Clinical outcome after complete response with immunotherapy in hepatocellular carcinoma.
Authors: Chen Pin-Jung , Kournoutas Ioannis , Sanford Alison , Kim Naomy , Adetyan Hasmik , Rezaee-Zavareh Mohammad Saeid , Kuo Alexander , Ayoub Walid , Kaymen Emily , Hendifar Andrew Eugene , Tran Nguyen H. , Yang Ju Dong 
Published: January 2025

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Background:
Immunotherapy has shown great efficacy in hepatocellular carcinoma (HCC). No clear consensus exists on when to stop the immune checkpoint inhibitor (ICI) after complete response (CR), and clinical course after stopping ICI remains unknown.
Methods:
We identified 138 HCC patients who received ICI at Cedars-Sinai Medical Center and Mayo Clinic Rochester from 2016-2023. Modified Response Evaluation Criteria In Solid Tumors (mRECIST) was used to assess treatment response. We further described the clinical course of patients who achieved CR after ICI discontinuation, including cancer recurrence, subsequent treatment, liver transplantation (LT) listing and outcomes.
Results:
The median age at ICI initiation was 68 years; 79% were male; 55.9% were white; 51.5% were BCLC stage C. 9.4% CRs, 25.4% partial responses, 39.9% stable diseases, and 25.4% progressive disease. Hepatitis C etiology was associated with higher likelihood of CR (P=0.005). Among 13 patients who achieved CR, 10 stopped ICI (60% for LT evaluation, 40% for toxicity). After stopping ICI, 40% had recurrence (Table). 3 patients underwent local therapy for recurrent HCC within Milan criteria and 1 patient restarted ICI for recurrence beyond Milan criteria. Among CR patients, 9 patients underwent LT evaluation after stopping ICI and 7 patients were waitlisted. After listing, 3 dropouts were observed, due to recurrent HCC beyond Milan criteria, sepsis leading to death, and personal preference. 4 patients underwent LT. 2 patients underwent local therapy before LT for recurrent HCC (Table). All transplanted patients had the last dose of ICI more than 1 year before LT (12, 21, 24, and 29 months). On explanted livers, 2 patients had no residual viable tumor and 2 patients had residual HCC within Milan criteria. 1 patient developed acute cellular rejection and was treated with immunosuppressants and maintained stable graft function. None had graft loss or evidence of HCC recurrence in the follow-up period at 8, 20, 28, and 51 months.
Conclusions:
Immunotherapy demonstrated excellent effects on a subset of HCC patients, including 9.4% who achieved CR. After stopping ICI, 40% had cancer recurrence but 3 out of 4 were within Milan criteria. 4 underwent successful LTs (2.9%) with excellent post LT outcome. Larger prospective data is needed to establish a protocol for ICI use, especially to determine the optimal timing for ICI discontinuation after CR.

BCLC at ICI initiation
ICI cycles before stopping, ICI
Recurrence after last ICI (days)
Within Milan at recurrence
Treatment(s) received after recurrence and outcomes
OS (days)

Patient 1
B
7, Nivolumab
730
No
Nivolumab. Died from GI bleeding
1065

Patient 2
B
64, Atezo/Bev
149
Yes
TACE with CR, followed by LT without recurrence.
1203

Patient 3
A
8, Nivolumab
1393
Yes
Y90 with CR. No recurrence.
1984

Patient 4
C
NA, Pembrolizumab
407
Yes
TACE and MWA with CR, followed by LT without recurrence.
1722