Clinical and molecular characterisation of primary refractoriness to atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma

Background

Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant and poorly understood clinical challenge.

Methods

We analysed 1296 patients with HCC and Child-Pugh A liver cirrhosis treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by Society for the Immunotherapy of Cancer (SITC) criteria as progressive disease in the first 6 months after treatment initiation. Patients who achieved complete response, partial response or stable disease for ≥ 6 months were classified as responders. We performed a multi-parametric analysis of pre-treatment tumour tissue including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry and RNA sequencing (RNAseq) to evaluate differences in the tumour microenvironment (TME) of PRef versus responding patients. We employed conditional inference tree analyses to provide a hierarchical organisation of determinants of PRef.

Results

Among 677 AB-real and 378 trial patients evaluable by SITC criteria, PRef identified inferior median OS in comparison with responding patients (AB-real: 7.3 vs. 31.5 months, HR 3.7, 95%CI 2.8–8.5, p<0.001; Trials: 10.8 vs. NR, HR 4.6, 95%CI 3.3–6.3, p<0.001). PRef patients exhibited higher baseline systemic inflammation (neutrophil-to-lymphocyte ratio, NLR ≥3), a distinctively immunosuppressive TME enriched in CD163 ⁺ tumour-associated macrophages and a higher T ^reg /T ^eff ratio. RNAseq of tumour tissue demonstrated lower intrinsic immunogenicity in PRef samples, characterised by repressed IFN-γ and T ^eff signatures, with elevated myeloid infiltration. Conditional inference tree analysis identified IFN-γ signature downregulation combined with NLR ≥3 as the strongest contributor of PRef.

Conclusions

PRef to A+B identifies a distinct biological entity characterised by unopposed systemic inflammation, myeloid cell infiltration and T-cell depletion. Targeting myeloid-mediated immunosuppression, particularly in patients with low IFN-γ signature expression and elevated NLR might enhance responsiveness to A+B.

Highlights

• Primary refractoriness to atezolizumab plus bevacizumab in hepatocellular carcinoma, as defined by SITC criteria, is associated with poor clinical outcomes.

• Tumour microenvironment profiling reveals an immunosuppressive phenotype characterized by high myeloid infiltration, reduced interferon-γ signalling, and T-cell depletion.

• The combination of systemic inflammation and low IFN-γ signature expression strongly predicts primary refractoriness and may inform therapeutic decision-making.