In a randomised, controlled, phase II study conducted to investigate the efficacy and safety of adjuvant use of a PD1 inhibitor following hepatectomy in patients with hepatocellular carcinoma (HCC) with microvascular invasion (MVI), adjuvant treatment with sintilimab substantially improved recurrence-free survival (RFS) compared to active surveillance. Furthermore, the results of subgroup analysis provide additional evidence of the advantages associated with adjuvant sintilimab irrespective of tumour characteristics. Specifically, benefits were present even in patients with tumour diameter >5 cm, multiple tumours or high-risk MVI grade.
The findings also indicate that adjuvant sintilimab has acceptable safety and good tolerability according to Drs. Yan-Fang Liu and Shu-Qun Cheng of the Naval Medical University in Shanghai, China, and study colleagues who published the findings on 19 January 2024 in the Nature Medicine.
Patients with MVI, characterised by the presence of tumour cells within small blood vessels adjacent to the primary tumour, have a higher risk of recurrence after HCC resection. This highlights the pressing need for effective adjuvant treatment to complement hepatectomy and improve outcomes, specifically in this high-risk subgroup of patients.
Previous investigations on adjuvant treatment options for HCC have predominantly focused on tyrosine kinase inhibitors (TKIs), with particular emphasis on sorafenib, a multikinase inhibitor that impedes angiogenesis and tumour cell proliferation. Despite initial enthusiasm, the current data on the efficacy of adjuvant sorafenib seem to be contradictory. The inconclusive outcomes emphasise the need for additional exploration and optimisation of adjuvant treatment strategies to address the specific challenges posed by MVI in patients with HCC.
Compared to TKIs, immune checkpoint inhibitors (ICIs) have distinct advantages as adjuvant treatment following hepatectomy. ICIs not only mitigate the risk of early recurrence by eliminating hidden residual disease, but also stimulate the immune system to decrease the occurrence of new-onset HCC. The IMbrave050 is a recent landmark study examining the effectiveness of atezolizumab in combination with bevacizumab compared to active surveillance as adjuvant treatment for high-risk HCC following resection or local ablation with midterm analysis yielding positive results.
In the latest study published in the Nature Medicine, the study team hypothesised that ICIs could reduce the risk of postoperative recurrence in patients with HCC with MVI. This multicentre, open-label, randomised, controlled phase II study was conducted to provide valuable insights into the role of ICIs in the adjuvant context. It was conducted at 6 hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a PD1 inhibitor, in these patients.
Eligible patients with HCC with MVI were randomised 1:1 into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of 8 cycles. The primary endpoint was RFS in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety.
From 1 September 2020 to 23 April 2022, a total of 198 eligible patients were randomly allocated and 99 received adjuvant sintilimab and 99 underwent active surveillance. After a median follow-up of 23.3 months, the study met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance with median RFS of 27.7 versus 15.5 months (hazard ratio 0.534, 95% confidence interval 0.360–0.792; p = 0.002). Considering the relatively short follow-up duration, further follow-up is needed to confirm the difference in OS.
Regarding safety, more than half of the patients in the sintilimab group in this study experienced at least one treatment-related adverse event (TRAE), with anaemia, pyrexia, fatigue, and increased ALT levels being the most common. However, only 8.1% of patients discontinued sintilimab due to AEs. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 TRAEs, the most common of which were elevated ALT levels (5.2%) and anaemia (4.1%).
The authors emphasised that although the conclusions are similar, their study has some differences in comparison to the IMbrave050. The IMbrave050 study enroled high-risk patients who had undergone either liver resection or radiofrequency ablation, whereas this study focused on patients with HCC complicated by MVI, a subgroup known for higher risk of early recurrence. In terms of treatment, IMbrave050 used the current first-line treatment for HCC, the combination of atezolizumab and bevacizumab and the current study used a single-agent PD1 inhibitor.
In terms of duration of treatment, IMbrave050 researchers have adopted the approach of administering maintenance immunotherapy for 1 year while in the current study, the study team chose a 6-month regimen of maintenance adjuvant treatment, which showed good safety and effectiveness. They reasoned that using an effective short-term monotherapy as adjuvant treatment would considerably alleviate the financial burden, especially in developing countries. Furthermore, a shorter duration of treatment can enhance patient compliance, and this improved adherence may, to a certain extent, improve the patients’ prognosis. The results of ongoing phase III studies, such as KEYNOTE-937 and CheckMate 9DX are eagerly anticipated.
The authors underlined that further efforts are needed to optimise the use of PD1 inhibitors, including identifying predictive biomarkers and determining the optimal timing and duration of treatment. Furthermore, the specific use of immune-based adjuvant treatment with PD1 or PD-L1 inhibitors and the potential need for synergistic combinations with other therapeutic modalities require continued exploration.
This work was supported by the National Key Research and Development Program of China, Shanghai Municipal Health Commission, and the National Natural Science Foundation of China.
Reference
Wang K, Xiang Y-J, Yu H-M, et al. Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial. Nature Medicine; Published online 19 January 2024. DOI: https://doi.org/10.1038/s41591-023-02786-7