Progress in the integration of radiation therapy and checkpoint inhibition in hepatocellular carcinoma

Management of hepatocellular carcinoma (HCC) remains a major challenge in clinical oncology. In addition to surgery, including liver transplantation, a range of effective local-regional/liver-directed therapies (LDTs) are available, including transarterial embolization, thermal ablation, and radiation therapy. Patient selection is key and multidisciplinary input is essential. Nonetheless, disease progression following LDT is common, both within the untreated liver as well as at distant sites. Vascular invasion by HCC in particular is associated with poor outcomes (1). Current Barcelona Cancer Liver Clinic (BCLC) guidelines call for patients with portal involvement by HCC (BCLC stage C disease) to be treated with systemic therapy (2). Local-regional therapies including surgery can play a role in selected patients with macrovascular invasion, but progression of disease both within and outside of the liver is common (3).

In line with established paradigms in the management of other solid tumors, the optimal treatment of HCC for many patients will potentially involve the combination of local and systemic therapies. Going beyond additive effects, synergy between local and systemic therapies for HCC would be ideal. Meaningful progress on the systemic front, however, has been incremental. For many years sorafenib, a tyrosine kinase inhibitor (TKI) with effect on multiple kinases, was the dominant agent for patients with advanced disease, although with modest survival benefits and notable toxicities (4). In recent years, however, sorafenib has been supplanted by more effective immunotherapy combination regimens that offer the possibility of long-term survival in a subset of patients. In the phase 3 IMBrave150 trial, the combination of bevacizumab and the programmed cell death ligand 1 (PD-L1) antagonist atezolizumab demonstrated improvement in overall and progression-free survival (PFS) versus sorafenib and also demonstrated improvements in secondary endpoints including response rate and quality of life (5). About 80% of the patients enrolled in this study had BCLC stage C disease, which reflects vascular invasion and/or extrahepatic metastatic disease. The dual immunotherapy regimen of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) also improved overall survival compared to sorafenib in the HIMALAYA phase III trial (6). Immunotherapies are also being applied in HCC management in traditional neoadjuvant and adjuvant approaches, with early signs of efficacy (7-10).

In the toolbox of LDTs, radiation therapy has proven to be a potent and valuable option for selected patients, including those with more advanced BCLC states such as macrovascular invasion. Concerns about treating patients with HCC in the setting of cirrhosis and other co-morbid conditions have been allayed by the use of high-precision, high-accuracy treatments often involving image-guidance, along with advanced X-ray or particle therapy delivery (11,12). High-dose proton beam therapy was recently shown to be non-inferior to radiofrequency ablation for the management of small, limited HCC, and in the RTOG/NRG 1112 trial, the sequential combination of radiation and sorafenib improved overall survival compared to sorafenib alone in a cohort of high-risk patients, most of whom (74%) had macrovascular invasion (13,14). The main issue, as with other application of other LDTs, has been continued progression of disease at non-targeted sites. Of great interest, however, is the potential synergy between radiation and immune checkpoint inhibitor therapy, as has been demonstrated in multiple preclinical models (15-17). This synergy holds the promise of enhanced disease eradication at directly irradiated sites as well as unirradiated macro- and micrometastatic disease (abscopal response). Clinical trials investigating this combination are active in a number of disease sites. Results to date show mixed findings, likely a reflection of multiple complex interactions between radiation therapy, the host immune response, and immunomodulating agents (18,19). Signals of synergy remain unpredictable, and the impact on survival outcomes is uncertain.

In the phase II NEXTRAH trial, Kim et al. investigated the combination of nivolumab and external beam radiation therapy (EBRT) in the treatment of 50 patients with HCC with macrovascular invasion (20). About half of the patients enrolled had some form of prior HCC-directed therapy, but only 10% had undergone prior systemic therapy. Ninety-four percent of patients had portal vein invasion, with smaller proportions having hepatic vein and caval involvement. The primary endpoint of the study was PFS. Patients were treated with 30–50 Gy of EBRT (median dose: 50 Gy) in conjunction with nivolumab delivered every 2 weeks. The PFS was 5.6 months, which compares to a PFS of 4 months for patients treated with nivolumab alone in the CheckMate 040 study and 3.7 months in the CheckMate 459 trial (21,22). High-grade toxicity was relatively minimal, with 6 (12%) of patients experiencing grade 3 or 4 treatment-related adverse events (5 cases of transaminitis and 1 case of pneumonitis). Toxicity was also minimal in a separate study of radiation followed by nivolumab or ipilimumab plus nivolumab (23). Of note, in a post hoc analysis comparing patients treated with proton beam versus X-ray therapy, improved overall survival was seen in the proton-treated group (16.9 vs. 9.1 months). Proton therapy can improve liver sparing relative to X-rays and may mitigate treatment-related lymphopenia relative to X-rays, possibly leading to superior antitumor immune response (24).

As a single-arm phase II study, and in the absence of correlative studies, a direct demonstration of synergy between the radiation and immune checkpoint inhibition approach in this study is not possible. The combination of these therapies was safe, but median PFS was <6 months, and long-term (2-year) PFS was <20%. Crucially, since the majority of patients in NEXTRAH had not received prior systemic therapy, it is important to view these results in the context of the evolving treatment landscape of systemic therapy for HCC. In IMbrave150, bevacizumab and atezolizumab achieved a median PFS of 6.8 months in patients with advanced disease, although direct comparison with the patients in NEXTRAH is of course challenging (5). Notably, the combination of EBRT with bevacizumab and atezolizumab demonstrated acceptable safety and a median overall survival of 16.1 months in a retrospective study (25).

Therefore, we are left with many questions which should provide fuel for further clinical and translational study. Probably the primary question is how to best combine EBRT and immune checkpoint inhibition to maximize any potential synergies. This a highly complex issue with numerous variables at play (26,27). These variables include but are not limited to timing of the therapies (concurrent or in some sequential form), radiation dose (high-dose/ablative versus lower-dose) and fractionation (single- versus multi-fraction), extent of radiation targeting (in patients with more than one macroscopic site of disease—irradiate a limited number or all sites?), and type of radiation therapy (X-rays? Ion beam therapy?) given the potential impact of different radiation modalities on circulating leukocytes. How do we use host and tumor-associated factors to predict responsiveness? These questions may also have different answers in the setting of other immunotherapy approaches not involving checkpoint inhibition. Studies attempting to uncover these answers will require a delicate balance, as the potential for increased toxicity, particularly in a population with often baseline compromised liver function, warrants caution. However, the data from NEXTRAH indicate that combining EBRT and checkpoint inhibition is a safe platform from which to build.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-83/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-83/coif). M.Y. has received grant/research support (to institution) from Bristol-Myers Squibb, Exelixis, Incyte, and Genentech, honoraria from Genentech, Exelixis, AstraZeneca, Replimune, Hepion, and Lantheus, support from Genentech for attending meetings and/or travel; and has numerous patents, owned and managed by Johns Hopkins University, equity in Adventris Pharmaceuticals. J.J.M. has received royalties from UpToDate and Springer, grant/research support (to institution) from Boston Scientific. The other author has no conflicts of interest to declare.

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