BLOCKADE OF THE PD‐1 CHECKPOINT WITH ANTI–PD‐L1 ANTIBODY AVELUMAB IS SUFFICIENT FOR CLINICAL ACTIVITY IN RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA (CHL)

Abstract

Introduction: Classical Hodgkin Lymphoma (cHL) is frequently accompanied by the 9p24.1 amplicon, which contains the PD-L1 and PD-L2 immune checkpoint genes and results in their overexpression. Blockade of PD-1/PD-L1 and PD-1/PD-L2 interactions with anti-PD-1 antibodies is clinically effective; however, it has not been established if blockade of the PD-1/PD-L1 interaction alone is sufficient for therapeutic effect. Avelumab is a fully human IgG1 monoclonal antibody that selectively binds to PD-L1, leaving the PD-1/PD-L2 interaction intact, thus enabling assessment of the contribution of PD-L2 in the clinical response to PD-1 checkpoint blockade. Methods: In the phase 1 JAVELIN Hodgkin study (NCT02603419), eligible patients (pts) with histologically confirmed cHL were required to have disease progression following either autologous (auto) or allogeneic (allo) stem cell transplant (SCT), or to be SCT-ineligible. Pts were randomised in equal proportions across 5 avelumab dosing regimens: 70 mg, 350 mg, 500 mg Q2W, 500 mg Q3W, or 10 mg/kg Q2W. Endpoints included safety (NCI CTCAE v4.03) and the objective response rate (ORR) by Response Criteria for Malignant Lymphoma. Results: As of Feb 9, 2017, 31 pts were randomised and had a median age of 38 years (range 22-81). Five and 8 pts had disease progression following auto-SCT and allo-SCT, respectively; the remaining pts were SCT-ineligible. Pts received a median of 6 cycles (range 1-23) of avelumab to date. In 30 pts analyzed for safety, the most common treatment-related adverse events (TRAEs) of any grade were infusion-related reaction (IRR; 26.7%), nausea (20.0%), rash (20.0%), and fatigue (13. 3%).Two pts (6.7%) discontinued treatment due to IRR. Grade ≥ 3 TRAEs occurred in 11 pts (36.7%); there were no treatment-related deaths. Two pts who had received prior allo-SCT developed grade 3 liver graft vs host disease (GVHD), which completely resolved after immunosuppressive therapy and discontinuation of avelumab. ORR across all 31 pts was 54.8% (95% CI 36.0-72.7) with 2 complete responses (CRs; 6.5%) and 15 partial responses (PRs; 48.4%). Responses were observed in all dosing groups (ORR range 14.3%-83.3%). ORR in the 5 post-auto SCT pts was 20.0% (95% CI 0.5-71.6) with 1 PR. ORR in the 8 post-allo SCT pts was 75.0% (95% CI 34.9-96.8) with 1 CR (12.5%) and 5 PRs (62.5%). Conclusions: Avelumab appears to have clinical activity with an acceptable tolerability profile in pts with heavily pretreated cHL. The ORR was similar to that observed with PD-1 inhibitors, indicating that targeting PD-L2 may not be necessary or sufficient for the therapeutic effect observed following PD-1 checkpoint blockade in cHL. The high ORR observed in the post-allo SCT setting suggests that checkpoint inhibitors may enhance the graft vs lymphoma response; however, more mature data are required to assess the benefit-risk of PD-1 checkpoint blockade regarding GVHD in this setting.