Immunotherapy for hepatocellular carcinoma: a “CRAFITY” approach to patient stratification

Hepatocellular carcinoma (HCC) is a challenging cancer predominantly arising on the background of cirrhosis of viral or non-viral origin. Thus, whilst the treatments for viral hepatitis have improved dramatically over the last 10 years, the obesity epidemic, and the associated rise in metabolic-associated (non-alcoholic) fatty liver disease (MAFLD), means that the incidence of HCC is increasing and better treatments for HCC are required. Whilst surgical treatment can be curative, it is often not a realistic option due to the stage of HCC at presentation. For many years the standard of care for unresectable HCC was sorafenib. The development of immunotherapy has been a landmark in cancer treatment. These therapies unleash cytotoxic T cell responses to cancer using antibodies that block T cell checkpoints (e.g., PD-1/PD-L1 and CTLA4). These agents rapidly gained approval for use in many different cancers. Initial studies in HCC using these molecules were encouraging, but not conclusive, and although these treatments were approved for use in the USA, did not garner worldwide approval as first-line treatments for HCC (1,2). However, in a landmark trial of unresectable HCC (IMbrave150) published in 2020, the combination of the PD-L1 blocking antibody Atezolizumab, and the VEGF inhibitor Bevacizumab, demonstrated a significant survival benefit over sorafenib, and has become the current standard of care (3).

With advent of new and successful therapeutics comes the question of how best to manage the use of these agents in the real world. In the current era of personalised medicine one key goal is to identify patients who will gain the most, and the least, benefit from these new agents. Scheiner and colleagues have attempted to answer this question in a retrospective study of individuals treated with either anti-PD1 or anti-PD-L1 (4). They studied a heterogeneous group of 292 patients with unresectable HCC from 14 European centres who had received at least one of these agents. Using a training cohort of 190 patients and a validation cohort of 102, they identified that a combination of alpha-fetoprotein (AFP) and C reactive protein (CRP) can predict the probability of response to therapeutic antibodies directed to PD1 and PD-L1. They have called this the CRAFITY (CRP and AFP in ImmunoTherapY) score.

The main strength of the study is that they have investigated parameters that are readily available to the clinical community. The parameters investigated were aetiology, whether the immunotherapy was gives as first-line treatment or after other therapeutics, Childs-Pugh class, ECOG performance status, radiological criteria including macrovascular invasion and the presence of extrahepatic metastasis, and laboratory values for AFP and CRP. In univariate analysis only AFP >100 ng/mL, CRP >1 mg/mL, performance status and Childs-Pugh class were significantly associated with overall survival. The AFP and CRP remained significant in multivariate analysis and were used to derive the CRAFITY score. In this clinical score one point was awarded for AFP >100 ng/mL and one for CRP >1 mg/mL, thus categorising the cohort into three groups scoring 0 (AFP <100 ng/mL and CRP <1 mg/mL), 1 (AFP >100 ng/mL or CRP >1 mg/mL) or 2 (AFP >100 ng/mL and CRP >1 mg/mL). In the training cohort of 156 individuals, they showed that the CRAFITY score predicted overall survival and also radiological response. Those with a CRAFITY score of 0, 1 or 2 had median survivals of 27.6, 11.3, and 6.4 months respectively. In the validation cohort the median survivals were 21.7, 13.9, and 8.4 months respectively. The concordance statistic (C-statistic) which provides an overall measure of the predictive accuracy of the score was a modest 0.62 and for both the training and validation cohorts. Additionally, the CRAFITY score correlated with radiological response, although as a retrospective study these radiological investigations were not standardized. The authors rationalize the utility of the score because CRP is a marker of on-going local and systemic inflammation, and both CRP and AFP may affect immune functions.

Whilst this is a good-sized study, including both training and validation cohorts, the retrospective nature of the work has led to the study of a heterogeneous cohort of individuals, and a lack of prospective criteria for inclusion. This is important as immunotherapy appears to be less beneficial in individuals with MAFLD (5). Obese individuals have impaired immune responses and so grouping into broad viral and non-viral categories may not sample the detail required to give the CRAFITY score a clinical utility within this group (6). Certainly, in the era of personalized medicine, it is now possible to sample the tumour directly and identify its immune characteristics. HCC has been separated into detailed molecular subclasses and it is of note that in the two major classes the proliferative and non-proliferative subtypes, high levels of AFP is associated with the proliferative class, and elevated CRP with the non-proliferative class (2). However, HCC can be further categorised based on immunological, epigenomic, genomic and histopathological features, and thus there is an opportunity for more detailed molecular diagnostics to stratify patients for available therapeutics (7). This approach is academically attractive, however in order for a full molecular stratification to be tenable diagnostic tests require wide availability and standardisation of molecular techniques, backed up by robust clinical data.

One variable that challenges any approach to stratification in HCC is the rapidly expanding field of immunotherapy, compounded by the opportunities for using different immunotherapy combinations (8). A simple score is unlikely to capture the nuances of novel combinations of new immunotherapy drugs, and this study did not consider the current standard of care of Atezolizumab and Bevacizumab. It is not clear how the addition of a VEGF inhibitor will change the utility of the CRAFITY score. Thus, whilst this study has identified some readily measurable parameters for patient stratification, the clinical utility of this score in the fast moving immunotherapy world is perhaps best summarised by the authors own conclusions that the CRAFITY score may “help with patient counselling, but prospective validation is required.” Until such validation is performed with current therapeutics, it is unlikely that it will form a key decision-making tool in the management of patients with HCC.

Acknowledgments

Funding: The author received funding through the CRUK Accelerator Award “HUNTER”.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2021-32/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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