Regulation of atrial natriuretic peptide secretion by a novel Ras-like protein

Atrial cardiomyocytes, neurons, and endocrine tissues secrete neurotransmitters and peptide hormones via large dense-core vesicles (LDCVs). We describe a new member of the Ras family of G-proteins, named RRP17, which is expressed specifically in cardiomyocytes, neurons, and the pancreas. RRP17 interacts with Ca2+-activated protein for secretion-1 (CAPS1), one of only a few proteins known to be associated exclusively with LDCV exocytosis. Ectopic expression of RRP17 in cardiomyocytes enhances secretion of atrial natriuretic peptide (ANP), a regulator of blood pressure and natriuresis. Conversely, genetic deletion of RRP17 in mice results in dysmorphic LDCVs, impaired ANP secretion, and hypertension. These findings identify RRP17 as a component of the cellular machinery involved in regulated secretion within the heart and potential mediator of the endocrine influence of the heart on other tissues

O-15 Randomized, phase 3 study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302) in the overall population and Europe/North America subgroup

Background: The global Phase 3 study RATIONALE 302 (NCT03430843) evaluated the efficacy and safety of second-line tislelizumab, an anti-PD-1 antibody, in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Here, we report data from the overall and Europe/North America (EU/NA) populations. Methods: Eligible adult patients had disease progression during or after first-line systemic therapy, ≥1 evaluable lesion per RECIST v1.1 and an Eastern Cooperative Oncology Group performance score (ECOG PS) of ≤1. Patients were randomized (1:1) to receive tislelizumab 200 mg intravenously Q3W or investigator-chosen chemotherapy (paclitaxel, docetaxel, or irinotecan) and treated until disease progression, intolerable toxicity, or withdrawal. Stratification factors included chemotherapy option, region, and ECOG PS. The primary endpoint was overall survival (OS) in all patients (ITT population). The key secondary endpoint was OS in PD-L1 positive (vCPS ≥10%) patients; other secondary endpoints included progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), health-related quality of life and safety. Results: 512 patients (overall population) were randomized to tislelizumab (n=256) or chemotherapy (n=256), of which 108 (21%) patients were enrolled into EU/NA subgroup (n=55 tislelizumab, n=53 chemotherapy). On 1 December 2020 (data cut-off), median follow-up was 6.9 and 6.8 months in the overall population and EU/NA subgroup, respectively. Tislelizumab improved OS vs chemotherapy in the overall population (median OS 8.6 vs 6.3 months; HR 0.70, 95% CI 0.57–0.85; p=0.0001); survival benefit was consistently observed in the EU/NA subgroup (median OS 11.2 vs 6.3 months; HR 0.55; 95% CI 0.35–0.87). Treatment with tislelizumab was associated with improved ORR (20.3% [95% CI 15.6%–25.8%] vs 9.8% [95% CI 6.4%–14.1%]) and median DoR (7.1 vs 4.0 months; HR 0.42, 95% CI 0.23–0.75) vs chemotherapy in the overall population. Improvement in ORR (20.0% [95% CI 10.4%–33.0%] vs 11.3% [95% CI 4.3%–23.0%]) and median DOR (5.1 vs 2.1 months; HR 0.42, 95% CI 0.13–1.39) was also observed in the EU/NA subgroup. Fewer patients had Grade ≥3 treatment-emergent adverse events (TEAE) with tislelizumab vs chemotherapy in both the overall and EU/NA populations (46% vs 68% and 56% vs 71%, respectively). Of these, fewer Grade ≥3 AEs were treatment-related with tislelizumab vs chemotherapy (overall: 19% vs 56%; EU/NA: 13% vs 51%). AEs leading to death were similar with tislelizumab vs chemotherapy (overall: 14% vs 12%; EU/NA: 6% vs 5%). Conclusions: Second-line tislelizumab demonstrated statistically significant and clinically meaningful improvement in OS versus chemotherapy in patients with advanced or metastatic ESCC. Tislelizumab demonstrated a tolerable safety profile. Efficacy and safety results from the EU/NA subgroup were consistent with the overall population. Clinical trial identification: NCT03430843

American Radium Society (ARS) and American College of Radiology (ACR) Appropriate Use Criteria Systematic Review and Guidelines on Reirradiation for Non-small Cell Lung Cancer (NSCLC)

Background: Reirradiation (reRT) for locoregional recurrences can provide durable control and improved symptoms and progression-free survival for select NSCLC patients. Thoracic reRT, however, is particularly challenging due to its considerable risk and the current lack of standardized approaches, guidelines and dose constraints. To date, no systematic review on the safety and efficacy of reRT for NSCLC exists, and no dedicated guidelines are available. Objectives: This ARS-ACR Appropriate Use Criteria Systematic Review and Guidelines on Reirradiation for NSCLC provides direct guidance on the safety and efficacy of reRT and recommends consensus dose constraints for thoracic reRT to minimize risks of high grade toxicities. Methods: A PRISMA systematic review assessed all studies published through 3/2019 evaluating toxicities, local control and/or overall survival for NSCLC thoracic reRT. Of 236 articles, 49 remained after exclusions (3 prospective) and formed the basis for these recommendations on: 1) the role of concurrent chemotherapy with reRT, 2) factors associated with toxicity from reRT and 3) what reRT modalities, dose-fractionation schemas and dose rates should be used. Composite dose constraints were also recommended. The available data suggest potential benefit in clinical outcomes with concurrent chemoradiation for reRT, but the decision should be based on patient performance status, tolerance to prior systemic therapy and other individual patient/tumor characteristics. There are no data to guide the use of concurrent targeted therapy or immunotherapy with reRT, and this is not recommended outside of a clinical trial. Acute esophagitis and pneumonitis and late pulmonary, cardiac/great vessel, esophageal, brachial plexus and spinal toxicities are dose limiting for reRT. Limited data exist regarding the use of hyperfractionation and low- or high-dose rate reRT for NSCLC. For conventionally fractionated reRT, intensity-modulated radiation therapy (IMRT) is recommended over 3D conformal radiation therapy (3DCRT) to increase dose conformality. Particle therapy may further reduce toxicities and/or enable safer reRT dose escalation compared with 3DCRT and IMRT. Stereotactic body radiation therapy (SBRT) can provide increased conformality and dose escalation and is optimal for primary-alone failures, but caution is needed for central reRT with SBRT. Recommended reRT composite dose constraints in 2 Gy equivalent dose are: esophagus V60 \u3c40% and DMax \u3c100-110 Gy, lung V20 \u3c40%, heart V40 \u3c50%, aorta/great vessels DMax \u3c120 Gy, trachea and proximal bronchial tree DMax \u3c110 Gy, spinal cord DMax \u3c57 Gy, and brachial plexus DMax \u3c85 Gy. Conclusions: For the first time, consensus dose constraints for thoracic reRT are recommended to minimize the risks of high-grade and potentially fatal toxicities from repeat radiotherapy. Additional prospective data are needed, and toxicities should be correlated with reRT course and composite dose constraints

43P MRTX-500: Phase II trial of sitravatinib (sitra) + nivolumab (nivo) in patients (pts) with non-squamous (NSQ) non-small cell lung cancer (NSCLC) progressing on or after prior checkpoint inhibitor (CPI) therapy

Background: Therapy with CPI has improved OS in a subset of pts with NSCLC. Mechanisms of CPI resistance, however, have been described, including an immunosuppressive tumor microenvironment (TME), which may recruit immunosuppressive myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized macrophages in the TME. Sitra, a spectrum-selective TKI targeting TAM (Tyro3/Axl/MerTK) receptors and VEGFR2, reduces the number of MDSCs and Tregs and increases the M1/M2-polarized macrophage ratio. It is hypothesized to overcome an immunosuppressive TME and augment antitumor immune responses. Methods: MRTX-500 (NCT02954991) is a phase II study evaluating sitra (120 mg QD) + nivo (Q2W or Q4W) in pts with NSQ NSCLC who have progressed on or after treatment, with a CPI-based regimen (anti-PD1/PD-L1) and/or platinum doublet chemotherapy. The primary endpoint is ORR per RECIST 1.1. Secondary endpoints include OS, PFS, and safety. We report updated efficacy data for pts with NSCLC with PCB (prior clinical benefit; CR, PR, or SD ≥12 weeks) from a CPI who were treated with sitra + nivo as either 2L or 3L therapy. Results: As of 17 October 2020, 68 pts with PCB (57% female; median age, 66 years; ECOG PS 0/1/2, 27%/66%/7%) were treated. Median follow-up was 28 months, median OS was 15 months (95% CI 9.3, 21.1),1- and 2-year OS rates were 56% and 32%, respectively. Median PFS was 6 months, and ORR was 16% (11/68), including 2 CRs. Median duration of response was 13 months. In all CPI-experienced pts evaluable for safety (n=124), treatment related adverse events (TRAEs) occurred in 91% of pts, with Gr 3/4 TRAEs occurring in 60% of pts. The most common (≥10%) Gr 3/4 TRAEs were hypertension and diarrhea. There were no Gr 5 TRAEs. Discontinuation rates for sitra and nivo due to any AE were 30% and 27%, respectively. Conclusions: Sitra + nivo demonstrated antitumor activity and encouraging OS compared to historical controls and no new safety signals were observed in pts with NSQ NSCLC who progressed on prior CPI. This combination is being evaluated in the phase III SAPPHIRE study. Previously presented at ESMO 2021, FPN (Final Publication Number): 1191O, Ticiana Leal et al. - Reused with permission. Clinical trial identification: NCT02954991

A Phase 1b Study of Telisotuzumab Vedotin in Combination With Nivolumab in Patients With NSCLC

Introduction: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate that has exhibited antitumor activity as monotherapy in NSCLC. Its potential activity combined with programmed cell death protein-1 inhibitors has not been previously evaluated. Methods: In a phase 1b study (NCT02099058), adult patients (≥18 y) with advanced NSCLC received combination therapy with Teliso-V (1.6, 1.9, or 2.2 mg/kg, every 2 wk) plus nivolumab (3 mg/kg, 240 mg, or per locally approved label). The primary objective was to assess safety and tolerability; secondary objectives included the evaluation of antitumor activity. Results: As of January 2020, a total of 37 patients received treatment with Teliso-V (safety population) in combination with nivolumab; 27 patients (efficacy population) were c-Met immunohistochemistry-positive. Programmed death-ligand 1 (PD-L1) status was evaluated in the efficacy population (PD-L1-positive [PD-L1+]: n = 15; PD-L1-negative [PD-L1-]: n = 9; PD-L1-unknown: n = 3). The median age was 67 years and 74% (20 of 27) of patients were naive to immune checkpoint inhibitors. The most common any-grade treatment-related adverse events were fatigue (27%) and peripheral sensory neuropathy (19%). The pharmacokinetic profile of Teliso-V plus nivolumab was similar to Teliso-V monotherapy. The objective response rate was 7.4%, with two patients (PD-L1+, c-Met immunohistochemistry H-score 190, n = 1; PD-L1-, c-Met H-score 290, n = 1) having a confirmed partial response. Overall median progression-free survival was 7.2 months (PD-L1+: 7.2 mo; PD-L1-: 4.5 mo; PD-L1-unknown: not reached). Conclusions: Combination therapy with Teliso-V plus nivolumab was well tolerated in patients with c-Met+ NSCLC with limited antitumor activity

1191O MRTX-500: Phase II trial of sitravatinib (sitra) + nivolumab (nivo) in patients (pts) with non-squamous (NSQ) non-small cell lung cancer (NSCLC) progressing on or after prior checkpoint inhibitor (CPI) therapy

Background: Therapy with CPI has improved OS across many tumor types, including in a subset of pts with NSCLC. Mechanisms of CPI resistance, however, have been described, including an immunosuppressive TME, which may include recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized macrophages within the TME. Sitra, a spectrum-selective TKI targeting TAM (Tyro3/Axl/MerTK) receptors and VEGFR2, reduces the number of MDSCs and Tregs while increasing the ratio of M1/M2-polarized macrophages, and thus is hypothesized to overcome an immunosuppressive TME and augment antitumor immune responses. Methods: MRTX-500 (NCT02954991) is a phase II study evaluating sitra (120 mg QD) + nivo (Q2W or Q4W) in pts with NSQ NSCLC who have progressed on or after treatment, with a CPI-based regimen (anti-PD1/PD-L1) and/or platinum doublet chemotherapy. The primary endpoint is ORR per RECIST 1.1. Secondary endpoints include OS, PFS, and safety. We report updated efficacy data for pts with NSCLC with PCB (prior clinical benefit; CR, PR, or SD ≥12 weeks) from a CPI who were treated with sitra + nivo as either 2L or 3L therapy. Results: As of 17 October 2020, 68 pts with PCB (57% female; median age, 66 years; ECOG PS 0/1/2, 27%/66%/7%) were treated. Median follow-up was 28 months, median OS was 15 months (95% CI 9.3, 21.1),1- and 2-year OS rates were 56% and 32%, respectively. Median PFS was 6 months, and ORR was 16% (11/68), including 2 CRs. Median duration of response was 13 months. In all CPI-experienced pts evaluable for safety (n=124), treatment related adverse events (TRAEs) occurred in 91% of pts, with Gr 3/4 TRAEs occurring in 60% of pts. The most common (≥10%) Gr 3/4 TRAEs were hypertension and diarrhea. There were no Gr 5 TRAEs. Discontinuation rates for sitra and nivo due to any AE were 30% and 27%, respectively. Conclusions: Sitra + nivo demonstrated antitumor activity and encouraging OS compared to historical controls and no new safety signals were observed in pts with NSQ NSCLC who progressed on prior CPI. This combination is being evaluated in the phase III SAPPHIRE study

The ATLAS EventIndex: a BigData catalogue for all ATLAS experiment events

The ATLAS EventIndex system comprises the catalogue of all events collected, processed or generated by the ATLAS experiment at the CERN LHC accelerator, and all associated software tools to collect, store and query this information. ATLAS records several billion particle interactions every year of operation, processes them for analysis and generates even larger simulated data samples; a global catalogue is needed to keep track of the location of each event record and be able to search and retrieve specific events for in-depth investigations. Each EventIndex record includes summary information on the event itself and the pointers to the files containing the full event. Most components of the EventIndex system are implemented using BigData open-source tools. This paper describes the architectural choices and their evolution in time, as well as the past, current and foreseen future implementations of all EventIndex components.Comment: 21 page

Specific features of the electronic, spin, and atomic structures of a topological insulator Bi2Te2.4Se0.6

The specific features of the electronic and spin structures of a triple topological insulator Bi2Te2.4Se0.6, which is characterized by high-efficiency thermoelectric properties, have been studied with the use of angular- and spin-resolved photoelectron spectroscopy and compared with theoretical calculations in the framework of the density functional theory. It has been shown that the Fermi level for Bi2Te2.4Se0.6 falls outside the band gap and traverses the topological surface state (the Dirac cone). Theoretical calculations of the electronic structure of the surface have demonstrated that the character of distribution of Se atoms on the Te–Se sublattice practically does not influence the dispersion of the surface topological electronic state. The spin structure of this state is characterized by helical spin polarization. Analysis of the Bi2Te2.4Se0.6 surface by scanning tunnel microscopy has revealed atomic smoothness of the surface of a sample cleaved in an ultrahigh vacuum, with a lattice constant of ~4.23 Å. Stability of the Dirac cone of the Bi2Te2.4Se0.6 compound to deposition of a Pt monolayer on the surface is shown.This study was supported by the Ministry of Education and Science of the Russian Federation, the St. Petersburg State University (project nos. 11.38.271.2014 and 15.61.202.2015), and the Russian Foundation for Basic Research (project nos. 12-02-00226, 13-02-91327, 14-08-31110, and 13-02-12110). The research was also performed at the Resource Center “Physical Methods of Surface Investigation” at St. Petersburg State University. We are also grateful to collaborators of the Helmholtz-Zentrum (Berlin) for financial and technical support.Peer reviewe

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)