A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors.

PURPOSE: Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors. METHODS: Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed. RESULTS: Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3-77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1. CONCLUSIONS: This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified. TRIAL REGISTRATION: Clinical Trials.gov number: NCT03006887.

A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer.

PURPOSE: Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. PATIENTS AND METHODS: Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. RESULTS: Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9-not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9-5.6; hazard ratio = 0.16; 95% CI, 0.10-0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0-78.8) in the lenvatinib arm and 0% (95% CI, 0-0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). CONCLUSIONS: Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.

Pharmacokinetic study of lenvatinib in Chinese patients with solid tumors.

Aim: To assess the pharmacokinetics of once-daily oral lenvatinib 24 mg in Chinese patients. Material & methods: Patients had any solid tumor (except hepatocellular carcinoma) that was resistant to standard antitumor therapies or for which no appropriate treatment was available. Results: Twelve patients were enrolled. Maximum plasma concentrations of lenvatinib were observed at 2 and 4 h (median) after single and multiple doses (day 15), respectively. Steady state was achieved within 8 days. The geometric mean maximum observed concentration at steady state was 258 ng/ml (coefficient of variance: 49.2%); and the geometric mean area under the concentration-time curve from zero to 24 h at steady state was 3090 ng•h/ml (coefficient of variance: 44.7%). No accumulation was seen after 15 days. Conclusion: Lenvatinib pharmacokinetic data in Chinese patients are consistent with data in multinational trials, supporting usage of the 24-mg dose. Clinical trial registration: NCT03009292 (ClinicalTrials.gov).

Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma.

PURPOSE: The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS: In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS: A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION: Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma.

OBJECTIVES: Despite improved outcomes associated with immunotherapies for non-small cell lung cancer (NSCLC), many patients do not respond to treatment. Therefore, there is still an unmet need for molecularly targeted therapies in this patient population. Fusions of the RET oncogene have been identified as driver alterations in patients with NSCLC. Lenvatinib is a multityrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, RET, and other targets. This study evaluated the safety and efficacy of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. MATERIALS AND METHODS: In this phase 2, multicenter, open-label study (NCT01877083), patients with RET-positive lung adenocarcinoma received oral lenvatinib 24 mg/day. The primary end point was objective response rate (ORR) by investigator review per Response Evaluation Criteria In Solid Tumors v1.1 criteria. The secondary end points included safety and tolerability, progression-free survival (PFS), and overall survival (OS). RESULTS: Of 536 patients who screened for study inclusion and exclusion, 25 patients with RET translocations (KIF5B-RET [n = 13] and CCDC6-RET [n = 12]) were identified and received lenvatinib. The overall ORR was 16% (95% CI: 4.5%-36.1%). At data cutoff (February 3, 2016), the median PFS was 7.3 months (95% CI: 3.6-10.2) and the median OS was not reached. Duration of response was not estimable at the time of data cutoff. All patients experienced a treatment-emergent adverse event (TEAE); 23 (92%) patients experienced a TEAE of ≥ grade 3, and 6 (24%) patients discontinued lenvatinib due to a TEAE. The most common TEAEs were hypertension (68%), nausea (60%), decreased appetite (52%), diarrhea (52%), and proteinuria (48%). CONCLUSIONS: Lenvatinib demonstrated activity in patients with RET fusion-positive lung adenocarcinomas; although the response rate was relatively low, the median PFS supports the activity of lenvatinib in these patients.

Sudden reversible pacemaker failure in a patient with cardiac sarcoidosis: an unfortunate case of ventricular septal pacing.

We report a case of sudden marked deterioration of ventricular stimulation threshold resulting in pacemaker failure 16 months after a ventricular septal lead implantation for atrioventricular block. Echocardiography revealed septal wall thinning at the electrode-tissue interface, which was not detected pre-operatively. Endomyocardial biopsy confirmed cardiac sarcoidosis. The increased threshold was reversible with prednisolone.

Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.

BACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

Tissue characterization of coronary plaques: comparison of integrated backscatter intravascular ultrasound with virtual histology intravascular ultrasound.

BACKGROUND: Integrated backscatter (IB) intravascular ultrasound (IVUS) and IVUS Virtual Histology (VH) have been developed for tissue characterization, but have never been compared directly. The purpose of this study was to compare the overall agreement between IB-IVUS and IVUS-VH in the tissue characterization of plaques from the same coronary arterial cross-section. METHODS AND RESULTS: Images were acquired from 46 coronary arteries from 25 cadavers. Of a total of 392 histology/IVUS image pairs, 152 pairs were diagnosed as Stary's type III, IV, Va, Vb and Vc, and compared for IB-IVUS, IVUS-VH and histology. In the qualitative comparison, the overall agreement between histological and IB-IVUS diagnoses was higher (kappa = 0.81, 95% confidence interval (CI): 0.74-0.89) than that of the IVUS-VH diagnoses (kappa = 0.66, 95%CI: 0.56-0.75). The % fibrosis area determined by IB-IVUS was significantly correlated with the relative area of fibrosis based on histology (r = 0.67, p < 0.001). In the quantitative comparison, the overall agreement between the histological and IB-IVUS diagnoses was higher (kappa = 0.83, 95% CI: 0.75-0.91) than that of the IVUS-VH diagnoses (kappa = 0.73, 95% CI: 0.63-0.83). CONCLUSION: Based on histology as the gold standard, IB-IVUS provided higher diagnostic accuracy than IVUS-VH for tissue characterization of coronary plaques.

Development of integrated backscatter intravascular ultrasound for tissue characterization of coronary plaques.

Tissue characterization of plaques of coronary arteries is important to clarify the process of acute coronary syndrome and prevent it. The purpose of this study is to develop an online integrated backscatter intravascular ultrasound (IB-IVUS) system and validate the diagnostic accuracy for the characterization of coronary plaques. A personal computer equipped with custom software was connected to an IVUS imaging system. Images were acquired from 242 segments of 46 coronary arteries from 25 cadavers obtained at autopsy. In the training study, a total of 724 regions-of-interests on color-coded maps were compared with histologic images. In the validation study, a total of 192 cross-sections of coronary arteries were evaluated. Receiver operating characteristic curve analysis showed that the cut-off points of -49 dB (area under curve = 0.98) and -29 dB (area under curve = 0.99) were the most reliable predictors of lipid pools, fibrosis and calcification. In the validation study, the analysis using IB values classified fibrous, lipid-rich and fibrocalcific plaque components with a high accuracy of 93%, 90% and 96%, respectively. The overall agreement between histologic and IB-IVUS diagnoses (n = 175) was high (Cohen's kappa = 0.81). The IB-IVUS system provides high diagnostic accuracy for analysis of tissue characteristics of coronary plaques.