EGFR and HER2 Gene Copy Number and Response to First-Line Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer (NSCLC)

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457 KEYNOTE-495/KeyImPaCT: interim analysis of a randomized, biomarker-directed, phase 2 trial of pembrolizumab-based combination therapy for non–small cell lung cancer (NSCLC)

BackgroundT-cell–inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) are clinically validated biomarkers that independently predict pembrolizumab response. This study investigated prospective TcellinfGEP and TMB assessment in evaluating first-line pembrolizumab-based combination therapies; the different treatment combinations evaluated may provide insight into the unique biology of each biomarker subgroup.MethodsKEYNOTE-495/KeyImPaCT is a group-sequential, adaptively randomized, multisite, open-label, phase 2 study investigating first-line pembrolizumab plus the VEGF/FGFR inhibitor lenvatinib, CTLA-4 inhibitor quavonlimab (MK-1308), or LAG-3 inhibitor favezelimab (MK-4280) in patients with advanced NSCLC. DNA and RNA were extracted from tumor tissue to determine TcellinfGEP and TMB; patients were assigned to one of four biomarker-defined subgroups (TcellinfGEPlowTMBlow, TcellinfGEPlowTMBhigh, TcellinfGEPhighTMBlow, TcellinfGEPhighTMBhigh) and randomly assigned 1:1:1 to receive pembrolizumab (200mg IV Q3W)+lenvatinib (20mg oral QD), pembrolizumab+quavonlimab (75mg IV Q6W), or pembrolizumab+favezelimab (200mg [n=30] or 800mg [n=34] Q3W; the initial prespecified dose was 200mg but changed to 800mg based on emerging data). The primary end point was investigator-assessed ORR per RECIST v1.1. Multiple interim analyses will be performed until the prespecified clinical signal is observed. The first interim analysis for each combination therapy occurred after ≥10 patients had ≥12 weeks of follow-up.ResultsAt the data cutoff (January 11, 2021), 208 patients were treated (pembrolizumab+lenvatinib, n=72; pembrolizumab+quavonlimab, n=72; pembrolizumab+favezelimab 200mg, n=30; pembrolizumab+favezelimab 800mg, n=34). The overall assay success rate for testing and determining TcellinfGEP and TMB was 94%. In patients treated with pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, or pembrolizumab+favezelimab, ORRs were generally highest in the TcellinfGEPhighTMBhigh subgroup (table 1); response rates were similar across combinations within this subgroup. ORR was low across combinations within the TcellinfGEPlowTMBlow subgroup. Treatment-related adverse events (TRAEs) occurred in 88%, 65%, 57%, and 59% of patients in the pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, pembrolizumab+favezelimab 200mg and pembrolizumab+favezelimab 800mg arms, respectively. Consistent with the known TRAEs of these agents, most TRAEs were grade 1 or 2 in severity except in the pembrolizumab+lenvatinib arm (grade 3–5, 63%). Three deaths from TRAEs occurred (pembrolizumab+lenvatinib [n=2], brain hemorrhage and myocardial infarction; pembrolizumab+favezelimab 800 mg [n=1], pneumonitis).Abstract 457 Table 1Confirmed ORR by Therapy and Biomarker StatusConclusionsThese data demonstrate the feasibility and clinical usefulness of prospective TcellinfGEP and TMB assessment to study the clinical activity of three first-line pembrolizumab-based combination therapies in patients with advanced NSCLC. Although sample sizes were small, the TcellinfGEPhighTMBhigh subgroup demonstrated the best response among the biomarker subgroups for all three combination therapies; further validation is needed to determine additional signals and may be addressed as more mature data become available.AcknowledgementsJeanne Fahey, PhD, of Merck & Co., Inc., Kenilworth, New Jersey, USA, provided critical review of the abstract. Elisha Dettman PhD, Mark Ayers MS, and Andrey Loboda PhD of Merck & Co., Inc., Kenilworth, New Jersey, USA, provided critical review of study translational data. Medical writing and/or editorial assistance was provided by Shane Walton, PhD, and Lei Bai, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrials.gov, NCT03516981Ethics ApprovalThe study protocol and all amendments were approved by the relevant institutional review board or ethics committee at each study site. All patients provided written informed consent to participate in the clinical trial

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death. Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference

Outcome Evaluation of Oligometastatic Patients Treated with Surgical Resection Followed by Hypofractionated Stereotactic Radiosurgery (HSRS) on the Tumor Bed, for Single, Large Brain Metastases.

The aim of this study was to evaluate the benefit of a combined treatment, surgery followed by adjuvant hypofractionated stereotactic radiosurgery (HSRS) on the tumor bed, in oligometastatic patients with single, large brain metastasis (BM).Fom January 2011 to March 2015, 69 patients underwent complete surgical resection followed by HSRS with a total dose of 30Gy in 3 daily fractions. Clinical outcome was evaluated by neurological examination and MRI 2 months after radiotherapy and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the irradiated volume, and brain distant progression as the presence of new brain metastases or leptomeningeal enhancement outside the irradiated volume. Surgical morbidity and radiation-therapy toxicity, local control (LC), brain distant progression (BDP), and overall survival (OS) were evaluated.The median preoperative volume and maximum diameter of BM was 18.5cm3 (range 4.1-64.2cm3) and 3.6cm (range 2.1-5-4cm); the median CTV was 29.0cm3 (range 4.1-203.1cm3) and median PTV was 55.2cm3 (range 17.2-282.9cm3). The median follow-up time was 24 months (range 4-33 months). The 1-and 2-year LC in site of treatment was 100%; the median, 1-and 2-year BDP was 11.9 months, 19.6% and 33.0%; the median, 1-and 2-year OS was 24 months (range 4-33 months), 91.3% and 73.0%. No severe postoperative morbidity or radiation therapy toxicity occurred in our series.Multimodal approach, surgery followed by HSRS, can be an effective treatment option for selected patients with single, large brain metastases from different solid tumors

Randomized Comparison of Helmet CPAP Versus High-Flow Nasal Cannula Oxygen in Pediatric Respiratory Distress

BACKGROUND: The current study aimed to compare the efficacy and safety of 2 noninvasive respiratory support methods, which included helmet CPAP and high-flow nasal cannula (HFNC) in children with respiratory distress admitted to a pediatric intermediate care unit. METHODS: This study was a prospective observational study conducted on children with respiratory distress (age 1-24 months) who were admitted to our acute and emergency operative unit. All included subjects were randomly treated with helmet CPAP or HFNC in a 1:1 fashion until their clinical picture, oxygen saturation, and arterial blood gas (ABG) parameters resolved. The efficiencies of helmet CPAP and HFNC were evaluated by breathing frequency, S , ABG pH, ABG P , ABG P , and P /F , recorded once at baseline and then after 1 and 6 h of treatment. Both noninvasive respiratory support modalities were compared with a control group of subjects with respiratory distress under standard therapeutic pharmaceutical protocols. RESULTS: We found that both helmet CPAP and HFNC were efficient in improving the clinical conditions of subjects with mild-to-moderate respiratory distress, although clinical response to helmet CPAP was more efficient and rapid compared with HFNC. Children who received respiratory support had a better clinical course in terms of hospitalization, days of intravenous rehydration therapy, and days of drug administration compared with the control group ( \u3c .001). CONCLUSIONS: Based on our knowledge, the present study is the first research comparing the effects of CPAP and HFNC in respiratory distress resolution in a pediatric intermediate care setting. It aims to identify the most efficient treatment to avoid pediatric ICU admissions and endotracheal intubation and reduce the administration of drugs and days of hospitalization

Azione antalgica di Hydrogel nell'orbitopatia basedowiana

La terapia dell'orbitopatia,nella fase acuta,si basa oltre che sulla correzione della turba endocrinologica,sulla protezione della cornea e sull'uso dei corticosteroidi ad alto dosaggio o di farmaci immunosoppressori o, in alternativa,sulla radioterapia orbitaria.Per attenuare la sintomatologia dolorosa,frequente nella fase acuta e che può inficiare la qualità della vita,data la componente flogistica,abbiamo voluto valutare gli effetti di una terapia antalgica mediante appliocazione sulla superficie palpebrale di un gel chirurgico criogenico decongestinante ( a contenuto di estratto di ananas più acido betaglicirretico),ad oggi utilizzato con risultati soddisfacenti in soggetti sottoposti a trattamenti chirurgici degli annessi oculari.Sono stati studiati in doppio cieco 50 soggetti ( 16 uomini e 34 donne, range età 35-46,5 anni) con orbitopatia basedowiana ( OB) di grado 3,in fase dinamica,secondo la classificazione dell'American Thyroid Association.Tutti i pazienti,egualmente distribuiti in due gruppi,erano in terapia tireostatica con MMI.Nessun effetto collaterale è stato riscontrato.All'esame clinico-strumentale-oftalmologico (visus,motilità oculare,fundus,esoftalmometria e tonometria) non si sono apprezzate variazioni significative pre e post trattamento in nessuno dei due gruppi.2 soggetti del gruppo placebo hanno riferito un miglioramento complessivo della sintomatologia, mentre nel gruppo trattato 24 soggetti hanno riferito un sensibile miglioramento come da questionario validato.Nel nostro studio la terapia con Hydrogel si è rivelata una valida strategia antalgica da associare ai farmaci ad azione sistemica