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Lessons Learned. Ramucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliary tract cancer, which is consistent with reports of other tumor cohorts within this phase Ia/b trial. Ramucirumab plus pembrolizumab did not demonstrate an improvement in overall survival when compared with historical controls in biomarker unselected, heavily pretreated patients with advanced or metastatic biliary tract cancer. Patients with programmed death‐ligand 1 (PD‐L1)‐positive tumors had improved overall survival compared with patients with PD‐L1‐negative disease. Background. Few treatment options exist for patients with advanced biliary tract cancer (BTC) following progression on gemcitabine‐cisplatin. Preclinical evidence suggests that simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR‐2) and programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) enhances antitumor effects. We assessed the safety and efficacy of ramucirumab, an IgG1 VEGFR‐2 antagonist, with pembrolizumab, an IgG4 PD‐1 antagonist, in biomarker‐unselected patients with previously treated advanced or metastatic BTC. Methods. Patients had previously treated advanced or metastatic adenocarcinoma of the gallbladder, intrahepatic and extrahepatic bile ducts, or ampulla of Vater. Ramucirumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous pembrolizumab 200 mg on day 1 every 3 weeks. The primary endpoint was safety and tolerability of the combination. Secondary endpoints included objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Results. Twenty‐six patients were treated at 12 centers in five countries. Hypertension was the most common grade 3 treatment‐related adverse event (TRAE), occurring in five patients. One patient experienced a grade 4 TRAE (neutropenia), and no treatment‐related deaths occurred. Objective response rate was 4%. Median progression‐free survival and overall survival were 1.6 months and 6.4 months, respectively. Conclusion. Ramucirumab ‐ pembrolizumab showed limited clinical activity with infrequent grade 3–4 TRAEs in patients with biomarker‐unselected progressive BTC.

Background: Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an antiePD-

When assessing differential gene expression from RNA sequencing data, commonly used statistical tests tend to have greater power to detect differential expression of genes encoding longer transcripts. This phenomenon, called “length bias”, will influence subsequent analyses such as Gene Ontology enrichment analysis. In the presence of length bias, Gene Ontology categories that include longer genes are more likely to be identified as enriched. These categories, however, are not necessarily biologically more relevant. We show that one can effectively adjust for length bias in Gene Ontology analysis by including transcript length as a covariate in a logistic regression model. The logistic regression model makes the statistical issue underlying length bias more transparent: transcript length becomes a confounding factor when it correlates with both the Gene Ontology membership and the significance of the differential expression test. The inclusion of the transcript length as a covariate allows one to investigate the direct correlation between the Gene Ontology membership and the significance of testing differential expression, conditional on the transcript length. We present both real and simulated data examples to show that the logistic regression approach is simple, effective, and flexible.

Introduction: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)positive NSCLC (cohort E) are reported (NCT02443324). Methods: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cellinflamed, Gajewski, and effector T cells) and CD274 gene expression. Results: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n ¼ 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ! 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry. Conclusions: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.