Novel carcinoembryonic antigen T-cell bispecific (CEA-TCB) antibody: Preliminary clinical data as a single agent and in combination with atezolizumab in patients with metastatic colorectal cancer (mCRC)

Abstract

Background: CEA-TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. Preclinically, CEA-TCB had potent antitumor activity, leading to increased intratumoral T-cell infiltration and activation, T-cell-mediated tumor cell killing and PD-L1/PD-1 upregulation. Methods: In 2 ongoing dose-escalation phase I studies, CEA-TCB is given asmonotherapy IVQW(S1) or in combination (QW)with atezolizumab 1200mgQ3W(S2) in patients with advanced CEA positive (≥20% of tumor cells expressing moderate or high) solid tumors. In S1, 80 patients (70 CRC) were treated at dose levels of 0.05-600 mg; in S2, 45 patients (35 CRC) at 5-160mg. In addition biomarker analysis and PK assays were conducted. Results: At doses≥ 60 mg (31 evaluable CRC patients in S1; 14 in S2), CT scans revealed signs of tumor inflammation within 48h of the 1st dose, consistent with CEA TCB mode of action. Two (6%) CRC patients in S1 (both microsatellite stable [MSS]) and 3 (21.5%) in S2 (2 MSS CRC, 1 MSI high) had confirmed partial response (PR; RECIST v1.1). Additionally, tumor reduction of≥10% tó30% (stable disease) was seen in MSS CRC patients (4 [13%] in S1 and 4 [29%] in S2). At weeks 4-6, 9 (29%) CRC pts in S1 and 7 (50%) in S2 had metabolic PR (FDG PET; EORTC criteria). At all doses in S1, the most common related AEs were pyrexia (58%), infusion-related reactions (IRRs; 55%) and diarrhea (40%). In S1 (out of 59 patients ≥ 40 mg), the most common grade ≥3 (G3) related AEs were IRRs (24%) and diarrhea (7%). Five patients experienced DLTs: G3 dyspnea, G3 diarrhea, G3 hypoxia, G4 colitis and G5 respiratory failure (G4 and G5 at 600 mg [exceeding MTD]). DLT events were likely associated by investigators with tumor lesion inflammation, per investigators. In S2, there was no evidence of new toxicities, with 2 DLTs at 160 mg (1 G3 ALT increase in a patient with liver metastases and 1 G3 maculopapular rash). Related AEs occurred mainly after doses 1 and 2. Data suggest almost linear PK in ADA negative; ADA increase CEA-TCB drug clearance and can lead to reduction or loss of exposure particularly at lower dose levels. In S1, at doses ≥ 60 mg, the OT biopsies demonstrated a significant increase (P=0.035, 3.6 fold) in Ki67+ CD3 T cells as compared to baseline (analysis ongoing for S2). Conclusions: Evidence of antitumor activity in advanced CRC was observed during dose escalation with CEA-TCB monotherapy. Enhanced activity and a manageable safety profile were seen in combination with atezolizumab. On-treatment increases of intratumoral CD3 T cells in line with the mechanism of action support that CEA-TCB is the first tumor-targeted T cell bispecific showing consistent biological activity in a solid tumor indication.