Introduction
Liver cancer has the sixth highest incidence among malignant tumors and the third highest in mortality rate worldwide with 781,631 deaths per year, and hepatocellular carcinoma (HCC) is the most common primary liver malignancy [
1]. Monitoring high-risk populations, such as patients with cirrhosis due to hepatis B virus, hepatitis C virus (HCV), alcohol abuse, and nonalcoholic steatohepatitis, has increased the early detection of patients with HCC [
2‐
4]. However, many patients are still diagnosed with advanced HCC in real-world practice.
Systemic therapies for advanced HCC have made significant progress in the past decade. Sorafenib, which was the first multikinase inhibitor for advanced HCC, improved overall survival (OS) compared with placebo in patients with advanced HCC in two randomized trials [
5,
6]. Based on these results, sorafenib became the standard of care for systemic therapy of advanced HCC worldwide in the late 2000s. In the late 2010s, several drugs showed efficacy in randomized clinical trials in both first-line and second-line settings in patients with advanced HCC. Lenvatinib showed non-inferior survival to first-line treatment using sorafenib, and regorafenib, cabozantinib, and ramucirumab showed significantly better survival compared with placebo as a second-line treatment [
7‐
10]. Furthermore, combination immunotherapies of atezolizumab plus bevacizumab and durvalumab plus tremelimumab were shown to significantly prolong OS compared with sorafenib treatment in patients with advanced HCC [
11,
12]. Two combination immunotherapy regimens and five molecular target agents were shown to be effective against advanced HCC in global phase 3 randomized control trials and a wide variety of sequential treatments are being developed for clinical practice [
5‐
12].
Ramucirumab is a human IgG monoclonal antibody that binds to the extracellular domain of VEGFR-2. It exerts its antitumor effects by inhibiting the interaction between VEGFR-2 and its ligand (mainly VEGF-A), thereby inhibiting endothelial cell proliferation and migration via downstream signaling [
13‐
19]. The REACH trial, which was the first randomized, double-blind, placebo-controlled phase 3 clinical trials in a second-line setting after sorafenib, showed that ramucirumab failed to prolong OS compared with placebo [
20]. A subgroup analysis of REACH trial revealed that ramucirumab was highly effective in patients with alpha-fetoprotein (AFP) levels > 400 ng/mL. Therefore, the REACH-2 trial compared ramucirumab and placebo in patients with advanced HCC after sorafenib in patients with AFP levels > 400 ng/mL [
10]. The findings of the REACH-2 trial revealed that ramucirumab showed survival benefits compared with placebo and led to the use of ramucirumab as standard second-line treatment for advanced HCC. The biological mechanism that might explain the potential correlation between baseline AFP and the survival benefit of ramucirumab is uncertain. Robert M, et al. reported that AFP-high tumors showed higher enrichment of VEGF signaling and overexpression of VEGFB and PGF [
21]. The overexpression of VEGFB and PGF ligands observed in AFP-high tumors might result in an enhanced activation of VEGFR1, as well as prevent VEGFA from binding VEGFR1. It means that the competition of VEGFA with the other ligands could favor its binding to VEGFR2. They conjectured a biological mechanism by which ramucirumab works against advanced HCC patients with AFP-high value as misbalance VEGFA signaling toward a preferential binding of VEGFR1.
In clinical practice, where multiple regimens are approved for advanced HCC, ramucirumab is used not only after sorafenib but also a post-treatment for various systemic therapies. However, little is known about the clinical outcomes of ramucirumab after other systemic therapies except sorafenib in patients with advanced HCC. Therefore, the present study aimed to evaluate the safety and effectiveness of various treatment lines of ramucirumab administration in real-world practice for patients with advanced HCC.
Discussion
We examined the safety and effectiveness of various treatment lines of ramucirumab administration in patients with advanced HCC in real-world practice using a retrospective cohort in Japan. Ramucirumab was approved as second-line therapy after sorafenib due to the findings of the REACH-2 trial, which was designed when sorafenib was the only standard first-line systemic therapy for advanced HCC. However, in clinical practice, ramucirumab is currently administered in a wide variety of lines since multiple agents are available for advanced HCC. The results of the present study suggest the possible use of ramucirumab at diverse time points during the clinical course of advanced HCC.
In the present study, we focused on the safety of ramucirumab for advanced HCC patients in clinical practice. Although grade ≥ 3 AEs were observed in seven (18.9%) patients, only three (8.1%) patients required discontinuation of treatment due to AEs (one patient with tumor collapse, one patient with duodenal ulcer bleeding, and one patient with proteinuria). In recent clinical practice, regorafenib and cabozantinib are used as second-or-later-line treatments for advanced HCC patients as well as ramucirumab. We previously reported that regorafenib caused a high rate of grade 3 or higher AEs such as palmar-plantar eruthrodysesthesia (20.5%) and elevated serum aspartate aminotransferase (13.6%) in advanced HCC patients treated in clinical practice [
26]. Similarly, other previous reports suggested that high rates of serious AEs and treatment discontinuation due to AEs occurred during regorafenib treatment in patients with advanced HCC [
27,
28]. Francesco T et al. demonstrated that 42.7% of patients had grade 3 or higher AEs and 11.7% discontinued treatment due to AEs during cabozantinib treatment for advanced HCC patients [
29]. Taken together with our results, ramucirumab would be the safest second-or-later-line treatment in patients with advanced HCC. Furthermore, as previously reported [
30‐
33], analysis of the transition in ALBI score during the first 12 weeks after ramucirumab administration showed that deterioration of liver function was not observed in the present cohort. In contrast to sorafenib and lenvatinib, which have been reported to worsen liver function after initiation of treatment [
34,
35], ramucirumab is considered to have an extremely low impact on liver function. In patients with advanced HCC, OS and PFS were correlated with duration of treatment using molecular target agents and impaired liver function is a known factor for preventing conversion to post-treatment [
36‐
38]. Molecular target agents with a low risk of decreasing liver function may be a treatment option for patients with advanced HCC.
Also, the effectiveness of this study, the median OS was 10.3 months and the median PFS was 2.7 months using both RECIST and mRECIST. These data were comparable to the findings of the REACH-2 trial, which reported an OS of 8.5 months and PFS of 2.8 months. Interestingly, the median PFS for the second-line and late-line groups were similar using both RECIST and mRECIST (second-line vs late-line: RECIST, 2.7 vs 2.7 months; P = 0.945; mRECIST, 1.8 months vs 3.5 months; P = 0.409). In the preset study, first-line treatment was either sorafenib or lenvatinib, except in one patient who received duruvarumab plus tremerimumab as a clinical trial. Surprisingly, only 2 out of 37 patients (5.4%) were administered ramucirumab as second-line treatment after sorafenib and most patients (64.9%) started ramucirumab as late-line treatment. To date, ramucirumab as well as regorafenib and cabozantinib have been shown to be effective second-line treatment agents in phase 3 studies. However, the clinical trials of these three agents were all designed based the use of sorafenib as the first-line treatment of advanced HCC. Our results revealed that ramucirumab was used in a variety treatments line of for advanced HCC patients in real-world clinical practice.
In the present cohort, 11 out of 19 patients (57.9%) were administered ramucirumab as a second-line treatment after lenvatinib and showed a median PFS of 3.6 months. This finding is comparable to previous reports but remains unsatisfactory. Kuzuya et al. reported a median time to progression of 3.0 months in 12 patients with advanced HCC who were treated with ramucirumab after lenvatinib [
30]. Similarly, Hiraoka et al. reported a median PFS of 2.0 months in patients with advanced HCC who were treated with ramucirumab after lenvatinib in [
31]. At present, lenvatinib is the leading molecular target agent used for advanced HCC due to its high response rate. However, there is no evidence for second-line treatment after lenvatinib. We recently reported that use of sorafenib may be less effective after lenvatinib [
39]. Taken together, our findings and the findings of previous studies indicate that ramucirumab may be a promising treatment option after lenvatinib in clinical practice.
In the present cohort, the median PFS was 7.3 months in patients who received ramucirumab after receiving sorafenib as first-line therapy. In addition, nine patients received ramucirumab after both sorafenib and regorafenib, including the patient shown in Fig.
4. We observed a favorable median PFS of 8.3 months in patients treated with sorafenib and regorafenib followed by ramucirumab. Although these results were derived from a small sample size, ramucirumab may a better treatment choice after sorafenib and regorafenib in patients with advanced HCC. We previously reported that sequential treatment of sorafenib and regorafenib was an effective treatment stream for advanced HCC in real-world practice [
40]. Conversion to ramucirumab after sorafenib and regorafenib may lead to prolongation of prognosis in patients with advanced HCC.
The present study indicates the usefulness of ramucirumab for advanced HCC patients in clinical practice. OS was significantly longer in patients with confirmed disease control at ≥ 4 weeks after ramucirumab administration compared with those without disease control at ≥ 4 weeks. We previously reported that OS was prolonged in patients with confirmed SD at least 4 weeks after sorafenib administration [
26]. For use of molecular target agents with less potential for tumor shrinking, such as sorafenib and ramucirumab, sustained control of tumor growth would be associated with survival in advanced HCC. It may be important to perform an initial radiological assessment 1 month after ramucirumab administration to determine whether patients would benefit from ramucirumab treatment. Early radiological evaluation during ramucirumab treatment may increase the likelihood of conversion to post-treatment when ramucirumab is refractory.
The present study had several limitations. First, in this study, we collected clinical data retrospectively. Although the results of our study showed that ramucirumab seemed to be safe in clinical practice, it is possible that we did not accurately collect data on all AEs that occurred during treatment. Second, the sample size of this study was small. It is often desirable to analyze factors contributing to safety and effectiveness from various perspectives using a variety of parameters. However, the sample size in this study was not large enough to perform such analyses. Third, our data dwelled on clinical outcomes of ramucirumab treatment when sorafenib or lenvatinib was used as the front-line treatment in patients with advanced HCC. Nowadays, combined immunotherapy is considered the first-line treatment for advanced HCC [
11,
12]. The safety and effectiveness of ramucirumab after combined immunotherapy still needs to be validated. In conclusion, the results of the present study confirm the potential use of ramucirumab for various treatment lines of advanced HCC. Moreover, the lower impact of ramucirumab on liver function could be advantageous in strategies for treating patients with advanced HCC. Early radiological assessment is appropriate after the initiation of ramucirumab treatment in patients with advanced HCC.
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