Lenvatinib Treatment Research Articles

The long-term clinical efficacy and safety of lenvatinib plus pembrolizumab in endometrial cancer: data from routine clinical practice in Russia

Background. Endometrial cancer (EC) treatment outcomes need to be improved. Immunotargeted therapy lead to long-term and delayed effects compared to chemotherapy. Estimation of long-term efficacy and quality of life are crucial when we are talking about efficacy in whole.Aim. To evaluate the long-term clinical efficacy of lenvatinib plus pembrolizumab therapy in patients with EC.Materials and methods. The study included 43 patients with stages I-IV EC with mismatch repair-proficient tumors and treatment duration of more than 9 months. We evaluated median progression-free survival, objective response, duration of treatment depending on the line of therapy, prevalence and type of adverse events, and correction regimens. Results. Lenvatinib plus pembrolizumab treatment was safe and efficacious in recurrent EC. Median of progression-free survival (patients with response or stabilization more than 9 months) is 10.2 months (95 % confidence interval 9.1-13.0), median of follow up is 9.7 (1.4-33.8) months. There were no complete responses, partial response was in 12 (28 %) patients, disease stabilization was in 31 (72 %) patients. Regarding safety, the overall rate of any-grade adverse events was 56.3 %. The most common treatment-related adverse events were fatigue (32.6 %), hypertension (23.3 %), and hypothyroidism (18.6 %). Dose reduction was performed in 22 (51.2 %) patients.Conclusion. The combination of lenvatinib plus pembrolizumab has long-term efficacy and manageable profile of safety. The presence of a significant pool of patients with durable response allows improving the survival rate of such patients in Russia.

Comparative Outcome Analysis of Lenvatinib Versus Sorafenib for Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in ~17% of patients. We aimed to retrospectively compare the outcomes of patients treated with different tyrosine kinase inhibitors (TKIs) for recurrent HCC post-LT. Patients with recurrent HCC post-LT between 2006 and 2019 were included. The impact of sorafenib and lenvatinib treatment for recurrent disease was assessed using survival analysis with an a priori multivariable Cox regression (alpha-fetoprotein [AFP] at recurrence, recurrence lesion diameter, single-site versus multisite metastases). Seven hundred fifty-four patients underwent LT for HCC, of whom 120 (15.9%) developed recurrence. Of these patients, 56 received TKIs: sorafenib (n = 42) or lenvatinib (n = 14). The median age at LT was 60.8 y (interquartile range, 54.0-66.2); 52 (93%) were men and 26 (46%) were within Milan criteria at listing. Baseline characteristics at recurrence were comparable between the 2 groups, including largest tumor diameter (P = 0.15), receipt of local therapies before TKI (P = 0.33), and single-site recurrence (P = 0.75), and time from interventional treatment to start of TKI (P = 0.44). The AFP at recurrence was higher in the sorafenib group (95.0 versus 3.0 µg/L, P < 0.001). The median overall survival (OS) after initiation of TKI treatment was longer in the lenvatinib group (15.0 mo [95% confidence interval [CI], 11.5-31.5] versus 7.8 mo [95% CI, 4.0-15.4]; P = 0.02) with a 2.3-fold a priori adjusted effect on OS (adjusted hazard ratio 2.32 [95% CI, 1.03-5.20], P = 0.04). Our findings suggest lenvatinib is a valuable treatment option for patients with HCC recurrence after LT.

Poor Tolerability of Lenvatinib in Elderly Patients with Advanced Hepatocellular Carcinoma after Disease Progression following First-Line Atezolizumab Plus Bevacizumab: A Multicenter Study

Introduction: We investigated the effectiveness of lenvatinib (LEN) after disease progression following first-line treatment with atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable hepatocellular carcinoma (HCC). Methods: One hundred and ten HCC patients treated with Atez/Bev as first-line systemic chemotherapy were enrolled and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response. We evaluated the treatment efficacy and prognosis after second-line LEN treatment, especially in elderly patients. Results: Of the 110 study patients, 88 patients (80%) were determined to have progressive disease (PD) during the observation periods, and 40 patients received second-line LEN therapy. The 40 patients included 13 patients who were unable to continue LEN until the initial evaluation due to adverse events (AE). The 27 patients who were able to continue LEN therapy (Group A) were significantly younger at initiation of Atez/Bev than those who could not continue (71 vs. 77 years old, p = 0.013). Comparing the OS and PFS between Group A and 44 patients that included 13 patients who were unable to continue LEN and 31 patients did not receive the second-line treatment (Group B), the former had significantly better OS than Group B (31.1 vs. 17.8 months, p = 0.035). Conclusions: The tolerability of second-line LEN therapy was lower in elderly patients, and the OS from the start of Atez/Bev therapy was different depending on the tolerability of second-line LEN therapy.

Stereotactic body radiotherapy versus lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity matching score analysis

Background and objectivesThe purpose of this study was to investigate the survival benefit of Stereotactic Body Radiotherapy (SBRT) versus lenvatinib as first-line therapy in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT).Materials and methods147 HCC patients with PVTT were included in this retrospective study, 70 were treated with SBRT and 77 of were treated with lenvatinib. Propensity score matching (PSM) analysis was employed to balance the differences in baseline characteristics between the two groups. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between the two groups. In addition, the safety of patients in both groups was also evaluated.ResultsAfter PSM, 38 patients were matched in each of the two groups. The median OS was 14.5 (95% CI: 10.1–18.9) and 11.1 (95% CI: 9.3–12.9) months in the SBRT and lenvatinib groups, respectively (P = 0.014). The median PFS was 6.8 (95% CI: 5.1–8.5) and 5.0 (95% CI: 3.0–7.0) months, respectively (P = 0.010). The 1-, 2-years OS rates in the two groups were 65.8% vs. 39.5% and 31.6% vs. 10.5%, respectively. The 6-, 12-months PFS rates in the two groups were 57.9% vs. 44.7% and 28.9% vs. 10.5%, respectively. In addition, the SBRT group had a better ORR than the lenvatinib group (52.6% vs. 23.7%, P = 0.009). Patients with good response to SBRT had better survival. Cox proportional hazard model showed that SBRT was an important prognostic factor for OS and PFS. The incidence of hypertension (34.2% vs. 0%) was higher in the LEN group, however, both treatment modalities were well tolerated in the two groups of patients.ConclusionIn HCC patients with PVTT, SBRT had a better survival benefit than Lenvatinib treatment as first-line therapy.

7911 High Dose Serial Radioactive Iodine Therapies Facilitated byAutologous Stem Cell Cryopreservation in a Patient with Exceptionally Avid Metastatic FTC

Abstract Disclosure: S. Paknikar: None. D. Toro Tobon: None. J. Durski: None. H. Alkhateeb: None. M.M. Ryder: None. Introduction: Radioactive iodine (RAI) therapy-induced myelosuppression is a dose-limiting toxicity for RAI avid metastatic differentiated thyroid cancers. We describe a patient with exceptionally RAI avid metastatic follicular thyroid cancer (FTC) who underwent autologous stem cell cryopreservation (ASCC) to enable high dose I-131 treatments. Case: A 60-year-old woman with T1bN0M0 FTC underwent two-stage thyroidectomy and three doses of I-131 between 2002-2007 (434 mCi cumulative activity) due to incomplete biochemical response. She presented to our institution in 2015 with rising thyroglobulin (Tg) levels and lung nodules that were intensely RAI avid. She enrolled in a clinical trial of selumetinib versus placebo (for 1 month) followed by 150 mci I-131. She had a profound response with an 80% reduction in Tg and 50% tumor shrinkage. The following year her Tg rose to 8381 ng/mL and she developed biopsy proven, well differentiated metastatic FTC in the hip and liver. Lenvatinib treatment resulted in partial tumor and Tg response but was halted due to grade 3/4 toxicities. Tumor genomic interrogation revealed NRAS, PIK3CA, and TSH-R activating mutations, providing a causal explanation of her intensely RAI avid and responsive disease. Repeat I-131 therapy was facilitated by GM-CSF stimulated ASCC (8.57 x10(6) CD34+ cells/kg for two cycles) as a tool to help mitigate future potential RAI-induced myelosuppression. The patient received 295 mci I-131 followed by a 98% decrease in Tg and 20-25% shrinkage of liver metastases. Transient pancytopenia ensued but did not require autologous stem cell transplantation (ASCT). Due to insurance issues, the patient was lost to follow-up for two years. She returned with cachexia from severe, untreated thyrotoxicosis due to widespread functional, thyroxine producing metastatic disease. Anti-thyroid drug therapy (ATD) restored euthyroid status with significant clinical improvement. A non-stimulated I-123 whole body scan showed diffuse RAI avid disease with 88% whole body radioiodine retention at 48h. She received 125 mci I-131 with initial tumor response but with progression of bone marrow, calvaria, and retinal metastases. Six months later, a final dose of 253 mCi I-131 (cumulative activity 1,370 mCi) resulted in mixed tumor responses. Unfortunately, resection of a RAI refractory calvaria lesion postoperatively resulted in serious complications. ASCT and salvage treatments could not be pursued due to her impaired functional status. The patient pursued hospice care and passed away 20 years after her diagnosis. Conclusion: We characterize a patient with NRAS, PIK3CA and TSH-R mutant metastatic, thyroxine-producing FTC whose recurrences over 20 years retained intense RAI avidity and response to I-131 therapy. In cases with potential benefit from multiple high dose RAI therapies, ASCT may be a tool to mitigate I-131-induced myelosuppression. Presentation: 6/1/2024

Lenvatinib for the Treatment of Hepatocellular Carcinoma After Liver Transplant

What Is the Issue? Liver transplant is 1 of the main curative therapies for liver cancer; however, hepatocellular carcinoma (HCC) recurrence presents in 10% to 20% of patients after liver transplant. Lenvatinib, an oral multikinase inhibitor drug, was approved for use in Canada as a first-line standard therapy for unresectable HCC, based on a pivotal trial that excluded patients who underwent a prior liver transplant. Data were scarce on the efficacy and safety of lenvatinib for treatment of HCC recurrence in patients who received a liver transplant, and were limited to a few case series and case reports. What Did We Do? We identified and summarized the literature on the evidence of the clinical effectiveness and safety of lenvatinib for the first-line treatment of patients with unresectable HCC recurrence after liver transplant. We searched key resources, including journal citation databases and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? We identified a multinational, multicentre, retrospective, single-arm chart review study evaluating the efficacy and safety of lenvatinib in patients with HCC recurrence after liver transplant. Lenvatinib was primarily used as a first-line treatment for most patients (n = 42; 93.3%) and as a second-line treatment for 3 patients (6.7%). The single-arm chart review study showed lenvatinib treatment had an overall response rate (ORR) of 20.0%, a median overall survival of 14.5 months, and a median progression-free survival (PFS) of 7.6 months. These findings were similar to those randomized to lenvatinib in the pivotal phase III REFLECT trial, which excluded patients who had a prior liver transplant. What Does This Mean? The findings of this report suggest that lenvatinib has a potential role as a first-line treatment of patients with HCC recurrence after liver transplant. As the current evidence is limited to a retrospective single-arm chart review study, which had several limitations (e.g., lack of sample size calculation, noncomparative, and retrospective design), further investigations are needed to establish the clinical efficacy and safety of lenvatinib as a first-line treatment for unresectable HCC recurrence after liver transplant.

Real-world safety and effectiveness of lenvatinib in unresectable hepatocellular carcinoma in Korea: post-marketing study.

Aim: This post-marketing surveillance study evaluated the safety and effectiveness of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma in Korea.Materials & methods: Adverse drug reactions (ADRs) and other safety and effectiveness end points were assessed in patients who initiated lenvatinib according to the approved label in republic of Korea.Results: Among 658 lenvatinib-treated patients, ADRs were reported in 57.8%; ADRs grade ≥3 in 13.5%. The most common grade ≥3 ADRs were asthenia (1.2%) and hepatic encephalopathy (1.2%). Physician-reported tumor responses (n=511) were complete (1.0%) or partial (12.9%) response and stable (45.2%) or progressive disease (40.9%); objective response rates were higher with longer lenvatinib treatment duration (p<0.001).Conclusion: Lenvatinib was generally well tolerated and effective in real-world clinical practice in Korea.Clinical trial registration: ClinicalTrials.gov NCT05225207.

Identifying risk factors of dose reduction or treatment discontinuation due to fatigue or gastrointestinal symptoms in patients receiving lenvatinib treatment for hepatocellular carcinoma

Introduction Lenvatinib (LEN) is the standard treatment for hepatocellular carcinoma (HCC). In clinical practice, gastrointestinal (GI) symptoms such as fatigue and loss of appetite often lead to dose reduction or treatment discontinuation. This study aimed to identify the predictors of patients who will experience dose reduction or treatment discontinuation owing to fatigue or GI symptoms during LEN treatment for HCC. Methods We retrospectively identified 99 patients who received LEN at the Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and December 2023. To investigate the risk factors for treatment discontinuation or dose reduction due to fatigue or GI symptoms during LEN administration, patients were divided into two groups based on whether treatment discontinuation or dose reduction occurred due to fatigue or GI symptoms during LEN administration (37 patients) or not (62 patients). We compared baseline characteristics between the two groups. Results Multivariate analysis revealed that body weight (odds ratio 4.310, 95% confidence interval 1.380–13.500; P = 0.002) was an independent risk factor that significantly contributed to treatment discontinuation or dose reduction owing to fatigue or GI symptoms during LEN administration. The cut-off value calculated using the body weight curve was 55.0 kg. Using this cutoff value, the sensitivity and specificity of body weight to detect treatment discontinuation or dose reduction due to fatigue or GI symptoms during LEN administration were 83.9% and 56.8%, respectively. Conclusion In clinical practice, patients weighing less than 55 kg who start with a full dose will likely experience weight loss or discontinuation during treatment.

GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma.

Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.

Survival Benefit of Lenvatinib Plus PD-1 Inhibitor with or Without HAIC in Advanced Hepatocellular Carcinoma Beyond Oligometastasis: a Multicenter Cohort Study.

The outcome between Lenvatinib plus programmed cell death protein-1 (PD-1) inhibitor and Lenvatinib in HCC beyond oligometastasis was unclear. In this multicenter, we compared the prognosis of Lenvatinib plus PD-1 inhibitor with Lenvatinib in HCC beyond oligometastasis. A total of 296 patients from six institutions were included. The patients were divided into two groups: (a) concurrent Lenvatinib plus PD-1 inhibitor treatment (Len+PD-1 group) and (b) Lenvatinib monotherapy (Len group). The primary endpoint was overall survival (OS), the second endpoint was progression-free survival (PFS) and efficacy. The median OS was 20.1 ± 1.2 (17.7-22.5) months and 15.7 ± 1.5 (12.8-18.6) months in the Len+PD-1 and Len groups, respectively. The 12-, 24-, and 36-month OS rates were 79.1%, 39.4%, and 10.7% in the Len+PD-1 group, and 76.3%, 29.7%, and 0% in the Len group, respectively. The OS and PFS rates of the Len+PD-1 group were significantly longer compared with the Len group (hazard ratio [HR], 0.88; 95% confidence index [CI], 0.49-0.94; P = 0.021) and (HR, 0.66; 95% CI, 0.50-0.87; P = 0.003). A subgroup analysis revealed that OS (HR, 0.57; 95% CI, 0.36-0.90; P = 0.016) was improved between the Len+PD-1 and Len groups with hepatic artery infusion chemotherapy (HAIC) treatment, whereas OS (HR, 1.11; 95% CI, 0.68-1.80; P = 0.689) was similar between the Len and Len+PD-1 groups without HAIC. Lenvatinib combined with PD-1 inhibitor significantly improves the survival of HCC beyond oligometastasis. For patients with HAIC, there was obviously significance between Len and Len+PD-1 groups.

Second-line Treatment Strategy in Unresectable Hepatocellular Carcinoma After First-line Atezolizumab Plus Bevacizumab.

Atezolizumab plus beva-cizumab (AteBev) are an integral part of first-line therapy for unresectable hepatocellular carcinoma (uHCC), whereas no second-line regimen has been developed for these patients. This study evaluated the efficacy of second-line therapy for uHCC following AteBev treatment. Sixty uHCC patients who were administered AteBev therapy were included in the study. Dynamic computed tomography was conducted after 6, 9, and 12 weeks, and blood tests were performed at baseline and after three weeks. After six weeks of AteBev therapy, 19 patients experienced partial response (PR), 12 had stable disease (SD), and 29 exhibited progressive disease (PD), with an overall response rate (ORR) of 31.7%. Of the 21 patients treated with lenvatinib as second-line treatment, one dropped out, nine experienced a compete response (CR) or PR, and 11 had SD or PD, resulting in an ORR of 45.0%. Serum levels of fibroblast growth factors (FGF)-19 increased substantially following lenvatinib therapy in the CR+PR group, although the levels decreased significantly in the SD+PD group. Soluble FGF-R4 levels did not differ significantly between the CR+PR group and the SD+PD group when assessed before and after lenvatinib treatment. Lenvatinib is useful as second-line treatment after Ate/Bev for uHCC patients who do not response to Ate/Bev treatment. Changes in serum FGF-19 levels after three weeks of AteBev therapy may serve as a biomarker for selecting lenvatinib as second-line therapy.

Impact of BMI and Body Composition on First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma.

The effects of body mass index (BMI) and body composition on the outcomes of systemic treatment for unresectable hepatocellular carcinoma (uHCC) remain unclear. In this retrospective study, patients with uHCC treated with lenvatinib (LEN) or atezolizumab+bevacizumab, were classified into high- (≥25 kg/m2) and low- (<25 kg/m2) BMI groups and evaluated for prognosis. Prognostic impact of body composition was also evaluated. Patients with a high BMI had lower skeletal mass index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) compared to those in the low-BMI cohort. The baseline Child-Pugh scores and Barcelona Clinic Liver Cancer stages were comparable between the two cohorts. The overall survival (OS) was better in the high BMI group compared to the low BMI group (median, 913 vs. 484 days; p=0.008). SMI had a strong influence on OS. Additionally, low BMI, VATI, SATI, and visceral-to-subcutaneous fat ratio (VSR) in the LEN treatment group were associated with shorter progression-free survival (PFS). Following systemic treatment for uHCC, patients with low BMI have a poor prognosis. Among anthropometric factors, low SMI is associated with poor OS. In the LEN treatment group, low VATI may impact PFS negatively.

TP53 mutations associate with poor response to lenvatinib treatment for advanced thyroid cancer

TP53 mutations associate with poor response to lenvatinib treatment for advanced thyroid cancer

Improving the response to lenvatinib in partial responders using a Constrained-Disorder-Principle-based second-generation artificial intelligence-therapeutic regimen: a proof-of-concept open-labeled clinical trial.

The main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)-based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability. A 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib-an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence. At 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded. The results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach.

Changes in Mutations of Cell-Free DNA and Liver Tumor Tissue in Patients with Advanced Hepatocellular Carcinoma before and after Introduction of Lenvatinib.

Cell-free DNA (cfDNA) is expected to contribute to the decision for treatment and prediction of effects with minimally invasion. We investigated the correlation between gene mutations before and after lenvatinib (LEN) treatment and its effectiveness, in order to find advanced hepatocellular carcinoma (HCC) patients who would benefit greatly from the therapy. We analyzed cfDNA before and 6-8 weeks after the start of treatment in 20 advanced HCC patients who started LEN. A next-generation sequencer was used for CTNNB1 and TP53. Concerning TERT promoter, -124C&gt;T and -146C&gt;T mutations are researched using digital PCR. In addition, we examined liver tumor biopsy tissues by the same method. Computerized tomography evaluation was performed at 6-8 weeks and 3-4 months to assess the efficacy. Frequencies of TERT promoter, CTNNB1, and TP53 mutations in pretreatment cfDNA were 45%, 65%, and 65%, but 53%, 41%, and 47% in HCC tissues, respectively. There were no clear correlations between these gene mutations and the disease-suppressing effect or progression-free survival. Overall, there were many cases showing a decrease in mutations after LEN treatment. Integrating the reduction of CTNNB1 and TP53 genetic mutations increased the potential for disease suppression. This study suggests that analysis of cfDNA in advanced HCC patients may be useful for identifying LEN responders and determining therapeutic efficacy. Furthermore, it has potential for selecting responders for other molecular-targeted drugs.

Clinical impact of a dose-escalation strategy for lenvatinib in differentiated thyroid cancer.

Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated. We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose. Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24mg/day, and the median dose at initial disease progression was 10mg/day. In the former, the median dose escalation was 6mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4months [95% CI 7.0-NA] vs. 3.9months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess. The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC.

Hand-foot syndrome in sorafenib and lenvatinib treatment for advanced thyroid cancer.

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. 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. 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. 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.

Impact of baseline hepatitis B virus viral load on the long-term prognosis of advanced hepatocellular carcinoma treated with immunotherapy.

Although the combination of lenvatinib and PD-1 inhibitors has become the standard regimen for the treatment of advanced hepatocellular carcinoma (HCC), real data on the impact of baseline hepatitis B virus (HBV)-DNA levels on the clinical efficacy of this regimen is still limited. To evaluate the effectiveness of camrelizumab combined with lenvatinib in patients with HCC at varying levels of HBV-DNA. One hundred and twenty patients with HCC who received camrelizumab and lenvatinib treatment were categorized into two cohorts: HBV-DNA ≤ 2000 (n = 66) and HBV-DNA > 2000 (n = 54). The main outcomes measured were overall survival (OS) and progression-free survival (PFS), while additional outcomes included the rate of objective response rate (ORR), disease control rate (DCR), and any negative events. Cox proportional hazards regression analysis revealed independent predictors of OS, leading to the creation of a nomogram incorporating these variables. The median PFS was 8.32 months for the HBV-DNA ≤ 2000 group, which was similar to the 7.80 months observed for the HBV DNA > 2000 group (P = 0.88). Likewise, there was no notable variation in the median OS between the two groups, with durations of 13.30 and 14.20 months respectively (P = 0.14). The ORR and DCR were compared between the two groups, showing ORR of 19.70% vs 33.33% (P = 0.09) and DCR of 72.73% vs 74.07% (P = 0.87). The nomogram emphasized the importance of antiviral treatment as the main predictor of patient results, with portal vein tumor thrombus and Barcelona Clinic Liver Cancer staging following closely behind. The clinical outcomes of patients with HBV-associated HCC treated with camrelizumab in combination with lenvatinib are not significantly affected by HBV viral load.

Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

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. 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. 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. 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.

The molecular landscape of pembrolizumab and lenvatinib treatment in endometrial cancer.

The molecular landscape of pembrolizumab and lenvatinib treatment in endometrial cancer.