Nivolumab-ipilimumab combo plus surgery improves survival in HCC

Patients with potentially resectable hepatocellular carcinoma (HCC) may receive neoadjuvant nivolumab plus ipilimumab therapy, followed by surgery, to improve their survival, suggests a study.

Moreover, an association has been observed between immunotherapy-induced tertiary lymphoid structure (TLS) formation and enhanced antitumour immunity.

“TLS induction within the tumour microenvironment plays a critical role in mediating the antitumour immunity induced by nivolumab plus ipilimumab therapy,” the investigators said. “Monitoring T-cell activation/exhaustion status in peripheral blood may help predict responses to immunotherapy.”

Forty-three patients met the eligibility criteria of this study and received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks. Tumour response was evaluated after two and four treatment cycles. After receiving immune checkpoint inhibitor (ICI)-based combination therapy, the patients underwent curative surgery or alternative treatments according to clinical guidelines.

The investigators then obtained serial tumour and peripheral blood samples for genomic and transcriptomic analyses and immune cell profiling.

Of the enrolled patients (37 men, 41 viral, 26 Barcelona Clinic Liver Cancer stage C, median tumour size 8.7 cm), 24 underwent surgery, and eight had a major pathological response (>90-percent tumour necrosis). [J Hepatol 2026;84:316-328]

At 4 years, the estimated progression-free survival rate was 44 percent (95 percent confidence interval [CI], 28‒59), while that of overall survival was 60 percent (95 percent CI, 42‒74). Objective response was significantly associated with increased interferon-γ and TLS signatures.

“In a mouse liver cancer model, B-cell depletion abolished the efficacy of anti-programmed death-1 (anti-PD-1) plus anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) therapy, supporting the mechanistic role of TLS,” the investigators said.

Furthermore, peripheral blood T-cell activation and exhaustion at baseline and postimmunotherapy, assessed using spectral flow cytometry and deep learning algorithms, were associated with both response and survival.

“Findings … indicate that neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may improve long-term survival in patients with potentially resectable HCC, immunotherapy-induced TLS formation is associated with enhanced antitumour immunity, and monitoring T-cell exhaustion in peripheral blood may aid in the prediction of response to immunotherapy,” the investigators said.

Neoadjuvant therapy

Due to the presence of the primary tumour as a source of tumour-related antigens, neoadjuvant ICI therapy may provide a stronger antitumour immune response than adjuvant therapy. [Hepatology 2021;74:483-490]

In patients with advanced melanoma, neoadjuvant anti-CTLA-4 plus anti-PD-1 therapy delivers more robust radiographic and pathological responses and increase event-free survival relative to anti-PD-1 monotherapy. However, higher doses of anti-CTLA-4 tend to increase the incidence of grade ≥3 immune-related adverse events (irAEs). [JAMA Oncol 2024;10:612-620; N Engl J Med 2024;391:1696-1708]

“In the present study, a lower dose of ipilimumab than that approved by the US FDA for advanced-stage HCC was employed to mitigate the risk of irAEs, and importantly, the occurrence of irAEs did not appear to delay surgery,” the investigators said.

“Future neoadjuvant regimens will need to further optimize safety profiles to increase the likelihood of tumour downstaging and curative surgery,” they added.