Evaluation of potential biomarkers for lenvatinib plus pembrolizumab among patients with advanced endometrial cancer: results from Study 111/KEYNOTE-146.

BACKGROUND: Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest. METHODS: Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell-inflamed gene expression profile (TcellinfGEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES). RESULTS: 93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or <175 mutations/exome) and mutation status. There were no correlations between TcellinfGEP and TMB, TcellinfGEP and microvessel density (MVD), or MVD and TMB. CONCLUSIONS: This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted. TRIAL REGISTRATION NUMBER: NCT02501096.

Adhesion Characterization and Enhancement between Polyimide-Silica Composite and Nodulated Copper for Applications in Next-Generation Microelectronics.

As the need for high-speed electronics continues to rise rapidly, printed wiring board (PWB) requirements become ever-more demanding. A typical PWB is fabricated by bonding dielectric films such as polyimide to electrically conductive copper foil such as rolled annealed (RA) copper and is expected to become thinner, flexible, durable, and compatible with high-frequency 5G performance. Polyimide films inherently feature a higher coefficient of thermal expansion (CTE) than copper foils; this mismatch causes residual thermal stresses. To attenuate the mismatch, silica nanoparticles may be used to reduce the CTE of PI. A nodulated copper surface can be used to enhance the Cu/PI adhesion by additional bonding mechanisms that could include a type of mechanical bonding, which is a focus of this study. In this investigation, a 90° peel test was used to measure the peel strength in copper/polyimide/copper laminates containing nodulated copper and polyimide reinforced with 0, 20, and 40 wt % silica nanoparticles. The influence of silica nanoparticles on the peel strength was quantitatively evaluated. Laminates incorporating polyimide films lacking silica nanoparticles had a ∼3.75× higher peel strength compared with laminates reinforced with 40% silica. Their failure surfaces were analyzed by using scanning electron microscopy (SEM), energy-dispersive X-ray analysis (EDX), and X-ray photoelectron spectroscopy to identify the mode of failure and to understand bonding mechanisms. The key bonding mechanism, mechanical interlocking, was achieved when the polyimide surrounded or engulfed the copper nodules when the laminate was created. Post-testing failure surface analysis revealed the presence of copper on the polyimide side and polyimide on the copper side, indicating mixed mode failure. An analytical model was developed to determine the impact of applied pressure, temperature, and time on the polyimide penetration and mechanical interlocking around the copper nodules. The model was validated by measuring the peel strength on another set of specimens fabricated using increased temperature and pressure that showed a 3× increase in peel strength compared to lower temperature/pressure processing conditions. This enhanced adhesion resulted from the lower polymer material viscosity at higher temperatures, which fosters deeper and more complete penetration around the copper nodules during processing at higher pressures for longer durations. The methodology of combining peel testing, viscosity and CTE measurement, SEM/EDX, surface chemical analysis, and penetration depth calculation developed herein enables the calculation of the desired processing parameters to enhance functionality and improve adhesion.

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study. METHODS: In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096. FINDINGS: Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7-20·1). 21 (39·6% [95% CI 26·5-54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events. INTERPRETATION: Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study. FUNDING: Eisai and Merck.

Myocardium of the superior vena cava, coronary sinus, vein of Marshall, and the pulmonary vein ostia: gross anatomic studies in 620 hearts.

INTRODUCTION: Radiofrequency ablation for atrial fibrillation (AF) frequently involves energy delivery at the ostia of the thoracic veins. Detailed evaluation of the myocardium extending into the caval veins, vein of Marshall, as well as at the pulmonary vein ostia has not been completely evaluated. METHODS AND RESULTS: Post-mortem assessment of 620 formalin-fixed hearts (mean age 60 ± 23 years, 44% female) was performed. The hearts were examined for integrity of venous structures and their atrial connections. Systematic gross anatomic evaluation including measurements on myocardial extensions in these veins was performed. Macroscopic myocardial extensions into pulmonary veins were noted in 99% of specimens evaluated and were circumferentially symmetric (99.6%). Myocardial extensions into the superior vena cava (SVC) occurred in 78% with the majority being circumferentially asymmetric (61%). Occasionally, myocardium extended into the azygos vein (6%). There were no myocardial extensions in the inferior vena cava (IVC). In some cases, the right atrial pectinate muscle extended into the coronary sinus (7%). The vein of Marshall was consistently located anterior to the left-sided pulmonary veins and posterior to the left atrial appendage, overlying the left atrial endocardial ridge. CONCLUSIONS: Myocardial extensions into the pulmonary veins are usually circumferential at the ostia validating the necessity for wide area rather than segmental ablation to isolate these veins during AF ablation. Myocardial extensions into the SVC are common and less likely to be circumferential, whereas extensions into the IVC are not present. The left atrial ridge is a reliable endocardial target for radiofrequency ablation of the vein of Marshall.