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In this work, we describe the development of targeted polymeric nanoparticles loaded with lenvatinib for the treatment of hepatocellular carcinoma (HCC). A synthetic brush copolymer (PHEA-g-BIB-pButMA-g-PEG-biotin) was synthesized from α-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) by a three-step reaction involving atom transfer radical polymerisation (ATRP) to graft hydrophobic polybutylmethacrylate pendant groups and further conjugation with biotinylated polyethylene glycol via carbonate ester. Subsequently, lenvatinib-loaded nanoparticles were obtained and characterized demonstrating colloidal size, negative zeta potential, biotin exposure on the surface and the ability to release lenvatinib in a sustained manner. Lenvatinib-loaded nanoparticles were tested in vitro on HCC cells to evaluate their anticancer efficacy compared to free drug. Furthermore, the enhanced in vivo efficacy of lenvatinib-loaded nanoparticles on nude mice HCC xenograft models was demonstrated by evaluating tumor burdens, apoptotic markers and histological scores after administration of lenvatinib-nanoparticles via intraperitoneal or oral route. Finally, in vivo biodistribution studies were performed, demonstrating the ability of the prepared drug delivery systems to significantly accumulate in the solid tumor by active targeting, due to the presence of biotin on the nanoparticle surface., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients., Patients and Methods: We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days., Results: In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1., Conclusions: Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib., (©2024 American Association for Cancer Research.)

Introduction: Bone metastases negatively affect prognosis in patients with advanced renal cell carcinoma (aRCC). We conducted a systematic literature review to identify clinical trial publications including patients with aRCC with and without bone metastases., Methods: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42022355436). MEDLINE and Embase databases were searched (September 2, 2022) to identify publications reporting efficacy and safety outcomes for patients with/without bone metastasis from clinical trials of systemic RCC therapies. Risk of bias was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Results: Of 526 publications screened, 19 were eligible: seven (from five studies) reported phase 3 trials, six reported phase 2 trials, one reported phase 1b/2 trials, and five were pooled analyses. Five publications reported moderate-quality evidence, while 14 were graded as low- or very low-quality evidence, suggesting a high potential for uncertainty. Five studies reported benefits of investigational therapies versus comparators in patients with and without bone metastases; these studies included cabozantinib, nivolumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab treatment arms. Data were also available for nivolumab plus ipilimumab. Bone metastases were consistently associated with poor prognosis in patients with aRCC. Preliminary data support the hypothesis that therapies targeting pathways implicated in the development of bone metastases may be beneficial, and warrant further investigation. However, data to support treatment decision-making are lacking., Conclusion: Our findings highlight the need for clinical data to assist in defining the optimal treatment for patients with aRCC and bone metastasis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Janet Brown: Honoraria: Novartis, Bayer, Amgen, Ipsen, MSD Oncology, Bristol Myers Squibb. Consulting or Advisory Role: Novartis, Bayer, Amgen, Ipsen, MSD Oncology, Bristol Myers Squibb. Speakers’ Bureau: Ipsen, Amgen, MSD. Research Funding: Amgen (Inst), Bayer (Inst). Travel, Accommodations, Expenses: Ipsen, MSD Oncology, Amgen, Novartis, Bayer. Daniele Santini: Honoraria: Speaker honoraria with AstraZeneca, MSD, BMS, Astellas, Janssenn, EISAI, Merck, Pfizer, Bayer, Novartis, AstraZeneca, Lilly. Consulting or Advisory Role: Advisory Board role with AstraZeneca, MSD, BMS, Astellas, Janssenn, EISAI, Merck, Pfizer, Bayer, Novartis, AstraZeneca, Lilly. Natalie Charnley: Honoraria: Lecture fees from Pfizer, Ipsen, and Janssen. Consulting or Advisory Role: Advisory boards with Pfizer, Ipsen, and Janssen. Alessia Ogareva: Employment: Employee of Ipsen. Alison Chisholm: Employee of Oxford PharmaGenesis. Robert Jones: Honoraria: Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Astellas, Janssen, MSD, Pfizer, Merck Serono. Consulting or Advisory Role: Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Novartis/AAA, Astellas, Janssen, MSD, Pfizer, Merck Serono. Research Funding: Received educational grants from Astellas, Bayer, Clovis and Exelixis., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Treatment recommendations for metastatic colorectal cancer (mCRC) do not differ by age group; nevertheless, aggressive multiagent chemotherapy comprising FOLFOXIRI+bevacizumab (triplet+bev) is routinely administered in younger patients. This study analyzed real-world data on index triplet+bev use and subsequent systemic therapies., Materials and Methods: This retrospective, observational cohort study was conducted in patients aged ≥ 18 years with mCRC, who were initiated on triplet+bev. Data were derived from the Optum de-identified electronic health record dataset., Results: Of 36,056 patients, 14%, 36%, and 50% were aged 18-49, 50-64, and ≥ 65 years, respectively. During the study period (2010-2021), triplet+bev use increased in patients aged 18-49 years (1%-4%) but remained at approximately 3% and 1% in patients aged 50-64 and ≥ 65 years, respectively. Patient demographics and clinical characteristics varied slightly; of patients receiving triplet+bev (n = 921) versus nontriplet+bev (n = 35,132) most were male (57% vs. 52%), resided in the Midwest (54% vs. 49%) and Northeast (18% vs. 14%) US regions, and had secondary malignancies (86% vs. 73%). Following triplet+bev, most patients received subsequent therapies (including continued triplet component therapies; 97%) or subsequent "new" therapies (therapies that did not include any agents comprising triplet+bev; 57%), most frequently EGFR inhibitors (28%) and regorafenib (21%), with a similar trend among all age groups., Conclusions: Overall, this study shows that younger patients with mCRC are more likely to receive first-line triplet+bev. These results also reveal that nonchemotherapy options are often used beyond first-line triplet chemotherapy for patients with mCRC., Competing Interests: Disclosure The data that support the findings of this study are available from Optum, which were used under license for the current study, and so are not publicly available. Interested researchers should contact Optum (https://www.optum.com). AB has received payments from Bayer for educational activities. HO, ZPV, and JX are employees of Bayer. ZPV reports stock ownership with Bayer. XF was an employee of Bayer at the time of the study. XF reports stock ownership with Jazz Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group., (© 2024. The Author(s).)

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Yamada received commercial research grants from Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, and Takeda Pharmaceutical Company Limited and speaking honoraria from Eli Lilly and Chugai-Roche. H. Kawachi received personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Eli Lilly Japan, and MSD outside the purview of the submitted work. A. Osoegawa received consultant honoraria from AstraZeneca and speaking honoraria from AstraZeneca, MSD Japan, Chugai Pharmaceutical, Bristol Myers Squibb, and Ono Pharmaceutical. T. Sakai received research grants from Otsuka Pharmaceutical, Taiho Pharmaceutical, and Oncolys BioPharma and a patent fee from JT Pharmaceutical. T. Yasuhiro and R. Kozaki are paid employees of Ono Pharmaceutical. S. Yano received research grants from Chugai-Roche and Boehringer-Ingelheim and speaking honoraria from Amgen, Chugai-Roche, Boehringer-Ingelheim, Novartis, and Pfizer. K. Takayama received research grants from Chugai-Roche and Ono Pharmaceutical and personal fees from AstraZeneca, Chugai-Roche, MSD-Merck, Eli Lilly, Boehringer-Ingelheim, and Daiichi-Sankyo. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The combination of targeted therapy and immunotherapy has improved the clinical outcomes of unresectable hepatocellular Carcinoma (HCC). However, the overall prognosis remains suboptimal. This study aims to evaluate the efficacy and safety of a novel combination of radiofrequency ablation (RFA) with lenvatinib plus sintilimab in unresectable HCC., Methods: In this retrospective study, patients diagnosed with unresectable HCC were included and divided into two cohorts: RFA combined with lenvatinib plus sintilimab (R-L-S group) and lenvatinib plus sintilimab (L-S group). The primary efficacy endpoints were objective response rate (ORR) and progression free survival (PFS). Adverse events were analyzed to assess the safety profiles., Results: The median follow-up periods for the entire cohort were 14.0 months. The R-L-S group (n = 60) had a significantly higher ORR than those with L-S alone (n = 62) (40.0% vs. 20.9%; p = 0.022). Moreover, patients in the R-L-S group had improved median PFS (12 vs. 8 months; p = 0.013) and median overall survival (24 vs. 18 months; p = 0.037), as compared with lenvatinib and sintilimab alone. No significant difference in treatment related adverse event (TRAE) of any grade between the two groups. The most common TRAEs of grade ≥ 3 were fatigue 10.0% (6/60) and hand-foot skin reaction 10.0% (6/60) in the R-L-S group and hand-foot skin reaction 11.3% (7/62) in the L-S group., Conclusion: In unresectable HCC patients, the incorporation of RFA to lenvatinib plus sintilimab demonstrated improved efficacy without compromising safety compared with lenvatinib plus sintilimab alone., (© 2024. The Author(s).)

Purpose: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC., Methods: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment., Results: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm., Conclusion: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

Objective: Treatment options for heavily pre-treated recurrent ovarian and endometrial cancer are limited. Lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has been efficacious in advanced endometrial cancer, but at the recommended dose level, high-grade adverse events occur and lead to drug discontinuation. This study evaluated the feasibility of low-dose lenvatinib plus anti-PD-1 therapy in patients with recurrent ovarian and endometrial cancer., Methods: This is a single-arm, protocol-based pilot study. Patients with recurrent ovarian cancer or endometrial cancer who had at least one line of previous therapy were included and given lenvatinib 8 or 12 mg daily (based on the patient's weight) and anti-PD-1 therapy. The primary endpoint was the objective response rate., Results: Twenty-one patients were enrolled, including 15 with ovarian cancer and six with endometrial cancer. All patients were pre-treated, and the median number of lines of previous treatment of the ovarian and endometrial cancer cohorts was three and two, respectively. After a median follow-up of 11.0 months (range 6.8-23.9), the objective response rate for the ovarian cancer and endometrial cancer cohorts was 46.7% (95% CI 21.3% to 73.4%) and 66.7% (95% CI 22.3% to 95.7%), respectively. The median duration of response for the ovarian cancer and endometrial cancer cohorts was 5.3 (95% CI 0 to 11.7) and 6.1 (95% CI 2.4 to 9.8) months, respectively. The median progression-free survival for the ovarian cancer and endometrial cancer cohorts was 4.1 (95% CI 2.6 to 5.6) and 6.6 (95% CI 1.7 to 11.5) months, respectively. No grade 4 or 5 adverse events occurred. Eight (38.1%) patients had a lenvatinib dose reduction. There was no discontinuation of lenvatinib alone, and only one patient discontinued both drugs due to adverse events., Conclusion: Low-dose lenvatinib in combination with anti-PD-1 therapy showed promising efficacy and favorable tolerability in patients with heavily pre-treated ovarian and endometrial cancer., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines., Methods: Patients with CRC in the Optum's de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group., Results: 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% (n = 66/310) to 45% (n = 178/393), the proportion who received standard dosing decreased from 79% (n = 244/310) to 55% (n = 215/393), the proportion who initiated their third treatment cycle increased from 36% (n = 113/310) to 46% (n = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1)., Conclusions: Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib., (© 2024. The Author(s).)

Backgrounds: Programmed death receptor 1 (PD-1) monoclonal antibody has been approved for the first and second-line treatments of hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of tislelizumab + regorafenib as a second-line treatment option for advanced HCC., Methods: Treatment-related adverse events (TRAEs) were the primary endpoints in this clinical trial comprising 28 patients with advanced HCC. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)., Results: According to the mRECIST 1.1 evaluation criteria, the ORR was 28.6%. Complete and partial response were observed in 3 and 5 patients, respectively; stable disease was observed in 12 patients (DCR, 71.4%). The median PFS was 6.4 months. The incidence of grade 1-2 and 3-4 TRAEs was 57.1% and 39.3%, respectively., Conclusion: This study suggests that tislelizumab + regorafenib can be used as a second-line treatment for advanced HCC., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Purpose: Lenvatinib achieves favorable therapeutic outcomes for patients with radioactive iodine therapy refractory differentiated thyroid cancer (DTC); however, its use is associated with a high incidence of adverse events. To avoid severe adverse events, planned drug holidays (PDH) have been proposed. This study aimed to evaluate treatment effects, identify prognostic factors, and investigate the usefulness of PDH in patients with unresectable DTC who received lenvatinib across the multi-institutions., Methods: Fifty-one patients with unresectable DTC treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated, and prognostic factors were assessed. OS, PFS, and time to treatment failure (TTF) were compared between patients with and without PDH. Lenvatinib administration schedule was evaluated in PDH., Results: The 3-year OS and PFS rate were 53.5% and 42.1%, respectively. Multivariate analysis revealed that presence of maximum size of lung metastasis ≥10 mm was independent prognostic factor for poorer OS and PFS, and histology other than papillary thyroid carcinoma was the independent prognostic factor for poorer PFS. Twenty-five patients (49%) treated with PDH. There were significant differences in OS, PFS, and TTF between patients with and without PDH. Various schedules were used in PDH. Eight (32%) patients required switch to the different administration schedule., Conclusion: Our results suggest that PDHs may extend OS, PFS, and TTF. In patients with PDH, various schedules used for lenvatinib administration highlight the difficulty in determining a uniform administration schedule. Therefore, it is crucial to consider the optimal lenvatinib administration schedule on a case-by-case basis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study., (© 2024. The Author(s).)

Objective: To evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and tislelizumab in the treatment of unresectable intrahepatic cholangiocarcinoma (ICC). Methods: The clinical data of 12 patients with unresectable ICC who received HAIC combined with lenvatinib and tislelizumab in the First Affliated Hospital of Soochow University from October 2021 to April 2023 were retrospectively analyzed. HAIC included gemcitabine plus oxaliplatin; this regimen was combined with lenvatinib and tislelizumab within 3-7 days after its initial administration. Relevant laboratory examinations were performed before each cycle of HAIC, and enhanced computed tomography/magnetic resonance imaging examinations were performed every 6-9 weeks. Tumor response to treatment was evaluated using the modified Response Evaluation Criteria in Solid Tumors. The objective response rate, disease control rate, progression-free survival, overall survival, and treatment-related adverse reactions of patients with ICC were statistically analyzed. Results: The objective response rate to HAIC combined with lenvatinib and tislelizumab was 6/12; the disease control rate was 8/12; the median progression-free survival was 11.8 months; and the median overall survival was 14.2 months. Three patients had grade Ⅳ adverse reactions (increased alanine aminotransferase and aspartate aminotransferase thrombocytopenia), while three patients had grade Ⅲ adverse reactions (increased total bilirubin, alanine aminotransferase, and aspartate aminotransferase). The remaining patients had grade Ⅰ-Ⅱ adverse reactions. There were no serious complications related to interventional surgery. Conclusions: Use of HAIC (gemcitabine plus oxaliplatin) combined with lenvatinib and tislelizumab in the treatment of unresectable ICC may be safe and feasible. Preliminary clinical studies have shown that this combination can improve the survival and prognosis of patients with ICC.

Aim: Lenvatinib mesylate (LEN) is an oral tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events. This study was aimed at investigating the incidence of LEN-induced palmar-planter erythrodysesthesia syndrome (PPES) and its relationship with patient demographics by analyzing clinical laboratory data of LEN-treated patients with HCC., Methods: This was a single-centre, retrospective study of patients with HCC who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration., Results: Overall, 75 patients with HCC were enrolled. LEN-induced PPES was found in 48.0% (36/75 patients). In these patients, alkaline phosphatase (ALP), γ-Glutamyl transpeptidase (γ-GTP) and monocytes (MONO) were significantly high (ALP: p = 1.32 × 10 -3 , γ-GTP: p = 4.25 × 10 -3 and MONO: p = 0.013). The cut off values of ALP, γ-GTP and MONO for LEN-induced PPES were estimated at 573 U/L, 89 U/L, and 310 counts/μL, respectively. In the multivariate analysis, γ-GTP and MONO were independent risk factors for LEN-induced PPES., Conclusions: High γ-GTP and high MONO were risk factors for LEN-induced PPES., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims/Background The combination of lenvatinib and programmed cell death protein 1 (PD-1) inhibitor has demonstrated significant efficacy in treating unresectable hepatocellular carcinoma. Our study aimed to evaluate the safety and efficacy of triple therapy that includes hepatic arterial infusion chemotherapy, lenvatinib and PD-1 inhibitor for treating unresectable hepatocellular carcinoma. Methods Patients with a primary diagnosis of advanced hepatocellular carcinoma between June 2020 and August 2023 were included in this study. Initially, 53 patients with hepatocellular carcinoma were enrolled. Then, 13 patients were excluded based on the inclusion criteria, resulting in 40 patients included for analysis. Among them, 31 patients received triple therapy, including 16 Barcelona Clinic Liver Cancer C stage, 12 Barcelona Clinic Liver Cancer-B, and 3 Barcelona Clinic Liver Cancer-A hepatocellular carcinoma patients. The primary endpoint was the objective response rate, while the secondary endpoints included the conversion resection rate, pathological complete response rate, pathological partial response rate, and treatment-related adverse events. Results The objective response rate was 80.65% at a median follow-up of 24.5 months (range: 12.6-55.8 months). Of the 14 patients (45.2%) who underwent conversion therapy and were eligible for surgery, 7 patients underwent liver resection and the remaining 7 patients underwent liver transplantation. The median interval between the start of triple therapy and surgery was 117 days, ranging from 25 to 215 days. The pathological complete response was observed in six patients (19.4%) and the pathological partial response rate in eight patients (25.8%). All adverse events occurred in 77.4% of the patients. Conclusion In patients with unresectable hepatocellular carcinoma, the combination of hepatic arterial infusion chemotherapy, lenvatinib, and PD-1 inhibitor exhibits favourable efficacy and well tolerability, achieving a desirable pathological complete response rate while maintaining manageable drug toxicity.

Objective: The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features., Methods: We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analyses were performed to verify which features could be correlated with HFS development., Results: HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups., Conclusion: HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

Background: Intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) beyond the up-to-11 criteria represent a significant therapeutic challenge due to high and heterogeneous tumor burden. This study evaluated the effectiveness and safety of transarterial chemoembolization (TACE) in combination with lenvatinib and tislelizumab for these patients., Methods: In this retrospective cohort study, patients with unresectable intermediate-stage HCC beyond the up-to-11 criteria were enrolled and divided into TACE monotherapy (T), TACE combined with lenvatinib (TL), or TACE plus lenvatinib and tislelizumab (TLT) group based on the first-line treatment, respectively. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to RESIST1.1 and modified RECIST, and adverse events (AEs)., Results: There were 38, 45, and 66 patients in the T, TL, and TLT groups, respectively. The TLT group exhibited significantly higher ORR and DCR than the other two groups, as assessed by either mRECIST or RECIST 1.1 (all P <0.05). Median PFS and OS were significantly longer in the TLT group compared with the T group (PFS: 8.5 vs. 4.4 months; OS: 31.5 vs. 18.5 months; all P <0.001) and TL group (PFS: 8.5 vs. 5.5 months; OS: 31.5 vs. 20.5 months; all P <0.05). The incidence of TRAEs was slightly higher in the TLT and TL groups than in the T group, while all the toxicities were tolerable. No treatment-related death occurred in all groups., Conclusions: TACE combined with lenvatinib and tislelizumab significantly improved the survival benefit compared with TACE monotherapy and TACE plus lenvatinib in patients with intermediate-stage HCC beyond the up-to-11 criteria, with an acceptable safety profile., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Shuangyan, Shi, Cai, Wu, Wang, Ma, Zhou, Mai, Wang, Lai, Chen, Chen and Guo.)

Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking ACH (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of ACH such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in ACH. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with ACH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models., Methods: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized., Results: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib., Conclusions: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted., (© 2024. The Author(s).)

Background: Tyrosine kinase inhibitors (TKIs) and immunotherapy have been proposed for advanced metastatic anaplastic thyroid cancer (ATC). We report a case of BRAF V600E-mutated ATC in which lenvatinib (L) plus pembrolizumab (P) enabled neoadjuvant treatment., Case Presentation: A male patient aged 65 years presented with a rapidly enlarging left latero-cervical mass. Fine needle aspiration was suggestive of ATC. Surgical consultation excluded radical surgery. While awaiting molecular profile analysis and considering the fast evolution of the disease, treatment with L and P was started. L was started at a dose of 14 mg daily, while P was started at the standard regimen (200 mg every 3 weeks). After 1 month, computerized tomography showed a reduction in the mass with almost complete colliquative degeneration, and the carotid artery wall was free from infiltration. Radical surgery was performed. Histology confirmed papillary thyroid cancer (PTC) in the left lobe and ATC with extensive necrosis in the left latero-cervical lymph node metastasis. The margins were free of tumors (R0). A BRAF V600E mutation was present in both PTC and ATC. At the 1-year follow-up, the patient was free of disease., Conclusion: L and P in combination also appeared to be effective as a neoadjuvant treatment for BRAF V600E-mutated ATC. This combination treatment could be used when there is an opportunity for complete resection of the cancer, and as soon as possible. The intermediate dose of 14 mg of L appeared to be well tolerated and effective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Barbaro, Forleo, Profilo, Lapi, Giani, Torregrossa, Macerola and Materazzi.)

Background: This study aimed to determine the effectiveness of postoperative adjuvant lenvatinib + PD-1 blockade for patients with early-stage hepatocellular carcinoma (HCC) with microvascular invasion (MVI)., Methods: A total of 393 patients with HCC (Barcelona Clinic Liver Cancer stage 0 or A) who underwent curative hepatectomy with histopathologically proven MVI were enrolled according to the inclusion and exclusion criteria and assigned to 2 groups: surgery alone (surgery-alone group) and surgery with lenvatinib and PD-1 blockade (surgery + lenvatinib + PD-1 group) to compare recurrence-free survival (RFS), overall survival (OS), recurrence type, and annual recurrence rate after the application of propensity score matching (PSM). The Cox proportional hazards model was used for univariate and multivariate analyses., Results: Overall, 99 matched pairs were selected using PSM. Patients in the surgery + lenvatinib + PD-1 group had significantly higher 3-year RFS rates (76.8%, 65.7%, and 53.5%) than patients in the surgery-alone group (60.6%, 45.5%, and 37.4%) (P = .012). The 2 groups showed no significant difference in recurrence types and OS. Surgery alone, MVI-M2, and alpha-fetoprotein of ≥200 ng/mL were independent risk factors for RFS (P < .05), and history of alcohol use disorder was an independent risk factor for OS (P = .022)., Conclusion: Postoperative lenvatinib + PD-1 blockade improved the RFS in patients with HCC with MVI and was particularly beneficial for specific individuals., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lenvatinib plus programmed death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy., Materials and Methods: This multicenter cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n =127) or LEN-P alone ( n =103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW)., Results: After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P <0.001; mPFS: 8.0 months vs. 3.0 months, P =0.001). After IPTW, the mOS [hazard ratio (HR)=0.384, P <0.001] and mPFS (HR=0.507, P <0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group's objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P <0.001; IPTW cohort: 66.1% vs. 27.8%, P <0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group ( P >0.05)., Conclusion: HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

In the phase 3 CLEAR trial, lenvatinib plus pembrolizumab (L + P) showed superior efficacy versus sunitinib in treatment-naïve patients with advanced renal cell carcinoma (aRCC). The combination treatment was associated with a robust objective response rate of 71%. Here we report tumor responses for patients in the L + P arm in CLEAR, with median follow-up of ∼4 yr at the final prespecified overall survival (OS) analysis. Tumor responses were assessed by independent review using Response Evaluation Criteria in Solid Tumors v1.1. Patients with a complete response (CR; n = 65), partial response (PR) with maximum tumor shrinkage ≥75% (near-CR; n = 59), or PR with maximum tumor shrinkage <75% (other PR; n = 129), were characterized in terms of their baseline characteristics. The median duration of response was 43.7 mo (95% confidence interval [CI] 39.2-not estimable) for the CR group, 30.5 mo (95% CI 22.4-not estimable) for the near-CR group, and 17.2 mo (95% CI 12.5-21.4) for the other PR group. The 36-mo OS rates were consistently high in the CR (97%), near-CR (86%), and other PR (62%) groups. Robust objective response rates were observed across International Metastatic RCC Database Consortium favorable-risk (69%, 95% CI 60-78%), intermediate-risk (73%, 95% CI 67-79%), and poor-risk (70%, 95% CI 54-85%) subgroups. The robust response to L + P supports this combination as a standard-of-care first-line treatment for patients with aRCC. PATIENT SUMMARY: The CLEAR trial enrolled patients with advanced kidney cancer who had not previously received any treatment for their cancer. Here we report results for tumor shrinkage observed in the group that received lenvatinib plus pembrolizumab combination treatment during the trial. Shrinkage of target tumors with this combination was long-lasting and was observed in patients irrespective of their disease severity. This trial is registered on ClinicalTrials.gov as NCT02811861., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort., Methods: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS)., Results: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock., Conclusions: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0-38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138., Competing Interests: Declaration of Competing Interest GMB declares grant/research support from Takeda, Rigel and IFM Therapeutics. M.K. declares consulting and honoraria from AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji; research funding and/or clinical trial support from AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, and Astra Zeneca; and stock options/royalties from Reata Pharmaceutical. H.K. declares research support from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer, honoraria from AbbVie, Actinium, Agios, Amgen, Immunogen, Orsinex, Pfizer, and Takeda, and an advisory role with Actinium. G.G-M. declares support from and an advisory role with Celgene Corporation, Astex, and Amphivena, and grant/research support 15 from Helsinn, Novartis, AbbVie, Onconova, H3 Biomedicine, and Merck. S.L grant/research support from Amgen and Astellas and consulting and honoraria from Guidepoint, Qual World, Gerson Lehman Group, Caris, Blueprint Medicines Corporation, Daiichi Sankyo, Recordati, Abbvie, and Arima and owns Abbvie stocks. The rest of authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC)., Methods: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0., Results: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs., Conclusions: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326)., Methods: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points., Results: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage., Conclusions: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC., (© 2024 Merck Sharp & Dohme LLC and The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: This meta-analysis was dedicated to evaluating the effectiveness and safety of Atezolizumab plus Bevacizumab (Atez/Bev) and Lenvatinib (LEN) as first-line systematic therapy for unresectable hepatocellular carcinoma (u-HCC)., Methods: The prospective protocol for this study was registered with the PROSPERO (Registration number: CRD42022356874). Literature searches were conducted in PubMed, EMBASE database Cochrane Library, and Web Science to determine all clinical controlled studies that reported Atez/Bev and LEN for treating u-HCC. We. evaluated as primary end-point overall survival (OS) and progression-free survival (PFS), as well as other outcomes such as tumor response and adverse events (AEs).Quality assessment and data extraction of studies were conducted independently by three reviewers. Mean difference (MD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. The meta-analysis was performed with RevMan 5.3 software., Results: 12 retrospective cohort studies (RCSs) involving a total of 4948 patients were finally included. The results showed that compared with LEN, Atez/Bev can improve the patient's PFS (HR = 0.80, 95% CI: 0.72 ~ 0.88; p < 0.0001) and reduce the rate of overall AEs (OR = 0.46 95% CI: 0.38 ~ 0.55, p < 0.00001) and grade ≥ 3 AEs (OR = 0.43; 95% CI: 0.36 ~ 0.51, p < 0.00001), while there is no difference between OS and treatment responses rate (objective response rate, disease control rate, complete response, partial response, progressive disease, and stable disease) between two groups. In addition, the subgroup analysis shows that Atez/Bev can promote the OS of patients with viral hepatitis. (HR = 0.79, 95% CI: 0.67 ~ 0.95; p = 0.01), while LEN has an advantage in improving OS in patients with Child-Pugh grade B liver function (HR = 1.98, 95% CI: 1.50 ~ 2.63; p < 0.00001)., Conclusion: Current evidence shows that compared with LEN, Atez/Bev has more advantages in PFS and safety in treating u-HCC and can improve the OS of patients with viral. LEN has advantages in improving the OS of patients with grade B liver function. However, more multicenter randomized controlled experiments are needed in the future to verify our results., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug-drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites., Methods: Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (I REG+ATO ), a carrier with regorafenib (II REG ), and atorvastatin with a carrier (III ATO ). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model., Results: A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the I REG+ATO group, the C max , AUC 0-t , and AUC 0-∞ of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the C max , AUC 0-t , and AUC 0-∞ of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC 0-t and AUC 0-∞ of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively., Conclusions: This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients., (© 2024. The Author(s).)

Purpose: Limited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC., Methods: Patient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups., Results: The study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn't reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3-4 adverse events (AEs) compared with others., Conclusion: In contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC., (© 2024. The Author(s).)

Backgrounds: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone ., Methods: A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups., Results: After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P < 0.001), disease control rate (DCR) (94.3%% vs. 72.9%, P < 0.001), and conversion rates before and after propensity matching were 44.1% and 41.4%, respectively, compared with the TACE group. The median progression free survival (PFS) was longer in the TLC group than in the TACE group (12.7 vs. 6.1 months, P = 0.005). The median overall survival (OS) was longer in the TLC group than in the TACE group (19.4 vs. 13.0 months, P = 0.023). Cox multivariate analysis with different modes of adjustment showed that treatment was an independent influencing factor of PFS and OS. The interaction analysis showed that cirrhosis and Child-Pugh stage an interactive role in the PFS of different treatment. Decreased AFP after treatment portends higher ORR and DCR., Conclusion: TACE combined Lenvatinib plus Camrelizumab regimen was safe and superior to TACE alone in improving PFS, OS, and tumor response rates for unresectable recurrent HCC patients., (© 2024. The Author(s).)

Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Wang et al.)

Background: Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC., Methods: Histologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate., Results: Nine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07-11.27) and 13.17 months (95% CI 2.78-23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183., Conclusions: GLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment., (© 2024. The Author(s).)

Background: The CRAFITY score serves as a simple and effective predictive model for individuals diagnosed with hepatocellular carcinoma (HCC) and subjected to treatment with atezolizumab and bevacizumab (Atez/Bev). However, no large sample size studies have reported the application of the CRAFITY score among HCC patients undergoing transarterial chemoembolization (TACE) in conjunction with lenvatinib. This research aims to assess the prognostic role of the CRAFITY score in the context of individuals with HCC receiving TACE in combination with lenvatinib., Methods: This retrospective analysis encompassed 314 individuals diagnosed with HCC who underwent the combination of TACE and lenvatinib at two medical facilities in China from August 2019 to August 2022 (comprising a training cohort of n = 172 and a validation cohort of n = 142). We investigated the prognostic values of overall survival (OS), progression-free survival (PFS), disease control rate, and objective response rate in the training cohort based on the CRAFITY scores. Furthermore, the predictive capacity of the model was corroborated through validation using an external cohort., Results: We included 174 and 142 patients treated with TACE plus lenvatinib in the training and validation cohorts, correspondingly. PFS and OS differed across all three groups in all training and validation cohorts, based on the CRAFITY score (p < 0.001). In both cohorts, the CRAFITY score effectively predicted tumor response (p < 0.001). Moreover, among the 121 patients who received TACE, lenvatinib, and immunotherapy, the CRAFITY score showed promising predictive efficacy in PFS and OS., Conclusions: The CRAFITY score, utilizing C-reactive protein and alpha-fetoprotein values, emerges as a dependable and pragmatic instrument for forecasting the effectiveness of TACE plus lenvatinib in individuals with unresectable HCC. This scoring system holds the potential to assist oncologists in making informed clinical decisions., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: This study aimed to investigate the efficacy and safety of CalliSpheres drug-eluting beads transarterial chemoembolization (DEB-TACE) combined with regorafenib in the second-line treatment of unresectable hepatocellular carcinoma., Methods: A retrospective analysis was made of 34 patients with unresectable hepatocellular carcinoma (HCC) that had progressed after first-line treatment in Linyi Tumor Hospital from October 2019 to June 2021. These patients were divided into observation group (n = 15) and control group (n = 19) based on their treatment plans, who were respectively treated with regorafenib alone and regorafenib combined with DEB-TACE. The objective response rate (ORR) and the disease control rate (DCR) were evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and the progression-free survival (PFS) and the overall survival (OS) were calculated; the factors influencing PFS and OS of patients were analyzed by the Cox proportional hazards model; and the adverse reactions to the treatments were observed and recorded., Results: After 2 months of treatment, the ORR and the DCR of the observation group were 73.3% (11/15) and 86.7% (13/15) respectively, both higher than 10.5% (2/19) and 47.4% (9/19) of the control group. Their differences are statistically significant (P < 0.05). There were no statistically significant differences in the incidences of regorafenib-related adverse reactions including hand-foot skin reactions, fatigue, hypertension, diarrhea, and proteinuria between the two groups (P > 0.05). In the observation group, the main adverse reactions to DEB-TACE such as fever, pain, nausea, and vomiting were relieved after symptomatic treatment, and no serious complications such as ectopic embolization of CalliSpheres drug-eluting beads occurred. As of July 31, 2022, the median follow-up time was 12.5 months, and the average was (14.00 ± 5.69) months. The median PFS was 9 months in the observation group, and 6 months in the control group, presenting a statistically significant difference (P < 0.05), and the median OS was 18 months in the observation group, and 12 months in the control group, also presenting a statistically significant difference (P < 0.05). The results of monofactor prognostic analysis showed that Child grade, AFP level, and treatment method had an influence on the PFS and the OS of liver cancer patients receiving regorafenib second-line treatment (P < 0.05), and the results of multifactor prognostic analysis showed that child grade and treatment method independently influenced the PFS of patients, while treatment method independently influenced the OS of patients (P < 0.05)., Conclusions: DEB-TACE combined with regorafenib is safe and feasible in the treatment of unresectable HCC, with good efficacy and mild adverse reactions., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment. Lenvatinib PK was best described by a 3-compartment model with simultaneous first- and zero-order absorption and linear elimination from the central compartment with significant covariates (body weight, albumin <30 g/dL, ALP>ULN, RR-DTC, RCC, HCC subjects, and concomitant CYP3A inhibitors). Except for body weight, none of the covariates have any clinically meaningful effect on exposure to lenvatinib. Longitudinal biomarker measurements over time were reasonably well defined by a PK/PD model with common EC 50 , E max , and a slope for disease progression for all biomarkers. Longitudinal tumor measurements over time were reasonably well defined by a tumor growth inhibition E max model, which in addition to lenvatinib exposure, included model-predicted relative changes from baseline over time for Tie-2 and Ang-2 as having significant association with tumor response. The developed PK/PD models pave the way for dose optimization and potential prediction of clinical response., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy., Methods: A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared., Results: The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 μmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels., Conclusions: Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable hepatocellular carcinoma (HCC), but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. We aimed to investigate the organ-specific response patterns among unresectable HCC patients treated with first-line atezolizumab-bevacizumab or lenvatinib., Methods: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intraabdomen based on a radiological evaluation adopted from RECIST v 1.1., Results: The median age was 60 years. Hepatitis B infection was the most common etiology (n = 270, 69.9%), and 291 (75.4%) patients had a viral etiology. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was overall higher in the atezolizumab-bevacizumab group than that in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9% and 33.3% vs. 15.0% for intrahepatic, lung, LN, and intraabdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6%, and 36.0% vs. 12.5%, respectively., Conclusion: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background: Conversion therapy for initially unresectable hepatocellular carcinoma (iuHCC) using lenvatinib combined with transcatheter arterial chemoembolization (TACE) plus a PD-1 inhibitor (LTP) has achieved promising results. However, further comparative research is necessary to evaluate the effectiveness and safety of conversion surgery (CS) for iuHCC., Methods: Data for 32 consecutive patients with iuHCC receiving CS and 419 consecutive patients with resectable HCC receiving initial surgery (IS) between November 2019 and September 2022 were collected retrospectively. After propensity score matching (PSM), 65 patients were selected., Results: Before matching, the CS group had longer EFS (not reached vs. 12.9 months, P < 0.001) and similar OS (not reached vs. not reached, P = 0.510) compared with the IS group. Similar results for EFS (P = 0.001) and OS (P = 0.190) were obtained after matching. The multivariable Cox model (HR = 0.231, 95% CI: 0.105-0.504; P < 0.001) and subgroup analyses confirmed that CS could improve EFS. The CS group had significantly lower incidence of microvascular invasion (MVI) than the IS group (3.1% vs. 50.4%, P < 0.001). Moreover, the two groups had similar safety profiles., Conclusions: CS is effective and safe for patients with iuHCC receiving LTP. LTP has the potential to reduce risk factors for postoperative recurrence, especially MVI, which may influence surgical decision-making., Competing Interests: Conflict of interest None., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is often diagnosed in advanced stages. Following sorafenib, lenvatinib (LENV) has been approved as a first-line treatment option for unresectable HCC. In the past few years, at least 9 large-scale cohort studies have examined the efficacy and safety of LENV compared to atezolizumab plus bevacizumab (ATE/BEV) in unresectable HCC, but there is currently no direct meta-analysis conducted for a comprehensive consolidation. To provide the most updated meta-analysis of the clinical efficacy and safety of ATE/BEV versus LENV for patients with unresectable HCC. Our studies comparing the efficacy and safety of ATE/BEV and LENV in unresectable HCC were systematically searched in PubMed, Embase, and Web of Science from inception to February 2023. Outcomes measured were overall survival (OS), progression-free survival (PFS), mortality, complete response (CR), partial response (PR), objective response rate (ORR), disease control rate (DCR), progressive disease (PD), stable disease (SD), and adverse events (AEs). Seven eligible studies involving 4428 patients (1569 in the ATE/BEV group and 2859 in the LENV group) were included in the narrative synthesis. All baseline characteristics were similar between the 2 groups except for Child-Pugh class B. Ultimately, our meta-analysis showed that the LENV group had longer OS and PFS than the ATE/BEV group. Moreover, patients on LENV were more likely to achieve SD, whereas those on ATE/BEV were more likely to achieve PR., (© 2024, The American College of Clinical Pharmacology.)

Background: Thymic carcinoma is a rare cancer with an aggressive clinical presentation and no organotypic symptoms. Despite using platinum-based chemotherapy as first-line treatment, the prognosis remains poor, necessitating a novel therapeutic strategy., Methods: The artemis trial is a Phase II, single-arm, multicenter study designed to evaluate the efficacy and safety of carboplatin, paclitaxel, lenvatinib, and pembrolizumab as first-line chemotherapy for patients with advanced or recurrent thymic carcinoma. A total of 35 patients will be enrolled in this study and will receive induction therapy every 3 weeks for up to 4 cycles, followed by pembrolizumab every 3 weeks, and daily lenvatinib as maintenance therapy for up to 31 cycles (for 2 years). Lenvatinib will be continued until disease progression or unacceptable toxicity based on the discretion of the attending physician., Conclusion: The primary endpoint of the study is the objective response rate, with secondary endpoints including progression-free survival, overall survival, duration of response, disease control rate, and safety profile., Trial Registration: ClinicalTrials.gov NCT05832827 Registered on April 27, 2023, https://classic., Clinicaltrials: gov/ct2/show/NCT05832827. Japan Registry of Clinical Trials (jRCT), jRCT2031230114. Registered on May 22, 2023, https://jrct.niph.go.jp/latest-detail/jRCT2031230114., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nowadays, the novel molecular targeting chemotherapy provides possibility of safe hepatectomy for progressive hepatocellular carcinoma (HCC). Further, combination of the conventional transarterial chemoembolization (TACE) may add an effect of tumor shrink. We present a successful radical hepatectomy for a large HCC located in segment 1 accompanied with the preoperative Lenvatinib (LEN)-TACE sequential treatment. We present a woman patient without any complaints who had a 7 cm-in-size of solitary HCC compressing vena cava and right portal pedicle. To achieve radical hepatectomy by tumor shrinking, LEN-TACE for 2 months. After confirming downsizing or devascularization of the HCC, we scheduled radical posterior sectionectomy combined with caudate lobectomy according to tumor location and expected future remnant liver volume from three-dimensional computed tomography simulation before surgery. Under the thoraco-abdominal incision laparotomy, we safely achieved scheduled radical hepatectomy without any vascular injuries. The postoperative course was uneventful and no tumor recurrence were observed for 1 year. Histological findings showed the Japan TNM stage III HCC with 70% necrosis. The multi-modal strategy of LEN-TACE followed by radical hepatectomy by confirming downsizing or devascularization in tumor is supposed to be useful and would be a preoperative chemotherapy option, and promising for curative treatment in HCC patients with progressive or large HCC, which may lead to safety by prevention surrounding major vascular injury., (© 2024. The Author(s).)

The aim of the present study was to determine whether the trough plasma concentrations (C 0 ) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C 0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C 0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C 0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C 0 of regorafenib is not maintained. Monitoring the C 0 of regorafenib regularly is necessary to guide dose adjustment., (© 2024. The Author(s).)

Objective: The purpose of this study was to investigate the efficacy and safety of lenvatinib in various types of solid tumors., Method: By searching PubMed, Web of Science, Cochrane, CNKI, Wanfang and other databases, all the literatures about the comparison of clinical efficacy of lenvatinib in the treatment of various solid tumors. According to the criteria of inclusion and exclusion of literature, two participants screened the literature, collated the data and evaluated the literature. RevMan 5.4 software was used for meta-analysis of the included literatures., Results: A total of 12 studies were included, including 5213 patients. Meta-analysis showed that, in terms of efficacy, the risk (HR) of prolonging PFS in the treatment of various solid tumors in the lenvatinib group was 1.91 times that in the control group (HR = 1.91, 95% CI: 1.58-2.31, p  < 0.00001), and the risk (HR) of prolonging OS was 1.27 times that in the single targeted drug group (HR = 1.27, 95% CI: 1.15-1.40, p  < 0.00001). In terms of safety, the risk of adverse events in the treatment of various solid tumors in the lenvatinib group was higher than that in the control group, especially in Endocrine Toxicities, Renal/Urinary Toxicities, Vascular Toxicities, Musculoskeletal/a Connective Tissue Toxicities and Metabolism/Nutrition Toxicities., Conclusions: Lenvatinib in various solid tumors can prolong OS and disease PFS of patients, improve the clinical benefit rate and improve the quality of life of patients. At the same time, there is a certain incidence of adverse events, and symptomatic intervention should be given in clinical medication.

Introduction: Systemic therapy is recommended for patients with advanced hepatocellular carcinoma (aHCC). However, drug resistance occurs over time when patients receive systemic therapy, resulting in cancer progression. Due to the lack of relevant clinical trials, optimizing subsequent treatments after cancer progression remains elusive., Patient Concerns: A 52-year-old male patient presented with epigastric discomfort and fatigue for almost 1 month with a past history of chronic hepatitis B virus infection for 30 years., Diagnosis: Based on the patient's performance status, tumor status assessed by computed tomography, liver function, he was diagnosed with HCC at BCLC stage C., Interventions and Outcomes: He first received transarterial chemoembolization (TACE) combined with sintilimab and lenvatinib as first-line treatment and experienced 10-month progression-free survival. After cancer progression, the patient participated in a clinical trial of ABSK-011, a novel fibroblast growth factor receptor 4 inhibitor, with a frustrating result. Then, the patient underwent TACE and received sintilimab plus lenvatinib again. Surprisingly, the tumor had a partial response, and the patient's serum alpha-fetoprotein returned to normal., Lessons: The combined treatment of TACE plus systemic therapy might be an appropriate subsequent treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)