CEA-CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. Preclinically, CEA-CD3 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.
In 2 ongoing dose-escalation phase I studies, CEA-CD3 TCB is given as monotherapy IV QW (S1) or in combination (QW) with atezolizumab 1200 mg Q3W (S2) in pts with advanced CEA positive (> 20% of tumor cells expressing moderate or high) solid tumors. In S1, 80 pts (70 CRC) were treated at dose levels of 0.05-600 mg; in S2, 45 pts (35 CRC) at 5-160 mg.
At doses ≥ 60 mg (31 evaluable pts with CRC in S1; 14 in S2), CT scans revealed signs of tumor inflammation within 48 h of the first dose, consistent with CEA-CD3 TCB mode of action. 2 (6%) CRC pts in S1 (both microsatellite stable [MSS]) and 3 (21.5%) in S2 (2 MSS CRC, 1 MSI high [out of 2]) had confirmed partial response (PR; RECIST v1.1). Additionally, tumor reduction of − 10% to − 30% (stable disease) was seen in MSS CRC pts (4 [13%] in S1 and 5 [36%] 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 (56%), infusion-related reactions (IRRs; 50%) and diarrhea (40%). In S1 (out of 59 pts > 40 mg), the most common grade ≥ 3 (G3) related AEs were IRRs (24%) and diarrhea (7%). Five pts 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 with tumor lesion inflammation, per investigators. In S2, there was no evidence of new or additive toxicities, with 2 DLTs at 160 mg (1 G3 ALT increase in a pt with liver metastases and 1 G3 maculopapular rash). Updated data will be presented.
Evidence of antitumor activity in advanced CRC and other CEA-expressing tumors was observed during dose escalation with CEA-CD3 TCB monotherapy. Enhanced activity and a manageable safety profile was seen in combination with atezolizumab.
Clinical trial identification
Legal entity responsible for the study
F Hoffmann-La Roche Ltd.
F Hoffmann-La Roche Ltd.
N.H. Segal: Advisory board and research funding from Genentech/Roche, MedImmune/AstraZeneca, Bristol-Myers Squibb, Merck and Pfizer. J. Saro: Employee of Roche and stock holder of Roche. I. Melero: Advisory board: Bristol-Myers, Roche-genentech, AstraZeneca, Lilly, Merck Serono, Bayer, Genmab, Alligator, Bioncotech, Tusk Grants from: Roche-Genetech, Bristol-Myers, Bioncotech. A. Marabelle: PI: Roche, Bristol-Myers Squibb, Merck, Pfizer, Lytix, Eisai, Astra Zen Kyowa Kirin Pharma, Novartis, Bristol-Myers Squibb, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Seattle Genetics, Flexus Bio, Pierre Fabre, Onxeo, Bayer, Daichii Sankyo, Imaxio, Sanofi, BioNTech. J.M. Cleary: Research funding to his institution from Merrimack Pharmaceuticals, Taiho Oncology, Merck, Roche, Abbvie, Precision Biologics, and Bristol-Myers Squibb. V. Karanikas, S. Bouseida, F. Sandoval, D. Sabanes: Roche employee. S. Sreckovic: Roche employee and in a possession of Roche stock. H.I. Hurwitz: Honoraria: Roche and Lilly Consultant: Roche, Bristol-Myers Squibb, Lilly, Novartis, Incyte, TRACON Pharma, Acceleron Pharma, GlaxoSmithKline, OncoMed Institutional Funding: Roche, GlaxoSmithKline, Novartis, TRACON Pharma, Bristol-Myers Squibb, Regeneron, Lilly, Macrogeneics, NCI. L. Paz-Ares: Scientific Advise to Roche, Bristol-Myers Squibb, MSD, AstraZeneca, Novartis, Lilly, Pfizer and Merck AG. J. Tabernero: Advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. All other authors have declared no conflicts of interest.