Novel Bispecific Antibody Effective for Heavily Pretreated mCRC

Guillem Argilés, MD

Treatment with CEA-TCB (RO6958688), an investigational CEA/CD3 bispecific antibody, showed a favorable safety profile and promising efficacy in patients with heavily-pretreated microsatellite stable (MSS) metastatic colorectal cancer (mCRC), with enhanced efficacy when combined with the PD-L1 inhibitor atezolizumab (Tecentriq), according to findings presented at the 2017 ESMO World Congress on Gastrointestinal Cancer.

As a monotherapy at doses ≥60 mg (n = 31), CEA-TCB showed a partial response (PR) rate of 6% and 39% of patients had stable disease (disease control rate [DCR], 45%). When combined with atezolizumab, PRs ranged from 12% to 18%, depending on the dose of CEA-TCB administered. The DCR rate ranged from 52% to 82% in the combination group. Efficacy was demonstrated in tumors with prior resistance to immunotherapies.

“Third-line and greater colorectal cancer is a disease setting with a high unmet medical need; these patients have developed resistance and no longer respond to standard therapies. Their tumors do not respond to immunotherapy, since 95% of these patients have microsatellite stable tumors, and only 5% of these tumors respond to the current anti-cancer immunotherapeutics,” said lead author Guillem Argilés, MD, Medical Oncologist, Vall d´Hebron Institute of Oncology in Barcelona, Spain. “CEA-TCB is a new treatment option that expands the benefit of cancer immunotherapy by unlocking cancer immunity.”

CEA-TCB has a 2-to-1 binding ratio, with 1 arm of the antibody binding directly to CD3 on T cells while the remaining 2 arms simultaneously bind to CEA on the tumor. The agent induces T-cell­ engagement and activation, with T-cell proliferation at the site of activation, according to Argilés.

“This flexible 2-to-1 format enables high-avidity binding and leads to selective tumor cell killing, that is independent of pre-existing immunity,” explained Argilés. “CEA-TCB has the potential to be efficacious in a broad range of CEA-expressing solid tumors and to expand the benefit of cancer immunotherapy to more patients.”

CEA-TCB was explored across 2 studies, the first study tested the agent as a monotherapy and the second with atezolizumab. Both enrolled patients with all types of CEA-expressing tumors; however, the efficacy analysis presented at the World GI conference focused on those with mCRC. “More than 90% of patients with metastatic colorectal cancer express high levels of CEA,” Argilés noted.

A majority of patients had MSS tumors (90% in study 1 and 92% in study 2). The most common metastatic sites were the lung and liver. All patients had an ECOG performance status of 0 (61% and 52%, respectively) and 1 (39% and 48%). More than half of patients had received ≥3 prior therapies (61% and 68%).

Across all doses of CEA-TCB in the combination arm for 25 evaluable patients, the PR rate was 12% and the DCR was 52%. In those treated with 80 mg to 160 mg of CEA-TCB (n = 11), the PR rate was 18% and the DCR was 82%.

Responses at the 80 mg and 160 mg doses in the combination arm were durable and ongoing, with up to 24 weeks of follow-up for some patients. In case reports, responses were seen at 4 weeks. The median duration of response and time to response were not yet available.

“CEA-TCB at dose of 60 mg and higher demonstrated clinical activity in mCRC,” Argilés said. “CEA-TCB has demonstrated encouraging anti-tumor activity as a monotherapy that was further enhanced in combination with atezolizumab.”

Most of the 125 patients across both studies experienced an adverse event (AE) of any grade. A majority of the AEs occurred during the first 2 doses of CEA-TCB and were primarily grade 1 and 2. In the monotherapy and combination groups the most common AEs were pyrexia (58% and 71%, respectively), infusion-related reaction (IRR; 55% and 40%), and diarrhea (40% and 56%). The most common grade 3/4 AEs were IRR and diarrhea, which occurred in 18% and 5% of patients with monotherapy and 11% and 13% of patients in the combination study, respectively.

Five patients in the monotherapy trial experienced a dose limiting toxicity (DLT), including grade 3 dyspnea at 40 mg, grade 3 hypoxia at 60 mg, grade 3 diarrhea at 300 mg, grade 4 colitis at 600 mg, and grade 5 respiratory failure at 600 mg of CEA-TCB. In the combination trial, 2 patients had DLTs, including grade 3 transient ALT increase at 160 mg and grade 3 rash at 160 mg of CEA-TCB.

It was determined that grade ≥2 IRRs correlated with post-infusion IL-6 spikes. A correlation was also seen between AEs related to tumor lesion inflammation, which were correlated to the dose and the number, size, and location of the lesion.

“Intratumoral pharmacodynamics changes were observed in responding patients in the comparison of baseline and on treatment biopsies taken at week 7, that included a reduction in CEA-expressing tumor cells, increases in proliferating T cells, increased PD-1—positive T cells, and upregulation of PD-L1 on immune cells,” said Argilés.

Argilés G, et al. 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). Presented at the ESMO 19th World Congress on Gastrointestinal Cancer; Barcelona, Spain; June 28 to July 1, 2017. Abstract LBA-004.

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In the first study, 80 patients received doses from 60 mg to 600 mg weekly of intravenous (IV) CEA-TCB. The monotherapy displayed clinical activity over the range of doses and no clear correlation between CEA-TCB dose and response was established. In the second study, 45 patients received the agent from 5 mg to 160 mg plus IV atezolizumab every 3 weeks at 1200 mg. A correlation between response was seen at the 80 mg and higher doses of CEA-TCB.