Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis

Abstract

Background: Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival.

Methods: In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0-1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival.

Findings: At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7-2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3-32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3-not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable-not evaluable] vs 28·3 months [12·8-43·8]; hazard ratio 0·26 [0·10-0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable-not evaluable] vs 32·8 months [15·0-50·5]; 0·19 [0·05-0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival.

Interpretation: The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials.

Funding: None.

Figure 1:. Study profile

Figure 2:. Pathological responses of surgical samples from patients after neoadjuvant immunotherapy and association with radiological responses

(A) Pathological responses assessed in the surgical samples by percentage of tumour regression (n=104). (B) The correlation between change in tumour size based on radiological assessment (RECIST criteria [version 1.1]) and pathological response of each surgical specimen. (C) Waterfall plot for the depth of pathological response, with different bar colours according to radiological response as per RECIST criteria (version 1.1); the dashed line represents major pathological response (70% tumour regression). RECIST=Response Evaluation Criteria in Solid Tumours.

Figure 3:. Association between major pathological response and pathological complete response and relapse-free survival

(A) Forest plot representing the HRs for relapse-free survival associated with different thresholds of pathological responses in the whole cohort (n=104). (B) Kaplan–Meier curves for relapse-free survival according to the occurrence of major pathological response; vertical dashed denote censored patients (C). Forest plot showing the association between the occurrence of major pathological response and improvement in relapse-free survival within each cohort of the NeoHCC study consortium; the size of the shapes (squares and diamond) denote effects size. Patients with available pathological assessment data were included (n=104). Imperial College London and St Bartholomew’s Hospital were part of the same clinical trial (NCT03682276). Patients treated at Mount Sinai Hospital within the clinical trial or the observational clinical study were centrally assessed for pathological response and data were pooled together. (D) Kaplan–Meier curves for relapse-free survival according to the occurrence of pathological complete response; vertical dashed denote censored patients. HR=hazard ratio.