Avelumab in Combination Regimens for Relapsed/Refractory DLBCL: Results from the Phase Ib JAVELIN DLBCL Study

Abstract

Background Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. Objective The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. Methods This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. Results Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. Conclusions The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. ClinicalTrials.gov Identifier NCT02951156. Key PointsAvelumab, an anti-programmed death ligand 1 (PD-L1) antibody, was assessed in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in combination with therapies hypothesized to augment antitumor immunity.The low level of clinical activity for avelumab combinations suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL.

Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers – how to push the gas after having released the brake

“…Interestingly, clinical activity correlated with increased levels of peripheral activated memory/effector CD8 + T cells. Also, other combination regimen of utomilumab with mogamulizumab (anti-CCR4) or avelumab (anti-PD-L1) appeared to be safe, but anti-tumour activity remained relatively small ( 99 , 100 ). Based on these experiences a very diverse landscape of second-generation 4-1BB agonists has recently been developed, with many entering clinical Phase 1 and 2 trials ( 101 ).…”

Epigenetic targets in B- and T-cell lymphomas: latest developments

“…However, due to insufficient clinical activity, the study was prematurely discontinued. 85 High levels of cytidine deaminase (CDA) were reported to decrease the half-life of decitabine and azacytidine. 131,132 Based on this observation, the effect of tetrahydrouridine (THU), a CDA inhibitor, was evaluated in relapsed B-and T-cell malignancies (NCT02846935, see Table 1).…”

Harnessing the Immune System: An Effective Way to Manage Diffuse Large B-Cell Lymphoma

“…In a multicenter, randomized, open-label, parallel-arm Ib study 29 adult patients with R/R DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and _zacytidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). As the antitumor activity in arms A and B was minimal (one PR in arm A, no responses in arm B and three CRs in arm C) the study was discontinued [ 24 ].…”