The results of this study demonstrate differential organ-specific responses to combined lenvatinib plus anti-PD-1 monoclonal antibodies in patients with advanced HCC. There have been previous reports of organ-specific responses to immunotherapy in the second-line treatment of HCC.(16, 17) However, to our knowledge, this is the first report of organ-specific responses to first-line combination treatment with lenvatinib plus anti-PD-1 antibodies in patients with advanced HCC.
All patients in this study received first-line treatment for advanced HCC. Compared with a similar population of patients with advanced HCC receiving first-line therapy with lenvatinib plus pembrolizumab in the Phase Ib Keynote 524 study, a higher proportion of those in the present study were HBsAg positive (85 vs. 19%), had AFP ≥ 400 ng/mL (65 vs. 30%), BCLC Stage C disease (76.7 vs. 71%) and MVTT (50 vs. 30%).(25) Our results show that first-line treatment with lenvatinib plus anti-PD-1 antibodies led to an ORR of 33.3%, a median DOR and PFS of 10.5 and 7.0 months and a median OS that was not reached. In comparison, patients in the Keynote 524 study achieved an ORR of 36% and a median DOR, PFS and OS of 12.6, 8.6 and 22 months, respectively.(25) These findings suggest that the combination of lenvatinib with a range of anti-PD-1 antibodies has a similar anti-tumor effect to lenvatinib plus pembrolizumab. In addition, the results of this study add evidence that combination therapy with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is associated with a higher ORR and longer DOR than lenvatinib or pembrolizumab monotherapy.(8)
Our study found a higher ORR and DOR in MVTT versus intrahepatic lesions. Furthermore, among 18 patients with a CR or PR in MVTT, six were able to achieve an R0 resection and, of these six patients, four were confirmed to have a pCR in MVTT. These findings provide evidence for the anti-tumor effectiveness of the combined lenvatinib plus anti-PD-1 antibody treatment strategy in HCC-related MVTT. Furthermore, of 33 patients in the present study with MVTT, 18 had differential tumor responses in intrahepatic tumors versus MVTT and among these patients 13 had a better tumor response for MVTT versus intrahepatic tumors. Although Kuo and colleagues previously reported higher ORRs for portal vein tumor thrombus versus intrahepatic lesions in patients receiving TKIs with or without immune checkpoint inhibitor therapy, patients in the present study received lenvatinib plus anti-PD-1 antibodies as a first-line treatment for advanced HCC, which is under investigation as a first-line therapy.(16, 17) In addition, in the present study, the OSRR in intrahepatic lesions and MVTT was 32.8% and 54.5%, which is slightly higher than reported by Kuo and colleagues among patients with advanced HCC receiving anti-PD-1 antibody monotherapy (intrahepatic: 14.7%; MVTT: 50%).(16) Possible reasons for this include patients in the present study receiving first-line treatment only, compared with all comers in the Kuo study, and the relatively strong anti-tumor effect of combined lenvatinib plus anti-PD-1 antibodies compared with single or double agent immune therapy. In support of the latter explanation, recent clinical trials in advanced HCC have shown a trend for higher ORRs overall with combined TKI and anti-PD-1 antibody therapy(13, 25) versus anti-PD-1 antibody monotherapy(26) or dual immune-therapy strategies.(27, 28) Finally, in the present study, the OSRR for lung metastases was similar to previous reports of immune checkpoint inhibitor monotherapy (37 vs. 40%(16) and 41.2%(17)). However, due to the small number of patients with lung metastasis included in the present study, the conclusions that can be drawn are limited.
In our study, a total of 10 patients had a best overall response of PD (they did not achieve SD, PR or CR). Of these patients, eight were judged to have PD based on intrahepatic disease progression. Of these eight patients, seven had the appearance of new intrahepatic lesions. Among 15 patients who initially achieved disease control (SD, PR or CR) and subsequently progressed while on treatment, 12 had intrahepatic disease progression, of which 10 were due to the appearance of new lesions. These results suggest that, for patients with advanced HCC receiving combined TKI plus anti-PD-1 antibody treatment, disease progression is predominantly due to intrahepatic disease.
The differential OSRRs observed in our study have important implications for treatment decision making in patients with advanced HCC, particularly for the use of locoregional and surgical treatment. Our findings show that combined lenvatinib and anti-PD-1 antibody therapy leads to a higher OSRR and DOR in MVTT than in intrahepatic lesions. This suggests a proportion of patients with BCLC Stage C disease may have an opportunity to completely irradicate MVTT and be down-graded to BCLC Stage B or A. Such patients would then gain an opportunity to receive locoregional therapy or surgical resection.(29) In our study, patients who achieved a treatment response in MVTT had longer OS than those without response. The presence of MVTT is known to be an important predictor of poor survival outcomes for patients with HCC receiving sorafenib.(30) However, compared with TKI monotherapy, combined TKI and anti-PD-1 antibody therapy can more effectively control or shrink MVTT and appears to offer better survival for patients.(13, 25) We propose that the longer survival times reported for such therapies is strongly related to control of MVTT. Therefore, careful evaluation of the response of MVTT to systemic therapy may improve the overall evaluation of response to treatment in patients with HCC.
The relatively low OSRR observed for intrahepatic tumors compared with MVTT in this study may be explained by the higher tumor burden associated with intrahepatic disease, which can prevent medication from entering tumors in this location, or could also be related to the immune function of the liver. Most cases of disease progression during treatment in the present study were due to the appearance of new intrahepatic lesions, highlighting the challenge of controlling intrahepatic disease during the treatment of HCC. Even patients with controlled intrahepatic disease may benefit from the concomitant use of locoregional (such as transarterial chemoembolization or radiotherapy) or surgical treatment to achieve comprehensive disease control. However, identifying effective combination treatments and optimal timing for adding surgical or locoregional therapies requires further investigation in controlled trials. Furthermore, the shorter DOR observed in the present study for intrahepatic lesions versus MVTT further highlights the potential benefit of the addition of surgical treatment or liver-directed therapy even for patients who achieve control of intrahepatic lesions during systemic therapy.
We recognize several limitations of this study. Firstly, the analysis included a relatively small number of patients which limits the strength of evidence and retrospective analyses have intrinsic limitations including delayed evaluation times and a lack of standardized processes compared with a prospective clinical trial. The data from the previously-reported controlled study may facilitate a more stringent analysis to re-examine the above findings. Secondly, there is currently no agreed standard for evaluating MVTT, and for this analysis we extended the RECIST v1.1 criteria to MVTT. The evaluation of MVTT response is a topic that requires further investigation in the future. Finally, while all patients received lenvatinib, anti-PD-1 monoclonal antibody treatment was not consistent for all patients, resulting in several different therapeutic combinations and the potential for therapeutic bias towards one combination over another. Nonetheless, we believe the phenomenon reported in this study is genuine, and warrants verification through the independent prospective investigation of fixed regimens.
In conclusion, in patients with advanced HCC, first-line treatment with lenvatinib plus anti-PD-1 antibodies resulted in a better tumor response in MVTT compared to intrahepatic lesions. We propose that complete MVTT necrosis can lead to downstaging and subsequent eligibility for surgical liver resection in a proportion of patients with advanced HCC. This combination treatment strategy may therefore allow selected patients with MVTT at HCC diagnosis to access surgical and locoregional treatments, with the potential for increased long-term survival versus current treatment options.