Biomarker analysis of patients with follicular lymphoma treated with ibrutinib in the phase 2 DAWN study

Abstract

Background: Ibrutinib, a first‐in‐class, oral, covalent inhibitor of Bruton's tyrosine kinase, has demonstrated robust clinical activity and is approved in various B‐cell non‐Hodgkin's lymphomas. To assess the efficacy and safety of ibrutinib in patients (pts) with follicular lymphoma (FL), the DAWN study (FLR2002, NCT01779791) investigated single‐agent ibrutinib in chemoimmunotherapy (CIT)‐refractory FL pts. Ibrutinib may exert immune‐modulatory effects on Tcell activity via inhibition of ITK, a key regulator of T‐cell activity, possibly through inhibition of T‐helper 2 (Th2)‐polarized CD4 T‐cells and activation of Th1 cells (Dubovsky, et al. Blood 2013). Here, we describe the effect of ibrutinib treatment on T‐cells and cytokines in pts in the DAWN study. Aims: To determine the effect of ibrutinib on circulating T‐cells, chemokines, and cytokines in ibrutinib‐treated CIT‐refractory FL pts. (Graph presented). Methods: The DAWN study was an open‐label, multicenter, single‐arm, phase 2 study of ibrutinib in pts with CIT‐refractory (i.e., ≥2 prior lines of therapy and progressive disease [PD] ≤12 months after last dose of a CIT regimen). All pts received ibrutinib (560mg QD) on a 21‐day cycle until PD or unacceptable toxicity. The primary end point was Independent Review Committee (IRC)‐ assessed overall response rate (ORR) (complete response [CR] + partial response [PR]). Flow cytometry assessed T‐cell subsets in peripheral blood at baseline (C1D1) and at cycle 3 (C3D1) for 57 pts (14 responders and 43 nonresponders); cytokine and chemokine analyses were performed at C1D1 and at cycle 2 (C2D1) for 50 pts (21 responders and 29 nonresponders). Results: Results from the DAWN study have been presented previously (Gopal A, et al. ASH 2016). Briefly, 110 pts with a median age of 61.5 years and a median of 3 prior therapies were enrolled. Ibrutinib achieved an ORR of 20.9% (CR rate, 10.9%) and a median duration of response of 19.4 months. Flow cytometry analysis revealed significant downregulation of CD4+CD25+CD127‐ Tregs at C3D1 in 14 responders (CR + PR, mean decrease 17 to 12.9% CD4, p=0.02) but not in 43 nonresponders (SD + PD, 11.5 to 10.4% CD4, p=0.17). From a large panel of inflammation‐related cytokines and chemokines, some of the most significant changes at C2D1 were the Th1 cytokines interferon (IFN)‐γ and interleukin (IL)‐12, both of which were increased in responders but decreased in nonresponders (p=0.0025 and p=0.035, respectively; Figure 1). Conversely, the chemokines IFN‐γ‐induced protein 10 (IP‐10) and monocytechemotactic protein 3 (MCP‐3) were decreased in responders but increased in nonresponders (p=0.022 and 0.016, respectively). Summary/Conclusions: Here we show immunomodulatory effects of ibrutinib in pts with CIT‐refractory FL, which may be related to response to therapy. In responding pts at early time points, downregulation of Tregs was observed, along with increases in Th1‐associated cytokines IFN‐γ and IL��12. This shift in T‐cell population may be linked to the antitumor response; in nonresponders, these cytokines were decreased but Tregs were not. Chemokine changes observed also indicate variation in chemoattraction of T‐cells and monocytes/ macrophages. These data suggest that immunomodulatory effects of ibrutinib could play a role in its antitumor activity in FL, so combinations with other immune‐oncology therapies may prove beneficial.