Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma

Abstract

Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient's weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8-12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p < 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.Cancers 2020, 12, 49 2 of 12 based on the two Phase III studies [4,5]. However, due to its various adverse events (AEs) and limited efficacy, identification of novel MTA compounds has been required. Recently, lenvatinib (Lenvima ® , Eisai Co., Ltd., Tokyo, Japan) was approved as a novel first-line MTA for unresectable HCC in the EU, USA, and Asia, including Japan, China, Korea, and Taiwan, based on the Phase III REFLECT trial [6].In order to optimize and maximize the therapeutic effects of pharmacotherapy, especially in the case of anticancer drug treatment, it is essential to appropriately evaluate the patient's condition before administration, sufficiently manage AEs after initiation, and keep the dose intensity (DI) high. The practicality of relative dose intensity (RDI), calculated as the percentage of the delivered DI divided by the standard DI, has been shown to be an indicator of the treatment intensity of anticancer drugs [7]. The correlations between RDI and therapeutic efficacy were reported in various types of cancers, including breast cancer [8], pancreatic ductal adenocarcinoma [9], renal cell carcinoma [10], malignant lymphoma [11], and HCC [12]. However, since lenvatinib is the first oral MTA that is dosed by the patient's weight (8 mg once...

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

“…In the present study, median PFS was 5.0 months, which was shorter than that in the phase 3 REFLECT trial, revealing median PFS was 7.4 months in the overall population and 7.2 months in the Japanese subset [18]. However, in real-world settings, median PFS ranging from 4.4 to 5.4 months has been reported, consistent with our results [19,20]. This may be explained by more patients in real-world settings being aged and having low ECOG-PS score and Child-Pugh score compared with the clinical trial.…”

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

“…This indicates that maintaining a higher dose is important to maintain a higher Cmax. Maintaining more than 70% RDI in lenvatinib has been reported to be an independent factor for a better therapeutic response and better PFS [32]. In the weekends-off protocol, the RDI can be maintained at 71.4%, and this might have, in part, accounted for the 50% improvement of a therapeutic effect in our study.…”

“…However, among the patients who required dose reduction due to AEs, a therapeutic response has also recovered again in 61.5% of the patients when the weekends-off administration was implemented using the original dose of lenvatinib. A recent study showed that Cmax and relative dose intensity (RDI) are important in the therapeutic effect of lenvatinib [32][33][34]. Ikeda et al and Tamai et al reported that the Cmax of lenvatinib is reduced by nearly 50% and the AUC is decreased by 55% when the dose is reduced from 12 mg to 8 mg [19,20].…”

Initial Experience of Ramucirumab Treatment After Lenvatinib Failure for Patients With Advanced Hepatocellular Carcinoma

“…According to the clinical practice guidelines on the management of HCC (3,4), both sorafenib and lenvatinib were recommended as the first-line systemic therapy options for patients with advanced stage HCC. Because the REFLECT trial reported superior antitumor response and progression-free survival (PFS) with lenvatinib over sorafenib (5,6), lenvatinib has been increasingly selected as the first-line therapy in clinical practice (7)(8)(9)(10). However, the outcomes of ramucirumab treatment after lenvatinib failure are unknown, because the REACH-2 trial was conducted on patients with prior sorafenib intake (1).…”