Atezolizumab and bevacizumab (atezo/bev) combination therapy is increasingly used for advanced hepatocellular carcinoma (HCC), substantially advancing the systemic chemotherapy for this type of tumor. High-quality evidence for post-atezo/bev salvage therapy is lacking; however, the number of nonresponse or intolerance cases with this regimen is increasing in real-world clinical practice. Therefore, an effective post-atezo/bev salvage therapy is imperative. Based on the results of the IMbrave150 trial, atezo/bev was confirmed as a highly potent treatment, substantially altering the treatment landscape of HCC [
1]. Currently, in almost all guidelines for the treatment of HCC, atezo/bev is recommended as the first-line therapy if there are no contraindications.
To select second-line therapy for non-response or intolerance to atezo/bev, two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, which were used mainly as firstline therapy before the approval of atezo/bev, are often chosen over other second-line agents because of their high anti-tumor objective response rate (ORR). Chon et al. [
2] compared the efficacy of sorafenib and lenvatinib as second-line therapy, which was initiated between August 2019 and December 2022 after the failure of atezo/bev in patients with HCC. This was accomplished through a multicenter retrospective observational study. This study is noteworthy for balancing the clinical characteristics of both groups through propensity score (PS) matching and providing new salvage evidence after atezo/bev failure. In the PS-matched cohort, the ORR was comparable between the lenvatinib and sorafenib groups; however, the disease control rate (DCR) was higher in the lenvatinib group. Additionally, progression-free survival (PFS) was also superior in the lenvatinib group (median: 3.5 months vs. 1.8 months), whereas OS did not differ substantially between the two groups (median, 10.3 months vs. 7.5 months).
A subset of patients who discontinued atezo/bev treatment in the IMbrave150 trial received TKIs. Yoo et al. [
3] analyzed cases, including those in phase III and I clinical trials, or given off-trial in daily clinical settings where TKIs were administered after atezo/bev. They reported a substantially higher median PFS in the lenvatinib group compared with that in the sorafenib group (6.1 months vs. 2.5 months), while there was no significant difference in median overall survival (OS) between the two groups.
In a phase III trial (REFLECT), lenvatinib demonstrated non-inferiority to sorafenib with OS as the primary endpoint. However, unlike sorafenib, lenvatinib exhibits a considerably high anti-tumor effect with an ORR according to the modified Response Evaluation Criteria in Solid Tumors, which considers the tumor blood flow status. Furthermore, real-world data prior to the advent of immune checkpoint inhibitors (ICIs) indicate that lenvatinib as a second-line therapy achieves comparable PFS to first-line therapy, especially in patients with good liver function classified as modified albumin-bilirubin grade 1/2a [
4]. Additionally, lenvatinib was administered as a second-line therapy for post-ICI treatment [
5]. In this cohort, although most patients received ICIs other than atezo/bev, the PFS and OS were favorable, with a median PFS of 10 months and an OS of 15 months. Considering that the median PFS of first-line atezo/bev in phase III clinical trials was 6.8 months [
1], lenvatinib administration showed very promising results as a post-ICI second-line therapy. As ICIs are antibody agents that maintain high serum concentrations and affect T-cell responses for months [
6], durable effects of ICIs can be expected after treatment cessation. From this perspective, the subsequent administration of lenvatinib may yield a temporary combination effect with ICIs, which may be attributed to the favorable PFS and OS of lenvatinib in the second-line setting after ICIs.
One mechanism proposed for the acquisition of resistance to ICIs involves the activation of the Wnt/β-catenin pathway in cancer cells, which is thought to impair the induction of dendritic cells and cytotoxic T lymphocytes into the tumor through the induction of activating transcription factor 3 (ATF3) and inhibition of C-C chemokine ligand (CCL) 4 and 5 [
7,
8]. Harding et al. [
9] reported on ICI resistance in HCC harboring activating mutations in β-catenin, and we also found an association between activation of the Wnt/β-catenin and shortened PFS on ICI therapy [
10]. Conversely, another report suggested that activating mutations in β-catenin are associated with increased fibroblast growth factor receptor 4 (FGFR4) signaling in tumor [
11]. Lenvatinib is a strong inhibitor of FGFR4, with high efficacy observed in cases with high expression of FGFR4 in HCC.12 Therefore, it is possible that lenvatinib may be effective for cases of resistance to ICI therapy attributed to activation of the Wnt/β-catenin pathway, which is associated with activation of FGFR4 signaling.
Considering these findings, lenvatinib should likely be considered as a second-line therapy after atezo/bev therapy in patients with good liver function. However, the effectiveness of lenvatinib is correlated with its relative dose intensity (RDI), and decreasing RDIs are observed as liver function declines [
13]. According to a report from a phase I clinical trial, lenvatinib serum concentrations increased in patients with Child-Pugh B compared to those in Child-Pugh A cases. Furthermore, dose adjustments based on body weight are required for lenvatinib administration; however, it is not clear how dose adjustments based on body weight should be made, considering the increase in blood concentrations in Child-Pugh B cases. When lenvatinib is used as second-line therapy or beyond, cases with compromised liver function may increase, which may make the administration of lenvatinib more challenging.
Sorafenib is characterized by strong inhibition of c-Raf and b-Raf serine/threonine kinases compared with lenvatinib. As a first-line therapy, sorafenib showed a lower ORR than that with lenvatinib. However, according to sorafenib clinical trials using large HCC cohorts, there was no significant difference in efficacy between starting doses of 800 mg and 400 mg. Therefore, initiation with 400 mg of sorafenib daily can be considered, particularly in patients with underlying conditions or impaired liver function, considering the risk of treatment interruption. Clinical trials exploring the safety and efficacy of Child–Pugh B showed no significant difference in PFS between Child–Pugh A and Child–Pugh B cases [
14,
15]. Child–Pugh B cases are limited to those with Child–Pugh scores of 7 or 8, and compared with Child–Pugh A cases, Child–Pugh B cases exhibit inferior OS. Regarding safety, although the overall incidence of adverse events (AEs) was similar, a higher incidence of severe and liver-related AEs was observed in Child–Pugh B cases. Nevertheless, given that an increase in cases with deteriorated liver function may be observed after the failure of first-line therapy, the abundant evidence of sorafenib in Child–Pugh B cases shows this agent as an option for second-line therapy.
In addition to these two TKIs, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor 2 (VEGFR2), can also be selected as a secondline therapy for patients with HCC with serum α-fetoprotein (AFP) levels of 400 ng/mL or higher. Kuzuya et al.16 reported 13 HCC cases for which ramucirumab was administered after atezo/bev, with an ORR of 5.4% and a DCR of 69.2%. They noted a substantial extension in survival among cases showing disease control and AFP reduction at six weeks after treatment initiation. Currently, a randomized comparative trial of lenvatinib and ramucirumab is being conducted for the treatment of advanced HCC with AFP values of 400 or higher after ICI treatment (SELECT-400). Additionally, the efficacies of regorafenib and cabozantinib have been investigated in patients with HCC who are unresponsive to ICIs, prompting expectations of comparative performance among molecular-targeted agents (
Table 1) [
17,
18].
Another large-scale phase III clinical trial (IMbrave251) is underway to investigate the significance of adding atezolizumab to sorafenib or lenvatinib as a second-line treatment for patients who have experienced disease progression after atezo/bev (
Table 1). This trial provides new evidence regarding post-atezo/bev therapeutic options. In addition to atezo/bev, the durvalumab and tremelimumab (durva/treme) combination is available as a first-line therapy, and exploration of the sequencing of these two combination immunotherapies is anticipated. In second-line therapy, no regimen is an option, and there are many challenges to be addressed regarding the efficacy and safety of regimens for second-line and subsequent treatments. There is ongoing discussion on whether to retry ICI-based regimens, such as durva/treme, or use TKIs for patients unresponsive to atezo/bev [
19]. Additionally, new drugs with different mechanisms of action and novel immunotherapies are being developed (
Table 1).
In contrast, Zhu et al. [
20] identified key molecular correlations of atezo/bev combination therapy using cases enrolled in the GO30140 phase 1b or IMbrave150 phase 3 trial. Zeng et al. [
21] developed artificial intelligence (AI) and found that AI applied to HCC digital slides predicted PFS in patients with HCC treated with atezo/bev. These efforts should play a critical role in achieving long survival with atezo/bev; they could also provide important information for the selection of ideal salvage therapy after atezo/bev.
Currently, several agents are available for systemic chemotherapy of HCC, making it difficult to conduct prospective comparative trials for all combinations when determining the sequence of drug therapy. Large-scale observational clinical studies are ongoing to address this issue (
Table 1) and provide new evidence based on real-world data to construct an ideal salvage therapy after ICI-based therapies for HCC.
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI: 24K10393, N. Nishida).
FOOTNOTES
-
Conflicts of Interest
The author has no conflicts to disclose.
Table 1.Ongoing clinical trials for salvage therapy after immune checkpoint inhibitors
Table 1.
|
Study title |
ID |
Enrollment |
Target |
Arm |
Endpoint |
|
Phase III |
|
|
|
|
|
|
(IMbrave 251) |
NCT04770896 |
554 |
Disease progression following prior Atezo/Bev combination treatment for HCC |
Experimental arm: Atezolizumab + (Lenvatinib or Sorafenib) |
Primary: |
|
A study of atezolizumab with lenvatinib or sorafenib versus lenvatinib or sorafenib alone in hepatocellular carcinoma previously treated with Atezolizumab and Bevacizumab |
OS |
|
Comparator arm: Lenvatinib or Sorafenib |
Secondary: |
|
PFS, ORR, TTP, DOR, TTCD, etc. |
|
(SUCCEED) |
jRCT1031210167 |
164 |
Intolerant or refractory to first-line systemic treatment containing immune check point inhibitor |
Experimental arm 1: Sorafenib |
Primary: |
|
Randomized phase III trial of Sorafenib versus Lenvatinib as a second-line treatment after immune check point inhibitor for advanced hepatocellular carcinoma |
OS |
|
Experimental arm 2: Lenvatinib |
Secondary: |
|
PFS, ORR, DCR, rate of AEs, rate of severe AEs, Child-Pugh progression rate, mALBI grade progression rate. |
|
(SELECT-400) |
jRCT1031210092 |
130 |
Intolerant or refractory to first-line systemic treatment containing immune check point inhibitor |
Experimental arm 1: Lenvatinib |
Primary: |
|
Randomized phase III trial of Lenvatinib versus Ramucirumab as a second-line treatment after immune check-point inhibitor for advanced hepatocellular carcinoma with alfa-fetoprotein >400 ng/mL |
OS |
|
Experimental arm 2: Ramucirumab |
Secondary: |
|
PFS, ORR, DCR, rate of AEs, rate of severe AEs, Child-Pugh progression rate, mALBI grade progression rate. |
|
Phase II |
|
|
|
|
|
|
Cabozantinib in hepatocellular carcinoma |
NCT04588051 |
20 |
Patients who stop immune check-point inhibitor due to progressive disease, the duration of immune check-point inhibitor must be 8 weeks or longer. |
Experimental arm: Cabozantinib |
Primary |
|
PFS |
|
Secondary |
|
OS, survival rate at 1 year, TTP, ORR, DCR, rate of AEs |
|
Regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma or spreading liver cancer who have been previously treated with PD-1/PD-L1 immune checkpoint inhibitors |
NCT04696055 |
95 |
Patients who progressed after only one prior line of systemic immunotherapy treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. |
Experimental arm: Regorafenib + Pembrolizumab |
Primary |
|
ORR by central assessment |
|
Secondary |
|
ORR by investigator assessment, DCR, rate of AEs, rate of severe AEs, safety-relevant change, dose modification |
|
A study of camrelizumab combined apatinib in hepatocellular carcinoma previously treated with immune checkpoint inhibitors (ICIs). |
NCT04826406 |
40 |
Patients with disease progression following prior immune checkpoint inhibitors |
Experimental arm: Camrelizumab + Apatinib |
Primary |
|
ORR by central assessment |
|
Secondary |
|
PFS, TTR, DOR, OS survival rate (6, 9, 12 months), rate of AEs, rate of severe AEs |
|
A study of the application of HAIC in advanced HCC previously treated with ICIs and antiangiogenic agents |
NCT05718492 |
100 |
Patients previously treated with immune checkpoint inhibitors and antiangiogenic agents |
Experimental arm: Hepatic arterial infusion (HAIC) using oxaliplatin, leucovorin, fluorouracil, and fluorouracil |
Primary |
|
ORR, PFS |
|
Secondary |
|
OS, tumor control, AEs |
|
Phase 2 study of WGI-0301 in combination with sorafenib for advanced HCC |
NCT06309485 |
60 |
Patients with disease progression or intolerance after systemic immunotherapy treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies |
Experimental arm: WGI- 0301 + Sorafenib |
Primary |
|
Comparator arm: Sorafenib |
ORR, |
|
Secondary |
|
AEs, severe AEs, DCR, DOR, PFS, TTP, OS |
|
QUILT-3.055: A study of combination immunotherapies in patients who have previously received treatment with immune checkpoint inhibitors |
NCT03228667 |
147 |
For HCC with progression on or after pembrolizumab, or with progression on or after nivolumab administered as a single agent or in combination with ipilimumab |
Experimental arm: N-803 + several immune checkpoint inhibitors |
Primary |
|
ORR, |
|
Secondary |
|
Disease specific survival, OS, TTR, DOR, AEs, PFS |
|
A study of E7386 in combination with pembrolizumab in previously treated participants with selected solid tumors |
NCT05091346 |
60 |
HCC progressed on treatment with an anti-PD-1/L1 mAb either as monotherapy, or in combination |
Experimental arm: E7386 + (pembrolizumab plus lenvatinib) |
Primary |
|
ORR, |
|
Secondary |
|
AEs, etc. |
|
Atezolizumab in combination with a multi-kinase inhibitor for the treatment of unresectable, locally advanced, or metastatic liver cancer |
NCT05168163 |
122 |
HCC progressed on Atezo/Bev as first line systemic therapy |
Experimental arm: Atezolizumab + (cabozantinib or lenvatinib) |
Primary |
|
OS, PFS, |
|
Comparator arm: cabozantinib or lenvatinib |
Secondary |
|
ORR, DOR, AEs |
|
Observational study |
|
|
|
|
|
|
(REFINE-IO) |
NCT06117891 |
300 |
Patients treated in a first-line setting with Atezo/Bev or another approved first-line ICI combo therapy. |
Not applicable |
Primary |
|
An observational study to learn more about how well a treatment works when given after treatment with atezolizumab and bevacizumab or another similar combination of drugs in adults with liver cancer that cannot be treated with surgery |
OS |
|
Secondary |
|
PFS, ORR, DOT, AEs |
|
(PRISM trial) |
UMIN000040488 |
2000 |
Patients who are scheduled to receive systemic therapy for unresectable HCC, excluding those with a past history of systemic therapy |
Not applicable |
Primary |
|
Prospective observational study of systemic therapy for unresectable HCC in Japan: Real World data of systemic therapy for HCC |
OS of each treatment regimen at each |
|
treatment line. |
|
Secondary |
|
PFS, ORR, DCR and TTF of each regimen at each treatment line. |
|
Grade 3 or greater AEs of each regimen at each treatment line. |
|
Drug exposure of each regimen at each treatment line. |
|
(HERITAGE trial) |
UMIN000046567 |
10000 |
HCC Patients after 2010 and registered in the National Liver Cancer Follow-up database. |
Not applicable |
Primary: |
|
Hepatoma registry of integrating and aggregating EHR (electric health record) |
OS, PFS, ORR |
|
HCC Patients who have received drug therapy. |
Secondary: |
|
Reason for stopping treatment, cost of treatment |
Abbreviations
atezolizumab and bevacizumab combination therapy
progression-free survival
post-progression survival
durvalumab and tremelimumab combination therapy
tyrosine kinase inhibitors
immune checkpoint inhibitors
activating transcription factor 3
fibroblast growth factor receptor 4
vascular endothelial growth factor receptor 2
tumor immune microenvironment
REFERENCES
- 1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-1905.
- 2. Chon YE, Kim DY, Kim M, Kim BK, Kim SU, Park JY, et al. Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after atezolizumab/bevacizumab failure: A real-world study. Clin Mol Hepatol 2024;30:345-359.
- 3. Yoo C, Kim JH, Ryu MH, Park SR, Lee D, Kim KM, et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational multicenter retrospective study. Liver Cancer 2021;10:107-114.
- 4. Hiraoka A, Kumada T, Tada T, Tani J, Kariyama K, Fukunishi S, et al. Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multicenter retrospective study. Sci Rep 2021;11:16663.
- 5. Aoki T, Kudo M, Ueshima K, Morita M, Chishina H, Takita M, et al. Exploratory analysis of lenvatinib therapy in patients with unresectable hepatocellular carcinoma who have failed prior PD-1/PD-L1 checkpoint blockade. Cancers (Basel) 2020;12:3048.
- 6. Osa A, Uenami T, Koyama S, Fujimoto K, Okuzaki D, Takimoto T, et al. Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients. JCI Insight 2018;3:e59125.
- 7. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231-235.
- 8. Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov 2019;9:1124-1141.
- 9. Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, et al. Prospective genotyping of hepatocellular carcinoma: Clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res 2019;25:2116-2126.
- 10. Morita M, Nishida N, Sakai K, Aoki T, Chishina H, Takita M, et al. Immunological microenvironment predicts the survival of the patients with hepatocellular carcinoma treated with anti-PD-1 antibody. Liver Cancer 2021;10:380-393.
- 11. Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 2017;19:1189-1201.
- 12. Yamauchi M, Ono A, Ishikawa A, Kodama K, Uchikawa S, Hatooka H, et al. Tumor fibroblast growth factor receptor 4 level predicts the efficacy of lenvatinib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol 2020;11:e00179.
- 13. Maruta S, Ogasawara S, Ooka Y, Obu M, Inoue M, Itokawa N, et al. Potential of lenvatinib for an expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma. Liver Cancer 2020;9:382-396.
- 14. Ogasawara S, Chiba T, Ooka Y, Kanogawa N, Saito T, Motoyama T, et al. Sorafenib treatment in Child-Pugh A and B patients with advanced hepatocellular carcinoma: safety, efficacy and prognostic factors. Invest New Drugs 2015;33:729-739.
- 15. McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A, et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a metaanalysis. Eur J Cancer 2018;105:1-9.
- 16. Kuzuya T, Kawabe N, Hashimoto S, Funasaka K, Nagasaka M, Nakagawa Y, et al. Clinical outcomes of ramucirumab as posttreatment following atezolizumab/bevacizumab combination therapy in advanced hepatocellular carcinoma. Anticancer Res 2022;42:1905-1910.
- 17. Yoo C, Byeon S, Bang Y, Cheon J, Kim JW, Kim JH, et al. Regorafenib in previously treated advanced hepatocellular carcinoma: Impact of prior immunotherapy and adverse events. Liver Int 2020;40:2263-2271.
- 18. Chan SL, Ryoo BY, Mo F, Chan LL, Cheon J, Li L, et al. Multicentre phase II trial of cabozantinib in patients with hepatocellular carcinoma after immune checkpoint inhibitor treatment. J Hepatol 2024;81:258-264.
- 19. Frenette C. How to choose second-line treatment for hepatocellular carcinoma. Clin Adv Hematol Oncol 2021;19:726-729.
- 20. Zhu AX, Abbas AR, de Galarreta MR, Guan Y, Lu S, Koeppen H, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med 2022;28:1599-1611.
- 21. Zeng Q, Klein C, Caruso S, Maille P, Allende DS, Mínguez B, et al. Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab-bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study. Lancet Oncol 2023;24:1411-1422.
Citations
Citations to this article as recorded by
- Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma
Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi
Clinical and Molecular Hepatology.2026; 32(1): e38. CrossRef - Second-Line and Subsequent Therapies after Atezolizumab Plus Bevacizumab Treatment in Hepatocellular Carcinoma: A Multicenter Prospective Cohort Study
Yuri Cho, Jeong-Hoon Lee, Baek-Yeol Ryoo, Ho Yeong Lim, Dong Eun Lee, Bo Hyun Kim, Joong-Won Park
Gut and Liver.2026; 20(4): 624. CrossRef - Correspondence to editorial on “Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after atezolizumab/bevacizumab failure: A real-world study”
Young Eun Chon, Dong Yun Kim, Hong Jae Chon, Do Young Kim
Clinical and Molecular Hepatology.2024; 30(4): 1005. CrossRef
