Hepatocellular carcinoma in the immunotherapy Era: A SEER-based era comparison across the U.S. FDA transition

In 2020, immunotherapy entered first-line care for hepatocellular carcinoma (HCC). It remained uncertain whether population-level survival improved thereafter and whether adding immunotherapy to chemotherapy in routine practice was associated with additional benefit.

A population-based SEER analysis was performed among HCC diagnosed in 2018-2022. Comparative analyses were performed between cases in the immunotherapy era (IEC) versus cases in the pre-immunotherapy era (PIEC). A prespecified chemotherapy subset compared chemotherapy + immunotherapy with chemotherapy alone. Competing-risks methods (Gray's test; Fine-Gray) were applied with cancer-related death (CRD) as the event.

In total, 12056 patients were included (PIEC 7291; IEC 4765). After matching (n = 8796), better survival was observed in IEC versus PIEC (HR 0.905, 95% CI 0.846-0.968; P = 0.004). In the matched cohort, a lower CRD risk was also observed for IEC (sHR 0.807, 95% CI 0.750-0.868; P = 7.33 × 10^-9) with a matched-strata Gray's P = 0.0105. In the chemotherapy subset (n = 3381; PSM n = 1884), the addition of immunotherapy was not associated with a statistically significant OS advantage after adjustment (HR 0.917; P = 0.166) or after matching (HR 0.914; P = 0.218), a pattern that remained consistent in the non-surgical subgroup (matched HR 0.885; P = 0.106). The matched CRD comparison was not significant (Gray's P = 0.96), whereas an unmatched Fine-Gray model suggested a protective association (sHR 0.803, 95% CI 0.701-0.919; P ≈ 0.001).

Diagnosis in the post-approval immunotherapy era was associated with modestly improved OS and lower CRD at the population level. However, because this was an era-based rather than regimen-level comparison, the observed association cannot be attributed solely to immunotherapy uptake.