JAMA Oncol: Anti-atecilizumab antibodies are associated with poor clinical prognosis in patients with advanced liver cancer

In the IMbrave 150 trial, the combination of atecilizumab and bevacizumab (Atezo/Bev) significantly changed the treatment outlook
for advanced hepatocellular carcinoma (HCC).
Although patients who responded to Atezo/Bev showed good survival outcomes, a small proportion showed primary resistance
.

Atecilizumab is immunogenic and may cause an adverse anti-drug antibody (ADA) response
.
This can interfere with atecilizumab-mediated effects, affect drug clearance and serum concentration or induce antibody neutralization
.

The study aimed to explore the clinical and immunological correlation
between elevated ADA levels and clinical outcomes in patients with advanced hepatocellular carcinoma after treatment with Atezo/Bev.

This cohort study prospectively enrolled 174 patients
with advanced hepatocellular carcinoma receiving first-line therapy with Atezo/Bev.
Serum ADA levels (competitive enzyme-linked immunosorbent assay)
are measured before treatment and at week 3 (day 1 of the second course of treatment [C2D1]).
The main evaluation is to assess the correlation
between positive ADA and treatment outcomes and T cell function.

After excluding patients with sample incligibility, loss to follow-up, and withdrawal from the trial, 132 (found cohort: 50; 82.
0% of men, median age 61 years; Validation cohort: 82, 85.
4% male, median age 61 years) patients were included in the analysis, of which 23 (17.
4%) patients detected a strong response to ADA at C2D1 (≥1000 ng/mL).

ADA levels at C2D1 were significantly higher in progressive patients than in responding patients (median level: 65.
2 vs 0 ng/mL).

Progression-free survival and overall survival in patients with different ADA levels in both cohorts

Both in the discovery and validation cohorts, high ADA levels at C2D1 were associated with reduced response rates with Atezo/Bev treatment compared with patients with low ADA levels (found cohort: 34 versus 11 percent; Validation cohort: 29 versus 7 percent), shorter progression-free lifetime (HR: discovery cohort: 2.
84, p=0.
005; validation cohort: 2.
52, p=0.
006), and shorter overall lifetime (HR: discovery cohort: 3.
30, p=0.
003; validation cohort: 5.
81, p=0.
001).

In multivariate Cox regression analysis, the clinical significance of high ADA levels remained after adjusting for various confounders, and was most significant
at levels of 1000 ng/mL or higher.
Patients with high ADA levels had reduced serum concentrations of atezozumab, impaired proliferation of CD8-positive T cells, and decreased
γ-interferon and α-tumor necrosis factor in CD8-positive T cells compared to patients with low ADA levels.

Taken together, the study found that in patients with advanced hepatocellular carcinoma treated with Atezo/Bev, a high elevation in ADA levels on day 1 of the second course of treatment may be associated with
a poor clinical prognosis.
High ADA levels may reduce exposure to atelizumab, which in turn weakens the anti-cancer effect
of the drug.

Original source:

Kim C, Yang H, Kim I, et al.
Association of High Levels of Antidrug Antibodies Against Atezolizumab With Clinical Outcomes and T-Cell Responses in Patients With Hepatocellular Carcinoma.
JAMA Oncol.
Published online October 20, 2022.
doi:10.
1001/jamaoncol.
2022.
4733