 T cells than pts with CMR at BL, and more overall CD4 (CD3+ CD4+) T cells at the end of cycle 4 (all P &lt; 0.05).

Conclusions: This biomarker analysis from CheckMate 744 suggests that different immunological parameters are associated with CMR vs non-CMR to nivo + BV induction in CAYA with R/R cHL. These include increased TAMs at BL in pts with CMR, changes in cytokine levels associated with macrophage biology, and greater numbers of naive lymphocytes and CD4 T cells in pts with non-CMR. TAMs have been reported to express high PD-L1 levels; thus, increased TAM numbers may sensitize pts to nivo + BV.

Citation Format: Charlie Garnett-Benson, Ron Ammar, Russell Crowe, Stephen Francis, Sahar Ansari, Alev Akyol. Biomarkers associated with complete metabolic response (CMR) to nivolumab and brentuximab vedotin (nivo + BV) for the treatment of children, adolescents, and young adults (CAYA) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the CheckMate 744 study [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 5222.