Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a bicenter retrospective study

Introduction Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. However, only scant data are available on the potential of immunotherapy as a second-line option after a prior ICI-based systemic therapy. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combinations.

Aims We aim to provide a proof of principle of effectiveness of sequencial checkpoint inhibitor combination treatment in HCC as a basis for future studies.

Methods The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies between January 2020 and December 2021 at two tertiary centers in Germany was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed.

Results Of 94 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, eight patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (75%) HCC and a preserved liver function as defined by Child-Pugh A (75%). None of the patients showed a radiographic response to prior immunotherapy. At a median follow-up of 13.1 months, ORR to ipilimumab and nivolumab was 25% with a DCR of 37.5%. Median PFS was 2.9 months, whereas the median OS was 7.5 months. Immune-related adverse events (irAE) of all grades occurred in 37.5% of patients with one grade III irAE.

Conclusion This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination treatments. This data provides the rationale for the prospective clinical evaluation of anti-PD-1/CTLA-4 combinations in patients who had received prior treatment with atezolizumab and bevacizumab or other PD-1/PD-L1 inhibitor-based combinations.

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Table 2 Overall response per RECIST v1.1 and mRECIST.

Variable	RECIST v1.1% (n)	mRECIST% (n)
Overall response rate	25 (2)	25 (2)
Complete response	0 (0)	0 (0)
Partial response	25 (2)	25 (2)
Stable disease	12.5 (1)	12.5 (1)
Disease control rate	37.5 (3)	37.5 (3)
Progressive disease	62.5 (5)	62.5 (5)
Ongoing response at cut-off	25 (2)	25 (2)

Table 1 Patient baseline characteristics.

Median age, range (years)	61 (31–82)
Female, n (%)	4 (50%)
HCC etiology, n (%)
Hepatitis B	2 (25%)
Hepatitis C	1 (12,5%)
Alcoholic	1 (12,5%)
NASH	1 (12,5%)
Idiopathic/non cirrhotic	3 (37,5%)
BCLC stage, n (%)
B	1(12,5%)
C	6 (75%)
D	1 (12,5%)
Extrahepatic metastases, n (%)	6 (75%)
Macrovascular invasion, n (%)	3 (37,5%)
AFP≥1000 μg/L, n(%)	5 (62,5%)
Child Pugh Grade
A	6 (75%)
B	1 (12,5%)
C	1 (12,5%)
ALBI grade
1	5 (62,5%)
2	2 (25%)
3	1 (12,5%)
Baseline ECOG performance status
0–1	7 (87,5%)
2	1 (12,5%)
Prior IO combination therapy
Atezolizumab with bevacizumab	5 (62,5%)
Nivolumab with lenvatinib	3 (37,5%)
Best response to prior IO combination therapy by RECIST v1.1
SD	5 (62,5%)
PD	3 (37,5%)
Lines of systemic therapies prior to ipilimumab+ nivolumab, n (%)
1	5 (62,5%)
2	1 (12,5%)
3 or more	2 (25%)
Therapies prior to any IO, n (%)
Prior local ablation	0 (0%)
Prior surgery	3 (37,5%)
Radiotherapy/TARE	1 (12,5%)
TACE	1 (12,5%)
Prior systemic treatment with TKI	3 (37,5%)
Sorafenib	3 (37,5%)
Cabozantinib	2 (25%)
Regorafenib	1 (12,5%)

ALBI, albumin-bilirubin grade; AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; IO, immunotherapy, NASH, non-alcoholic steatohepatitis; PD, progressive disease; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TKI, tyrosine kinase inhibitor.

 

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Publication History

Article published online:
19 August 2022