Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC).

Abstract

3002 Background: CEA CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. In preclinical models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and upregulates PD-1/PD-L1. Methods: Intwo ongoing dose-escalation phase I studies, RO6958688 is given as monotherapy (S1) i.v. QW or in combination (QW) with atezolizumab 1200 mg Q3W (S2) in adult patients (pts) with advanced CEA+ solid tumors. In S1, 80 pts (mCRC: 68) were treated at dose levels from 0.05 mg to 600 mg; in S2, 38 pts (mCRC: 28) from 5 mg to 160 mg. In S1, a Bayesian logistic regression model with overdose control guided dose escalation. Data cutoff 25.01.17. Results: At doses ≥60mg (36 pts in S1; 10 in S2), CT scans revealed tumor inflammation within days of first dose, consistent with the mode of action of RO6958688. 2 (5%) pts in S1 (both microsatellite stable (MSS) and 2 (20%; 1 MSS) in S2 had a partial response (RECIST v1.1). Preliminary tumor size reduction ( > -10% and < -30% [stable disease]) was observed in 4 (11%) additional pts in S1 and 5 (50%) in S2. At week 4-6 FDG PET scan assessment, 10 (28%) pts with mCRC in S1 and 6 (60%) in S2 had a metabolic partial response (EORTC criteria). At all doses in S1, the most common related AEs were pyrexia (56.3%), infusion related reaction (IRR, 50%) and diarrhea (40%). The most common grade ≥ 3 (G3) related AEs were IRR (16.3%) and diarrhea (5%). 5 patients experienced DLTs: G3 dyspnea, G3 diarrhea, G3 hypoxia, G4 colitis and G5 respiratory failure (G4-5 at 600mg). DLT events were likely associated with tumor lesion inflammation. In S2, there was no evidence of new or additive toxicities, with 1 DLT at 160 mg (G3 transient increase of ALT in a patient with liver metastases). PK/PD data are reported separately. Conclusions: Evidence of antitumor activity was observed with RO6958688 monotherapy in ongoing dose escalation. Activity appeared to be enhanced with doses in combination with atezolizumab, with a manageable safety profile. Updated data will be presented. Clinical trial information: NCT02324257 and NCT02650713.

A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities

“…In contrast, solid tumors may take longer treatment (e.g., months) to have significant impact on tumor burden . Therefore, for solid tumors, synapse concentration is mainly determined by the drug concentration during cytokine release (Eq.…”

Immunotherapy in colorectal cancer treatment: actual landscape and future perspectives

“…Klein et al [48] recently evaluated carcinoembryonic antigen (CEA)-IL2v (RG7813), an engineered IL-2 variant (IL-2v) with abolished IL-2Rα (CD25) binding fused to an antibody targeting CEA to increase immune infiltration and activates NK and T cells both in the periphery and within tumors. In two ongoing dose-escalation phase I studies, Tabernero et al [49] proved the antitumor activity of CEA CD3 TCB (RG7802, RO6958688), a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells, in 11% of adult patients with advanced CEA+ solid tumors who received RG7802 as monotherapy and in 50% of patients to whom the antibody was given in combination with with atezolizumab 1200 mg Q3W.…”

Some aspects of immunotherapy in colon cancer

“…Объективный эффект и контроль болезни в группе монотерапии зарегистрированы у 6 и 45 % пациентов соответственно, в группе комбинации -у 18 и 82 %. У 5 больных была зарегистрирована дозолимитирующая токсичность, включающая одышку, диарею, гипоксию, колит, дыхательную недостаточность, которые в большинстве своем являлись проявлениями провоспалительного действия исследуемого препарата [64].…”