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Introduction: PACIFIC established consolidative durvalumab for LA-NSCLC, but only about half of patients completed a year of therapy. Data on treatment patterns and outcomes after durvalumab are limited., Methods: Our analysis included patients from a US nationwide database with LA-NSCLC who received consolidative durvalumab between 2017 and 2023 and had subsequent systemic therapy, classified as PD-L1 monotherapy, PD-L1+chemotherapy, chemotherapy alone, PD-L1+CTLA4, or targeted therapy (TT). Time to next treatment (TTNT) was analyzed from durvalumab start and finish to next line of therapy initiation. Overall survival (OS) from start of postdurvalumab therapy was analyzed using Kaplan Meier methodology., Results: Our cohort included 751 patients, median age 68 (IQR, 61-74), 53% female, 80% White, 91% ECOG 0-1, 90% smoking history, and 53% nonsquamous histology. The most common postdurvalumab treatment was chemotherapy alone in 349 (46%), followed by PD-L1+chemotherapy in 147 (20%), PD-L1 monotherapy in 114 (15%), and TT in 104 (14%). Median duration of durvalumab treatment was 5.5 months (IQR 2.3-10.6); only 9% of patients received a full year of durvalumab, and 64% started next treatment within a year of initiation. Patients treated with chemotherapy-containing regimens had shorter TTNT from durvalumab start/end, as well as shorter median OS [10.8 (5.6-18.8) months for chemotherapy and 12.9 (6.0-24.2) months for chemoimmunotherapy, versus 23.8 (8.7-34.5) months for PD-L1 monotherapy and 30.1 (9.5-NR) months for TT (P < .001)]., Conclusion: Patients treated with systemic therapy after consolidative durvalumab, particularly those requiring chemotherapy-based treatment, have poor outcomes and are in need of improved treatment strategies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Limited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20., Methods: We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression., Results: Among 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004)., Conclusions: In a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer of the cells lining the pleural cavity with a low overall incidence. The National Cancer Database (NCDB) released in August 2022 updated data that reflect the newest trends in MPM., Methods: The NCDB was queried for patients diagnosed with MPM between 2004 and 2020. Variables collected included demographics, tumor characteristics, and treatment. Student's t-test and independent-samples proportions test were used for means analysis. Survival was assessed by the Kaplan-Meier method using SPSS version 28., Results: A total of 41,074 patients were diagnosed with mesothelioma, with a steady incidence (0.25%) between 2004 and 2017. The mean age of diagnosis was 70 (SD 13). 73.2% of the patients were males, 69% had no comorbidities, and 93.3% were white. More patients were diagnosed at Stage 1 after 2008 (p < 0.001). Since 2010, there has been a significant increase in patients offered treatment with 73.9% receiving some therapy (p < 0.01): 50.5% received chemotherapy, 27.6% surgery, 8.6% radiation, and 5.4% immunotherapy. The median overall survival was 10.3 months from diagnosis [95% CI: 10.2-10.5]. Risk factors associated with 30-day mortality from surgical intervention included age (OR = 1.02, p < 0.001), male gender (OR = 1.3, p = 0.03), poorly differentiated grade (OR = 2.1, p < 0.001), Stage 4 (OR = 1.4, p = 0014), and epithelioid histology (OR = 0.51, p = 0.03)., Conclusion: The current management of MPM is based on stage and histologic subtype. Due to the small numbers of patients at most academic centers, the NCDB provides a robust dataset to draw upon broad data points in treatment discussions with patients., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: The role of postoperative radiotherapy (PORT) in patients with resected locally advanced non-small-cell lung cancer (NSCLC) remains controversial due to the radiation techniques used in randomized trials. We conducted a retrospective cohort study evaluating contemporary PORT techniques to evaluate the safety of PORT and risk of death from intercurrent disease ., Materials and Methods: We analyzed consecutive patients with NSCLC treated in a single center that underwent PORT for pN2 disease and/or positive margin, with 3-dimensional conformal radiotherapy (3DRT), intensity modulated radiotherapy , or proton RT (PRT), between 2008 and 2019. Clinical details were collected including intercurrent deaths, defined as death without cancer recurrence. Kaplan-Meier and Cox-Proportional Hazards Models were used., Results: Of 119 patients, 21 (17.6%) received 3DRT, 47 (39.5%) intensity modulated radiotherapy, and 51 (42.9%) PRT. Median follow-up was 40 months (range 8-136) and median RT dose was 5040cGy. Most patients (65.5%) received sequential adjuvant chemoRT; 18.5% received concurrent chemoRT. The rate of grade 3 toxicities was 9.2%. There were 13 (10.9%) deaths from intercurrent diseases, including 6 from second primary cancers and 2 from cardiopulmonary diseases. There were 2 additional deaths from cardiopulmonary disease in patients with cancer progression at time of death. Mean, V5Gy, V30Gy heart doses and mean lung doses were significantly lower with PRT. Three-year OS and disease-free-survival were 70.1% and 49.9%., Conclusion: PORT using contemporary techniques was well tolerated with acceptable toxicity and low rates of intercurrent deaths. Proton therapy significantly reduced heart and lung doses, but radiotherapy modality was not associated with differences in intercurrent disease., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Patients with thoracic malignancies are at increased risk for mortality from coronavirus disease 2019 (COVID-19), and a large number of intertwined prognostic variables have been identified so far., Methods: Capitalizing data from the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure, and a tree-based model to screen and optimize a broad panel of demographics and clinical COVID-19 and cancer characteristics., Results: As of April 15, 2021, a total of 1491 consecutive eligible patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection procedure then identified the following seven major determinants of death: Eastern Cooperative Oncology Group-performance status (ECOG-PS) (OR = 2.47, 1.87-3.26), neutrophil count (OR = 2.46, 1.76-3.44), serum procalcitonin (OR = 2.37, 1.64-3.43), development of pneumonia (OR = 1.95, 1.48-2.58), C-reactive protein (OR = 1.90, 1.43-2.51), tumor stage at COVID-19 diagnosis (OR = 1.97, 1.46-2.66), and age (OR = 1.71, 1.29-2.26). The receiver operating characteristic analysis for death of the selected model confirmed its diagnostic ability (area under the receiver operating curve = 0.78, 95% confidence interval: 0.75-0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90%, and the tree-based model recognized ECOG-PS, neutrophil count, and c-reactive protein as the major determinants of prognosis., Conclusions: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS was found to have the strongest association with poor outcome from COVID-19. With our analysis, we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The availability of targeted therapies has transformed the management of advanced NSCLC; however, most patients do not undergo guideline-recommended tumor genotyping. The impact of plasma-based next-generation sequencing (NGS) performed simultaneously with diagnostic biopsy in suspected advanced NSCLC has largely been unexplored., Methods: We performed a prospective cohort study of patients with suspected advanced lung cancer on the basis of cross-sectional imaging results. Blood from the time of biopsy was sequenced using a commercially available 74-gene panel. The primary outcome measure was time to first-line systemic treatment compared with a retrospective cohort of consecutive patients with advanced NSCLC with reflex tissue NGS., Results: We analyzed the NGS results from 110 patients with newly diagnosed advanced NSCLC: cohorts 1 and 2 included 55 patients each and were well balanced regarding baseline demographics. In cohort 1, plasma NGS identified therapeutically informative driver mutations in 32 patients (58%) (13 KRAS [five KRAS G12C ], 13 EGFR , two ERRB2 , two MET , one BRAF , one RET ). The NGS results were available before the first oncology visit in 85% of cohort 1 versus 9% in cohort 2 ( p < 0.0001), with more cohort 1 patients receiving a guideline-concordant treatment recommendation at this visit (74% versus 46%, p  = 0.005). Time-to-treatment was significantly shorter in cohort 1 compared with cohort 2 (12 versus 20 d, p  = 0.003), with a shorter time-to-treatment in patients with specific driver mutations (10 versus 19 d, p  = 0.001)., Conclusions: Plasma-based NGS performed at the time of diagnostic biopsy in patients with suspected advanced NSCLC is associated with decreased time-to-treatment compared with usual care., (© 2022 The Authors.)

Targeted therapies have dramatically changed the treatment paradigm for a select group of patients with non-small cell lung cancer (NSCLC) whose tumors harbor targetable genetic aberrations. Patients with such genetic changes enjoy excellent responses to tyrosine kinase inhibitors (TKIs), but resistance is nearly inevitable. Resistance to first line TKIs is heterogeneous and multifactorial-multiple resistance mechanisms have been reported, and different metastatic foci in the same patient may have distinct resistance mechanisms. The recent approval of next-generation TKIs specific to particular resistance mechanisms, and the likely future approval of others, necessitates the acquisition of repeat molecular analysis at time of progression. Tumor tissue has traditionally been the preferred source to detect oncogenic driver and resistance mutations, but tissue biopsies are invasive and often difficult to obtain. The use of circulating tumor DNA (ctDNA), so-called "liquid biopsies", has emerged as a promising technique to molecularly profile tumors non-invasively and is becoming increasingly utilized in the routine management of lung cancer. This review will describe the current role of ctDNA in the management of lung cancer, and explore emerging data that point towards its increasingly important role in clinical care., Competing Interests: Conflicts of Interest: C Aggarwal: Consultant Services: Roche, BMS, Eli Lilly; Research/Grant support: Takeda, Macrogenics, Roche. E Carpenter: Commercial research support from Janssen/Johnson & Johnson. RB Cohen: Consultant Services: Takeda, Zymeworks, BMS. CJ Langer: Consultant services: Bristol-Myers Squibb Company; ImClone Systems Incorporated; Pfizer Inc.; Eli Lilly and Company; AstraZeneca Pharmaceuticals LP; Novartis Pharmaceuticals Corporation; Genentech, Inc.; Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals, Inc.; Celgene; Abbott Laboratories; Biodesix; Clariant; CarisDx; ARIAD Pharmaceuticals, Inc.; Boehringer Ingelheim Pharmaceuticals, Inc.; Synta Pharmaceuticals Corp; Clovis Research/grant support: Pfizer Inc.; Eli Lilly and Company; GlaxoSmithKline; Clovis; Merck; Nektar; Advantagene; Inovio; Ariad; Celgene; DSMC member: Amgen, Synta, Peregrine, SWOG, Incyte, Lilly CME: PIK; PER; NOCR; CCO; RTP, MLG. J Bauml: Consultative Services: Clovis, BMS, Astra Zeneca, Celgene, Merck, Genentech, Guardant Health, Boehringer Ingleheim; Research/Grant Support: Merck, Incyte, Carevive Systems, Novartis, Bayer. M Marmarelis, JC Thompson and TL Evans have no conflicts of interest to declare.

Introduction: Community-acquired bloodstream infections have not been studied related to diabetes mellitus in the critically ill., Hypothesis: We hypothesized that the diagnosis of diabetes mellitus and poor chronic glycemic control would increase the risk of community-acquired bloodstream infections (CA-BSIs) in the critically ill., Methods: We performed an observational cohort study between 1998 and 2007 in 2 teaching hospitals in Boston, Massachusetts. We studied 2551 patients 18 years or older, who received critical care within 48 hours of admission and had blood cultures obtained within 48 hours of admission. The exposure of interest was diabetes mellitus defined by International Classification of Diseases, Ninth Revision, Clinical Modification, code 250.xx in outpatient or inpatient records. The primary end point was CA-BSI (<48 hours of hospital admission). Patients with a single coagulase-negative Staphylococcus positive blood culture were not considered to have bloodstream infection. Associations between diabetes groups and bloodstream infection were estimated by bivariable and multivariable logistic regression models. Subanalyses included evaluation of the association between hemoglobin A1c (HbA1c) and bloodstream infection, diabetes and risk of sepsis, and the proportion of the association between diabetes and CA-BSI that was mediated by acute glycemic control., Results: Diabetes is a predictor of CA-BSI. After adjustment for age, sex, race, patient type (medical vs surgical), and acute organ failure, the risk of bloodstream infection was significantly higher in patients with diabetes (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.10-1.82; P = .006) relative to patients without diabetes. The adjusted risk of bloodstream infection was increased in patients with HbA1c of 6.5% or higher (OR, 1.31; 95% CI, 1.04-1.65; P = .02) relative to patients with HbA1c less than 6.5%. Furthermore, the adjusted risk of sepsis was significantly higher in patients with diabetes (OR, 1.26; 95% CI, 1.04-1.54; P = .02) relative to patients without diabetes. Maximum glucose did not significantly mediate the relationship between diabetes mellitus diagnosis and CA-BSI., Conclusions: A diagnosis of diabetes mellitus and HbA1c of 6.5% or higher is associated with the risk of CA-BSI in the critically ill., (© 2013.)

To test the hypothesis that concomitant targeting of the epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-β) may offer a novel therapeutic approach in pancreatic cancer, EGFR silencing by RNA interference (shEGFR) was combined with TGF-β sequestration by soluble TGF-β receptor II (sTβRII). Effects on colony formation in 3-dimensional culture, tumor formation in nude mice, and downstream signaling were monitored. In both ASPC-1 and T3M4 cells, either shEGFR or sTβRII significantly inhibited colony formation. However, in ASPC-1 cells, combining shEGFR with sTβRII reduced colony formation more efficiently than either approach alone, whereas in T3M4 cells, shEGFR-mediated inhibition of colony formation was reversed by sTβRII. Similarly, in vivo growth of ASPC-1-derived tumors was attenuated by either shEGFR or sTβRII, and was markedly suppressed by both vectors. By contrast, T3M4-derived tumors either failed to form or were very small when EGFR alone was silenced, and these effects were reversed by sTβRII due to increased cancer cell proliferation. The combination of shEGFR and sTβRII decreased phospho-HER2, phospho-HER3, phoshpo-ERK and phospho-src (Tyr416) levels in ASPC-1 cells but increased their levels in T3M4 cells. Moreover, inhibition of both EGFR and HER2 by lapatinib or of src by SSKI-606, PP2, or dasatinib, blocked the sTβRII-mediated antagonism of colony formation in T3M4 cells. Together, these observations suggest that concomitantly targeting EGFR, TGF-β, and src may constitute a novel therapeutic approach in PDAC that prevents deleterious cross-talk between EGFR family members and TGF-β-dependent pathways.