Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial
Open accessAbstract
Background Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma.Methods In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed.Findings Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab.Interpretation Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma.Funding Bristol Myers Squibb and the US National Institutes of Health.
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In the nivolumab-ipilimumab study, ipilimumab was more effective in patients with cold tumours.
“the study of nivolumab–ipilimumab revealed that ipilimumab is more effective in patients with cold tumours, supporting the theory that CTLA4 blockade might be most beneficial in patients lacking pre-existing antitumour immunity15.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [15]
The Discussion reports that nivolumab plus ipilimumab generated major pathological responses in tumours with low baseline immune infiltration, whereas nivolumab alone required high baseline infiltration. But it presents this as a finding to test further and says the small study was not powered to formally compare outcomes between arms; the claim’s definitive statement that ipilimumab was more effective overstates the evidence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe estimated duration of neoadjuvant approaches is around 6-8 weeks, though longer time frames might be justified based on a regimen's clinical activity.
“The estimated duration of neoadjuvant approaches — aimed to achieve a balance between exposure to ICIs and prevention of tumour progression — is estimated to be around 6–8 weeks, but longer time frames might be justified based on clinical activity of a regimen13,15.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [15]
The Methods (Procedures; page not available) schedule surgery at week 6, and the Discussion (page not available) suggests that some patients might have developed a response with continued treatment. The paper does not estimate a general 6–8-week duration for neoadjuvant approaches or establish that this duration balances ICI exposure against tumour progression. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe use of ICIs as neoadjuvant treatment before liver resection for patients with hepatocellular carcinoma has been explored in several single-centre phase 1 and 2 clinical trials.
“The use of ICIs as a neoadjuvant treatment before liver resection for patients with hepatocellular carcinoma has been explored in several single-centre phase 1 and 2 clinical trials.”
From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [8]
The Methods (Study design and participants; page unavailable) describe a single-centre phase 2 trial of nivolumab with or without ipilimumab before liver resection in patients with hepatocellular carcinoma. That supports the claim's general point, but this paper documents one phase 2 trial, not several phase 1 and 2 trials. (LLM, conf=0.86)
Experimental — accuracy not yet measuredClinical studies have been inconsistent with the choice of a cutoff of major pathological response, with some studies adopting 70% and other studies adopting 90%, and the 70% threshold has not received multicentre validation.
“Clinical studies have been inconsistent with the choice of a cutoff of major pathological response, with some studies adopting 70%7,8,25 and other studies adopting 90%,9,10 and the 70% threshold has not received multicentre validation.”
From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [8]
The Discussion (page unavailable) reports one patient with major pathological response and more than 70% necrosis, and describes this as a small, single-centre study. It does not establish 70% as the study’s cutoff for major pathological response or assess whether that cutoff has received multicentre validation. The citations attached to the 90% cutoff refer to other studies, not this one. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEarly-phase clinical studies of neoadjuvant immune-checkpoint inhibitors in hepatocellular carcinoma, as monotherapy or combination therapy, have reported favourable outcomes.
“In parallel, early phase clinical studies testing ICIs in HCC, either as monotherapy or in combination, in the neoadjuvant setting have reported favourable outcomes13–15.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [15]
In a study of perioperative nivolumab with or without one dose of ipilimumab in HCC, significant tumour necrosis occurred in 33% of 9 nivolumab-treated patients and 27% of 11 nivolumab-ipilimumab-treated patients.
“Significant tumour necrosis occurred in 33% of 9 patients treated with nivolumab and 27% of 11 patients treated with nivolumab–ipilimumab.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [15]
CTLA4 blockade might be most beneficial in patients lacking pre-existing antitumour immunity.
“the study of nivolumab–ipilimumab revealed that ipilimumab is more effective in patients with cold tumours, supporting the theory that CTLA4 blockade might be most beneficial in patients lacking pre-existing antitumour immunity15.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [15]
Preoperative use of ICIs in patients with hepatocellular carcinoma has been explored in several small, early-phase studies, in which heterogeneous therapeutic combinations were tested, mainly with safety and feasibility being the primary endpoints assessed.
“Preoperative use of ICIs in patients with hepatocellular carcinoma has been explored in several small, early-phase studies, in which heterogeneous therapeutic combinations were tested, mainly with safety and feasibility being the primary endpoints assessed.7–12”
None of these studies were individually powered to robustly investigate predictive factors of efficacy from neoadjuvant ICI therapy, particularly long-term survival outcomes including relapse-free survival.
“However, none of these studies were individually powered to robustly investigate predictive factors of efficacy from neoadjuvant ICI therapy, particularly with regards to long-term survival outcomes, including relapse-free survival.”
These pioneering studies have shown the safety and feasibility of a perioperative ICI treatment approach.
“Collectively, these pioneering studies have shown the safety and feasibility of a perioperative ICI treatment approach.7–12,25”
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References 35 · Cited by 274
Research works printed but not linked: 2
- [7]Yau T, Park JW, Finn RS, CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Annals of Oncology. 2019; 30: 874-+.
- [21]Sangro BMI, Yau T, Safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma: interim analysis of dose-escalation cohorts from the phase 1/2 CheckMate 040 study. Presented at: 10th Annual International Liver Cancer Association Conference; September 9–11, 2016; Vancouver, Canada. Abstract O–019..
- Authors
- Kaseb, A. O., Hasanov, E., Cao, H. S. T., Xiao, L., Vauthey, J.-N., Lee, S. S., Yavuz, B. G., Mohamed, Y. I., Qayyum, A., Jindal, S., Duan, F., Basu, S., Yadav, S. S., Nicholas, C., Sun, J. J., Singh Raghav, K. P., Rashid, A., Carter, K., Chun, Y. S., Tzeng, C.-W. D., Sakamuri, D., Xu, L., Sun, R., Cristini, V., Beretta, L., Yao, J. C., Wolff, R. A., Allison, J. P., & Sharma, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kaseb, Ahmed Omar
- Sharma, Padmanee
- ORCID
- Kaseb, Ahmed Omar
- Hasanov, Elshad
- Cao, Hop Sanderson Tran
- Xiao, Lianchun
- Vauthey, Jean-Nicolas
- Lee, Sunyoung S
- Mohamed, Yehia I
- Qayyum, Aliya
- Jindal, Sonali
- Duan, Fei
- Basu, Sreyashi
- Yadav, Shalini S
- Nicholas, Courtney
- Sun, Jing Jing
- Rashid, Asif
- Chun, Yun Shin
- Tzeng, Ching-Wei David
- Xu, Li
- Sun, Ryan
- Beretta, Laura
- Yao, James C
- Wolff, Robert A
- Allison, James Patrick
- Sharma, Padmanee
- Venue
- The Lancet Gastroenterology & Hepatology
- Publisher
- Elsevier BV
- Published
- 2022-03
- Volume
- 7
- Issue
- 3
- Pages
- 208-218
- ISSN
- 2468-1156 (ISSN-L)
- 2468-1253
- PMC
- PMC8840977
- OpenAlex
- W4205460569
- Cited by
- 274
- References
- 35
- Citations by year
- 2026: 42 · 2025: 74 · 2024: 67 · 2023: 62 · 2022: 29
- FWCI
- 34.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet. Gastroenterology & hepatology (acceptedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P30CA016672, P50 CA217674)
- Bristol-Myers Squibb
- University of Texas MD Anderson Cancer Center
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- nivolumab, ipilimumab, perioperative immunotherapy, adjuvant immunotherapy, neoadjuvant immunotherapy, immune checkpoint inhibitors, combination immunotherapy, safety and tolerability, adverse events, progression-free survival, overall response, resectable liver cancer, immune-related adverse events, alanine aminotransferase elevation, hyperinflammation
- MeSH terms
- Antineoplastic Agents, Immunological, Ipilimumab, Nivolumab, Progression-Free Survival, Aged, Alanine Transaminase, Antineoplastic Combined Chemotherapy Protocols, Aspartate Aminotransferases, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Perioperative Care
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