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We report our experience working with cardiac sonographers (SONO) in outpatient settings between April 2019 and December 2022. Our observation focused on 7 outpatient cardiac centers in the Auvergne Rhône Alpes region, 35,743 patients had at least one consultation between April 2019 and December 2022. In total, 23,657 patients an echocardiogram (ECHO) performed (66%). Seven SONOs were involved, supervised by 15 cardiologists. All ECHOs were technically performed based on a standard acquisition protocol. Data was saved on a dedicated cloud-based Picture Archiving and Communication System (PACS) allowing the cardiologist to check the image quality, results and complete the report, automatically included in the electronic health record. Out of a total of 25,686 ECHO (i.e., an average of 1.1 ECHO/patient), ∼19,800 (77%) were performed by SONOs (range from 72% to 92% depending on the medical center). In total, ∼2000 ECHO (∼10%) required technical expertise and additional acquisition of images by the referring cardiologist (range from 5% to 25% depending on the experience level of the SONO). Based on a study sample, the average ECHO acquisition time was 12 ± 7 minutes. Thus, over the entire period of 33-month period, the total medical time saved was estimated up to 4,700 hours. Teamwork is mandatory to improve access to outpatient care in cardiology. Working with cardiac sonographers is efficient and saves cardiologists up to 700 hours/SONO/year of medical time. This organizational workflow should be paired with dedicated imaging data management systems and HER (Fig. 1). [ABSTRACT FROM AUTHOR]

Purpose: Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1-2 years duration. We hypothesized that smaller, shorter duration, "Proof of Concept" (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur.Methods: Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)> or =25 kg/m(2), symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m(2), with eight index knees graded as Kellgren-Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF x ThCtAB), with changes in other regions considered as secondary endpoints.Results: Anatomical mal-alignment ranged from -1.9 degrees to 6.3 degrees , with mean 0.9 degrees . With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF x ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was -2.1% [95% confidence interval (CI) (-4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (-2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT x ThCtAB) at 6 month follow-up (-1.5%, 95% CI [-2.9, -0.2]), but was not significant at the 5% level after correction for multiple comparisons.Conclusions: The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed. [ABSTRACT FROM AUTHOR]

The patient contribution to medical data may save medical time and shorten the decision-making process. However, the medical impact of potential errors in this natural data is unclear. We aimed to evaluate the differences between data completed by patient and trained medical teams using a cardiology preconsultation medical form. In total, 476 consecutive patients scheduled for an outpatient consultation (January 2020) were included. Patients filled a preconsultation form (risk factors, symptoms and prior results) using a digital platform. This data was completed during the medical consultation by a trained outpatient care team and compared to the information provided by patients. An error was defined as either a missing or a wrong value, and a percentage was calculated for each parameter. In total, 387 patients (83%) were included in the analysis (72 did not fill the form, 8 did not show up). The filling rate averaged 83.6 ± 12%. The global error % averaged 16.5 ± 5% (13.4% missing values). The following parameters had an error % of more than 10%: results of prior tests (echocardiography 43%, exercise test 25%, Doppler 24%), renal failure (32%), Blood pressure (23%), cholesterol level (20%), family cardiac history (15%), personal cardiac history (12%), history of diabetes (11%). All other parameters had an error % of less than 5% (symptoms, smoking, alcohol, BMI). Despite these significant missing or erroneous data, the availability of this information allowed significant improvement of the care path and more than 80% of patients reported improved commitment and understanding of medical decisions. Actively including patient in the medical care process is an important issue and is made easy using e-cardiology tools. The results of this study should be considered when building digital platforms. Some of the parameters with important errors should be verified from multiple sources before using them in the future decision-making algorithms. [ABSTRACT FROM AUTHOR]

Summary: Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where normal food intake is inadequate. These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in nephrology patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards and are based on all relevant publications since 1985. They were discussed and accepted in a consensus conference. Because of the nutritional impact of renal diseases, EN is widely used in nephrology practice. Patients with acute renal failure (ARF) and critical illness are characterized by a highly catabolic state and need depurative techniques inducing massive nutrient loss. EN by TF is the preferred route for nutritional support in these patients. EN by means of ONS is the preferred way of refeeding for depleted conservatively treated chronic renal failure patients and dialysis patients. Undernutrition is an independent factor of survival in dialysis patients. ONS was shown to improve nutritional status in this setting. An increase in survival has been recently reported when nutritional status was improved by ONS. The full version of this article is available at www.espen.org. [Copyright &y& Elsevier]

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum–pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum–pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum–pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67–1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8) for osimertinib and platinum–pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16–0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum–pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum–pemetrexed arm. In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum–pemetrexed, which possibly reflects the high crossover rate of patients from platinum–pemetrexed to osimertinib. ClinicalTrials.gov NCT02151981 ; https://clinicaltrials.gov/ct2/show/NCT02151981. • Median OS with osimertinib was 26.8 months versus 22.5 months with platinum–pemetrexed (HR 0.87, 95% CI 0.67–1.12; P = 0.277). • The lack of a significant survival benefit could reflect high percentage (73%) of platinum–pemetrexed to osimertinib crossover. • Analysis of OS adjusted for crossover showed an HR of 0.54 (95% CI 0.18–1.60). • Among patients receiving subsequent anticancer therapy, platinum chemotherapy was the most common after osimertinib (65%). • Grade ≥3 (possibly treatment-related) adverse events were observed less frequently with osimertinib (9% versus 34% with platinum–pemetrexed). [ABSTRACT FROM AUTHOR]

Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72–1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85–1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9–43.1), 30.4% (24.7–36.3), and 30.5% (24.7–36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. ClinicalTrials.gov : NCT02369874. • OS was not significantly different for durvalumab or for durvalumab plus tremelimumab compared with SoC. • The study was not designed to assess OS between immunotherapies, but adding tremelimumab did not appear to enhance durvalumab activity. • Failure to meet the primary end point may have been impacted by factors resulting in an unexpectedly long OS for the SoC arm. [ABSTRACT FROM AUTHOR]

Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients with advanced EGFR -mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25–75 mg p.o. twice a day; continuous or intermittent), savolitinib (600–800 mg p.o. once a day), or durvalumab (3–10 mg/kg intravenous every 2 weeks). At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm—diarrhea (75%), rash (58%), nausea (47%); savolitinib arm—nausea (67%), rash (56%), vomiting (50%); durvalumab arm—rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. NCT02143466. • Patients with advanced EGFR -mutant NSCLC received osimertinib 80 mg combined with selumetinib, savolitinib or durvalumab. • Feasible dosing strategies were identified for osimertinib plus selumetinib or savolitinib. • Osimertinib plus durvalumab was not feasible due to increased reporting of interstitial lung disease. • Responses were seen in all treatment arms, warranting further analysis of the feasible combinations identified. • Osimertinib-based combinations represent a compelling approach now being investigated broadly to further improve outcomes. [ABSTRACT FROM AUTHOR]

Background: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. Patients and methods: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. Results: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. Conclusion: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. [ABSTRACT FROM AUTHOR]

Background In AURA3 (NCT02151981), osimertinib, a 3rd-generation EGFR-TKI, significantly prolonged progressionfree survival (PFS) and improved response rate vs plt-pem in pts with centrally confirmed EGFR T790M advanced NSCLC and progression on a prior EGFR-TKI. Here we report mature OS data. Methods Adult pts were randomised 2:1 to receive oral osimertinib (80 mg once daily) or intravenous pem (500 mg per m2 of body surface area) + carboplatin (target area under the curve 5)/cisplatin (75 mg per m2), every 3 weeks, ≤6 cycles. Treatment beyond progression (RECIST 1.1) was allowed if clinical benefit continued. Pts receiving plt-pem could cross over to osimertinib on disease progression. Asymptomatic CNS metastases were allowed. Primary endpoint was investigator-assessed PFS. OS and safety are reported as secondary endpoints. Data cut-off (DCO): 15 March 2019. Results In total, 419 pts were randomised (osimertinib, n = 279; plt-pem, n = 140); 99 pts (71%) crossed over to osimertinib from plt-pem. At DCO, 188 pts (67%) in the osimertinib arm vs 93 pts (66%) in the plt-pem arm had died, including 66/99 (67%) crossover pts; median OS 26.8 mo (95% confidence interval [CI] 23.5, 31.5) vs 22.5 mo (95% CI 20.2, 28.8) respectively, hazard ratio (HR) 0.87 (95% CI 0.67, 1.12; p = 0.277); survival rate at 24 mo was 55% vs 43% and at 36 mo was 37% vs 30%. Time to first subsequent treatment showed a large, clinically meaningful numerical advantage towards osimertinib, HR 0.21 (95% CI 0.16, 0.28; p < 0.001); time to second subsequent treatment, HR 0.87 (95% CI 0.69, 1.11; p = 0.263). In both arms, 99% pts had any adverse event (AE). Any AE grade ≥3 causally related to study treatment was 9% vs 34% for osimertinib and plt-pem respectively. Most common AEs were diarrhoea, 44% (grade ≥3, 1%), and nausea, 49% (grade ≥3, 4%), with osimertinib and plt-pem respectively. Conclusions A numerical advantage in OS was observed for pts receiving osimertinib vs plt-pem, with the majority of pts in the plt-pem arm having crossed over to osimertinib. The safety profile of osimertinib remains consistent with previous findings. Clinical trial identification NCT02151981. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, who provided medical writing support funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. T.S.K. Mok: Honoraria (self): ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, Hengrui Therapeutics Inc. Ignyt; Advisory / Consultancy: ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, geneDecode Co. Ltd. (un; Leadership role: AstraZeneca PLC, Hutchison Chi-Med; Research grant / Funding (institution): AstraZeneca, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, XCovery; Shareholder / Stockholder / Stock options: Shareholder: Hutchison Chi-Med, Sanomics Ltd. Stock option: Clearbridge Biomedics (now Biolidics Ltd.), Loxo-Oncology, OrigiMed Co. Ltd. Virtus Medical Group; Full / Part-time employment: The Chinese University of Hong Kong; Officer / Board of Directors: Remunerated: AstraZeneca PLC, Hutchison Chi-Med Non-remunerated: American Society of Clinical Oncology (ASCO) Asian Thoracic Oncology Research Group (ATORG) Chinese Lung Cancer Research Foundation Limited (CLCRF) Chinese Society of Clinical Oncology (CS. J-Y. Han: Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, Lilly; Research grant / Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. M-J. Ahn: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Merck, Sharp & Dohme, Ono Pharmaceutical, Lilly, Roche; Advisory / Consultancy: Alpha Pharmaceutical, Takeda. S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. S-W. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. F.A. Shepherd: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: AstraZeneca. J. Laskin: Research grant / Funding (institution): AstraZeneca, Roche, Boehringer Ingelheim, Pfizer; Honoraria (self): AstraZeneca, Roche, Pfizer. H. Akamatsu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Honoraria (institution): Chugai; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution): Boehringer Ingelheim. W-C. Su: Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. M. Sebastian: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Roche, Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Boehringer Ingelheim, Celgene, Takeda, Bristol-Myers Squibb, MSD; Honoraria (self), Advisory / Consultancy: Lilly. H. Mann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Miranda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. G. Laus: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Papadimitrakopoulou: Honoraria (self): F Hoffman-La Roche; Advisory / Consultancy: Nektar Therapeutics, AstraZeneca Pharmaceuticals, Arrys Therapeutics, Merck&Co, LOXO Oncology, Araxes Pharma, F.Hoffman-LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly &Co, Novartis Pharmaceuticals Corp. Takeda ; Research grant / Funding (institution): Eli Lilly &Co, Novartis, Merck, AstraZeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]