A real-world study of the efficacy of second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor.

Objective: The incidence and mortality of hepatocellular carcinoma are still high according to National Cancer Center of China. Atezolizumab plus bevacizumab has become one of the standard regimens for the first-line treatment of unresectable hepatocellular carcinoma. However, some patients still use lenvatinib in combination with immunotherapy instead of a standard "atezolizumab-bevacizumab" regimen as a lower risk of bleeding in patients with esophagogastric varices. However, there is no evidence for second-line therapy after progression on lenvatinib combined with PD-1 inhibitor in unresectable hepatocellular carcinoma till now. Herein, we aim to investigate second-line treatment among these patients.

Methods: Thirty-three patients with unresectable hepatocellular carcinoma with esophagogastric varices were admitted to the Second Affiliated Hospital of Nanchang University from January 2019 to December 2023. They were treated with lenvatinib in combination with PD-1 inhibitor as first line. The efficacy was conducted according to the RECIST1.1 criteria. The endpoints included objective response rate (ORR), disease control rate (DCR), median overall survival (OS), and median progression free survival (PFS).

Results: We identified a total of 225 patients with unresectable hepatocellular carcinoma with esophagogastric varices who received first-line lenvatinib in combination with PD-1 inhibitor, of whom 33 (14.7%) received second-line therapy. 21 patients (63.6%) were treated with regorafenib combined with PD-1 inhibitor, 6 patients (18.2%) with apatinib plus PD-1 inhibitor, 4 patients (12.1%) with bevacizumab plus PD-1 inhibitor, and the remaining 2 patients with regorafenib or sorafenib as monotherapy, respectively. Of the 33 patients, 2 (6.1%) were evaluated as partial response (PR), 16 (48.5%) had stable disease (SD), and 15 (45.4%) experienced progression (PD). The ORR was 6.1%, and the DCR was 54.6%. Median PFS was 4.5 months, median OS was 7.2 months, and the 12-month OS rate was 27.3%. Overall survival follow-up was done in 37 patients without second line treatment whose baseline levels were matched with those of the treatment group. The OS was 7.2 months in second line treatment group versus 3.0 months in control group (p = 0.04). As for different treatments in a second line, The ORR of regorafenib in combination with PD-1 inhibitor was 9.5%, the DCR was 47.6%, the median PFS was 4.2 months, and the median OS was 5.9 months. None of the patients treated with apatinib plus PD-1 inhibitor got PR, the DCR was 83.3%, the median PFS was 8.7 months, and the median OS was 9.1 months. None of the patients treated with bevacizumab plus PD-1 inhibitor got PR, the DCR was 25.0%, the median PFS was 2.2 months, and the median OS was 6.0 months.

Conclusions: The second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor is effective. Regorafenib or apatinib combined with PD-1 inhibitor might be the preferred options.