Teamwork makes the dream work?—dissecting the role of triple therapy: radiotherapy combined with sintilimab plus bevacizumab for hepatocellular carcinoma and malignant portal vein invasion

Life expectancy for patients affected by unresectable hepatocellular carcinoma (HCC) has significantly improved in the last 5 years, thanks to the introduction of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in clinical practice. For the first time, the combination of bevacizumab and atezolizumab in the ImBrave150 trial demonstrated, a survival benefit over sorafenib, standard-of-care pharmacological treatment in patients with advanced HCC (1).

Various combinations of PD-1/PD-L1 blockade agents, associated or not with antiangiogenics, have later proved their efficacy in first line treatment of advanced HCC, including the combination of sintilimab, an anti PD-1 antibody, and bevacizumab studied in the ORIENT-32 phase III trial (2). While available regimens undeniably increased the probability of survival, some tumor features still have a significantly negative prognostic impact on long-term survival and still constitute an unsolved treatment challenge.

In particular, malignant portal vein tumor thrombus (PVTT) characterized by the tumoral involvement of the portal vein, is one of the tumor features associated with a worse prognosis, to the point that patients with extensive involvement of portal vein trunk or superior mesenteric vein involvement have often been excluded from phase 3 trials (2,3).

Different strategies have been used and analyzed to address the challenge of effectively treating extensive portal vein tumor infiltration, mainly including the combination of systemic and loco-regional treatments to control both advanced HCC and PVTT. A wide variety of treatment options have been reported in this setting, including transarterial radioembolization (TARE) (4), hepatic arterial infusion chemotherapy (5), and radiotherapy (6).

Unfortunately, the majority of data reported so far for treating this tumor feature come from retrospective studies, which are intrinsically hampered by selection bias (7).

Among the few prospective data, Zhu et al. recently published the report of a multicenter, single-arm phase 2 study investigating the efficacy of sintilimab plus bevacizumab combined with external radiotherapy as first-line treatment in patients with HCC and PVTT (8).

Main exclusion criteria included the neoplastic invasion of the superior mesenteric vein, presence of extrahepatic metastasis, infiltrative HCC, and significant liver dysfunction (Child-Pugh class B or C); while the key inclusion criterion was the presence of PVTT up to grade III according to the Cheng’s classification (9) which is characterized by PVTT extending till the main portal vein associated with a limited intrahepatic tumor burden.

The trial was conducted on 46 patients with HCC and portal vein tumor (PVT) in three different tertiary hospitals in China.

All patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) as per the ORIENT-32 trial schedule and intensity modulated radiotherapy (IMRT), administered in 10 fractions between 30–50 Gy, started after the second cycle of sintilimab plus bevacizumab. After the end of IMRT, systemic treatment was withheld for 2 weeks and then restarted with the same schedule until either disease progression, unacceptable toxicity, or withdrawal of consent.

The majority of patients had a hepatitis B virus (HBV) infection (82.6%) and were mainly male (89.1%) with a median age of 53 years. Notably, more than half of the population had Cheng’s type I or II PVTT, while only 45.7% had Cheng’s type III, importantly no information regarding the number of cirrhotic patients was reported.

This study primarily aimed to assess the efficacy and safety of this treatment. Table 1 shows the efficacy outcomes evaluated during the study compared to available retrospective and prospective evidence (10-12).

The majority of patients, 27 out of 46 (58.7%) in this trial, achieved an objective radiological response (ORR) according to mRECIST (modified Response Evaluation Criteria in Solid Tumors) criteria, notably including 5 (10.9%) complete response with a median duration of response of 6.2 months after an overall 26.0 months period of follow-up.

Interestingly, the dose intensity, meaning the ratio of drug received from the patient compared to the one meant to be received, was 100% for Sintilimab and 88.9% for bevacizumab, a significantly higher figure than what was previously reported in trials on advanced HCC.

Only 2 patients did not experience any adverse event (AE) during the study, while 65.2% of the patients experienced a severe AE (grade ≥3). The most common severe AEs were a decrease in platelet count (n=4, 8.7%) and arterial hypertension (8.7%). Despite not being severe, 45.7% of the patients developed an increase in either aspartate aminotransferase (AST) or alanine aminotransferase (ALT), 28.3% developed hypoalbuminemia, and 26.1% had hyperbilirubinemia of any grade during the trial. In a translational analysis, the authors performed a whole-exome gene sequencing for all 46 patients showing how PCMTD1 gene mutation was associated with worse overall and progression-free survival.

Although promising some results of this trial need a critical analysis. First of all, the primary outcome of the study, ORR, and disease control rate (DCR) were surprisingly high at 58.7% and 100%, respectively. Remarkably, these results were much higher than the 30% and 70% previously reported by multiple trials on PD1/PD-L1 blockade plus anti-vascular endothelial growth factor (VEGF) and also higher than results from retrospective studies on radiotherapy plus systemic treatment. However, it is crucial to underline that prospective trials on frontline systemic treatment included patients with extrahepatic disease in up to 73% of the cases in the ORIENT-32 (2); this selection bias influences the radiological response outcome which should not be compared with those reported by frontline systemic therapy.

Secondly, in terms of safety, 28% of patients experienced a decrease in albumin of any grade, and 43.5% of them showed an increase in ALT serum levels compared to the 8%, and 26.5% respectively reported in the ORIENT-32 trial. This demonstrates that the addition of radiotherapy to sintilimab plus bevacizumab is not without cost it is known that radiation-induced liver disease (RILD) affects up to 66% of the patients exposed to radiation therapy (13). Although in this trial the risk of RILD is mitigated by the use of IMRT and no patient enrolled in this trial experienced severe consequences due to the aforementioned side effects, we must carefully weigh the impact of RILD. We know that cirrhotic patients are more prone to complications from RILD (14), therefore considering that the population included in the trial was mainly composed of non-cirrhotic patients we must not overlook this risk.

Another key point to be pointed out is the high prevalence of limited grade PVTT (1–2 according to Cheng’s type) compared to a similar trial (12). Patients enrolled in this trial achieved a 24.0-month median overall survival and a 13.8-month progression-free survival. Despite these figures being remarkable considering the population enrolled, these numbers are surely positively influenced by the selection of a high number of low grade PVTT, which is known to be associated with a better outcome compared to the infiltration of the main portal vein which still constitutes the main therapeutical challenge.

Furthermore, the tolerability and safety of this combination treatment in cirrhotic patients and patients with other etiologies without rapid effective etiological therapies is still to be proven.

Lastly, as discussed by the authors, the geographically limited enrollment represents an obstacle to the generalizability of the results.

Conclusions

In this paper, Zhu et al. provide much needed data on the use of combined systemic treatment and radiotherapy in patients with HCC and tumor portal vein infiltration. Most interestingly, they were able to provide prospectively generated data which is lacking in this setting. The results that emerged from this trial are certainly intriguing, in particular, the authors reported a 24-month local DCR of 80.4%, which is particularly impressive both in absolute percentage and in duration of response.

These findings confirm that advanced HCC with PVTT, which is still associated with a dismal prognosis in patients with advanced HCC, might represent a potential target for the combination of radiotherapy and systemic treatment. However, since it is not correct to compare outcomes both in terms of response or survival with available evidence from trials in advanced HCC, it is reasonable to imagine that future studies should either compare their results with alternative treatments for non-metastatic HCC with PVTT, such as TARE or only pharmacological combination therapy, which is the current standard of care. Despite in this setting, overall survival remains the relevant endpoint, new trials could consider also reporting the local disease control and the conversion rate to curative treatment, which yields clinical significance in the era of multimodal treatment and therapeutic hierarchy (15) and despite not necessarily impacting overall survival, it might generate a limited number of long-term survivors also in this unfavorable patient population.

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-24-43/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-43/coif). F.P. received honoraria in the past 2 years from AstraZeneca, Bayer, Bracco, Esaote, Eisai, Exact Sciences, GE, Ipsen, MSD, Roche, Samsung, and Siemens Healthineers for attending advisory boards, speaker bureaus, and consultancies. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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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