Comparing PD-L1 with PD-1 antibodies combined with lenvatinib and hepatic arterial infusion chemotherapy for unresectable hepatocellular carcinoma
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Background A combination of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and immune checkpoint inhibitors (ICIs) yields a high tumor response rate and survival benefit in unresectable hepatocellular carcinoma (uHCC). However, the selection criteria for different ICIs remain unclear. This study aims to compare the efficacy and safety of PD-1/PD-L1 antibodies combined with HAIC and lenvatinib. Methods This retrospective study included 184 patients with uHCC treated with HAIC+lenvatinib+PD-1/PD-L1 antibody from June 2019 to January 2022. We utilized propensity score matching (PSM) to select and match 60 patients treated with HAIC + durvalumab + lenvatinib (HDL) against 60 patients treated with HAIC + PD-1 antibodies + lenvatinib (HPL) to compare the efficacy and safety profiles of these two groups. Results After PSM, the baseline characteristics were well-balanced between the HDL and HPL groups. The overall survival (p = 0.293) and progression-free survival (p = 0.146) showed no significant difference. The objective response rate (ORR) was higher in the HDL group compared to the HPL group according to modified RECIST (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040), respectively. The incidence of grade 3 or 4 adverse events (AEs) was 10.0% and 18.3% (p = 0.191) in the HDL and HPL groups, respectively. Conclusions PD-L1 antibody appears to be a preferable companion in the combination therapy of HAIC + ICIs + lenvatinib compared to PD-1 antibody, showing higher ORR and relatively lower incidence of severe AEs. Further prospective studies involving a larger patient population are warranted.Keywords:
Lenvatinib
Lenvatinib is an oral molecular target agent that blocks vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, RET , and KIT . It is noninferior, but not statistically superior, to sorafenib with regard to overall survival, according to the findings of a phase 3 trial of lenvatinib versus sorafenib as first-line therapy for advanced hepatocellular carcinoma (HCC) (the REFLECT trial) (1). Nowadays, lenvatinib has been approved all over the world and has become the second front-line tyrosine kinase inhibitor in patients with advanced HCC. The recommendations for starting lenvatinib therapy for advanced HCC are different from those for other molecular target agents in patient with advanced HCC in that dose is based on body weight (≥60 kg: 12 mg once daily; <60 kg: 8 mg once daily). The aim of this article is to discuss the weight-based dosing of lenvatinib for advanced HCC.
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Abstract The purpose of this study was to investigate the relationships among plasma concentrations (C 0 ) of lenvatinib, angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in thyroid cancer patients. The median change rates of Ang-1 and Ang-2 at 1 month after treatment from baseline in all patients were − 15.3% and − 48.4%, respectively. However, the change of Ang-1 and Ang-2 at 1 month from baseline did not correlate with lenvatinib C 0 . In patients with partial response (PR) and stable disease to lenvatinib, Ang-2 at 1 month were significantly lower than Ang-2 at baseline ( P < 0.001 and P < 0.05, respectively), but were not significantly lower in patients with progressive disease. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of the change rate of Ang-2 of -49.83%. In patients who continued treatment with lenvatinib for 1 year, Ang-2 at 1 month and 1 year were significantly lower than those at baseline (each P < 0.001). The change of Ang-2 at 1 month after treatment from baseline rather than simply the Ang-2 level at baseline may be important as a biomarker of the inhibitory effect of angiogenesis by lenvatinib.
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Treatment of advanced hepatocellular carcinoma (HCC) has reached a plateau after the approval of sorafenib in 2007. Several molecularly targeted therapies have failed to show significant improvement in survival outcomes compared with sorafenib, due to flaws in the design of clinical trials or failure to understand and correct for the competing co-morbidity of liver dysfunction. Lenvatinib is a multitargeted tyrosine kinase inhibitor with potent antiangiogenic effects, and has recently been approved for differentiated thyroid cancer. Lenvatinib has shown highly promising response data in Phase I/II clinical trials in HCC, although with some concerns regarding its toxicity profile. The pivotal Phase III REFLECT trial comparing lenvatinib to sorafenib has been completed, and the results of this trial will determine whether lenvatinib represents a breakthrough in the current crisis affecting HCC drug development.
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There is a number of unresolved issues regarding the systemic therapy administration for hepatocellular carcinoma (HCC). Their solution is facilitated by accumulating real‑world study results. Lenvatinib therapy is a recognized drug with a good efficacy and safety profile for the treatment of HCC. Subanalyses of the REFLECT study showed that the absence of stratification by baseline AFP and baseline liver function, as well as the lack of options for subsequent drug therapy after lenvatinib, also affects the outcomes. Once these factors are taken into account, the hypothesis of superiority of lenvatinib to sorafenib and other drugs can be tested. Real‑world clinical studies have demonstrated positive results of lenvatinib therapy in patients with Child‑Pugh class B liver function, provided recommendations on the sequence of systemic therapy after lenvatinib and on the use of lenvatinib in patients with BCLC stage B, along with considering the possibility of lenvatinib monotherapy and the prospects for its use in patients with nHCC. Further real‑world studies of lenvatinib for HCC in the Russian population are required.
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Background/Aim: Neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor prognosis for radioactive iodine ablation refractory differentiated thyroid cancer (RR-DTC). Little is known whether NLR can be a tumor marker for RR-DTC patients treated with lenvatinib. Patients and Methods: We retrospectively analyzed RR-DTC patients treated with lenvatinib. NLR was calculated at 4 points before and during lenvatinib treatment. Results: The median NLR value increased at the start of lenvatinib treatment, compared to 6 months prior to initiation of lenvatinib treatment. The median overall survival was significantly longer in patients with the lower NLR (<3) at the start of lenvatinib treatment. The median NLR values decreased when the patients achieved best tumor response, and increased again upon disease progression. Conclusion: NLR values vary before and during lenvatinib treatment, suggesting that this ratio can reflect disease activity of RR-DTC. NLR can supportively be used as a tumor marker of RR-DTC and an indicator for starting lenvatinib treatment.
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Two tyrosine kinase inhibitors, lenvatinib and sorafenib, are available systemic therapies for patients with metastatic differentiated thyroid carcinoma. However, the treatment options for carcinoma refractory to both lenvatinib and sorafenib are limited. Here, we present a case of metastatic papillary thyroid carcinoma that showed resensitization to rechallenge with lenvatinib. A 72-year-old woman who had been diagnosed with papillary thyroid carcinoma with multiple lymph node and lung metastases progressed with the emergence of subcutaneous metastasis after 3 years of response to initial lenvatinib. Five months after switching to sorafenib, the tumor was enlarged with increased contrast enhancement on computed tomography, suggesting progressive disease. Three months after the reintroduction of lenvatinib, marked tumor shrinkage and a decrease in its contrast enhancement were seen. Rechallenge with lenvatinib showed tumor resensitization. Therefore, rechallenge with lenvatinib may be a treatment option in patients who have experienced progressive disease after initial response to lenvatinib and subsequent sorafenib.
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症例は慢性C型肝炎に罹患し飲酒習慣もある60歳代男性で,原発性肝細胞癌の一部に破裂予防の肝動脈塞栓術施行後,lenvatinib 8 mg/日を開始した.約1カ月で腫瘍に感染し,抗生剤治療不応かつ経皮的ドレナージ困難にて,lenvatinibを一週間休薬し,開腹下感染腫瘍切除術を施行した.術後創部治癒に問題なく,lenvatinibを4 mg/日で再開したが,肝障害,倦怠感,食思不振で35日間休薬した.dexamethasone併用して再開し,8 mg/日まで増量したが動脈血流減少せず,lenvatinib血中濃度が低値であった.12 mg/日に増量後,有害事象なしに血中濃度は上昇し,動脈血流も低下した.腫瘍感染の治療困難例は耐術能が許せば,lenvatinibの適切な休薬で外科的治療も選択でき,また,lenvatinib血中濃度による投与量の調整は有効な可能性がある.
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Lenvatinib is a tyrosine kinase inhibitor (TKI) more effective against hepatocellular carcinoma (HCC) than sorafenib, making lenvatinib a first-line treatment option for patients with unresectable HCC. In patients treated with sorafenib, post-progression survival (PPS) rather than progression-free survival (PFS) is essential for overall survival (OS). However, the importance of PPS for OS in patients treated with lenvatinib is uncertain, and optimal treatment after lenvatinib failure has not yet been established.The present study investigated the correlations of PFS and PPS with OS in studies of HCC patients treated with lenvatinib by weighted linear regression analysis. Furthermore, the contribution of treatment regimens after lenvatinib failure to OS were evaluated in daily clinical practice.An analysis of 20 studies with 4,054 patients found that PPS had a stronger correlation with OS (r=0.869, p<0.001) than did PFS (r=0.505, p=0.007). Analysis of 79 patients with unresectable HCC treated with first-line lenvatinib showed that subsequent treatment was the most significant contributor to OS. Second-line sorafenib was administered to 25 patients, with late transition to third-line treatment being highest among patients who received second-line treatment.PPS contributes significantly to OS in HCC treatment with TKIs, with multi-sequential treatment being a key determinant of longer OS.
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There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
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