This prospective study was designed to evaluate the efficacy and safety of ramucirumab, particularly considering the shift in treatment of advanced HCC to the combination of Atez/Bev and lenvatinib. Although we were unable to reach its planned enrollment, it provided valuable data on the use of ramucirumab in the current treatment landscape for advanced HCC.

The primary endpoint of the study, the 6-month PFS rate for ramucirumab, was 14.3%, with a median PFS of 3.7 months, which was generally consistent with the efficacy of ramucirumab in the REACH-2 trial. The swimmer’s plot data showed that only 5 of 17 patients had disease progression at the first radiological evaluation, identifying them as “early progression patients,” indicating that ramucirumab achieved a degree of disease stabilization in a significant proportion of the participants. In actual clinical practice in Japan, ramucirumab will be administered often in the future as a follow-up treatment to either Atez/Bev or lenvatinib, mirroring the approach in this study. Although the combination of Atez/Bev is still awaiting approval, real-world data on ramucirumab in 79 patients who had received at least one or two prior therapies have been reported [18]. In this cohort, most patients had previously been treated with lenvatinib, showing a PFS of 3.2 months for those who received one or more prior treatments. Conversely, a retrospective study examining the effectiveness of ramucirumab after lenvatinib treatment in a small patient group reported a PFS of 2.0 months [19]. A recent retrospective study by Kuzuya et al., investigating the efficacy of ramucirumab following Atez/Bev, reported a TTP of 3.0 months [20]. Our prospective study’s findings align closely with these reports, indicating our results as reasonable and representative of the efficacy of ramucirumab in a real-world clinical setting.

The incidence of AEs during ramucirumab treatment in our study was significantly higher than that in the REACH-2 study. Specifically, we noted hypertension in 58.8% of all grades and 23.5% of grade ≥ 3 in our study compared with 25% of all grades and 13% of grade 3 or higher in REACH-2. In addition, proteinuria was common and a significant contributor to dose reduction or discontinuation of ramucirumab therapy. Although sorafenib, a tyrosine kinase inhibitor with VEGF inhibitory activity, has a relatively mild inhibition compared with other tyrosine kinase inhibitors approved for HCC [21,22,23], such as lenvatinib, our patient cohort had previously received bevacizumab, an anti-VEGF antibody, and lenvatinib as first- and second-line therapy. This prolonged and intense inhibition of the VEGF pathway may have increased the frequency or severity of AEs associated with VEGF inhibition. In our study, the high rate of adverse event-related discontinuation of ramucirumab and the treatment history described above may have influenced these results. In addition, the enrollment of only Japanese patients with advanced HCC who were older than those in the REACH-2 study may also be a contributing factor.

In this study, liver function slightly declined during ramucirumab treatment, which was consistent with previous findings [24]. Both Child–Pugh and ALBI scores remained largely unchanged from baseline to the end of therapy. Preservation of liver function for treating advanced HCC is equally important as tumor control in prolonging prognosis [25]. Currently, eight treatment regimens showed efficacy in international phase 3 trials for advanced HCC and are approved in Japan [26,27,28]. These regimens were specifically designed for patients with well-preserved liver function and are classified as Child–Pugh A. Thus, the preservation of liver function is a prerequisite for the approval of treatments for advanced HCC. Although several small studies have reported the safety and efficacy of existing treatments in Child–Pugh B patients, these results were not supported by a high level of evidence [11, 29,30,31,32]. To effectively sequence multiple approved agents, Child–Pugh A liver function should be preserved, thereby expanding the range of posttreatment options, whereas decline in liver function severely limits these options [25]. Notably, in our cohort, 13 of 17 patients could transition to some form of posttreatment.

Currently, combination immunotherapy, including Atez/Bev, is highly recommended as first-line treatment for advanced HCC [26,27,28]. For patients who are ineligible for this combination immunotherapy, existing VEGF tyrosine kinase inhibitors are generally considered, with preference for lenvatinib as a first-line alternative in real world practice in Japan [33]. However, the standard of care for patients who are either refractory or intolerant to combination immunotherapy remains unclear. In clinical practice, the median PFS with lenvatinib following Atez/Bev was between 2.0 and 6.1 months, indicating a trend toward shorter PFS compared with its use as first-line therapy [11, 34,35,36,37]. Furthermore, some studies, including our study, showed that the efficacy of other treatments, such as sorafenib, regorafenib, cabozantinib, and ramucirumab, after Atez/Bev does not exceed that of lenvatinib [20, 38, 39]. The exact role of ramucirumab in this setting remains to be determined. In addition, the use of ramucirumab in most countries and regions is limited to patients with AFP levels > 400 ng/mL, a criterion based on the REACH-2 study [17], which limits the patient population eligible for this treatment. The difficulty of enrollment in our study and the small size of most real-world clinical reports on this topic underscores this limitation. Unfortunately, our study results did not clarify the optimal positioning of ramucirumab in the latest treatment sequence for advanced HCC. Notably, ramucirumab showed efficacy comparable to that of REACH-2 in the most recent sequential treatment regimen, with preservation of liver function and a high rate of progression to subsequent treatments. As treatment options expand, a subset of patients with advanced HCC may be able to sequence multiple agents. In such scenarios, maintaining ramucirumab as an option for patients with AFP levels ≥ 400 ng/mL is critical to prolong patient survival.

Our study has several limitations that warrant mention. The primary constraint is the small sample size. Although the efficacy demonstrated in this study, which included a limited number of cases, is considered comparable to that of the REACH-2 trial, further validation of the efficacy of ramucirumab in patients with AFP ≥ 400 ng/mL in later-line treatment is necessary. This is particularly important within the current therapeutic framework, where Atez/Bev combination therapy is established as a first-line treatment. To confirm our findings, validation in a larger prospective cohort is essential. Furthermore, this study is limited to patients who have received prior treatment with Atez/Bev and lenvatinib. Patients who received first-line treatment with Atez/Bev followed by the first-generation tyrosine kinase inhibitor sorafenib and subsequently chose ramucirumab were not enrolled. This is due to the fact that in real-world clinical practice in Japan, lenvatinib is overwhelmingly the tyrosine kinase inhibitor of choice for first-line treatment [33]. Moreover, it is currently expected that the combination therapy of durvalumab and tremelimumab, durvalumab monotherapy, as well as regorafenib and cabozantinib, may be used prior to ramucirumab. Given the current diversification of sequential therapies for advanced HCC, prospectively verifying the safety of ramucirumab in all sequence patterns is challenging, which can be considered a limitation of this study. Lastly, the timing of imaging evaluations based on our trial design may have an impact on the efficacy assessment. In this study, the initial imaging evaluation was performed 4 weeks after the start of treatment. Compared to the REACH-2 trial, which conducted the initial evaluation 6 weeks after treatment initiation, there is a possibility of overestimating the efficacy. Our study prioritized the evaluation of the safety and efficacy of ramucirumab in real-world clinical practice in Japan, and therefore, we chose the commonly selected timepoint of 4 weeks after treatment initiation for the initial evaluation. However, this point should be taken into consideration when interpreting the results of this study.

In conclusion, our study supports the use of ramucirumab in advanced HCC, particularly after Atez/Bev or lenvatinib, highlighting its role in preserving liver function and providing additional treatment options for patients with advanced HCC. Further research and real-world data are essential to optimize advanced HCC treatment strategies.