Abstract
Aim: The present study evaluated the efficacy and safety of ramucirumab (RAM) in clinical practice as post-treatment, following atezolizumab plus bevacizumab (Atz/Bev) for advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels of ≥400 ng/ml. Patients and Methods: Of the 77 patients treated with Atz/Bev at our institution, 13 patients for whom RAM was introduced as post-treatment following Atz/Bev were enrolled in this retrospective study. There were 9 patients (69.2%) with Child-Pugh A and 11 patients (84.6%) for whom RAM was initiated as 3rd- or later-line therapy. The median AFP level was 2259 ng/ml. Results: The objective response rate by Response Evaluation Criteria in Solid Tumours at 6 weeks was 15.4%, and the disease control rate was 69.2%. The median time to progression was 3.0 months; AFP level decreased at 2 weeks in 11 patients (84.6%) and at 6 weeks in seven patients (53.8%). The most common adverse events (AEs) within 6 weeks were ascites, peripheral oedema, and proteinuria, while grade 3 AEs occurred in six patients (46.2%). Albumin-bilirubin scores at both 4 and 6 weeks were significantly worse than those at baseline. Conclusion: In HCC patients with AFP levels of ≥400 ng/mL, RAM after Atz/Bev is expected to be an effective treatment option. Careful attention should be paid to the development of AEs and deterioration of liver function, especially when RAM is used as 3rd- or later-line therapy. Additional studies are needed to confirm the efficacy and safety of RAM as 2nd-line treatment after Atz/Bev in Child-Pugh A patients.
Following the positive results of the IMbrave150 study (1), atezolizumab plus bevacizumab (Atz/Bev) combination therapy is widely used as 1st-line treatment in clinical practice for patients with advanced hepatocellular carcinoma (HCC) (2). In addition to Atz/Bev, there are five other effective systemic agents [sorafenib, lenvatinib, regorafenib, ramucirumab (RAM) and cabozantinib] for advanced HCC, and sequential treatment with these agents is considered important for prolonged therapeutic benefits (3). According to the Clinical Practice Guidelines for the Treatment of Hepatocellular Carcinoma (4), all these five agents are equally recommended as 2nd-line therapy for patients with advanced HCC after disease progression (PD) with Atz/Bev. However, since the IMbrave150 trial did not provide detailed results on post-treatment after Atz/Bev failure, the established regimen for post-treatment after Atz/Bev is unknown.
Since 2019, RAM, a human IgG1 monoclonal antibody that inhibits ligand activation of vascular endothelial growth factor receptor 2 (VEGFR-2), is available as 2nd-line therapy after sorafenib for patients with advanced HCC with alpha-fetoprotein (AFP) levels of ≥400 ng/mL, based on positive results from the REACH-2 study (5). In clinical practice, RAM has been used not only after sorafenib, but also after lenvatinib, and has been reported to be particularly useful with minimal effects on liver function (6–9). However, there have been no reports on the outcomes of RAM after Atz/Bev. In this regard, the aim of the present study was to investigate the efficacy and safety of RAM as post-treatment for Atz/Bev in clinical practice.
Patients and Methods
Patients. Of the 77 HCC patients who were treated with Atz/Bev at our institution from October 2020 to November 2021, 13 patients started RAM as post-treatment for Atz/Bev. The reasons for discontinuation of Atz/Bev were PD in 12 patients and adverse events (AEs) in one patient. These 13 patients were included in the present study and their treatment outcomes were retrospectively evaluated. This study was approved by the Ethics Committee of Fujita Health University School of Medicine (HM17-152) and was conducted in accordance with the 1975 Declaration of Helsinki. For RAM treatment, written informed consent was obtained from each patient. However, since this was a retrospective study, informed consent was waived for this study.
RAM administration and evaluation of adverse events and changes in liver function. RAM was administered intravenously once every 2 weeks at a dose of 8 mg/kg. AEs were assessed according to the Common Terminology Criteria for Adverse Events version 5.0 (10). If drug-related AEs occurred, the dose was reduced or the drug was temporarily interrupted until symptoms resolved to grade 1 or 2, according to guidelines provided by the manufacturer; RAM treatment was continued until potentially fatal AEs occurred or until tumour progression was observed clinically. Albumin-bilirubin (ALBI) scores (11) were examined at baseline and at weeks 2, 4 and 6, to assess changes in liver function.
Evaluation of antitumour response and AFP response. Antitumour response was assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) (12). Four-phase (i.e., unenhanced, late arterial, portal and equilibrium) contrast-enhanced CT (CE-CT) studies were performed on a predetermined schedule at baseline and 6 weeks after the start of RAM, and every 4-10 weeks thereafter. AFP levels were measured as a tumour marker of HCC, and were analysed at baseline and at 2, 4 and 6 weeks after the start of RAM. For each patient, the AFP ratio at each particular time point was calculated relative to the value at RAM initiation. To investigate the AFP trend before RAM treatment, the AFP ratio at the start of RAM was calculated relative to the value at 6 weeks before RAM initiation.
Statistical analysis. Statistical analysis was performed using Easy R (EZR) version 1.29 (Saitama Medical Center, Jichi Medical University, Japan) (13). Time to progression (TTP) after RAM initiation was defined as the period from the date of RAM initiation to the date of the first radiologically confirmed evidence of PD, according to RECIST. Overall survival (OS) was calculated as the period from the date of RAM initiation to the date of death or last hospital visit, and RAM treatment duration was calculated as the period from the date of treatment initiation to the date of treatment discontinuation. TTP, OS and duration of treatment with RAM were assessed by the Kaplan-Meier method, and differences in survival were evaluated by the log-rank test. The changes in ALBI score within 6 weeks were evaluated by Friedman test and Wilcoxon rank-sum test. A p-Value <0.05 was considered statistically significant.
Results
Baseline characteristics. The baseline characteristics of the 13 HCC patients at RAM initiation are shown in Table I. Median patient age was 70 years (range=38-85 years). There were 10 males (76.9%), six patients (46.2%) with non-viral aetiology HCC, and nine patients (69.2%) with Eastern Cooperative Oncology Group – performance status of 0, respectively. Four patients had a Child-Pugh score of 5, five had a score of 6, and four had a score of 7. Nine patients (69.2%) had Barcelona Clinic Liver Cancer stage C disease. The median AFP level was 2259 ng/mL (range=427-407,999 ng/ml). The median duration of observation was 4.8 months (range=1.6-12.4 months).
Patient baseline characteristics.
In all 13 patients, the treatment just prior to RAM was Atz/Bev. RAM was initiated in two patients as 2nd-line therapy (Atz/Bev to RAM), 10 patients as 3rd-line therapy (all 10 had switched from lenvatinib to Atz/Bev to RAM), and in one patient as 5th-line therapy (sorafenib to regorafenib to lenvatinib to Atz/Bev to RAM).
Concerning the clinical outcomes of Atz/Bev just before RAM, the antitumour response by RECIST at 6 weeks after Atz/Bev initiation was stable disease (SD) in six patients and PD in seven patients, with an objective response rate (ORR) of 0% and disease control rate (DCR) of 46.2%, respectively. The median TTP with Atz/Bev by RECIST was 1.6 months (range=1.3-7.7 months). The median AFP level 6 weeks before the start of RAM was 932 ng/mL (range=132-17,496 ng/ml), and when the AFP ratio 6 weeks before the start of RAM was 1, the median AFP ratio at the start of RAM was 2.30 (range=0.94-3.64). Prior to the start of RAM, 11 of the 13 patients (84.6%) had an upward trend in AFP levels.
Efficacy. Regarding anti-tumour efficacy at 6 weeks by RECIST, there were no complete responses (CR), two partial responses (PR), seven cases of SD, three of PD, while the response was not evaluated (NE) in one case. ORR and DCR were 15.4% and 69.2%, respectively. The median TTP was 3.0 months (range=1.3-7.7 months). Changes in AFP ratios within 6 weeks after the start of RAM are shown in Figure 1. The median AFP ratios at 2, 4 and 6 weeks were 0.84 (range=0.33-1.24), 0.99 (range=0.25-1.20) and 0.71 (range=0.22-1.46), respectively. An AFP ratio of ≤1.0 was seen in 11 patients (84.6%) at 2 weeks and in seven patients (53.8%) at 6 weeks. An AFP ratio of ≤0.8 was seen in five patients (38.5%) at 2 weeks and in seven patients (53.8%) at 6 weeks. The median OS was 4.8 months (range=1.6-12.4 months). The median OS in patients with DC at 6 weeks was significantly longer than that in patients with non-DC (8.7 months vs. 1.9 months, respectively, p=0.0011) (Figure 2A). The median OS in patients with AFP reduction at 6 weeks was significantly longer than that in patients without AFP reduction (8.7 months vs. 3.9 months, respectively, p=0.0166) (Figure 2B).
Changes in AFP ratios at baseline and weeks 2, 4 and 6 after ramucirumab initiation. AFP, Alpha-fetoprotein.
Comparison of cumulative overall survival (A) between 6W DC and non-6W DC groups, and (B) between 6W AFP reduced and non-6W AFP reduced groups. DC, Disease control; AFP, alpha fetoprotein; MST, median survival time; M, month; W, week.
Safety. Table II shows the frequency of AEs within 6 weeks after RAM initiation in the 13 patients. The most common AEs were ascites (n=8, 61.5%), peripheral oedema (n=8, 61.5%), proteinuria (n=7, 53.8%), hypothyroidism (n=6, 46.2%), appetite loss (n=6, 46.2%), generalized fatigue (n=3, 23.1%), hepatic coma (n=2, 15.4%), bleeding (n=2, 15.4%) and hand-foot syndrome (n=2, 15.4%). Grade 3 AEs occurred in six patients (46.2%). These included two cases each of ascites, peripheral oedema, and hepatic coma, and one case each of proteinuria and bleeding. In two patients, both grade 3 ascites and grade 3 peripheral oedema occurred. Grade 4 AEs were not observed. The median treatment duration of RAM was 2.8 months (range=0.5-7.7 months).
Adverse events within 6 weeks of RAM administration (n=13).
Changes in ALBI score within 6 weeks were evaluated in all 13 patients (Figure 3). The median ALBI scores±standard error (SE) at baseline and weeks 2, 4 and 6 were –2.18±0.14, –2.16±0.13, –1.80±0.17 and –1.57±0.2, respectively (p=0.0125, Friedman test). ALBI scores at both 4 and 6 weeks were significantly worse than those at baseline (p=0.0186 and p=0.0107, respectively, Wilcoxon rank-sum test).
Changes in ALBI scores at baseline, 2, 4 and 6 weeks after ramucirumab initiation. The median ALBI scores±SE at baseline and weeks 2, 4 and 6 were –2.18±0.14, –2.16±0.13, –1.80±0.17 and –1.57±0.2, respectively (p=0.0125, Friedman test). ALBI scores at both 4 and 6 weeks were significantly worse than those at baseline (p=0.0186 and 0.0107, respectively, Wilcoxon rank-sum test). ALBI, Albumin-bilirubin; SE, standard error.
Discussion
To the best of our knowledge, this is the first study to investigate the outcomes of RAM as a post-treatment following Atz/Bev for advanced HCC in clinical practice. In the present study, the DCR at 6 weeks according to RECIST was 69.2%, and the median TTP was 3.0 months. Reduction in AFP levels was seen in 11 patients (84.6%) at 2 weeks and in seven patients (53.8%) at 6 weeks. The most common AEs were ascites, peripheral oedema, and proteinuria. Grade 3 AEs occurred in six patients (46.2%) within 6 weeks. The ALBI score within 6 weeks tended to worsen over time.
Regarding the antitumour response to RAM after sorafenib, the REACH-2 trial (5) reported an ORR of 4.6% and a DCR of 59.5% by RECIST, and the progression free survival (PFS) period was 2.8 months. In clinical practice, the antitumour response of RAM after lenvatinib by RECIST has been reported as an ORR of 0.0-3.8%, DCR of 28.6-80.0%, and PFS of 1.4-3.8 months (7, 8, 14–18). In the present study, the ORR at 6 weeks by RECIST was 15.4%, the DCR was 69.2%, and the median TTP was 3.0 months. Our results suggest that RAM after Atz/Bev can be expected to have almost the same efficacy as after sorafenib or lenvatinib in terms of DC. Regarding the trend of AFP levels after the initiation of RAM, our previous study (7) investigating the outcomes of patients who received RAM after lenvatinib reported that the median AFP ratios at 2, 4 and 6 weeks were 1.01, 1.09 and 1.23, respectively, and that an AFP ratio of ≤1.0 was seen in five patients (50%) at 2 weeks and in three patients (30%) at 6 weeks. On the other hand, in the present study, median AFP ratios at weeks 2, 4 and 6 were 0.84, 0.99 and 0.71, respectively, and an AFP ratio of ≤1.0 was seen in 11 patients (84.6%) at 2 weeks and in seven patients (53.8%) at 6 weeks. Comparison of the previous and current studies suggests that it might be possible to expect a greater decrease in AFP with RAM after Atz/Bev treatment rather than after lenvatinib treatment.
Inhibition of angiogenic signalling by the VEGF-VEGFR pathway is important in the treatment of advanced HCC (19). VEGFR-2 is known to have the greatest association with VEGF-induced tumour angiogenesis (20). There are three ligands for VEGFR-2: VEGF-A, C and D. Bevacizumab (1) is a single antibody to the ligand VEGF-A, while RAM inhibits the binding of the ligands VEGF-A, C and D to VEGFR-2. It was previously reported that serum VEGF-A levels were suppressed, while serum VEGF-C and D levels were elevated in colorectal cancer patients with confirmed PD on bevacizumab-containing regimens (21). This suggests that one possible mechanism for the antitumour effect of RAM after failure of Atz/Bev is that RAM exerts its antitumour effects by potently blocking the binding of not only VEGF-A, but also of VEGF-C and VEGF-D to VEGFR-2 in patients refractory to Atz/Bev. It has been reported that nivolumab, a PD-1 antibody, continues to bind to PD-L1 on lymphocytes for about 5 months after discontinuation of its administration for non-small cell lung cancer (22). In other words, if a tyrosine kinase inhibitor (TKI) is administered immediately after immune-checkpoint inhibitor (ICI) administration, it might result in a pseudo-combination therapy-like effect of the ICI and TKI, and the anti-tumour effect of both might be expected. Aoki et al. reported that the outcome of lenvatinib after ICI treatment was better than that of lenvatinib used as 1st-line treatment (23). In the present study of patients treated with RAM after Atz/Bev, we experienced cases in which antitumour responses, such as AFP reduction and tumour shrinkage, were confirmed. Therefore, it is possible that atezolizumab, which persisted in the body even after discontinuation of Atz/Bev, continued to exert its antitumour effect, producing a pseudo-combination therapy-like effect with RAM, thus explaining the favourable antitumour effect of RAM after discontinuation of Atz/Bev.
RAM is known to be a well-tolerated agent with a low incidence of serious AEs and low impact on worsening liver function (5, 6). In the REACH-2 trial, the incidence of severe RAM-related AEs was low, at 11.0%, and changes in ALBI score were similar to those of placebo (5). However, in the present study, grade 3 AEs occurred in six patients (46.2%) within 6 weeks, and ALBI scores at both 4 and 6 weeks were significantly worse than the baseline ALBI score. In the present study, one of the reasons for the high occurrence rate of grade 3 AEs and deterioration of liver function might be that in most patients (84.6%), RAM was initiated as 3rd- or later-line therapy, so the baseline might have been worse than if it had been used as 2nd-line therapy. In the present study, the most common AEs were ascites, peripheral oedema, and proteinuria. Since both bevacizumab and lenvatinib have anti-VEGF effects, the development of ascites, peripheral oedema and proteinuria might be more likely to occur when RAM is used after these drugs. In contrast, the incidence of loss of appetite and general fatigue was low, similar to those reported in the past, suggesting that RAM is overall well tolerated.
There are several limitations to this study. First, the present study was a retrospective, non-randomized study. Second, the sample size was small and included patients treated with RAM as 3rd- or later-line therapy and those with Child-Pugh B disease.
In conclusion, in HCC patients with baseline AFP levels of ≥400 ng/mL, RAM is expected to be an effective treatment option after Atz/Bev. Careful attention should be paid to the development of AEs and deterioration of liver function, especially when RAM is used as 3rd- or later-line therapy. Additional studies are needed to confirm the efficacy and safety of RAM as 2nd-line treatment after Atz/Bev in Child-Pugh A patients.
Footnotes
Authors’ Contributions
Conceptualization: Teiji Kuzuya; Methodology: Teiji Kuzuya; Formal analysis and investigation: Teiji Kuzuya and Naoto Kawabe; Data curation, Teiji Kuzuya, Naoto Kawabe, Senju Hashimoto, Kohei Funasaka, Mitsuo Nagasaka, Yoshihito Nakagawa, Ryoji Miyahara, Tomoyuki Shibata, Takeshi Takahara, Yutaro Kato, Atsushi Sugioka; Writing - original draft preparation: Teiji Kuzuya; Writing - review and Editing: Naoto Kawabe; Supervision: Atsushi Sugioka and Yoshiki Hirooka. All authors approved the final draft of the manuscript.
Conflicts of Interest
Teiji Kuzuya received lecture fees from Eisai, Bayer, Eli Lilly Japan and Chugai Pharmaceutical. All the other authors declare no competing interests.
- Received February 6, 2022.
- Revision received February 21, 2022.
- Accepted February 22, 2022.
- Copyright © 2022 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
