CD20-TCB, a Novel T-Cell-Engaging Bispecific Antibody, Can be Safely Combined with the Anti-PD-L1 Antibody Atezolizumab in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. CD20-TCB has demonstrated highly promising single-agent activity in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients (pts) (Dickinson et al. ICML 2019). Preclinical data demonstrate CD20-TCB-induced programmed cell death protein 1 (PD-1) and programmed cell death-ligand-1 (PD-L1) upregulation on T cells and tumor cells. We hypothesized that the combination of T-cell engagement by CD20-TCB and PD-L1 inhibition by atezolizumab could lead to additive anti-tumor activity in B-NHL.

We report preliminary data from NP39488 (NCT03533283), an ongoing Phase Ib study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy (objective response rate [ORR] and complete response [CR] rate per modified Lugano 2014 criteria) of CD20-TCB in combination with atezolizumab in R/R B-NHL pts. A single dose of 1000mg obinutuzumab (G) is administered on Day −7 of Cycle 1 as pretreatment (Gpt) to mitigate for potential cytokine release syndrome (CRS). CD20-TCB is initiated on Day 1 of Cycle 1 and given in a q3w schedule. From Cycle 2 onwards, atezolizumab (1200mg) is added and given on the same day as CD20-TCB. CD20-TCB dose-escalation is ongoing and is guided by the modified continual reassessment method-escalation with overdose control (mCRM-EWOC).

As of June 25, 2019, 38 pts with aggressive B-NHL (n=33; diffuse large B-cell lymphoma [DLBCL], transformed [tr] follicular lymphoma [FL], primary mediastinal large B-cell lymphoma, mantle cell lymphoma, tr lymphoplasmacytic lymphoma, tr Waldenstrom`s macroglobulinemia) or indolent B-NHL (n=5; FL) had received CD20-TCB doses from 0.07mg to currently 6mg. Pts (52.6% male) had a median age of 67 years (range: 38-82) and a median of three prior treatment lines (range: 1−10); 84% had refractory B-NHL. Two dose-limiting toxicities (Grade [Gr] 3 tumor flare at 6mg during Cycle 1 and Gr 3 myopathy at 1.8mg during Cycle 2) were transient and resolved completely. The most frequent adverse event (AE) was CRS (42%; 16/38 pts), with 24% Gr 1 (n=9), 18% Gr 2 (n=7), and no Gr ≥3 (according to Lee criteria, Lee et al. Blood 2014;124:188-95). The most common AEs (>20%) were pyrexia (37%), anemia (29%), fatigue (24%), neutropenia (21%), diarrhea (21%), and decreased appetite (21%). The most common Gr ≥3 AEs (>10%) were neutropenia (18%) and anemia (13%), with a single Gr 5 unrelated pneumonia. Three pts experienced a transient Gr ≥3 neurotoxicity (Gr 4 polyneuropathy, Gr 3 trigeminal nerve herpes zoster infection, and Gr 3 post-infection encephalopathy), all of which resolved.

Thirty-six pts reached their first response assessment or withdrew early and were eligible for efficacy analysis. Across all doses, ORR and CR rates by investigator assessment were 36% (13/36 pts) and 17% (6/36), respectively (indolent NHL: 4/5 and 3/5 pts; aggressive NHL: 9/31 and 3/31 pts). All CRs are ongoing at the time of abstract submission. CD20-TCB exposure and receptor occupancy (RO%) increased dose-dependently across the dose-range evaluated, and are expected to be further optimized (Djebli et al. ASH 2019). At the higher CD20-TCB doses investigated, a trend towards increased clinical activity was observed (ORR of 60% [9/15 pts] in the 4mg and 6mg cohorts combined).

The combination of CD20-TCB and atezolizumab has manageable safety in R/R B-NHL pts. No new safety signals or signs of increased immune-related AEs were detected, and the overall safety profile was consistent with that reported with single-agent CD20-TCB (Dickinson et al. ICML 2019). Dose escalation is ongoing and aims to optimize the dose and schedule of CD20-TCB when combined with atezolizumab using the established exposure-response model for CD20-TCB (Djebli et al. ASH 2019). Updated safety, efficacy, and biomarker data will be presented.