Safety and Immunogenicity of the mRNA-1273 COVID-19 Vaccine in Solid Organ Transplant Recipients.

BACKGROUND: Immunosuppressed individuals, including solid organ transplant recipients (SOTRs), are at high risk for severe COVID-19. METHODS: This open-label, phase 3b trial evaluated mRNA-1273 in 137 adult kidney and 77 liver SOTRs and 20 immunocompetent participants. In Part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received 2 doses. In Part B, an additional 100-µg dose was offered ≥4 months post-primary series. Here, we report interim trial results. RESULTS: mRNA-1273 was well-tolerated in SOTRs. Four serious adverse events were considered vaccine-related by the investigator in 3 SOTRs with pre-existing comorbidities. No vaccine-related biopsy-proven organ rejection events or deaths were reported. mRNA-1273 elicited modest neutralizing antibody (nAb) responses after dose 2 and improved responses after dose 3 in SOTRs. Post-dose 3 responses among liver SOTRs were comparable to post-dose 2 responses in immunocompetent participants. Post-additional dose responses were increased in SOTRs regardless of the primary series vaccination. In liver SOTRs, post-additional dose responses were ∼3-fold higher versus post-dose 2 but were lower than immunocompetent participant responses. Most kidney SOTRs received multiple immunosuppressants and had reduced antibody responses versus liver SOTRs. CONCLUSIONS: mRNA-1273 (100 µg) was well-tolerated and dose 3 and the additional dose improved antibody responses among SOTRs.

Noncoding RNA mutations in cancer.

Cancer is driven by both germline and somatic genetic changes. Efforts have been devoted to characterizing essential genetic variations in cancer initiation and development. Most attention has been given to mutations in protein-coding genes and associated regulatory elements such as promoters and enhancers. The development of sequencing technologies and in silico and experimental methods has allowed further exploration of cancer predisposition variants and important somatic mutations in noncoding RNAs, mainly for long noncoding RNAs and microRNAs. Association studies including GWAS have revealed hereditary variations including SNPs and indels in lncRNA or miRNA genes and regulatory regions. These mutations altered RNA secondary structures, expression levels, and target recognition and then conferred cancer predisposition to carriers. Whole-exome/genome sequencing comparing cancer and normal tissues has revealed important somatic mutations in noncoding RNA genes. Mutation hotspots and somatic copy number alterations have been identified in various tumor-associated noncoding RNAs. Increasing focus and effort have been devoted to studying the noncoding region of the genome. The complex genetic network of cancer initiation is being unveiled. This article is categorized under: RNA in Disease and Development > RNA in Disease.

STUB1/CHIP: New insights in cancer and immunity.

The STUB1 gene (STIP1 homology and U-box-containing protein 1), located at 16q13.3, encodes the CHIP (carboxyl terminus of Hsc70-interacting protein), an essential E3 ligase involved in protein quality control. CHIP comprises three domains: an N-terminal tetratricopeptide repeat (TPR) domain, a middle coiled-coil domain, and a C-terminal U-box domain. It functions as a co-chaperone for heat shock protein (HSP) via the TPR domain and as an E3 ligase, ubiquitinating substrates through its U-box domain. Numerous studies suggest that STUB1 plays a crucial role in various physiological process, such as aging, autophagy, and bone remodeling. Moreover, emerging evidence has shown that STUB1 can degrade oncoproteins to exert tumor-suppressive functions, and it has recently emerged as a novel player in tumor immunity. This review provides a comprehensive overview of STUB1's role in cancer, including its clinical significance, impact on tumor progression, dual roles, tumor stem cell-like properties, angiogenesis, drug resistance, and DNA repair. In addition, we explore STUB1's functions in immune cell differentiation and maturation, inflammation, autoimmunity, antiviral immune response, and tumor immunity. Collectively, STUB1 represents a promising and valuable therapeutic target in cancer and immunology.

All-Trans Retinoic Acid Promotes a Tumor Suppressive OTUD6B-ß-TrCP-SNAIL Axis in Esophageal Squamous Cell Carcinoma and Enhances Immunotherapy.

ß-TrCP is an E3 ubiquitin ligase that plays important roles in multiple human cancers including esophageal squamous cell carcinoma (ESCC). Analysis of ESCC patient samples reveal that only protein level but not transcript level of ß-TrCP associated with patient prognosis, suggesting regulators of ß-TrCP protein stability play an essential role in ESCC progression and may be novel targets to develop ESCC therapies. Although ß-TrCP stability is known to be mediated by the ubiquitin-proteasome system, it is unclear which enzymes play a major role to determine ß-TrCP stability in the context of ESCC. In this study, OTUD6B is identified as a potent deubiquitinase of ß-TrCP that suppress ESCC progression through the OTUD6B-ß-TrCP-SNAIL axis. Low OTUD6B expression is associated with a poor prognosis of ESCC patients. Importantly, all-trans retinoic acid (ATRA) is found to promote OTUD6B translation and thus suppress ESCC tumor growth and enhance the response of ESCC tumors to anti-PD-1 immunotherapies. These findings demonstrate that OTUD6B is a crucial deubiquitinase of ß-TrCP in ESCC and suggest combination of ATRA and anti-PD-1 immune checkpoint inhibitor may benefit a cohort of ESCC patients.

High Expression of DLGAP5 Indicates Poor Prognosis and Immunotherapy in Lung Adenocarcinoma and Promotes Proliferation through Regulation of the Cell Cycle.

Background: Lung adenocarcinoma (LUAD) is one of the most common types of cancer in the respiratory system, with a high mortality and recurrence rate. The role of disc large-associated protein 5 (DLGAP5) in LUAD progression and tumor microenvironment (TME) remains unclear. This study is aimed at revealing the functional role of DLGAP5 in LUAD based on bioinformatics analysis and experimental validation. Methods: Differential expression analysis, protein-protein interaction (PPI) network, and Cox regression analysis were applied to screen potential prognostic biomarkers. The mRNA and protein levels of DLGAP5 were analyzed using The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. The CCK-8 and colony formation assays were performed to assess the effect of DLGAP5 on cell proliferation. RNA sequencing (RNA-seq) and enrichment analyses were utilized to explore the biological functions of DLGAP5. Furthermore, flow cytometry was used to explore the role of DLGAP5 on the cell cycle. The ssGSEA algorithm in the R package "GSVA" was applied to quantify immune infiltrating cells, and the tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict the efficacy of immunotherapy. Moreover, analyses using the cBioPortal and MethSurv databases were performed to evaluate the mutation and methylation of DLGAP5, respectively. Finally, the prognostic value of DLGAP5 was estimated using the TCGA and the Gene Expression Omnibus (GEO) databases. The nomogram model was constructed using the TCGA-LUAD cohort and evaluated by adopting calibration curves, time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results: DLGAP5 mRNA and protein abundance were significantly elevated in LUAD, and knockdown of DLGAP5 remarkably suppressed lung cancer cell proliferation through induction of cell cycle G1 arrest. In addition, DLGAP5 expression was positively correlated with Th2 cells and negatively correlated with B cells, T follicular helper cells, and mast cells. LUAD patients with high DLGAP5 expression may be resistant to immunotherapy. Hypermethylation levels of the cg23678254 site of DLGAP5 or its enhanced expression were unfavorable for the survival of LUAD patients. Meanwhile, DLGAP5 expression was associated with TNM stages, tumor status, and therapy outcome. Notably, the prognostic model constructed based on DLGAP5 expression exhibited great predictive capability, which was promising for clinical applications. Conclusion: DLGAP5 promotes lung cancer cell proliferation through regulation of the cell cycle and is associated with multiple immune infiltrating cells. Furthermore, DLGAP5 predicts poor prognosis and response to immunotherapy in lung adenocarcinoma.

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy.

Since tyrosine phosphorylation is reversible and dynamic in vivo, the phosphorylation state of proteins is controlled by the opposing roles of protein tyrosine kinases (PTKs) and protein tyrosine phosphatase (PTPs), both of which perform critical roles in signal transduction. Of these, intracellular non-receptor PTPs (PTPNs), which belong to the largest class I cysteine PTP family, are essential for the regulation of a variety of biological processes, including but not limited to hematopoiesis, inflammatory response, immune system, and glucose homeostasis. Additionally, a substantial amount of PTPNs have been identified to hold crucial roles in tumorigenesis, progression, metastasis, and drug resistance, and inhibitors of PTPNs have promising applications due to striking efficacy in antitumor therapy. Hence, the aim of this review is to summarize the role played by PTPNs, including PTPN1/PTP1B, PTPN2/TC-PTP, PTPN3/PTP-H1, PTPN4/PTPMEG, PTPN6/SHP-1, PTPN9/PTPMEG2, PTPN11/SHP-2, PTPN12/PTP-PEST, PTPN13/PTPL1, PTPN14/PEZ, PTPN18/PTP-HSCF, PTPN22/LYP, and PTPN23/HD-PTP, in human cancer and immunotherapy and to comprehensively describe the molecular pathways in which they are implicated. Given the specific roles of PTPNs, identifying potential regulators of PTPNs is significant for understanding the mechanisms of antitumor therapy. Consequently, this work also provides a review on the role of non-coding RNAs (ncRNAs) in regulating PTPNs in tumorigenesis and progression, which may help us to find effective therapeutic agents for tumor therapy.

A novel metabolic-immune related signature predicts prognosis and immunotherapy response in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is one of the most frequent types of lung cancer, with a high mortality and recurrence rate. This study aimed to design a RiskScore to predict the prognosis and immunotherapy response of LUAD patients due to a lack of metabolic and immune-related prognostic models. Methods: To identify prognostic genes and generate a RiskScore, we conducted differential gene expression analysis, bulk survival analysis, Lasso regression analysis, and univariate and multivariate Cox regression analysis using TCGA-LUAD as a training subset. GSE31210 and GSE50081 were used as validation subsets to validate the constructed RiskScore. Following that, we explored the connection between RiskScore and clinicopathological characteristics, immune cells infiltration, and immunotherapy. In addition, we investigated into RiskScore's biological roles and constructed a Nomogram model. Results: A RiskScore was identified consisting of five genes (DKK1, CCL20, NPAS2, GNPNAT1 and MELTF). In the RiskScore-high group, LUAD patients showed decreased overall survival rates and shorter progression-free survival. Multiple clinicopathological characteristics and immune cells infiltration in TME, in particular, have been linked to RiskScore. Of note, RiskScore-related genes have been implicated to substance metabolism, carcinogenesis, and immunological pathways, among other things. Finally, the C-index of the RiskScore-based Nomogram model was 0.804 (95% CI: 0.783-0.825), and time-dependent ROC predicted probabilities of 1-, 3- and 5-year survival for LUAD patients were 0.850, 0.848 and 0.825, respectively. Conclusion: The RiskScore, which integrated metabolic and immunological features with DKK1, CCL20, NPAS2, GNPNAT1, and MELTF, could reliably predict prognosis and immunotherapy response in LUAD patients. Moreover, the RiskScore-based Nomogram model had a promising clinical application.

Characterizing mobile element insertions in 5675 genomes.

Mobile element insertions (MEIs) are a major class of structural variants (SVs) and have been linked to many human genetic disorders, including hemophilia, neurofibromatosis, and various cancers. However, human MEI resources from large-scale genome sequencing are still lacking compared to those for SNPs and SVs. Here, we report a comprehensive map of 36 699 non-reference MEIs constructed from 5675 genomes, comprising 2998 Chinese samples (∼26.2×, NyuWa) and 2677 samples from the 1000 Genomes Project (∼7.4×, 1KGP). We discovered that LINE-1 insertions were highly enriched in centromere regions, implying the role of chromosome context in retroelement insertion. After functional annotation, we estimated that MEIs are responsible for about 9.3% of all protein-truncating events per genome. Finally, we built a companion database named HMEID for public use. This resource represents the latest and largest genomewide study on MEIs and will have broad utility for exploration of human MEI findings.

EIF3H promotes aggressiveness of esophageal squamous cell carcinoma by modulating Snail stability.

BACKGROUND: Overexpression of eukaryotic translation initiation factor 3H (EIF3H) predicts cancer progression and poor prognosis, but the mechanism underlying EIF3H as an oncogene remains unclear in esophageal squamous cell carcinoma (ESCC). METHODS: TCGA database and the immunohistochemistry (IHC) staining of ESCC samples were used and determined the upregulation of EIF3H in ESCC. CCK8 assay, colony formation assay and transwell assay were performed to examine the ability of cell proliferation and mobility in KYSE150 and KYSE510 cell lines with EIF3H overexpression or knockdown. Xenograft and tail-vein lung metastatic mouse models of KYSE150 cells with or without EIF3H knockdown were also used to confirm the function of EIF3H on tumor growth and metastasis in vivo. A potential substrate of EIF3H was screened by co-immunoprecipitation assay (co-IP) combined with mass spectrometry in HEK293T cells. Their interaction and co-localization were confirmed using reciprocal co-IP and immunofluorescence staining assay. The function of EIF3H on Snail ubiquitination and stability was demonstrated by the cycloheximide (CHX) pulse-chase assay and ubiquitination assay. The correlation of EIF3H and Snail in clinical ESCC samples was verified by IHC. RESULTS: We found that EIF3H is significantly upregulated in esophageal cancer and ectopic expression of EIF3H in ESCC cell lines promotes cell proliferation, colony formation, migration and invasion. Conversely, genetic inhibition of EIF3H represses ESCC tumor growth and metastasis in vitro and in vivo. Moreover, we identified EIF3H as a novel deubiquitinating enzyme of Snail. We demonstrated that EIF3H interacts with and stabilizes Snail through deubiquitination. Therefore, EIF3H could promote Snail-mediated EMT process in ESCC. In clinical ESCC samples, there is also a positive correlation between EIF3H and Snail expression. CONCLUSIONS: Our study reveals a critical EIF3H-Snail signaling axis in tumor aggressiveness in ESCC and provides EIF3H as a promising biomarker for ESCC treatment.

EIF3H Orchestrates Hippo Pathway-Mediated Oncogenesis via Catalytic Control of YAP Stability.

EIF3H is presumed to be a critical translational initiation factor. Here, our unbiased screening for tumor invasion factors has identified an unexpected role for EIF3H as a deubiquitylating enzyme that dictates breast tumor invasion and metastasis by modulating the Hippo-YAP pathway. EIF3H catalyzed YAP for deubiquitylation, resulting in its stabilization. Structure-based molecular modeling and simulations coupled with biochemical characterization unveiled a unique catalytic mechanism for EIF3H in dissociating polyubiquitin chains from YAP through a catalytic triad consisting of Asp90, Asp91, and Gln121. Trp119 and Tyr 140 on EIF3H directly interacted with the N-terminal region of YAP1, facilitating complex formation of EIF3H and YAP1 for YAP1 deubiquitylation. Stabilization of YAP via elevated EIF3H promoted tumor invasion and metastasis. Interference of EIF3H-mediated YAP deubiquitylation blocked YAP-induced tumor progression and metastasis in breast cancer models. These findings point to a critical role for YAP regulation by EIF3H in tumor invasion and metastasis. SIGNIFICANCE: This work demonstrates that EIF3H is a novel bona fide deubiquitinase that counteracts YAP ubiquitylation and proteolysis, and stabilization of YAP by EIF3H promotes tumor invasion and metastasis.

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis.

BACKGROUND: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations. METHODS: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks. CONCLUSIONS: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.

USP26 promotes esophageal squamous cell carcinoma metastasis through stabilizing Snail.

Snail is an important transcription factor of epithelial-mesenchymal transition (EMT) and related to poor prognosis and distant metastasis of tumor patients. Snail is a liable protein and degraded by ubiquitin-proteasome system. There are various E3 ligases mediating its degradation, but the deubiquitinating enzyme reversed Snail degradation is not fully understood. In this study, we screened a DUB library and found USP26 is a potent deubiquitinase mediating Snail stabilization. We also identified that USP26 is a booster of esophageal squamous cell carcinoma (ESCC) cell migration and invasion, and it is highly expressed in ESCC samples. Our observation demonstrates that USP26 is a novel deubiquitinating enzyme of Snail and it provides a potential target for the therapy of esophageal cancer metastasis.

Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial.

BACKGROUND: Predictive biomarkers of patients likely to benefit from anti-programmed death 1 inhibitor therapy have clinical relevance. We examined whether line of therapy or tumour programmed death ligand 1 (PD-L1) expression affects the efficacy and safety of pembrolizumab, compared with ipilimumab, in advanced melanoma. METHODS: Of 834 patients enrolled in the randomised, open-label phase III KEYNOTE-006 study, 833 were included in this analysis. Patients were randomly assigned 1:1:1 to receive pembrolizumab 10 mg/kg every 2 or 3 weeks (for 24 months) or ipilimumab 3 mg/kg every 3 weeks (for four doses) until disease progression/intolerable toxicity. This analysis evaluated progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Data cut-off: 03 November 2016. RESULTS: Of the patients, 60.3% were male, 65.9% were treatment naive and 80.6% had PD-L1-positive tumours (median follow-up was 33.9 months). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in treatment-naive (PFS 31.0% versus 14.6%; OS 58.0% versus 44.7%) and previously treated patients (PFS 25.7% versus 11.3%; OS 49.2% versus 37.9%). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in patients with PD-L1-positive tumours (PFS 33.2% versus 13.1%; OS 58.4% versus 45.0%) and similar in PD-L1-negative tumours (PFS 14.9% versus NR [no data at 24 months for a PFS estimate]; OS 43.6% versus 31.8%). Safety of pembrolizumab by subgroup was consistent with previous reports. CONCLUSIONS: Findings support pembrolizumab monotherapy as standard of care in patients with advanced melanoma, regardless of first- or second-line therapy or PD-L1 status. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.

Dopamine alleviated acute liver injury induced by lipopolysaccharide/d-galactosamine in mice.

Dopamine (DA), a crucial neurotransmitter, not only functions in the central nervous system but also plays important roles in the modulation of inflammation. Several studies suggest that DA might suppress the inflammatory response both in vitro and in vivo. In the present study, the potential effects of DA in a mouse model with lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury were investigated. The results show that DA-treated LPS/D-Gal-exposed mice had reduced incidence of histologic lesions, lower plasma aminotransferases and improved the survival rates compared to LPS/D-Gal-exposed mice. Treatment with DA also suppressed LPS/D-Gal-induced production of TNF-α, phosphorylation of c-jun-N-terminal kinase (JNK), cleavage of caspase-3, up-regulation of hepatic caspase-3, caspase-8, and caspase-9 activities and reduced the count of TUNEL-positive hepatocytes. These data indicate that DA attenuated LPS/D-Gal-induced fulminant liver injury in mice, which implies that DA might have value for the prevention of inflammatory liver disease.

OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability.

Snail is a key regulator of epithelial-mesenchymal transition (EMT) and plays an important role in tumor progression and metastasis. Snail is rapidly degraded in the cells and its protein level is critically controlled. Although several E3 ligases regulating Snail degradation have been defined, the deubiquitinases (DUBs) responsible for Snail deubiquitination are less studied. We identified ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) as a DUB that stabilizes Snail through preventing its ubiquitination and proteasomal degradation. Functionally, OTUB1 facilitates metastasis of esophageal squamous cell carcinoma (ESCC) through promoting Snail protein stability. Moreover, OTUB1 is highly expressed in ESCC and higher expression of OTUB1 predicts poor prognosis. These findings suggest that OTUB1 is an essential regulator of Snail and plays a critical role in facilitating esophageal cancer progression.

Deubiquitinating enzyme PSMD14 promotes tumor metastasis through stabilizing SNAIL in human esophageal squamous cell carcinoma.

The epithelial-mesenchymal transition (EMT) transcription factor SNAIL is associated with distant metastasis and poor prognosis of esophageal squamous cell carcinoma (ESCC) patients. The proteolysis of SNAIL is mediated by the ubiquitin-proteasome system. Several E3 ligases have been characterized to promote SNAIL ubiquitination and degradation. However, the reverse process - deubiquitination of SNAIL remains largely unknown. In this study, we performed a mass spectrometry to examine the interaction between SNAIL and deubiquitinating enzyme(s). Subsequently, the deubiquitinating enzyme PSMD14 was identified to target SNAIL for deubiquitination and stabilization. Furthermore, knockdown of PSMD14 significantly blocks SNAIL-induced EMT and then suppresses tumor cell migration and invasion in vitro and tumor metastasis in vivo. In addition, the high expression level of PSMD14 predicts poor prognosis for esophageal cancer patients. These findings suggest PSMD14 as a bona fide deubiquitinating enzyme to regulate SNAIL at the post-translational level and provide a promising therapeutic strategy against tumor metastasis of esophageal cancer.

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).

BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.

Pembrolizumab versus Ipilimumab in Advanced Melanoma.

BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients.

PURPOSE: Dinaciclib is a novel selective inhibitor of cyclin-dependent kinase (CDK)1, CDK2, CDK5, and CDK9. We conducted a phase I study to investigate the effects of dinaciclib when administered with rituximab. METHODS: In this phase I nonrandomized dose-escalation 3 + 3 trial, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) were treated with dinaciclib and rituximab. Dinaciclib was administered intravenously (IV) over 2 h on days 1, 8 and 15 in cycles 2-13 (28-day cycles). Rituximab 375 mg/m(2) was administered IV on days 1, 8, 15 and 22 in cycle 1 (28-day cycle) and on day 1 during cycle 3-13. Rituximab was not administered in cycle 2. Rituximab and dinaciclib were given alone in cycles 1 and 2, respectively, and in combination in cycles 3-13. Primary objectives included determination of the recommended phase II dose of dinaciclib and evaluation of pharmacokinetics (PK) when administered with rituximab. RESULTS: Five patients completed the study due to early termination. All presented with drug-related adverse events (AEs), but no dose-limiting toxicities were observed. The most commonly observed toxicities included hematological, digestive and metabolic AEs. However, no tumor lysis syndrome has been reported in the study. Four patients achieved stable disease, and one patient achieved complete response according to 2008 iwCLL criteria at cycle 3. PK samples were collected from 5 patients, and no obvious interaction between dinaciclib and rituximab was observed. CONCLUSIONS: Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.

Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer.

OBJECTIVES: Dinaciclib (MK-7965, formerly SCH 727965), a novel, small-molecule inhibitor of cyclin-dependent kinases, has been shown to induce apoptosis in preclinical studies of human tumor cell lines, including non-small cell lung cancer (NSCLC) cells. Erlotinib, an epidermal growth factor receptor inhibitor, is approved for the treatment of advanced NSCLC as second- or third-line therapy. This phase 2, randomized, multicenter, open-label study compared dinaciclib with erlotinib in patients with previously treated NSCLC. MATERIALS AND METHODS: The study was comprised of 2 parts: in part 1, patients were randomized to either intravenous (IV) dinaciclib (50 mg/m2) or oral erlotinib (150 mg) using an adaptive Bayesian design that adjusted the randomization ratio in favor of the more active arm, and in part 2, patients who had progressed on erlotinib were permitted to cross over to receive dinaciclib at the same dosage as in part 1. Patients were followed until disease progression or death, initiation of nonstudy cancer treatment, discontinuation, or withdrawal of consent. The primary efficacy end point was time-to-progression (TTP) in part 1 and objective response rate (ORR) in part 2. RESULTS: Based on Kaplan-Meier estimates, the median TTP was 1.49 months (95% confidence interval [CI]: 1.31, 2.63) following initial treatment with dinaciclib, compared with 1.58 months (95% CI: 1.38, 2.83) with erlotinib. No objective responses were observed following initial treatment with dinaciclib. Common severe (grade 3 or 4) drug-related adverse effects included neutropenia, leukopenia, vomiting, and diarrhea. CONCLUSIONS: Dinaciclib, administered IV, was well tolerated at the 50 mg/m2 dose, but does not have activity as monotherapy in previously treated NSCLC. Evaluation of dinaciclib in combination with other agents for other indications including breast cancer and multiple myeloma is in progress.