Adjuvant immunotherapy in hepatocellular carcinoma: effective for Asian only, or for all patients?

Surgical resection and ablation are curative therapeutic approaches in hepatocellular carcinoma (HCC). However, the risk of recurrence after hepatic resection remains high, occurring in 40% to 70% of patients (1). Risk of recurrence increases with tumor size, number of lesions, level of serum alpha-fetoprotein (AFP), and the presence of vascular invasion (2,3). Currently, there is no regulatory approval for adjuvant treatment, neither intra-arterial treatment nor systemic treatment, due to the lack of demonstrated benefit.

The larger global study conducted to date in this setting evaluated sorafenib versus placebo. The phase 3 randomized STORM trial (4) failed to reduce relapse-free survival, the primary endpoint. One thousand one hundred and fourteen patients were randomized to treatment with sorafenib or placebo for a maximum of 4 years. The median duration of treatment in the sorafenib arm was only 12.5 months, suggesting poor tolerance of long-term sorafenib in this setting, which probably limited the potential for reducing recurrence. Median recurrence-free survival (RFS) was 33.3 months [95% confidence interval (CI): 27.6–44.0] for patients who received sorafenib and 33.7 months (95% CI: 27.6–39.0) for patients who received placebo [hazard ratio (HR) =0.940; 95% CI: 0.780–1.134, one-sided P=0.26]. These results, despite the high unmet need for the adjuvant setting of HCC, did not justify proposing adjuvant treatment rather than surveillance only (5).

In advanced stage, immunotherapy emerged as a new standard of care for HCC. Thus, it is currently evaluated in the adjuvant setting, with now two randomized trials having reported preliminary results.

The first to present results was the global phase 3 randomized trial IMbrave050 (6), which compared active surveillance versus atezolizumab plus bevacizumab for 1 year, for 662 patients with a resected of ablated HCC with a high risk of recurrence. Patients considered at high risk of recurrence were those with ≤3 tumors with one >5 cm, or ≥4 tumors less than 5 cm or presence of vascular invasion and/or low differentiation, or for tumors ablated (≤4 tumors between 2 and 5 cm).

RFS was significantly improved (adjusted 95% CI: 0.53–0.98; P=0.012), but the median was not reached in both arms, due to the short follow-up (median follow-up: 17.4 months). Moreover, after 12 months of treatment, the curves seemed to get closer, and long-term benefit was very uncertain. Overall survival (OS) data was immature. Toxicity was mainly related to bevacizumab. These results were encouraging but should be taken with caution. Physicians await more follow-up and data for overall survival before including such a strategy in clinical practice.

The recent report of another randomized trial conducted in China added significant information in this context (7). This randomized phase 2 trial evaluated a 6-month regimen of sintilimab, an anti-PD-1 antibody, versus active surveillance for resected HCC patients. One hundred and ninety-eight Chinese patients were randomized. In this population, 75.8% in the active surveillance arm and 70% in the sintilimab arm had hepatitis B; more than half had a tumor size up to 5 cm (51.5% in the surveillance group and 58.6% in the sintilimab group); 40.4% patients had microvascular invasion in the sintilimab arm versus 44% in the surveillance arm. This represents a population at high risk of recurrence of HCC, which is the adequate population to test adjuvant treatment.

The median RFS was significantly improved (HR =0.534; 95% CI: 0.360–0.792; P=0.002), with a median of 27.7 months (95% CI: 25.6 months–not reached) in the sintilimab group and 15.5 months (95% CI: 10.7–22.3 months) in the active surveillance group. The 1-year RFS rate in the sintilimab group was 76.8% (95% CI: 68.9–85.6%), compared to 55.6% (95% CI: 46.6–66.3%) in the active surveillance group. Very interestingly, albeit the follow-up is still relatively short, and in contrast to IMbrave050, the OS data does suggest some trends for potential benefit of immunotherapy. The safety profile is as expected for an anti-PD-1 monotherapy. Most adverse events (AEs) were grade 1 or 2; 12.4% of patients experienced grade 3 or 4 AEs, the most common were elevated transaminases and anemia.

In the advanced setting, the global phase 3 trial of pembrolizumab Keynote-240 failed to demonstrate statistically significant benefit over placebo despite a clear trend, while the phase 3 trial conducted in Asia with a similar design, Keynote-394, did result in significant results (8,9). The Keynote-240 included 24% of patients from Asia (without Japan), in which the OS was significantly improved (HR =0.59; 95% CI: 0.37–0.95), while the Keynote-394 included 85% of patients from China, with 15% from Korea and Malaysia. This might suggest that including a more homogeneous population might improve the chance of positivity of the trial. There might be differences in efficacy of immunotherapy driven by the differences in the population included. There were initial concerns about the different efficacy according to etiology, notably with experimental data suggesting lower efficacy, notably in the population suffering from non-alcoholic steatohepatitis (10). However, recent analysis of data from clinical trials does not suggest less efficacy in non-viral HCC (11). While no population seems clearly to derive no benefit of chemotherapy, this benefit seems to be more prominent in male, patients with macrovascular invasion and/or extrahepatic spread, or non-viral etiology (12). Moreover, regarding recurrence of HCC, and competitive risks of other complications of HCC, the results might differ in China as opposed to the Western world. As hepatitis B virus (HBV) is the main etiology in China, with a risk of HCC without cirrhosis, and with the potential benefit of HBV treatment to prevent recurrence, conducting trials in different populations is important to rule out differences in efficacy according to patients’ population. In the adjuvant setting, the data of the trial by Wang et al. suggest that benefit and reduces the risk of recurrence in a high-risk selected Chinese population with an acceptable safety profile (7). In the IMbrave050, there did not seem to be more effect in the Asian population, with a similar or better trend for benefit in the rest of the world (HR =0.61) as compared with the Asia-Pacific region (HR =0.80).

The optimal duration of adjuvant therapy has still to be determined, as atezolizumab-bevacizumab was administered for 1 year but seems to be associated with loss of effect afterward, while sintilimab was a 6-month regimen with prolonged benefit. Also, the role of combination therapy, more effective in the advanced setting, should be better studied. Finally, neoadjuvant approaches might also be of interest and further studied.

Other phases III trials are ongoing to evaluate immune checkpoint inhibitors in this setting with other anti-PD-(L)1 antibodies, such as nivolumab with the CheckMate 9DX trial (NCT03383458); pembrolizumab with the KEYNOTE-937 trial (NCT03867084) and durvalumab +/− bevacizumab with the EMERALD-2 trial (NCT03847428). These different clinical trials, as the longer follow-up of the IMbrave050 trial might help to better understand the true value of immunotherapy in the adjuvant setting: is it providing cures in patients from all regions of the world, or is the benefit limited to specific populations, such as the Asian 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-24-54/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-54/coif). J.E. has received consulting fees from Roche, AstraZeneca, MSD, BMS and support for attending meetings from Roche, AstraZeneca and MSD. The other author has 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.

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